This year's rheumatology course will also treat vasculitis, which until last year was clinical

immunology.

DEFINITION: What is rheumatology?

Rheumatology is a branch of internal medicine that deals with diseases of the musculoskeletal
system.
There are often doubts about the relationship between rheumatology and orthopedics: the
substantial difference between these two specialties is that the former is medical, while the
latter is surgical. Rheumatologists are the specialists who deal with diseases of the
musculoskeletal system from the medical point of view, therefore elaborating diagnosis and
therapy; orthopedists, on the other hand, deal with musculoskeletal diseases with purely
surgical therapy.

RHEUMATIC DISEASES
Rheumatic diseases can cause disorders and/or damage:
- all the structures that make up the locomotor system (joints, tendons, ligaments,
muscles, bones, etc.).
- other tissues of the body (connective tissue, epithelial, nervous). Many rheumatic
diseases, in fact, give rise to systemic manifestations.

Rheumatology is one of the most internistic branches of internal medicine (and this is
underlined by the fact that many systemic diseases can manifest themselves in the locomotor
system, as it has a high vascularization - from last year's unwinding).
Very often the visceral or musculoskeletal alterations are of a phlogistic nature, on an immune
or autoimmune basis (we will return to all these concepts during the course).

According to ISTAT data from 2005, rheumatic diseases are some of the most common diseases
in the population. The most common chronic diseases, in fact, are:
 arthrosis/arthritis (18.3%)
 hypertension (13.6%)
 allergic diseases (10.7%)

Clearly, not all rheumatic diseases are frequent: the two most common diseases are
osteoarthritis (72.6%) and extra-articular rheumatism (12.7%), together accounting for 85% of
rheumatic diseases.
Fortunately, these diseases have a limited severity and are treated by general practitioners. The
most serious cases, however, are followed by specialists such as rheumatologists, orthopedists
or physiatrists (depending on the situation).

The physiatrist is a transversal specialist figure, who aims at cardiovascular, neurological, or

musculoskeletal rehabilitation, using a physiotherapeutic approach.
The purpose of physiatric intervention in rheumatology is to relieve painful symptoms, which
are an important component of rheumatic diseases.

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The remaining 15% of rheumatic diseases are rheumatoid arthritis, spondylarthritis, gout,
connective tissue, rheumatic fever and other more inflammatory diseases, which affect the
musculoskeletal system and, in some cases, the viscera. These pathologies, if not properly
treated, can compromise the functionality of the apparatus but also the life of the patient
himself.
Fortunately, they are less frequent.

The following table shows the subdivision of the topics that will be dealt with by the teachers.

This year, vasculitis will be

treated by Professor Sfriso,
because (like some other
rheumatic diseases) they can be
followed by both clinical
immunologists and
rheumatologists. Immunology,
compared to rheumatology,
however, is more concerned with
the allergological aspect.

In this first lesson a classification

of rheumatic diseases and the structures they involve will be made. In the next lessons the
individual diseases will be treated in more detail.
Probably there will also be organized exercises in the ward, aimed at learning the objective
articular examination, i.e. the one that investigates the alterations to the skeleton. [The
rheumatic patient, of course, must also be given a general objective examination (i.e., heart,
chest, etc.), all the more so because rheumatic diseases can also have systemic manifestations].

MUSCULOSKELETAL SYSTEM COMPONENTS

ARTICLES:

 Synarthrosis: they are immobile joints, so they have no real joint

mechanics. Among these, the sutures (present, for example,
between the bones of the skull) are those in which simple
connective tissue is interposed between the bones; the
sychondrosis (in particular the sacro-iliac) and the symphysis (like
the pubic one), on the other hand, between the articular garments present cartilaginous
tissue.

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 Ampharthrosis: these are semi-mobile joints, usually consisting of flat or almost flat
bone surfaces, with the interposition of a cartilaginous disc. There are, for example,
between the vertebrae, which are bones with flat surfaces. These joints allow very small
movements in all directions.
 Diarthrosis: these are mobile joints with a synovial membrane. They are particularly
affected in rheumatic diseases, because they bear the load more and have a synovial
membrane, a spongy tissue, easy target of the inflammatory process.
They may have different shapes and make different movements:
- Trocleo-arthrosis, consisting of a
concave throat (trochlea) within which a
convex, spool-shaped face is inserted
(e.g. between the humeral trochlea and
ulna). They allow flexion and extension
movements.
- Trochoid: it is a bone cylinder wrapped
in a fibrous ring that runs over a slightly
hollow surface (a trochoid, for example, is
the joint between the radius capital and
the ulna; or the joint between the atlas
and the epistropheus). Allows for
pronation and supination movements.
- A saddle, consisting of two surfaces,
each with two curves, one concave and
the other convex (it is present, for
example, between the carpus and metacarpus of the thumb, as well as between the
sternum and clavicle). Allows flexion, extension, abduction and adduction movements.
- Condylar-arthrosis: consists of an enlarged convex (ovoid) protrusion within a concave
surface, also enlarged (present for example between the radius and the carpus;
between the metacarpus and the phalanges; at knee level). Allows flexion, extension,
abduction and adduction movements.
- Enarthrosis, formed by a spherical surface (head) placed within a cavity (e.g. the hip
joint, or the one between the scapula and humerus). Allows movements of flexion,
extension, abduction, external rotation and internal rotation (extra movement
compared to condylar-arthrosis).

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The figure on the right shows an example of
diarthrosis/condylarthrosis with a synovial
membrane:
They stand out:
 The synovial membrane (in red), which
covers the inside of the joint cavity. This
membrane is formed by the
SYNOVIOCITES, which can be divided into
three types:
o type A, macrophage-like
o type B, fibroblast-like
o type C, mixed.
 The iuxta-articular cartilage, protecting the bone.
 The two joint ends, the iuxta-articular bone.
 Synovial fluid: a plasma dialysate enriched with hyaluronic acid and produced by
synovial membrane synovial cells.
 The menisci (in some joints): cartilages present at the sides of the joint to increase the
congruity between the two articular bone heads.
 The intra-articular ligaments, which stabilize the joint.
 The joint capsule (outer capsule).

This complex of structures must withstand static and dynamic loads and be resistant over time.

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MUSCULES:
 Muscle bands
 Muscles

TENDONS AND TENDON BAGS:

 Entesi (the final segment of a tendon or ligament that enters the bone).
 Tendons
 Bags
 Extra-articular ligaments

OSSA

OTHER ORGANS AND APPARATUS INVOLVED IN RHEUMATIC DISEASES

Cute, nerves, vessels, mucous membranes, lungs, heart...

CLASSIFICATION OF RHEUMATIC DISEASES

Summary list:
1. Primary arthritis and spondylarthritis (inflammatory joint rheumatism)
2. Connective and vasculitis (systemic rheumatic diseases)
3. Arthritis from infectious agents
4. Microcrystal and dysmetabolic arthropathies
5. Arthrosis (osteoarthrosis)
6. Non-traumatic painful diseases of the rachis
7. Extra-articular rheumatism
8. Neurological, neurovascular and psychic syndromes
9. Bone Diseases
10. Congenital connective tissue diseases
11. Neoplasms and related syndromes
12. Other diseases with possible rheumatological manifestations
13. Miscellaneous

1. ARTICLES AND SPONDILO-ENTHESOARTRITIS (inflammatory joint rheumatism)

1.1 Chronic primary arthritis of the adult:

- Rheumatoid arthritis: it is one of the most important inflammatory diseases affecting
the joints. It affects about 1% of the population.
- Adult Still's disease: systemic form characterized by fever and lymphadenopathy. It is
one of the most common forms of juvenile idiopathic arthritis, but in adults it is a rare
disease.
It is also classified as autoinflammatory disease, being linked to alterations of
inflammosome (an intracellular receptor complex responsible for the production of

5
 interleukin-1). This pathogenetic aspect is very important for the therapy: patients are
treated with new biotechnological anti-IL-1 drugs and have a much better prognosis
than in the past.
- Rheumatoid nodulosis
- Felty syndrome, characterized by lymphoproliferation, splenomegaly and leukocyte
reduction.1
- Caplan's syndrome
- Undifferentiated chronic arthritis: includes conditions that suggest inflammatory joint
involvement but do not present sufficient evidence to make a specific diagnosis (e.g.
rheumatoid arthritis). The forms are not well distinguishable and are placed in a sort of
limbo in which they can then evolve into a differentiated form, remain stable or go into
remission.

1.2 Chronic primary juvenile arthritis: forms that will be treated during paediatrics.
- Systemic Arthritis (Still's Disease)
- Polyarthritis seropositive for rheumatoid factor
- Seronegative polyarthritis for rheumatoid factor
- Chronic childhood oligoarthritis

1.3 Spondyloarthritis - adult entesoarthritis

The main target of these diseases is mainly entesis, i.e. that final segment of tendon or ligament
that is inserted into the bone.
- Ankylosing spondylitis: it's the most severe form. It mainly affects young adult males
(usually rheumatic diseases are prevalent in women); if not treated early, it leads to
stiffening of the entire spine, with progressive kyphosis and great functional limitation
(from last year's uncoil).
- Psoriatic arthritis
- Enteropathic spondyle-enthexaarthritis:
 Arthritis of ulcerative colitis
 Crohn's disease arthritis
- Reactive enthesoarthritis spondyle: enteroarthritis or uroarthritis can be either
enteroarthritis or uroarthritis, depending on whether the arthritis-inducing germ affects
the gastrointestinal or urethral system. Germs cause an infection in a localized structure
(such as the intestine or urethra) and then, through immunological mechanisms, cause
inflammation in the joints.
 Reiter's syndrome: a disease that can give uroarthritis. One of the most
characteristic is that which develops from Mycoplasma and Chlamydia urethritis
(atypical or non gonococcal urethritis). Arthritis can occur 1-2 weeks after the
episode of urethritis and is not due to the pathogen itself but to the response it
evokes in the immune system (from last year's coils).
 Acute joint rheumatism, which, before the antibiotic era, was one of the most
frequent causes of heart valve problems. Nowadays, in the elderly population there

1
According to orpha.net, the triad consists of rheumatoid arthritis, splenomegaly and neutropenia.

6
 are still some cases of valvulopathy secondary to this disease. In rheumatic disease,
first an infection with Streptococcus B-haemolytic type A infection develops in the
tonsils and then, about ten days later, manifestations can develop in the joints, heart
or CNS by activation of immunological processes. Thanks to the spread of antibiotics,
the spread of this disease has been greatly reduced.
 Other HLA - B27 related reactive arthritis
- SAPHO syndrome (an acronym for synovitis, acne, pustulosis, hyperostosis, osteitis).
- Undifferentiated spondyle-enthexaarthritis: clinical forms that suggest a spondyle-
arthritis but that cannot be clearly classified among the named pathologies.

1.4. Spondyloarthritis - youthful entesoarthritis:

- Ankylosing spondylitis
- Psoriatic arthritis
- Enteropathic spondyle-enthexaarthritis
- Undifferentiated spondyle-enteredarthritis

1.5. Transient or recurrent arthritis:

- Palindromic rheumatism: episodes of inflammatory arthritis, usually affecting large
joints. In most cases they are episodes that limit themselves and then reappear,
associated with a re-increase in inflammation rates, giving a true picture of arthritis.
- Intermittent hydration: usually occurs during adolescence with effusion into the large
joints, in the absence of inflammation.
- Transient hip synovitis: it is a benign picture that arises in children. Here, too, there is a
joint deposit, but it has a tendency to resolve.
- Sindrome RS3PE: (Remitting Seronegative Symmetrical Synovitis with Pitting Edema)
- Familial Mediterranean fever → Autoinflammatory disease

2. CONNECTIVITIES AND VASCULES (the most typically systemic rheumatic diseases):

- Systemic lupus erythematosus
- Systemic sclerosis or scleroderma
- Idiopathic inflammatory myopathies
- Sjögren's syndrome
- Overlap syndromes, in which there is overlap of different diseases in the same
patient.
- Undifferentiated connectors
- Systemic vasculitis: they give an inflammatory picture of vessels of different caliber,
which, then, go to occlusion, with consequent necrosis of the tissue downstream, or
to aneurysmatic evolution. The vasculitis usually have to be classified according to
the size of the vessels they affect: therefore, small, medium and large vessels are
divided into vasculitis. It should be pointed out that they mainly affect a certain type
of pots, but they can also partially affect pots of different calibre than the main type.
Most of these diseases are autoimmune based and it is possible to recognize a
specific auto-antibody marker.

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3. ARTHRITIS FROM INFECTIOUS AGENTS:

3.1 Infectious Arthritis:

- by gram-positive bacteria: they are among the most violent arthritis that can develop.
For example, Staphylococcus Aureus arthritis can destroy and turn a joint into a bag of
pus within a few days. These conditions should therefore be diagnosed and treated
early.
- by gram-negative bacteria
- by mycobacteria
- by spirochaetes
- virus

It often happens that the most sneaky forms are those treated with the greatest care, also
because they are the most frequent. With biotechnological drugs it is possible to treat these
rheumatic diseases much better, however, modifying the reactivity of the immune system and
causing the development of opportunistic infections also at the level of the joints. One can have
blurred pictures that, in reality, turn out to be infectious arthritis from opportunistic germs.

3.2 Reactive or post-infectious arthritis:

- from gold-pharyngeal infections
- from urogenital infections
- from enteric infections

They are similar to diseases classified as spondylarthritis.

Classifications are never unequivocal: a disease can be classified in several ways. For example,
Still's disease in adults can be classified as a variant of rheumatoid arthritis but also as an
autoinflammatory disease (depending on whether the classification is clinical or pathogenic).
From a clinical point of view, reactive arthritis is classified within spondyle-arthritis; from a
pathogenetic point of view, it can be classified among arthritis by infectious agents, where the
latter, however, do not affect the joint, but act as a trigger, triggering an immune process that
affects joints far from the site of the initial infection.

4. MICROCRYSTAL AND DYSMETABOLIC ARTHROPATHIES

 Microcrystalline arthropathies: among these classically there is gout, arthritis linked to
the deposition of uric acid crystals; similar to gout, chondrocalcinosis, due to the
deposition of calcium pyrophosphate (this monoarthritis, which particularly affects the
knee, is the most frequent in the elderly). Then there are the forms of hydroxyapatite,
i.e. from basic calcium phosphate: these forms are rarer and sometimes even serious.
The inflammation is induced by the presence of microcrystals in the joint: these are
incorporated by neutrophils, triggering the inflammatory reaction.
In the pathogenesis of gouty arthropathy inflammosome has been implicated, which
also seems to be part of the pathogenesis of atherosclerosis. It is no coincidence that
atherosclerosis is accelerated in all autoimmune or immunophlogistic diseases. Patients

8
 with Lupus or rheumatoid arthritis typically die of cardiovascular events, infections or
neoplasms.
The fundamental examination is arthrocentesis and the demonstration of the presence
of crystals in synovial fluid is a pathognomonic element for the diagnosis (one of the few
rheumatic diseases with this characteristic).
So, to recap, some of these arthropathies are due to:
o Monosodium urate (typically in the hyperuricemic patient), which can cause
gout. This pathology can affect one or more joints.
o Calcium pyrophosphate, which can trigger chondrocalcinosis (the most common
monoarthritis in the elderly).
o Basic calcium phosphate, which can cause hydroxyapatite, a rare and serious
disease.
 Ongoing arthropathies of metabolic diseases (such as hemochromatosis, Wilson's
disease, etc.). These forms are rarer.

5. OSTEOARTROSIS
It mainly affects the cartilage. It is one of the most frequent rheumatic diseases in the
population.
During the course of the disease there may be inflammatory processes (although it is a
degenerative disease), mainly due to mechanical causes. However, the inflammatory process is
often mild and subclinical.
It splits into shapes:
 Primary: mainly genetic forms (the typical form is arthrosis of the hands, with hard
nodules at the proximal and distal interphalangeal joints, called Heberden and Bouchard
nodules). It mainly affects women and is often found within the same family.
It can be distinguished in: localized, generalized, erosive fingers.
 Secondary: the incorrect movement of cartilage (due to trauma, genetic causes that
cause skeletal abnormalities, or overload). accelerates the process of joint degeneration
and, therefore, the development of osteoarthrosis.
Other causes of abnormal joint movement can be: developmental abnormalities,
biomechanical disorders, metabolic and endocrine diseases, hereditary connective
tissue diseases, haematological diseases, arthritis, endemic arthrosis.

Question: What is the difference between arthrosis and arthritis?

Answer: We will come back to this topic later, but for now it is enough to know that arthrosis is
a degenerative process, in which inflammation (when present) plays a minimal role, while
arthritis is typically an inflammatory picture. There may be problems in differential diagnosis
between some localized arthrosis (such as that of the hand) and rheumatoid arthritis (also
involving the hand).
Another aspect to remember is that arthralgia is joint pain in general, while arthritis is joint pain
due to inflammation (therefore associated with heat and redness).

6. PAINFUL, NON-TRAUMATIC RACHIS AFFECTIONS

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The causes are different, but very often of a postural nature (because there is a condition, for
example, of scoliosis, or prolonged assumption of incorrect posture). Another typical cause is
insufficient physical activity: in fact, postural gymnastics and movement are the main therapy
for this type of arthritis (drugs, on the other hand, relieve pain but do not solve the problem.
Physiotherapy also alleviates symptoms, but kinesiotherapy is the real curative therapy).
They can be distinguished in:
 Cervicalgia (pain in the cervical spine)
 Dorsalgie
 Lombalgie
They are further divided into: degenerative, muscular, inflammatory, neurological, neoplastic,
visceral.
At the lumbar level the causes of pain can also be others, such as herniated disc or the presence
of a bone tumor (structural causes, however less frequent).

QUESTION FOR EXAMINATION (from last year's draft) 7.

E
Difference between physiotherapy and kinesiology - Physiotherapy is an analgesic
treatment using physical therapies (such as magnetotherapy, biodynamic currents,
vasodilating therapy). Kinesiology, on the other hand, is based on specific physical
exercises for the pain complained of by the patient. In the case of acute pain, analgesic
XTRA-ARTICULAR RHEUMATISM
 Locate them:
o Entesopathies: they arise in an acute way, for identifiable causes (such as the
tennis player's elbow, which affects the epicondyle of the elbow, or the golf
player, which affects the epitroclea; yarrow tendonitis; shoulder or hip
periatritis). They're usually isolated. They can also be of traumatic origin. If
multiple entheses are involved, they constitute one of the symptoms of
spondylarthritis: the latter, in fact, should be hypothesized especially if the
patient is young and manifests enthesitis in multiple sites.
o Tenosinoviti
o Bursitis
o Bandages
 Loco-regional painful syndromes
o Periarthritis of the shoulder
o Hip Periarthritis
 Generalized
o Fibromyalgia: frequent disease, due to a disorder of the pain process. The
patient with fibromyalgia is hyperalgesic, due to a lowering of the pain threshold.
He presents widespread pain and great tiredness.
This pathology should be treated as the depressive syndrome, therefore with
serotonin reuptake inhibitors, because it is due to a reduction of serotonin at the
CNS level. Serotonin, in fact, rules:
 The pain threshold: low serotonin levels cause low pain thresholds

10
  Sleep: Patients sleep badly, and are tired when they wake up.
 The tone of the mood
The patient with fibromyalgia may have only one of these altered systems, or
even two or three. In any case, it should be treated with these drugs, which
increase serotonin in the bloodstream.
o Chronic fatigue syndrome: like fibromyalgia, but characterized by the prevalence
of fatigue over pain.
o Polyenthesopathies (non-inflammatory in nature)
 Hyperostostic dysmetabolic, very similar form to osteoarthrosis
 Secondary

8. NEUROLOGICAL, NEUROVASCULAR AND PSYCHIC SYNDROMES

- Compression neuropathies, often linked to inflammatory joint diseases, such as
herniated disc sciatalgia or carpal tunnel syndrome. The median nerve passes through
the carpal canal; if the tendons of the flexor muscles of the fingers are inflamed, they
swell, causing compression of the median nerve and consequent paresthesias at the
level of the fingers.
- Neurogenic arthropathies (e.g. Charcot's neuropathy)
- Neuroalgodystrophic syndromes (secondary to trauma)
- Chest outlet syndromes
- Raynaud's phenomenon: common and most characteristic manifestation of all
connective tissue (especially systemic ones). It consists of an acrospasm of the small
terminal arteries (mainly of the fingers and toes, but in some cases also of the earlobes
or the tip of the nose), due to a physiological stimulus of vasoconstriction, in particular
by activation of the sympathetic (from emotion or fright) or by passage from hot to cold
environments.
It is characterized by 3 phases:
o Ischemic, where the ends appear white. It is an
expression of the complete cessation of blood
circulation in the terminal artery system due
to the spasm of the muscles of the terminal
arterioles.
o Cyanotic, where the ends are blue. This is
followed by the beginning of blood flow back
into the microvessel system. Due to the
previous ischemia, the microvases are in a
state of vasodilation, which can also be
maximal. The phenomenon is due to the
release of local vasoactive substances
(thromboxane, bradykinins, prostacyclines,
serotonin). The hemoglobin is currently desaturated: hence the cyanotic
appearance of the fingers.
o Erythematosa (reactive phase), characterized by red ends. It depends on the
further change in the relationship between blood flow and microvascular

11
 capacity. It occurs when the flow is particularly abundant and the microvessel
system is still enormously dilated.
Typically the phenomenon includes all three phases, but it can also occur only with the
ischemic phase or only with the cyanotic phase. It may involve all fingers or just some of
them. It may be an isolated phenomenon, but a substantial proportion of patients with
this problem have or will have systemic connectivitis, so it will need to be kept under
control.
Two examinations are fundamental in the presence of this phenomenon: the dosage of
ANA (anti-nucleus autoantibodies) and videocapillaroscopy, through which the nail bed
is observed to detect changes in the capillary vessels.

9. BONE DISEASES
- Osteoporosis: bone mass reduction and cortical thinning in the presence of normal
calcification.
- Osteomalacie: normal bone mass associated with reduced calcification.
- Paget's disease: localized alteration of bone remodeling. The bone is structurally altered
and not resistant.
- Aseptic osteonecrosis
- Osteomyelitis (from bone infections)
- Bone Neoplasms

10. CONGENITAL CONNECTIVE TISSUE DISEASES

These are hereditary diseases due to mutations in the proteins that make up connective tissue,
therefore they mainly affect tendons, joints, skin, bones, heart valves (all structures rich in
connective tissue). Patients often have ligamentous hyperlassicity.
[These diseases will not be treated, as they are primarily of paediatric interest].
- Marfan syndrome
- Ehlers-Danlos syndrome
- Osteogenesis imperfecta
- Chondrodystrophy
- Elastic Pseudoxanthoma
- Bullous epidermolysis

11. NEOPLASMS AND RELATED SYNDROMES

There are important connections between rheumatic diseases and tumors. There are
neoplasms that develop after a long period of time after the onset of rheumatic disease, so it is
suspected that it is the pathologist itself or the therapy that causes the onset, neoplasms that
occur simultaneously with rheumatic diseases (paraneoplastic forms) and joint and tendon
neoplasms.

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 SCREENING APPLICATION

Neoplasms and rheumatic diseases - Important Topic: In the genesis of neoplasms the
crucial role of inflammation is recognized and, in fact, chronic inflammatory diseases can
sometimes be associated with tumors. Nowadays, people with rheumatic diseases
(rheumatoid arthritis, SLE, etc.) do not die from the disease itself, but from associated
complications such as infections, cardiovascular diseases and neoplasms.

An important aspect is autoimmunity, which could be a phenomenon of protection against

neoplasms, due to the role of tumor control of the immune system, but which can also be

12. OTHER DISEASES WITH POSSIBLE RHEUMATOLOGICAL MANIFESTATIONS

13. MISCELLANEOUS

EVALUATIONS FOR THE DIAGNOSIS AND MONITORING OF RHEUMATIC

DISEASES

ANAMNESIS
It is expressed in an internal-generalistic part and in a specific part for the skeletal muscle
apparatus and organs potentially affected by rheumatic diseases.
 Symptoms affecting the musculoskeletal system
1. Pain (one of the most frequent symptoms in rheumatology):
 Localization
o Site (the pain will be more superficial or deeper, depending on the
structure of the affected musculoskeletal system)
o Extension
o Irradiation (in the case of discopathy, where there is an involvement
of a nerve root, the pain will radiate to different areas depending on
the disc concerned)
 Pattern of joint involvement
o Articular, which can be distinguished into monoarticular,
oligoarticular (2 to 4 affected joints), polyarticular (with 5 or more
joints involved).
o Extra-articular, which can be localized (as in shoulder periarthritis) or
generalized (as in fibromyalgia).
 Duration of the event

13
 o Acute pain (< 6 weeks)
o Chronic or persistent pain (> 6 weeks)
 Debut
o Acute (typical of disc herniation: lumbago develops as a result of a
triggering event, such as, for example, the act of lifting a weight)
o Subacute (especially in inflammatory diseases)
o Chronic
 Chronology
o It's about the time of day when the pain manifests itself. Mechanical
pain (e.g. in spondyloarthrosis) is more frequent during the day due
to the activity that stresses the joint, while inflammatory pain (e.g. in
spondyloarthritis) also occurs at rest and at night. Inflammatory pain,
if overloaded, can still exacerbate.
 Variations due to position, therapy, movement (chronic diseases worsen with
movement, inflammatory diseases, on the other hand, improve), climatic
conditions (humidity does not cause rheumatic diseases, as is often believed,
but exacerbates pain, triggering muscle contraction and the release of
bradykinins).
 Associated symptoms
2. Post-inactivity rigidity or stiffness (especially in the morning)
3. Muscle weakness
4. Fatigability
5. Limitation of movements
 General symptoms: fever, lack of appetite, asthenia, tiredness
 Symptoms affecting other organs and equipment
 Acrosensitivity to cold (Raynaud's phenomenon)
 Others
 Associated diseases (comorbidity)
A disease typically associated with chronic inflammatory diseases is chronic interstitial
pneumonia. This pneumonia is expressed with different pictures: UIP (usual interstitial
pneumonia, typical of rheumatoid arthritis), NSIP (non-specific interstitial pneumonia,
the most frequent form) and LIP (PI Lymphocytic, typical of Sjogren's syndrome). [From
last year's uncoil.]
 Familiarity

OBJECTIVE EXAMINATION
 General
 Musculoskeletal system
 Inspection: swelling, joint and spinal deformities, redness can be detected.
 Palpation, to feel any heat in the joints (thermotatto), swelling.
 Digitopressure, which assesses the painfulness of the joint: if the patient has an
inflamed joint and pressure is applied to it, the pain increases and the limb is retracted
suddenly and abruptly.

14
  Active and passive mobilization: it consists of moving the joints in the various planes of
movement
o Pain in passive mobilization: joint problem
o Pain in both active and passive mobilization: even or only extra-articular problem
 Particular maneuvers: they are carried out when the patient reports a certain symptom
(for example, the Lasègue maneuver, to assess the involvement of the sciatic nerve,
which consists in the flexion of the thigh on the pelvis with the leg in extension; the
Finkelstein test, to verify the presence of De Quervain's tenosynovitis).

LABORATORY TESTS AND IMAGING

 Lab tests
 Blood and urine
 Synovial liquid
 Articular ultrasound: a very important diagnostic tool. It is also possible to do an ultrasound
of muscles, vessels (if vasculitis is suspected), salivary glands (to assess Sjogren's syndrome).
 Radiography and other imaging techniques, such as videocapillaroscopy, in which the
bottom of the nail bed is observed to assess any capillary changes, MRI and CT.

SIGNS IN RHEUMATIC DISEASES

 Joint signs
 Signs charged to the rachis
 Signs charged to entheses, tendons and bags
 Muscle Signs
 Signs charged to other organs and apparatus

 Signs of joint inflammation

In case of inflammation there will be redness, heat, deformity,
impaired movement.
The first image on the right shows an inflammation of the first
metatarsophalangeal joint, often affected by gout. In the image
depicting the hand, however, the inflammation is more
nuanced: perhaps it is an initial form of arthritis, which can be
investigated with acupressure.
A less important clinical presentation usually indicates a lower
severity of the disease: for example, mild swelling associated
with low pain may express a low level of inflammation. Gout
and all forms due to microcrystals are the most inflammatory.

Joint deformities

Hands deformed in the wind in a patient with rheumatoid

arthritis. This type of deformation is less and less frequent
thanks to the therapies.
15
 Case of big toe valgus (big toe valgus is very often a
familiar form). Can complicate in bursitis (due to the use
of a shoe that is too tight).

Ankle valgism with windblown toes altered due to

arthritis.

Knee valgism: deviation of the knee from the axis between the
femur and tibia forming an obtuse angle open laterally to the
outside of the body (open L-shape).

Varism of the knees: the deviation forms an obtuse angle open to

 Signs charged to the rachis
At the inspection it is possible to assess the presence of alterations to the column. In the
anteroposterior sense, you may have: cervical hyperlordosis, dorsal hyperciphosis, lumbar
hyperlordosis. On a lateral level, you may have various forms of scoliosis. There are
restrictions on active and passive movements. The simple inspection allows to evaluate
these alterations.

 Signs charged to entheses

To detect a compromise of the tendon, the manoeuvre to be carried out is the movement
against resistance. In the epicondylitis of the elbow, for example, the hand is flexed against
resistance, so that the muscles that have the epicondyle as an attack point contract and
possibly cause pain.

16
 The figure on the left shows the main locations of the
entheses.

 Calcaneal spur

Case of enthesitis calcifica. The X-ray will show calcaneal

spurs, calcium deposits that develop under the heel as a
result of fascial inflammation. The painful
symptomatology is transitory and the spurs remain
radiologically evident even when the symptomatology
disappears. They are not specific to spondylarthritis, as they
are also found in the population.

SCREENING APPLICATION

Main target of spondyloarthritis - spondyloarthritis are mainly characterized by entesis

engagement. But what are the diseases that affect entesis? There are 30 entheses in the
human body. Some pathologies affecting entheses are epicondylitis of the elbow,
epitrocleitis, periarthritis of the shoulder, trochanteritis at the hip level, yarrow tendonitis,
goose leg tendonitis, etc...

 Signs of inflammation of the bags

The picture on the left shows a swollen olecranon bag. The inflammation
is so intense that it causes erythema and exfoliation of the skin. The heat
due to inflammation (similar to that due to solar erythema) makes the
epithelium desquamate.

Measurements in rheumatology
Nowadays, in order to use certain drugs in the therapy of rheumatological diseases, it is
necessary to justify their use. This is done by measuring the following characteristics:
 Pain - analog scales, dynamometers, self-assessment questionnaires
 Painfulness - Ritchie's test, evaluation of tender points
 Morning stiffness - duration in minutes
 Muscle weakness - manual muscle test (MMT); dynamometer

17
  Asthenia and functional incapacity - self-assessment questionnaires

LABORATORY

INVESTIGATIONS IN RHEUMATOLOGY
Laboratory investigations are very important in Rheumatology because the clinical
manifestations of rheumatic diseases are rarely pathognomonic and specific (only a limited
number are) and moreover, when present, they tend to appear in advanced stages (rarely in
the early stages of the disease itself). It is clear, therefore, that it is not possible to rely on them
in order to make an early diagnosis and in this sense the laboratory is becoming increasingly
indispensable, as it helps the clinician in the differential diagnosis of very similar pathologies
from the symptomatological point of view.
The main basic rheumatological tests to be requested from the laboratory are:
 Phlogosis Indices (ESR, PCR, fibrinogen).
 Protein profile.
 Immunological parameters: it has already been said that at the base of rheumatic
diseases there is an immunophlogous disease, therefore an inflammation due to
alterations in the immune response.
Immunological parameters are therefore very useful and tend to be positive in the early
stages of the disease (if required after a clinical suspicion, therefore, often allow to
confirm or exclude a diagnostic hypothesis).
 Uricemia and uricuria: especially important for the diagnosis of gout.
 Muscle enzymes (CPK, LDH, myoglobin): useful for example for idiopathic inflammatory
myopathies.
 Bone metabolism (calcium, phosphoremia, calciuria, phosphaturia, PTH and vitamin D).
 Antistreptolisin title.
The main indices that will be treated in this lesson will be the inflammation indices and
immunological parameters, while we will also mention the analysis of synovial fluid, a very
important examination in the field of rheumatic diseases; the other examinations, more specific

18
for some well-defined rheumatic diseases, will be treated together with the pathologies of their
interest.
PHLOGOSIS INDEXES: VES AND PCR
Phlogosis indices are very early markers of inflammatory disease and rheumatic disease is an
inflammatory disease, so it will be altered early on PCR and ESR.
Increased ESR is an indirect indicator of increased acute phase proteins produced in the liver
under the influence of pro-inflammatory cytokines (especially IL-6).
ESR measures the ability of red blood cells to aggregate and precipitate. Acute phase proteins
determine the aggregation of red blood cells among themselves, exasperated capacity if their
concentration increases, in this condition red blood cells precipitate more rapidly, increasing
ESR. The basic mechanism is that the red blood cells expose negative charges on their surface,
which would tend to move them away from each other; however, the acute phase proteins
have positive charges on the surface and for this reason they tend to mask the negative charges
on the surface of the red blood cells, stimulating their aggregation and thus speeding up
sedimentation.
The ESR measurement is performed by placing the patient's blood in a 300 mm graduated tube
with a diameter of 2.5 mm, placed vertically, where the erythrocytes will tend to precipitate at
a certain speed. Going to read the result one hour after inserting the blood into the tube, you
will evaluate the erythrosedimentation index.

PCR is the main acute phase protein (produced by the liver always in response to IL-6) required
in tests for rheumatic diseases, but it also has an important physiological role in the innate
immune response.
PCR has in fact numerous tasks, for example: it binds antigens exposed by microorganisms,
nuclear antigens and cellular debris to facilitate their elimination, increases both in infections
and in all inflammatory conditions, activates the complement, stimulates the production of the
same pro-inflammatory cytokines by endothelial cells and stimulates macrophages. It therefore
plays a very important role in the defense of the body, increasing significantly in inflammation
conditions and thus representing an important test for clinicians.
PCR is a more reliable and precise inflammation index than ESR, as it is more sensitive (it rises
and falls faster in case of pathology and/or inflammation) and less influenced by other factors
that typically affect ESR.
ESR is affected by many conditions related to acute phase proteins and, above all, it is affected
by qualitative and quantitative variations in red blood cells. For example:
- In an anaemic subject (i.e. with a reduced number of red blood cells) ESR is more basic
than normal simply because he has less red blood cells.
- If the viscosity of the plasma increases as a result of an increase in the number of
immunoglobulins, ESR is high.
- Other factors that lead to a higher level of ESR than the norm are older age and female
gender.
All these confusing factors make PCR a better indicator than ESR. Normally, however, in
rheumatological analysis the dosage of both of the above indicators is required, but nowadays
this practice should be correct and only PCR should be required with some exceptions, e.g. in
connective tissue and lupus PCR increases little, while ESR is more sensitive.

19
PROTEIN PROFILE
The protein profile (or protidogram) is another routinely required
examination for the determination of rheumatic diseases, as there are
several variations in it that may indicate certain well-defined pathological
conditions:
 Albumin decreases in case of inflammation and nephrotic
syndrome, a common condition in SLE patients.
 The α2 protein profile is the inflammatory protein, so the α2 peak
increases in case of inflammation.
 β2 proteins increase in case of nephrotic syndrome (SLE).
 Gamma globulins increase in case of autoimmune disease, i.e.
when there is a large production of autoantibodies. They may decrease in case of
nephrotic syndrome (SLE or gammaglobulin loss) or in conditions of acquired
immunodeficiency (immunosuppressive therapy).

The characteristic profile of

inflammatory pathologies
therefore foresees the
simultaneous reduction of albumin
and increase of α2 proteins.

IMMUNOLOGICAL PARAMETERS
As said, the inflammation that occurs in rheumatic diseases is an immunophlogosis, i.e.
inflammation induced by changes in the immune system. This is reflected in the fact that,
among rheumatological tests, many are tests aimed at identifying immunological alterations.
As a first level test, gammaglobulins (seen above) and immunoglobulins, whose levels reflect
the levels of circulating antibodies, both protective and possible autoantibodies, may be
required.
Subsequently, more specific (second-level) tests may be required with which the individual
immunoglobulins can be dosed:
- Rheumatoid factor (IgM) is one of the most common and, together with anti-citrulline
antibodies, is characteristic of rheumatoid arthritis.
- Anti-nuclear antibodies are more typical than connective tissue.

20
 - Anti-phospholipid antibodies distinguish the clinical syndrome known as
"antiphospholipid antibody syndrome".
- Neutrophil cytoplasmic antibodies (ANCA) are typical of vasculitis.
- Cryoglobulins are typical of cryoglobulinemias.
Autoantibodies in autoimmune diseases are mostly IgG, in particular they belong to the
subgroup IgG1.
Other level two exams include:
 Dosage of circulating immune complexes: less and less required because an increase in
them is very non-specific as it is influenced by too many factors.
 Dosage of C3 and C4: these are factors of the complement that increase during
inflammation, they are required mainly to investigate their decrease: they tend to
decrease when consumed because there is a massive activation of the complement due
to an important immunological reaction.
 HLA typing: serves instead to identify factors that predispose to certain rheumatic
diseases. HLA B27, typical of ankylosing spondylitis, is frequently investigated.
Let's look at some of these immunological parameters in more detail:
Rheumatoid factor (FR)
It is usually an IgM class antibody (it is the most widely dosed immunoglobulin class, but there
are also IgG and IgA classes). Its function is to bind the Fc fragment of the IgG and for this
reason it is believed to be a physiological and protective immune factor, whose purpose would
be to facilitate the elimination of immunoglobulin-microorganism complexes (particularly
phagocytosis) during infection or autoantibodies during rheumatic pathology.
In rheumatoid arthritis (a disease in which FR is the first characteristic indicator), it probably
forms later, with the aim of eliminating previously formed anti-citrulline autoantibodies.
There are various methods of dosing the FR:
- The oldest method is the agglutination test with sheep red blood cells sensitized with
rabbit IgG (Waaler Rose). In this test the patient's serum is brought into contact with the
red blood cells of sheep and, if rheumatoid factor is present, the aggregation of the red
blood cells is observed.
A variant of this test is the latex test, which uses human latex particle IgG. In the
presence of FR, the latex particles aggregate.
- Today they use mainly nephelometry and ELISA methods.
Human IgGs are used in nephelometry, which aggregate together in the presence of the
factor in the patient's serum. Aggregation increases the turbidity of the solution that is
read by the nephelometer according to a precise scale. In this way, quantitative
evaluations are also possible, as more turbidity will be measured in the serum where FR
is present.

21
Rheumatoid factor is present in about 65-75% of patients with rheumatoid arthritis, especially
in patients with active disease. It has a negative prognostic meaning, i.e. it indicates a more
aggressive and therefore erosive disease with a worse prognosis.
However, it is not entirely specific, as it is present, albeit in very small quantities, in 1-4% of the
general population (increasing slightly in the elderly, a condition that applies approximately to
all autoantibodies) and in many other diseases. Rheumatoid factor is indeed more frequently
found in Sjogren's syndrome, and not in rheumatoid arthritis, as one is led to think (this
peculiarity of FR behaviour is frequently requested at the examination). It is also very frequent
in infections, mixed cryoglobulinemias, connective tissue and chronic inflammatory
immunoinduced diseases. It is thought that its increase in all these pathologies is linked
precisely to its probable protective function.

In the FR assay, it is important to also assess the titre, i.e. the extent of the increase: low levels
of FR have higher sensitivity but lower specificity in the diagnosis of rheumatoid arthritis,
compared to high levels of
FR. This specificity is
lower especially in
relation to other diseases
that enter into differential
diagnosis with rheumatoid
arthritis itself, such as
reactive arthritis or
osteoarthrosis. With higher
titration levels, however,
sensitivity is
lowered in favour of greater
specificity.
This shows that FR is an index that
can be found altered in many
clinical conditions, but that its
different titration (i.e. the different
amount of increase in its value)
makes it possible to make a
differential diagnosis. In particular,
its levels are only moderately
altered in the vast majority of
conditions (e.g. osteoarthritis,
reactive arthritis and Sjogren's
syndrome), while in other diseases
(such as rheumatoid arthritis) RF reaches very high levels (even in rare healthy subjects with
altered RF the titration remains low, without ever reaching levels close to those reached in
rheumatoid arthritis) (see table below).

22
Anti-citrulline antibodies
Today it is considered the main antibody to rheumatoid arthritis. Citrulline is a non-standard
amino acid, i.e. it is not normally incorporated into proteins during their synthesis. It is
produced from arginine by substitution of an amine group by a carboxyl group by the enzyme
PAD (peptidil-arginine-deaminase); it has been observed, among other things, that a genetic
variant of PAD can be a predisposing factor for rheumatoid arthritis. PAD is activated with very
high intracytoplasmic calcium concentrations, which are not reached normally but only in
certain situations, such as during apoptosis. When PAD activates and forms citrulline, the
synthesis of citrullinated peptides can occur, against which the production of antibodies is
directed.
Anti-citrulline antibodies have a similar sensitivity to FR, but are much more specific.
They are important because they also form long before the onset of the symptoms of the
disease (even 14-15 years before). This applies to all autoantibodies present in rheumatic
and/or autoimmune diseases, i.e. also FR). Because of this feature, they can be used to make an
early diagnosis of disease.
They also seem to be predictive of a more serious and more rapidly progressive disease.
They also have a pathogenetic as well as diagnostic role, which will be resumed by talking about
arthritis.

Anti-nuclear antibodies (ANA)

These are also usually IgG type.
This generic title actually groups together many subtypes of antibodies, directed against both
nuclear antigens and cytoplasmic antigens: therefore anti-nuclear antibodies are not only
antibodies directed against nuclear antigens (which are however the majority), but also
directed against cytoplasmic antigens (present in rheumatic, autoimmune or connective tissue
diseases).
In addition, they are antibodies directed against non-specific antigens, i.e. not directed against
antigens of a specific cell type but against ubiquitous antigens in all cells. The explanation of this
phenomenon was reached after the discovery of the phenomenon of apoptosis, during which
self-segregated antigens in the nucleus and/or cytoplasm can come into contact with the
immune system, leading to the formation of this category of autoantibodies.
It is likely that these antibodies are present in each individual with a well-defined biological
function (e.g. the removal of cellular debris that is formed during apoptosis), although in
healthy subjects not affected by rheumatic and/or autoimmune diseases they are present in
such low concentrations that they cannot be titrated. In pathological conditions, on the other
hand, as with the FR, they increase significantly.

23
Historically, ANAs have been identified thanks to the observation of the LE phenomenon,
described in 1949, in which phagocytosis of cellular and/or nuclear debris by a neutrophil
occurs in the presence of anti-nuclear antibodies, which facilitate their elimination.
These antibodies are now being dosed through:
- Immunofluorescence: exploits anti-human IgG antibodies marked with fluorescent
substances and therefore detectable by microscopy. A tissue or cell culture is placed on
a slide and then the patient's serum is added and, if ANAs are present in the slide, they
bind to their nuclear or cytoplasmic
antigens and their binding is then
captured by the further addition of
the laboratory marked anti-IgG
antibodies mentioned above (this is
an indirect immunofluorescence
method).
- Cell culture: usually carcinomatous
cells of the human larynx.
- ELISA methods on extractive or
increasingly recombinant antigens.
These different methods have different
specificity and sensitivity in the determination of antibodies and, among all of them,
immunofluorescence is still considered to be the reference method (even the new modern and
automated methods are not able to replace immunofluorescence as the reference method, as
they do not have an acceptable reliability at the moment).
The characteristics that are evaluated through these methods are:
 The fluoroscopic panels, which depend on the location zone of the ANAs. The different
location of the ANAs determines different fluorescence patterns and different patterns
correspond to different ANAs. Some of the main patterns are:
- Peripheral pattern: with fluorescence around the nucleus, associated with anti-
dsDNA antibodies (also called native anti-DNA antibodies). These antibodies are
specific for SLE (present in 60-70% of patients). They are detected by direct
immunofluorescence/ELISA or by indirect immunofluorescence applied on a
preparation containing the protozoon Crithidia luciliae, which contains a lot of
double helix DNA in the kinetoplast.
- Diffuse or homogeneous pattern, where the fluorescence is distributed
throughout the core.
- Dotted pattern, associated with anti-ENA antibodies, directed towards
deoxyribonulceic macromolecular complexes (called ENA notes) present in the
cytoplasm and nucleus and participating in many physiological cellular processes
(enzymatic functions, replication, transcription, splicing).
- Nucleolar pattern, where fluorescence is concentrated at nucleolus level,
associated with antibodies present in scleroderma, such as anti-PM-Scl, anti-
polymerase III antibodies or others.
 The antibody titer.
 The immunoglobulin class.

24
  Antigenic specificity (with other more specific tests).
ANAs are found in many clinical conditions (summary image on the side), for example in
systemic connective tissue, rheumatoid arthritis, in some viral diseases (e.g. hepatitis, where
polyclonal activation of B lymphocytes occurs), in organ-specific autoimmune diseases (e.g.
thyroiditis and autoimmune hepatitis), in some neoplasms (e.g. B lymphomas). they can
actually be found also in the healthy elderly population (over 60 years).
Another very important parameter that must
be evaluated in the ANA assay is the antibody
titer. The graph shows how the frequency of
incidence in the general population decreases
as the antibody titer increases.
The antibody titer cut-off that is generally
considered positive is the 1:80 level, although
this level is not very high and can lead to false
positives. More correctly, a level that is
considered frankly positive is definitely a level
of 1:320 (although, as said, 1:80 and 1:160 are also accepted as levels. The false positives
resulting from the use of these two not too stringent cut-offs must be clarified by evaluating the
remaining clinical and biohumoral
picture).

Specific ANA antibodies are also very

important in the precise diagnostic
direction. for example, in SLE, anti-
dsDNA ANAs are very often found,
whereas anti-ssDNAs are more non-
specific and are also found, for example,
in infections. The classic method to
detect anti-dsDNA ANAs is the
immunofluorescence test on a
monoflagellated protozoon, Crithidia
luciliae, which has a kinetoplast rich in dsDNA: the protozoon is used as a substrate and is
covered by the patient's serum; if anti-dsDNA ANAs are present in this, a localized fluorescence
in the kinetoplast will be detected, which determines the positivity of the test. The antibody
titer must also be evaluated for specific antibodies; moreover, it is pointed out that these
specific antibodies are normally not present in healthy subjects, unlike aspecific ANAs which, as
said, can be. Usually the anti-NAEs (which include all the specific antibodies, by means of a
screening test) are dosed first and in case they are positive the various antibody specificities
(anti-dsDNA, anti-ENA, etc.) are required to orient themselves between one pathology and
another (second level test).
Anti-ENA antibodies (extractable nuclear antigens) are a particular type of antibodies directed
against large dessosiribonucleoprotein macromolecular complexes contained within the
nucleus and, in some cases, in the cytoplasm. The antibody response may also recognize
different epitopes of the same antigenic complex. ENA antigens are however numerous

25
macromolecular complexes essential for the cell and involved in its normal physiology, as they
have many roles (they are involved in DNA replication, DNA coiling, transcription, RNA splicing
and acetylation, mitotic division, peptide synthesis and transport, etc.).
What is essential to know about these specific autoantibodies is that many of them are
indicative of very specific pathologies (see table below). These autoantibodies, together with FR
and anti-citrulline antibodies, are often required for testing). In addition, some of these
antibodies are associated not only with very specific pathologies, but in particular with some
precise clinical manifestations of them, e.g. the native anti-DNA antibody is associated with
ongoing SLE nephritis lupica, while the anti-polymerase III antibody is associated with
scleroderma renal crisis in scleroderma.
These autoantibodies are therefore useful both from a diagnostic and from a prognostic and
phenotyping point of view.
As can be seen from the table (must be learned for the examination):
 Anti-Sm antibodies are most frequently found in SLE together with anti ds-DNA and anti-
P proteins.
 Anti-centromere are more typical of scleroderma, as are anti-scl70.
 The anti-PM-Scl can be found in scleroderma, polymyositis and, above all, in the overlap
form of these two pathologies.
 Anti-U1RNPs are found in SLE, but are practically always present in overlap connective
tissue (mixed connective tissue, MCTD). This is one of those cases of clinical syndrome
characterized by the positivity of an antibody.
 The anti-RO/SSAs may be present in all connective tissue (they are therefore not very
specific), even if they are present with different frequency. They also have the peculiar
characteristic of overcoming the placenta from the 15th week of gestation, like all IgG1,
but with greater aggressiveness than the norm → they can determine a congenital
atrioventricular blockage pattern in the child.
(anti-SSA antibodies are often required to be tested in all their facets).
 Anti-LA/SSB antibodies, like anti-SSA, can be found in all pathologies but they are
specific to Sjogren's syndrome (a pathology that can also be associated with other
connective tissue, explaining why anti-SSB antibodies are very common in rheumatic
diseases).
 Anti-Jo-1 and anti-Mi-2 are typical of polymyositis.
 Anti-Ku can be detected in many diseases (such as anti-SSA).
In any case, in the study of the single pathologies during the lessons we will return to the
specific and single antibody positivities (here presented in summary).

26
A parenthesis is owed regarding anti-SSA antibodies, because of their characteristic of being
strongly aggressive towards the pregnant fetus. From the 15th week onwards the placenta
becomes more and more permeable as childbirth approaches, until it reaches a situation where
the concentration of immunoglobulins in the fetal blood may even be higher than in the
maternal blood (especially in the last 4 weeks). The newborn is then born with the maternal
IgGs in the circle, which serve to protect it and which are eliminated around the 9th week of
life. The newborn receives not only protective antibodies but also potentially harmful
autoantibodies. Before the 9th week, in fact, 5% of children of anti-SSA positive mothers (even
in the absence of SLE) can develop what is improperly called neonatal lupus (probably because
of lupus-like symptoms). The symptomatological picture is quite varied and includes skin
manifestations (photosensitivity), myocarditic, hepatitis and thrombocytopenic manifestations
that generally resolve after antibody clearance. In 1-2% of cases, however, a congenital
atrioventricular block may be complete and non-reversible. Sometimes the blockage already
develops during the uterine life (18-25 weeks) and can therefore be diagnosed with fetal
echocardiography. If the blockage is first degree, it usually resolves spontaneously. However, if
the blockage is of a higher degree, it can lead to intrauterine death or require the placement of
a pacemaker immediately after birth. It is important to stress how this can happen even in the
absence of symptoms on the mother's part. It may happen to have a mother with a child with
congenital asymptomatic congenital AV block to which positive anti-SSA antibodies are dosed. It
should also be borne in mind that if a woman who has already had a child with AV block (1-2%
probability) has a second pregnancy, she will have a 20% probability of having another child
with AV block (so maternal factors not yet fully known are probably involved).
Anti-phospholipid antibodies
Despite the misleading name, antiphospholipid antibodies are not directed against
phospholipids but against proteins associated with phospholipids. Among these proteins, the
main ones are β2-glycoprotein-1 and prothrombin, although there are many others that can be
associated with these phospholipids. (Test question: What are the antiphospholipid antibodies
directed towards? They are directed towards proteins associated with phospholipids such as,
principalmeente, β2 glyprotein I and Proprombin, but also many others and so on ).
The β2-glycoprotein-1 is a circulating anticoagulant normally present in circulation that under
certain conditions, in predisposed subjects, can become antigenic, inducing the production of
antibodies, the Ab anti-β2GP1 that cause the so-called antiphospholipid antibodies syndrome,
present in two variants:
 Internalistic form: in which antiphospholipid antibodies are associated with arterial and
venous thrombosis, which can affect any district of the body.
 Variant called "obstetric syndrome": in which positivity to antiphospholipid antibodies is
associated with obstetric complications. Before the discovery of these antibodies,
patients with these antibodies had an abortion even in the terminal stage of pregnancy
in 80% of the cases, but since they were discovered, they are tested and the therapy for
this syndrome is done, with different results, with up to 70-80% of pregnancy successes.
The professor says it is one of the great successes in medicine in recent years.
These antibodies are determined by an ELISA test. It is recalled that the first test used was for
the test for the dosage of Ab anti-cardiolipin (a-CL), in which it was seen that the positivity
derives from the fact that washing liquids were used where bovine β2GP1 was present, which

27
binds to the phospholipid cardiolipin and is the true antigenic substrate. This test, without the
washing fluids containing this protein, can be positive in case of infectious disease, so it is not
specific. The next step was the development of ELISA tests where human β2GP1 was present. In
both tests, for ab anti-CL and ab anti-β2GP1, I look for IgG and IgM.
The third test used for the determination of antiphospholipid antibodies is a test for Lupus
Anticoagulant (LA), a hemocoagulative test that results positive (with PT elongation -
prothrombin time) in the presence of Ab antiphospholipids, essentially Ab anti-β2GP1 and Ab
anti-prothrombin.
ANCA (neutrophil cytoplasm antibodies)
They are diagnostic markers, therefore specific, of systemic vasculitis, which affect small
vessels. Mainly such vasculitis are granulomatosis with polyangiitis (the old Wegener's
granulomatosis) and microscopic polyangiitis, where there is frequent positivity to ANCA.
There is also a third one: eosinophilic granulomatosis with polyangiitis, but the detection of
ANCA antibodies in it is less frequent.
They are identified by two techniques:
- Indirect immunofluorescence on ethanol-fixed granulocytes:
ethanol fixation allows myeloperoxidase to escape from the
bluish granules of the neutrophils to settle around the
nucleus, while Serin-Protease 3 (or PR3) remains in the
granules.
If a different fixative, e.g. formaldehyde, was used, both PR3
and MPO would remain in the granules, remaining indistinguishable.
Immunofluorescence also allows to distinguish P-ANCA, including anti-MPO,
characterized by peri-nuclear positivity, from C-ANCA, including anti-PR3, with
cytoplasmic positivity.
In the image on the right, anti-MPO antibodies can be seen on the right, with positivity
around the nucleus, while on the left, cytoplasmic positivity, typical of anti-PR3
antibodies, can be seen.
- ELISA test for specific Ag: towards the anti-PR3 Ab, typical of granulomatosis with
polyangiitis, and the anti-MPO Ab, typical of micro-polyangiitis, while in the eosinophilic
granulomatosis with polyangiitis both are found at 50%.
There is a tendency to perform both of these techniques, because if they are both positive the
specificity increases considerably.
Question: Why is indirect immunofluorescence used here, while direct immunofluorescence is
used for ANAs? No, even before, the indirect one was used. All antibodies are determined by
indirect immunofluorescence, the same procedure is always used, although different cells can
be used as substrate. The patient's serum is then added and a detector system is used, such as a
protein labeled with fluorescein, which allows you to see the fluorescence where it is distributed.
The ELISA is always an indirect enzyme immunoassay.
Cryoglobulin
They are a class of proteins bound to components of the complement, which has the
characteristic of precipitating at low temperatures. The sample is taken with a syringe kept at
body temperature, then the sample is refrigerated at 4°, and after 48-72h the precipitate of
immunoglobulin and complement is formed and finally the precipitate can be quantified.

28
They are also found in small vessel vasculitis (e.g. in mixed cryoglobulinemia, once called
"essential" because of unknown pathogenesis, it is now known to be caused by viral infections,
especially HCV).
There are three types of cryoglobulins, distinct according to the constitution of the precipitate:
- Type 1: they are single monoclonal, present in lymphoproliferative diseases, first of all in
multiple myeloma.
- Type 2: they are mixed with a monoclonal component and can occur in HCV and
lymphoproliferative diseases.
- Type 3: they are mixed and polyclonal and are found in HCV, infectious diseases, chronic
inflammatory and connective diseases. They are the most frequent typology found in
cryoglobulinemic vasculitis, which are always in small vessels, which tend to affect the
same districts: skin, kidney, lung.

SYNOVIAL FLUID EXAMINATION

It's crucial in rheumatology. It is particularly important in patients with joint
swelling where arthrocentesis, extraction method with appropriate syringes
and needles of synovial fluid is possible.
In synovial fluid they are analysed/executed:
Chemical-physical characteristics:
 Volume (in mL): high in case of inflammation. In psoriatic arthropathy in particular, the
samples evacuate 90-100mL, compared to the normal 2-3mL. Already the fact of
evacuating so much liquid can therefore suggest an etiology and consequently a
therapeutic approach.
 Appearance: normally it's clear. The murkier it is, the more inflammatory the picture.
The appearance may also be opalescent due to the presence of corpuscles, such as "rice
bodies" (composed of cartilaginous debris or synovial membrane residues, typical of
rheumatoid arthritis).
 Colour: citrine yellow, golden yellow, greenish yellow (in case of infection) or
haemorrhagic.
 Viscosity: normally it is as viscous as egg white, due to the polymerization of hyaluronic
acid with some proteins (by electrostatic bonds) and "spins" from the syringe. In an
inflammatory picture, on the other hand, there is a depolymerization of these elements
with a macroscopically more fluid synovial fluid which, similar to water, drips from the
syringe.
This examination can therefore be useful in the distinction between arthritis and non-
inflammatory joint effusion.
Mucin test: use 4cc of 2% acetic acid with 1ml of synovial fluid, if the latter remains intact, the
picture is not inflammatory, if it becomes brittle it is.

29
Cytology: so the leukocyte count. The latter is the most useful examination for assessing the
degree of inflammation, which is therefore all the more serious the higher the count/mm³:
- Less than 2 x 103 per mm3: non-inflammatory liquid
- [2-5] x 10³: mildly inflammatory liquid
- [5-50] x 10³: frankly inflammatory fluid
- More than 50 x 103: highly inflammatory liquid. It is mainly found in septic arthritis but
also, more rarely, in microcrystalline arthritis (severe joint inflammation - gout, chondro-
calcinosis or pseudo-gout) and finally in rheumatoid arthritis.
Searching for crystals under the microscope: they are different in composition, shape and size.
They are typical of precise pathologies, so much so that the discovery of some of these crystals
in a sample of synovial fluid is pathognomonic and already allows the differential diagnosis
between monoarthritis. It is therefore an examination of fundamental diagnostic importance,
one of the most useful in rheumatology.
It mentions the crystals of:
- Uric acid/mono-sodic acid: needle-shaped, often intracellular, typical of gout.
- Hydroxyapatite: smaller, amorphous clusters typical of osteoarthrosis.
- Calcium pyrophosphate: parallelepiped-shaped, typical of chondro-calcinosis or pseudo-
calcinosis, more frequent cause of mono-arthritis in the elderly.
Microbiological, cultural or microscopic analysis (the most useful immediate test is Gram
staining), in case of suspected infectious, septic arthritis.

Protein examination:
The protein concentration
in synovial fluid is usually 1/3
of the plasma concentration
and, in general, the increase in
protein content is an index of local inflammation and reflects the degree of it. Values > 4 g/dl
are usually pathological.
This test, together with the measurement of enzymes, cytokines, complement, has less
relevance than the previous ones: they are performed only for research purposes, and not
routine.
To summarize: the examination of synovial fluid, where it is extractable (not always so) is
essential in suspicion of rheumatic disease, particularly in mono-arthritis.
Parenthesis on septic arthritis

30
Septic arthritis, mainly caused by St. Aureus, presents with a synovial fluid already at a first
purulent observation. The slide below shows the germs responsible for septic arthritis. In the
past, pathogens such as Gram+ were more frequent, but nowadays opportunistic germs such as
mycobacteria and fungi are also found. The reason for the spread of Gram+ as a pathogen is as
follows: Some time ago, glass syringes were used for arthrocentesis, which were not properly
sterilized and which led to bacteria entering the joint. This risk has been significantly reduced by
the aseptic maneuvers used today. Today, however, we find opportunistic germs, because they
are the result of various immunosuppressive and immunomodulating therapies.

RHEUMATOID ARTHRITIS
DEFINITION
Rheumatoid arthritis is a chronic
inflammatory disease that mainly
affects the diarthroid joints, i.e. those with a synovial membrane, precisely because the first
target of rheumatoid arthritis is this membrane, but it can potentially affect any other organ
and apparatus (with the so-called extra-articular manifestations of rheumatoid arthritis).
At the joint level the inflammation induced by the rheumatoid process is very serious and
intense and, if not detected and treated adequately, leads to erosion and destruction of the
iuxta-articular bone heads and ankylosis of the joint, with deformity and functional loss of the
same.
The patient with advanced rheumatoid arthritis is severely debilitated in daily life and is
therefore to be considered a serious illness. Today there are effective drugs available which, the
earlier they are administered, the better the prognosis.
A healthy diarthrosis, as in the picture, presents:
articular capsule, synovial membrane, articular cartilage
protecting the two bone heads, and bare areas (called
bare areas), at the junction between membrane and
cartilage, which are not covered by either. It is at this
level that the first bone erosions are formed, it is
therefore necessary to examine these areas in Rx to
determine whether the
process is erosive or not.
The image on the left
instead represents a
joint affected by rheumatoid arthritis: liquid accumulates, the
synovial cloth becomes hypertrophic, as if it were neoplastic,

31
and erodes the surfaces of the bones starting from the coffin areas, between the cartilage and
the beginning of the synovial membrane.

EPIDEMIOLOGY
It is the most frequent inflammatory arthropathy, the prevalence is 1 in 100 (1% of the
population), the incidence is 20-40/100,000/year. The ratio of females:males is 4:1, more
frequent between 40 and 60 years, but no age is spared and cases are possible in juvenile age
(idiopathic juvenile arthritis) or in old age, senile.

PATOGENESIS (frequent application for examination)

The pathogenesis of AR is very important for two reasons:
1. It is the clearest among the pathogenesis of autoimmune rheumatic diseases.
2. It is a model for understanding the mechanisms of such diseases.
It involves genetics, epigenetics, environmental factors and immunity.
Genetic predisposition is important: there is concordance between homozygous (15-40%) and
heterozygous (3.5-6%) twins and first-degree relatives (1-2%). The fact that there are 60% of
homozygous twins who do not agree with the disease implies the existence of environmental
pathogenetic factors, which are equally important in pathogenesis.
They're involved:
 HLA genes: HLA DRB1 in particular is strongly associated with genetic predisposition to
an amino acid sequence called shared epitope, which is common to all the alleles in this
locus. This sequence is placed at a key point in the pocket of the class II HLA that
normally contacts the hypothetical autoantigen and presents it to the T lymphocyte.
 Genes not HLA:
- PAD I4, (peptidyl-arginine-deaminase, enzyme responsible for the deamination
of arginine into citrulline).
- PTPN22, gene involved in innate immunity.
- NFkB, gene for the known nuclear transcription factor.
- CTLA4, a gene for a protein expressed on the surface of T lymphocytes that acts
as a receptor preventing uncontrolled activation of these cells. This receptor is
the target of both drugs used in rheumatology (Abatacept, a monoclonal CTLA4
Ig antibody, to silence lymphocyte activation) and oncology (the "check point
inhibitors", antibodies that exploit an opposite mechanism, i.e. they bind to this
protein and activate it in order to facilitate the elimination of cancer cells by T
lymphocytes).
Environmental factors are necessary to cause disease in a genetically predisposed subject. The
core of the pathogenesis of rheumatoid arthritis are the mucous membranes, those barriers
that separate the inside of the organism from the outside, therefore some specific

32
environmental factors that act on them and that are involved in the pathogenesis with a
significant association have been identified:
 Physical factor: cigarette smoke acts on the bronchial mucosa
 Infectious factors:
- Porphyromonas Gingivalis acts on the gingival mucosa
- Prevotella Copri acts on intestinal mucosa
These factors are the main ones (for which the certainty is greater), but others have also been
identified. They act on the respective mucous membranes by inducing the citrullinisation of
certain proteins contained in them, forming citrullinated peptides that are carried by APCs to
satellite lymph nodes and presented to T lymphocytes. These peptides are recognized as non-
self and an auto-antibody response is activated against them: this explains the state of
autoimmunity, characterized by anti-citrulline autoantibodies, which are the diagnostic and
even pathogenetic markers of the disease.
These antibodies, however, are not sufficient to lead the patient to the typical
symptomatological picture of AR: he remains asymptomatic, in the so-called pre-clinical phase
of the disease (i.e. preclinical antibodies anti-citrulline but no manifestation).
The transition phase from asymptomatic to symptomatic stage (i.e. to the clinical phase of the
disease) is more complex: active triggering factors such as infectious, microvascular and
biomechanical are considered necessary. Example of biomechanical factors occurs when a
predisposed subject performs an articular overload. This causes local subclinical inflammation
leading to increased synovial apoptosis, calcium penetration in synovial cells, activation of the
enzyme PADI4, then citrullinisation of synovial membrane proteins such as fibrinogen, vimentin,
α-enolase and collagen. These citrullinated proteins on the synovial membrane induce the
production of anti-citrulline autoantibodies and become the target, with the formation of
immune complexes and consequent complement activation. There is therefore an amplification
of inflammation in the synovial membrane which would lead to the appearance of the clinical
picture.
In addition, there may also be additional local production of anti-citrulline antibodies at the
level of the synovial membrane itself, demonstrated by the presence of germination centres in
it.
These germination centers are generated by a call of inflammatory cells in situ, which follows
the inflammation: granulocytes and macrophages, accompanied by the production of cytokines,
migrate to the inflammatory site, such as B lymphocytes, plasma cells (germination centers)
and T lymphocytes. All this is finally conveyed to the final target cells which are the osteoclasts,
which are involved in the formation of joint erosion and therefore the destruction of the joint:
this is the final stage of the rheumatoid process.
[From last year's uncoils]: another mechanism has been proposed as a possible trigger of
disease: it is the link between Ab anti citrulline and superficial antigens of osteoclasts, which
induces the production of IL-8, a chemotactic factor, that near the coffin areas, i.e. the bare
areas of the joint, recalls neutrophils starting the inflammation process.
Question: Does rheumatoid arthritis still occur in a non-genetically predisposed person? No, if
there's no predisposition, you don't have a disease. However, there are some minor genes, not
mentioned in this lesson, that could be associated with the disease, even if in a weaker way

33
(NdS: therefore, even if negative for the major genes, therefore apparently without genetic
predisposition, the subject could have the minor genes, therefore genetics is always influential).
THE ROLE OF THE RHEUMATOID FACTOR
In the pathogenesis, until now, the rheumatoid factor has not been mentioned. It is an immune
effector, with a defence task of the organism: after the formation of anti-citrulline antibodies,
the rheumatoid factor is produced with the function of eliminating the immunocomplexes
formed by citrullinated peptides with anti-citrulline autoantibodies. High values are found in
arthritis because, again for genetic reasons, this production mechanism does not limit itself.
In

conclusion, rheumatoid factor is a diagnostic and prognostic marker (subjects with high
rheumatoid factor have a worse prognosis), but it is not directly involved in the pathogenesis of
the disease (as are anti-citrulline antibodies).
Question: Why that 1-4% of healthy subjects who have high rheumatoid factor? These subjects
probably develop the rheumatoid factor because they have had infectious/inflammatory
processes that induced it and have some genetic factor that prevents effective clearance of the
formed factor. In this case the production of the factor is not a consequence of the genesis of
anti-citrulline autoantibodies, but an anti-bacterial and anti-viral response.
One of the characteristic markers of acute joint rheumatism is the anti-streptolisinic titer: TAS,
which measures β-hemolytic steptococcus antibodies of group A. Once one is cured of the
infection of this germ, the titre normally drops, but in some subjects this does not happen and
the titre remains high: they probably belong to the same category of individuals in which after
an infection they develop the rheumatoid factor, which remains at high values, without disease.

Rheumatoid arthritis (continued)

In this lesson the concept of rheumatoid arthritis is taken up again: we have already described
in the last lesson its pathogenesis, some epidemiological features (1% of the population is

34
affected). The pathogenesis of AR is one of the most clarified among those of autoimmune
diseases and represents an important reference model.
Prof. recalls that in etiopathogenesis intervene:

 genetic factors
 environmental factors: in particular smoke and infectious agents act on the airways and
the digestive system by inducing citrulination of mucous membrane peptides. This
induces an autoimmune response against these peptides (mediated by anthri-citrulline
antibodies) initiating the asymptomatic phase.
Subsequently an event induces subclinical inflammation at the joint level, leading to
apoptosis of the synovial membrane cells and also here the formation of citrullinated
peptides. The binding of circulating anti-citrulline antibodies to the citrullinated peptides
of the synovial membrane results in the amplification of the inflammatory process
leading to the development of typical rheumatoid synovitis.
Please note that this process, explained in the last lesson and resumed now, is one of the
frequently asked questions to the examination precisely because the pathogenesis is
very interesting, complete and gives an idea of how an immunophlogosis develops.
Once rheumatoid synovitis (the inflammatory process affecting the synovial membrane) is
established, there are three main cytokines that guide the maintenance of this synovitis and the
progression of the disease: IL1, TNFalfa and IL6. These are the first cytokines that have become
the target of biotechnological drugs (of which something has already been anticipated),
allowing to modify the prognosis and therefore the natural history of the disease.

SYMPTOMS

The onset of the disease can occur in several ways:

 Gradual and insidious: this often happens

 Acute
Also, the debut may be:

 Symmetrical polyarticular: it occurs in most cases, affecting 5 or more joints,

symmetrically in the left and right parts of the body.
 Monooligoarticular: occurs less frequently. Mimics seronegative spondyloarthritis.
The distribution of arthritis is different: in AR symmetrical polyarticular commitment is
more common; in seronegative spondylarthritis mono-oligoarticular commitment is
more common.
 Palindromic: there are initial episodes of arthritis with local inflammation and also
increased inflammation rates. Episodes of inflammation resolve and then reappear
afterwards: they follow each other over time until the AR becomes persistent.
 Polymalgic: refers to a specific pathology, rheumatic polymalgia.
The latter is a fairly common disease, especially in people over the age of 60, but the
frequency of the disease increases progressively with increasing age.

35
 This disease is characterized by pain in the scapular and pelvic cingulate girdle
(shoulders and hips) and there is also a considerable increase in ESR and PCR systemic
phlogosis indices. In addition, the disease is associated with Horton's
syndrome/vasculosis/arteritis (vasculitis of large vessels).
The disease responds well to cortisone and little to NSAIDs. Therefore cortisone can be
used ex adiuvantibus (= diagnosis related to the time of remission of the disease
following a given treatment, NdS). The pathology responds quickly to cortisone which is
then used as an aspect to strengthen the diagnosis.

Sometimes even rheumatoid arthritis can begin in this polymalgia-like manner, with
pain in the scapular and pelvic cingulate girdle. This occurs especially in the elderly,
where therefore it is necessary to make a differential diagnosis between AR and
rheumatic polymyalgia.
The AR can show up with:

 general symptoms of disease: asthenia, muscle weakness, loss of appetite, fever. These
are general symptoms that can accompany the onset of diseases that, while affecting
the musculoskeletal system, are systemic in nature.
 without general symptoms
Once the disease has stabilized, there is synovial inflammation with polyarticular involvement,
symmetrical distribution and centripetal pattern. This means that it starts with the small distal
joints (wrists, ankles) and then goes towards elbows, shoulders, knees, hips. This is an
additional character, i.e. the small distal joints are added to (and do not replace) the more
proximal ones. The course is chronic and untreated, undertreated or poorly treated forms
evolve with joint erosion, leading to ankylosis and therefore functional loss.
The pcs with AR do not die of joint pain, but from complications (ankylosis disability because
they cannot walk, take objects).

One question the teacher asks in the exam is to talk about erosive arthritis. The Prof says that
he doesn't only ask vertical questions (Tell me about...), but also transversal questions because
he wants to see us make connections between the various pathologies.
You have to answer:

1. first say what joint erosion is: interruption of the cortical surface of the bone often
accompanied by loss of substance from the underlying trabecular bone
2. Then specify which imaging techniques to use to demonstrate erosive arthritis: standard
Rx first, but you can also do ultrasound, CT and MRI.
CT is a method that involves exposure to a lot of radiation, while MRI is safer.

The image
on the left
shows X-
rays of
very

36
 advanced disease pictures. In fact, with the standard Rx I detect advanced erosion,
which can no longer be repaired.
Generally, however, an attempt is made to find erosion at an early stage in order to
intervene with therapy effectively. In fact, with ultrasound or MRI I can show erosion at
a very early stage, so that I can repair it in time. Joint erosion is a sign of a more severe
prognosis of disease.

All diseases can have a more or less serious course: AR has a spectrum of progression-
activity-velocity different from pcs to pcs. The occurrence of joint erosion at an early
stage of AR already tells us that it is an aggressive disease and it is imperative to act
promptly.
3. Say in which diseases you can detect bone erosion:
o Rheumatoid arthritis: typical erosive disease. The synovial cloth erodes the
juxtarticular bone from the coffin areas,
o Septic arthritis: perhaps the most erosive of all, especially when it comes to
Gram+ coconuts (staphylococci in particular). In a few days the joint is destroyed,
so we need to make an extremely early diagnosis.
o microcrystal arthritis: gout and chondrocalcinosis. They are characterized by
inflammations so intense that they destroy the juxtarticular bone; they are not
always erosive but they can be,
o psoriatic arthropathy: it is associated with the presence of skin psoriasis. 30% of
pcs with psoriasis on the skin have arthropathy. Psoriatic arthropathy is classified
as spondylarthritis. There are different phenotypes:
- Rheumatoid-like with typical characteristics of AR (polyarticular
symmetrical), can be erosive;
- mutilating, very rare, with acrolysis of the distal phalanges,
o Ankylosing spondylitis: there is no erosive arthritis per se, but there is erosion of
enthesitis following enthesitis; therefore it is not joint erosion but bone erosion,
o SLE: a disease that usually gives non-erosive symmetrical polyarthritis, but in
some cases can have erosions.
o Overlapping connectors: overlapping of several pathologies including AR (which
therefore confers erosive character)
SYMPTOMS

Inflammatory joint pain and usually long-lasting joint stiffness are the two main symptoms of
AR. Articular stiffness is also present in pcs with osteoarthrosis, but it is usually of shorter
duration than AR; there is a 30 min cut-off, but this is taken as an approximate reference and
not as a precise measure.
Other symptoms are general symptoms of illness and symptoms from extra-articular
manifestations.

Characteristics of inflammatory pain. Usually he rises at rest, especially at night. Non-

inflammatory joint involvement occurs during the day with joint load and motion, and is
reduced with rest. Instead, inflammatory pain occurs at rest, during the night.
37
The peak of maximum pain intensity occurs after prolonged inactivity (> 60 min). By doing
moderate physical activity with a modest load, the pain generally subsides. On the other hand,
major joint overload (even in completely healthy pcs) tends to induce inflammation, leading to
subclinical synovitis (which we discussed in the pathogenesis of AR). So the more overloaded
the pz, the more serious/important the symptomatology of the disease becomes and the more
therapy we have to give it.

In conclusion, we can summarize by saying that the characteristics of inflammatory pain are:

 Onset at rest, often at night

 Peak of maximum intensity, after prolonged inactivity
 Prolonged post-inactivity rigidity (>60 min)
 Attenuation with moderate physical activity
 Worse with overload
OBJECTIVE EXAMINATION

We have to evaluate:

 the signs of joint inflammation (we've seen some of them already),

 the location and distribution of arthritis,
 joint deformities,
 the presence of synovial cysts,
 extra-articular alterations, including rheumatoid nodules and muscle hypo-atrophy
Signs. It's the swelling, the redness, the heat of the skin above the joint.

Joint seats. The small joints are involved first: hands, wrists, forefoot,
ankles; then gradually all other diarthrodial joints are also involved,
including the cervical spine. So in the end there will be possible
involvement of: hands (metacarpophalangeal and interphalangeal joints),
wrists, forearms, ankles, elbows, shoulders, hips, knees,
temporomandibular joint, cervical spine (C1-C2).

Joint deformities.
In the picture below you can see an initial involvement of the hands, with
a slight swelling of the joints, including the wrist; there is no erythema above the joint and
probably not even heat to the touch.

38
The picture below shows an initial picture with tenovaginitis (synonymous with tenosynovitis,
NdS) which often accompanies arthritis. Here is tenovaginitis of the flexors, on the proximal
interphalangeal joints.

The following image shows a more advanced case with subluxation of the metacarpophalangeal
joints. So you see deformities.

39
In the image below there is an even greater deformation with fingers in the wind, you can see
ulnar deflection of the fingers.

The image on the right shows a more complex

swan-neck finger shape, where there is a
hyper-extension of the proximal
interphalangeal joint and a hyperflexion of the
distal interphalangeal joint. Here you can
particularly appreciate a Z thumb.

The same type of

deformation can
occur in the feet
(picture on the left).
Another harmful
event can occur in the
feet: a subluxation of
the metatarsal-
phalangeal joint with
sliding of the bag that
protects the
metatarsal heads
from the load.

The bags contain synovial fluid, as if they were well-organized synovial cysts. They are located
near bone prominences to protect them from mechanical trauma. Subluxation means a
deflection/dislocation of the joint, resulting in loss of correctness of movement.
In this case you see bursae in the metacarpophalangeal joint and you see that there is
subluxation (deflection of the joint with dislocation), with consequent displacement also of the
bursa. In this way the heads remain uncovered, are more exposed to the load and there is
mechanical damage.

40
You can also have the valgism of the big toe as a consequence of joint dislocation; this is also a
dislocation that you can have in normal people on a genetic basis, while in those who have AR
you have on an inflammatory basis.

Synovial cysts. Baker's cyst is important: when the knee swells as a result of inflammation (it
occurs in the AR but also in any other condition that
leads to effusion to the knee) and the pz walks on it, it
increases the load and pressure on the synovial
compartment. This leads to the subsequent formation
of a posterior cyst (picture on the side). It's like pressing
a balloon so that air collects where there is no
resistance.
The same happens here: a collection of liquid is formed
where there is no resistance, i.e. in the popliteal cable.
Valve mechanisms can be formed so that the liquid
enters the cyst until the cyst bursts the inflammatory
synovial material flows into the subcutaneous tissues of
the leg.

These cysts were once wrongly diagnosed as thrombophlebitis because the cysts give a clinical
picture similar to superficial thrombophlebitis (swelling, heat, redness); now, however, in PS
they do the ultrasound and immediately realize that there is a cyst. If there is a cyst, the pz goes
straight to rheumatology counseling for treatment. If the pz has AR obviously treats the
underlying disease, but sharply empty the knee, infiltrate with cortisone and make a tight
bandage on the leg to collapse the walls of the cyst and close it.
Baker's cyst formation is very common, but it is not the rule that it breaks, it may or may not
happen.

Involvement of the cervical spine. Usually the

articulation between atlas (C1) and epistropheus
(C2) is affected. The image shows the tooth of the
epistropheus, the anterior arch of the atlas and the
transverse ligament. This joint rotates the skull
around the tooth of the epistropheus, which is
surrounded by synovial tissue, which can then be
targeted by the AR.

Synovitis can erode the tooth and compress the

posterior cervical cord. Compression may increase
gradually. You may also have an upper tooth dislocation with increasing impairment.
This type of injury is important to recognize because the pcs must be stabilized: for example, if
they leave by car and the roads are not perfectly smooth the condition can worsen and
therefore they must wear a cervical collar while driving; or if the pcs must be intubated the
neck must be extended and therefore the anaesthetist must be much more cautious.

41
Extra-joint events. AR is a disease that mainly affects joints with a synovial membrane
(diarthrodial joints), but can also give extra-joint disorders and manifestations. These are
divided into 4 groups:

1. Localization of the rheumatoid inflammatory process in locations other than the joint
o Rheumatoid nodules: detectable on the skin, on the lungs
o Rheumatoid vasculitis: of the skin, kidney, vasa nervorum
o Serositis: pleurisy, pericarditis
These three are manifestations of the rheumatoid process.

2. Disease complications
o Amyloidosis in the kidney and heart: it is consequent to the persistence of the
inflammatory process; we see little in AR thanks to the therapies, but it is seen
more in pz with autoinflammatory diseases (e.g. family Mediterranean fever,
TRAPS).
o Muscular hypotrophy from disuse: if the patient has AR he moves less and
muscular hypotrophy arises
o Osteoporosis: it can be both systemic (expression of joint hypomobility;
osteoporosis is caused by loss of bone mass and can occur by immobilization -
e.g. astronauts in the absence of gravity-load) and juxtarticular (inflammatory
substances that are released during synovitis act on the bone).
o Early atherosclerosis: we have already said that it is largely influenced by the
inflammatory state and therefore in the pz with immunophlogistic disease there
is an acceleration of the atherosclerotic process.
Some time ago a study was done in which they took 50 pcs with AR dead from
myocardial infarction and as a control they took 50 pcs dead from myocardial
infarction at the same age without AR. They saw that in those with AR they did
not find an extension of atherosclerosis, the plaques were less large and less
frequent, but were more vulnerable because they were more inflamed.
3. Complications of the therapy: the drugs not only guarantee considerable benefits, but
also have side effects. The main drugs used in this pathology are:
o NSAIDs: GI manifestations (gastritis, gastric ulcer, esophagitis) and renal
manifestations with IR. You have a higher risk of IR as you get older, so in the
elderly rather than using NSAIDs better to use analgesics such as Paracetamol.
o Cortisone: especially if used for prolonged periods of time can give myopathy
(muscle hypostenia), osteoporosis, infections, atherosclerosis, cataracts,
hypertrichosis, gastritis, if used in chronic causes weight gain and typical fat
distribution.
o Immunosuppressants and biological drugs: infections, neoplasms.
4. Syndromes associated to AR (they do not depend on the rheumatoid process, but can be
equally often associated)
o Sjogren's syndrome and other connective disorders (overlap forms)

42
 o Chronic interstitial pneumonia or pulmonary interstitiopathy. For AR, the
frequency of this complication varies from 10 to 30%. It is usually a
histopathological manifestation of type UIP (Usual Interstitial Pneumonia) and
therefore similar to that of idiopathic pulmonary fibrosis. In the other connective
tissue, instead, it is associated with NSIP (Nonspecific Interstitial Pneumonia)
patterns.
o Thyroiditis: are autoimmune diseases that are often associated with AR or other
connective tissue. Thyroiditis is often associated with rheumatic diseases: about
one third of pcs with rheumatic diseases can have thyroiditis associated and this
is explained by the partly common genesis (autoimmunity).
These in the image on
the left, are rheumatoid
nodules with a central
area of fibrinoid
necrosis with
macrophages arranged
in a palisade; around
them are inflammatory
cells (lymphocytes,
neutrophil
granulocytes).

Usually the rheumatoid nodule forms near a vase that has been damaged. In fact, they are
found in the areas most exposed to trauma (extensor surfaces of the elbow, finger joints, ischial
and sacral prominences, occipital area and Achilles tendon). The nodules can often be
subcutaneous, or they can also be visceral.
The skin nodules can be solitary or multiple and their diameter can vary from less than half a
cm to several cm. They can also be superficial (at the level of the epidermis and are mobile) or
deep (subcutaneous) adhering to underlying tissues such as periosteum, tendons and bags.
The subcutaneous nodules are found in correspondence of the bony prominences, therefore in
the areas easily subjected to the traumas: typically extensor surface of the elbows, small
articulations of the hands, in who is in a wheelchair near the sacrum, in who wears glasses, they
can appear on the nose. In the image below you can see some examples.

Rheumatoid nodules also indicate severity

of disease. They are usually found in HLA
DR1+ pcs with the shared epitope, with FR
and anti-citrulline antibodies positive.

VASCULITE

43
Vasculitis in rheumatoid arthritis is in small vessels and manifests itself mainly as skin vasculitis.
It therefore gives rise to manifestations that are:
 Purple or petechiae (this manifestation can be confused with purpura of coagulative
origin; the difference is that the vasculitic purpura is detected and palpable, while the
other is flat and not palpable);
 Ulcers;
 Digital necrosis;
 Gangrene.
These manifestations are from top to bottom more and more serious and reflect the interest of
vases with larger and larger diameters.
Usually in rheumatoid arthritis there is a picture of leukocytoclastic vasculitis (i.e. with damage
to the leukocytes in or around small vessels). This picture is also common to granulomatosis
with polyangiitis and micro-polyangiitis.
It is important to remember that vasculitis in rheumatoid arthritis also manifests itself with:
 Neuropathy, especially peripheral neuropathy, especially multiple mononeurite (for
vasa nervorum involvement);
 Nephropathy, though less frequent.
Vasculitis in rheumatoid arthritis is very similar to other associated ANCA vasculitis: both are
small vessel vasculitis and also involve nerves and kidney, although in the case of associated
ANCA there is more frequent renal involvement and there is also lung involvement.
The presence of vasculitis indicates the severity of the disease and is often associated with:
 FR, often in a high title;
 CCP antibodies;
 HLA DRB1;
 Rheumatoid nodules;
 Joint erosions;
 Increased morbidity and mortality.

LABORATORY INVESTIGATION

Rheumatoid arthritis is characterized by:

 Increased phlogosis indices: ESR, PCR, alpha1 globulins and alpha2 globulins, fibrinogen
(acute phase protein);
 Positivity of the rheumatoid factor, often with rather high titres (remember that RF is
also present in other diseases, particularly more frequently in Sjogren's syndrome);
 Positivity of citrulline antibodies (they also appear long before the disease);
 Normocytic normocytic anemia due to ineffective erythropoiesis;
 Examination of synovial fluid showing inflammatory evidence (GB greater than 2000 on
mmc).

IMAGING

44
Radiography and magnetic resonance imaging (more sensitive in detecting erosion) are used.
Ultrasound can also be used.
The early alterations highlighted are:
 Tumefactions of the periarticular soft parts;
 Iuxtarticular osteoporosis;
 Articular erosion (in coffin areas): as mentioned in the last lesson, coffin areas are
intrarticular areas without cartilage and synovial membrane and are those where
erosive lesions appear first, where they should be looked for early on imaging;
 Reduction of joint rhyme.

In these images there are therefore the sites where early erosion, metacarpophalangeal joints
and proximal interphalangeal joints are most frequent.

45
The MRI, on the right, is much more sensitive in highlighting early erosion than the MRI, on the
left.
The late alterations (the ones I must try to prevent) highlighted are:
 Extensive subchondral erosions, pseudocyst and geodi;
 Diffuse iuxtarticular osteoporosis;
 Disappearance of the joint rhyme;
 Dislocations, subluxations and dislocations.

In the images we see typical late alterations.

The use of ultrasound can be detected:
 Tumefaction and fluid in the joint;
 Joint erosions;
 With the ecodoppler you can see the blood flow, which if it is abundant is an indication
of inflammation.

CRITERIA FOR CLASSIFICATION

46
These are a series of characteristic clinical manifestations of the disease to which a score is
associated; the patient must have a minimum score to be classified as sick. In reality they have
no diagnostic purpose, they only aim to standardize the cases in the various hospitals and
research centres, to identify the population with minimum characteristics in order to have
certainty of diagnosis. These criteria, however, do not have the maximum sensitivity and
specificity, there may be FP and FN, so the diagnosis of a patient can be made even if the
patient does not reach a minimum score. In the diagnosis are useful to indicate which are the
most frequent manifestations of the disease.
The most important criteria for the diagnosis between the various criteria are:
 Interest of small joints, especially if more than 10 joints;
 Positivity of rheumatoid factor and citrulline antibodies, with high levels.
Other criteria with less weight are:
 Increase in PCR and ESR;
 Symptoms last longer than 6 weeks.

DIFFERENTIAL DIAGNOSIS

At an early stage there is DD with:

 Virus or postviral arthritis;
 Early-stage spondylarthritis;
 Early Connectivity.
At a more advanced stage there is DD with:
 Microcrystal arthritis;
 Primary osteoarthrosis.

PROGNOSIS

47
If untreated, the natural history of the disease leads to debilitating erosive evolution within 2
years and increased mortality; 75% of untreated patients have erosive lesions in the first year.
Precisely for this reason, early diagnosis is important, in order to have a treatment that can
change the course of illness and the onset of disability. The window for early treatment is
within 6 months of the onset of the disease. Once this window is passed, even if the drugs
manage to control the inflammation, there is a separate trend in the progression of the lesions
with inevitable increase in damage and onset of disability (as can be seen in the picture below).

Warning signs for the prognosis are:

 Interest of three joints;
 Interesting metacarpophalangeal and metatarsophalangeal joints;
 Squeeze test / positive eaves sign (pain appears if you press on the metatarsophalangeal
joints);
 Morning joint stiffness for more than 30 minutes.

THERAPY

Therapy includes:
 NSAIDS;
 Cortisonics: only in the initial phase or during exacerbations;
 DMARDs (Disease Modifying Antirheumatic Drugs)
o Antimalarial (Hydroxychloroquine and Chlorine)
o Immunosuppressants (Methotrexate, Leflunomide, Cyclosporin A)
o Biological drugs (TNFalfa inhibitors, antiCD20, CTLA4 Ig, IL6 inhibitors)
o Small molecules inhibitors (Jak kinase inhibitors).

MEASURES IN RHEUMATOID ARTHRITIS

 Indices of disease activity;

 Outcome measures;
 Criteria for improvement;
 Remission criteria.

48
They serve to define which patients have certain characteristics, to define the treatment based
on them and to evaluate the clinical outcome.

Connectivity

I am:
 LES
 Systemic Sclerosis
 Idiopathic inflammatory myopathies
 Sjogren
 Undifferentiated connectivity
 Overlap syndromes
They are called systemic connective tissue because they are diseases characterized by an
inflammatory process affecting many organs and apparatuses, all of which have in common the
connective tissue, which acts as supporting tissue. However, not all connective tissue affects
primarily and primarily the connective, e.g. Sjogren's syndrome is an epithelitis (affects
epithelium exocrine glands) and myopathies affect the muscle. More correctly they are
autoimmune rheumatic diseases (mainly affecting the musculoskeletal system), a term that is
not commonly used.
These diseases have a genetic predisposition that depends on many genes, the number of
which varies from disease to disease. These genes either belong to the HLA system or are genes
that code for proteins and enzymes of the immune system (cytokines, antigen coreceptors,
signal transmission molecules, co-stimulatory molecules, apoptosis control molecules, antigen-
removing molecules and immune complexes). Alterations in these genes therefore predispose
to immune dysfunctions, which then added to environmental factors give rise to the disease.
Many of these genes are disease-specific, but many others are common to several diseases.
Precisely for this reason we can find associations of several diseases in the same subject
(overlap syndromes) and different diseases in the same family (which will have similar genetic
background). We can see an example of this in the image below.

49
There will therefore be some common and similar early manifestations among the different
diseases, which will lead to a diagnosis of undifferentiated connectivitis (CTD):
 General demonstrations;
 Raynaud's phenomenon;
 Non-erosive arthritis;
 Edema on the fingers;
 ANA positivity.

More advanced common manifestations:

 Chronic interstitial pneumonia;
 Esophageal hypotonia.
Undifferentiated connective tissue in 1/3 of cases remains undifferentiated for a long time, in
1/3 of cases it evolves towards another connective tissue (if it shows typical symptoms of a
disease), in 1/3 of cases it goes into remission.
Then there are the specific manifestations of disease, usually skin and antibody:
 LES: skin rash, anti nDNA, anti Sm;
 SSc: skin sclerosis, anti Scl70, anti Cenp;
 PMDM: myositis, skin rash, anti Mi2, anti Jo1;
 SSp: Sicca syndrome, anti SSB;
 AR: erosive arthritis, anti citrulline antibodies, FR positive.

50
The table above shows that there are symptoms common (in black) to many diseases and other
symptoms that are specific (in red).

The professor recommends reviewing this table before the exam, to recapitulate the
manifestations, which are sometimes very similar among the various diseases.
An example of a question can be "tell me about chronic interstitial pneumonia": briefly define
what it is, how the diagnosis is made, in which connectivitis is typical and with what
characteristics (AR form UIP; scleroderma NSIP; Sjogren NSIP or LIP; rare in SLE where acute
pneumonia is more frequent).
Another question may concern renal involvement in connective tissue.
Student question on AR: If antibodies are already present before the disease, how do you go
about diagnosing the disease? I mean, how do you go from the subclinical transition phase to
the clinical phase? There are two hypotheses:
1) the patient with a genetic predisposition and anti citrulline antibodies is subjected to joint
overload, thus generating a synovial subclinical inflammation. This leads to synovial cell
apoptosis with calcium release and activation of the enzyme PADI, formation of new
citrullinated peptides. Citrulline antibodies bind to these peptides and amplify synovial
inflammation;
2) citrullinated peptides are also present on the surface of the osteoclasts, anti citrullin
antibodies bind and activate the osteoclasts that produce IL8 (chemokine), which attracts new
inflammatory cells.

51
Professor's question: What do you do with a patient who has positive antibodies (for screening)
and no clinical manifestation? Answer in the next lesson.

AUTOINFLAMMATORY DISEASES

Autoinflammatory pathologies are newly identified pathologies characterized by episodes of

apparently spontaneous and unprovoked inflammation originating from alterations in the
mechanisms of innate immunity. Just as autoimmune diseases have a pathological basis
involving immunity, in this case it is innate and non-adaptive immunity.
The host has a strong predisposition, as in the case of the first identified monogenic diseases,
FMF and TRAPS and involving mechanisms of innate immunity that control the first
inflammatory response against stimuli of damage. This results in apparently unprovoked
episodes of inflammation.
The first definition of the term is quite recent and dates back to 1999, just after the discovery of
mutations in the genes underlying these diseases.

In this graph there is a continuous

spectrum of pathologies that involve
in different ways mechanisms of
adaptive immunity and innate
immunity. At the extremes there are
purely autoimmune pathologies
linked to alterations of single genes
and, on the other hand,
autoinflammatory pathologies linked
to mutations of genes of innate
immunity. In between, in various
positions, there are pathologies
caused by different elements, partly
related to innate immunity and partly
to adaptive immunity (such as SLE).
In seronegative spondyloarthritis
there is an important component of
innate immunity, but it is a disease that is part of the continuum between inflammation and
autoimmunity.

There are other monogenic

autoinflammatory diseases such as
familial Mediterranean fever and TNF
receptor syndrome, slowly beginning to
recognize even polygenic diseases such as
adult Still's disease, Behcet's syndrome,
Crohn's disease that

52
 are likely to involve mechanisms of innate immunity, without monogenic heredity, therefore,
they are likely to be multifactorial diseases with a strong self-inflammatory basis.
The scope of these diseases is rapidly expanding thanks to the greater sensitivity of doctors and
the methods used, such as the study of the human genome, which makes it possible to identify
new diseases.

MECHANISMS
The mechanisms of innate immunity are
countless and complex.
They see at the center a series of molecular
platforms, first of all, the inflammosome
connected to intracellular sensors that
determines the activation of certain
proteins with a key role in inflammation.
The main one of these is interleukin-1β.
This is activated through a caspase-
dependent mechanism: the inflammosome
transforms the Pro-caspase into a caspase
that cleaves the pro-IL-1β into IL-1β, the
secreted and active form.
This is just one of the mechanisms involved,
it is important because it is at the basis of
many self-inflammatory diseases.

TYPES OF MUTATIONS
In this diagram on the left we see other
possible sites of mutation, which are the
cause of self-inflammatory diseases.
In the centre is inflammosome
with different proteins: NLRP3
and pyrin, which lead to an
increase of IL-1β.
There are also other proteins that
may be involved such as the
enzyme mevalonate kinase
(MVK), PSTP1P1, NOD2 and the
TNF receptor (TNFR1).
Although the mutations involve different
types of proteins, including those
external to the inflammosome, these mutations converge in a mechanism that leads to the
production or activation and release of IL-1β.

CLASSIFICATION

53
 1. Cryopyrinopathies
2. Periodic Fever
3. Granulomatous syndromes
4. Rain syndromes.
These diseases are linked to the fact that they have common inflammation mediators,
particularly IL-1β.
The main features to remember are:
- Sudden febrile episodes
- Elevation of systemic phlogosis indices: increase in PCR, increase in all acute phase
proteins such as serumamyloid A.
- Skin rash.
- Serositis
- Lymphadenopathy
- Artriti
- Crises interspersed with periods of well-being and normalization: they allow one to
suspect such pathologies.

1. CRYOPYRINOPATHIES

FEATURES
They are rare, autosomal dominant diseases due to mutations in the NALP-3 or CIAS-1 gene
that encodes for a CRIOPIRIN protein that plays a key role in the activation from Pro-caspase to
caspase and therefore in the release of IL-1β.

TYPOLOGIES
They are distinguished in three different forms:

I. Familiar cold urticaria, FACS

II. Muckle-Wells syndrome, MKW
III. Chronic infantile neurological cutaneous and articular syndrome, CINCA o NOMID.

They are also classified according to severity, from the mildest to the most severe.
There is in fact a continuous spectrum of manifestations ranging from simple febrile urticaria,
followed by exposure to cold, to a very serious pathology, which arises in the neonatal age and
which involves joint and neurological disorders compromising the development of the child.

I. FAMILIAL COLD URTICARIA (FACS)

The picture shows a form of hives, usually not itchy.
It is a long known pathology, first described in 1940 without
yet knowing the mechanisms of inflammation.

54
Clinical manifestations:
- Rush urticarioids that are accompanied by high fever that is short-lived, within 24 h.
- Altralgias and conjunctivitis after exposure to cold can accompany the main symptom.
Exposure to the cold can also be a simple approach to the supermarket fridge.

II. MUCKLE-WELLS SYNDROME (MWS)

First described in 1962.

Clinical manifestations:
- Recurring hives-like skin rashes,
- Fever,
- Chills,
- Malaise and pain in the limbs not necessarily a consequence of exposure to cold.

There can also be late complications:

- Neurosensory Deafness
- Amyloidosis AA: pathology caused by the accumulation in various tissues of serum
amyloid A, is an acute phase protein normally produced by the liver during the
inflammatory response that has the ability to form fibrils that are deposited in various
tissues and are not removed.

With chronic inflammation there is a continuous production of serumamyloid over time. The
organ most affected is the kidney, renal amyloidosis leads to terminal renal failure with the
need for dialysis.
Very often, in addition to the acute episode a subclinical form persists, the patient is fine but
has slightly increased PCR values.

III. CHRONIC INFANTILE NEUROLOGICAL CUTANEOUS AND ARTICULAR SYNDROME

(CINCA/NOMID)
Discovered in 1982, it is the most serious of the three.

Clinical manifestations:
- Permanent skin rash from the first days of life, not triggered by exposure to the cold
- Fever
- Lymphadenopathy
- Severe CNS impairment with endocranial hypertension that quickly leads to hearing and
visual impairment in a short time.
- Chronic arthropathy that leads to bone erosion and dimorphism typical of the face
(frontal prominence draft nose and saddle, hypoplasia of the face), there is a bone
involvement that leads to bone overgrowth especially of knees, hands and feet.

55
The picture on the side shows the
exons involved in the three
pathologies seen.
Every year, new polymorphisms
are added to this gene. Rather
than talking about three distinct
pathologies we could talk about a
continuous spectrum linked to the
altered functionality of this
platform.
This spectrum ranges from the
simplest forms (FCAS) to the most
severe forms (CINCA/NOMID). At
the basis of all the damage caused
in patients there is an
overproduction of Il-1β.
There are various inflammosomes and NLRP3 is just one among many, a mutation of NLRP12 is
accompanied by autoinflammatory diseases.

2. PERIODIC FEVERS:
I. Familial Mediterranean fever, FMF.
II. Mevalonate kinase deficiency (Hyper-IgD), MDK
III. Periodic receptor-associated syndrome for TNF, TRAPS

COMMON FEATURES
- Acute, sudden, seemingly spontaneous febrile attacks
- Elevation of systemic phlogosis indices
- Skin manifestations (rash)
- Artriti
- Very frequent infections (sterile inflammation of the pleura, pericardium, peritoneum)
- Crisis interspersed with periods of variable duration of well-being and normalisation of
inflammatory indexes.

I. FAMILY MEDITERRANEAN FEVER (FMF)

FMF is a widespread disease in the Mediterranean basin, it is an autosomal recessive genetic
disease even if cases of heterozygous patients manifesting the disease have been described
(obviously the genetic aspect of the disease is not yet fully understood).
It is a one-mutation disease of the MEFV gene, located on the short arm of the chromosome 16
encoding for the pyrine/marenostine protein (expressed mainly in nucleated polymorphs and
cytokine-activated monocytes). Pyrin is involved in the activation of inflammosome, therefore,
the final product is IL-1β.
The picture beside shows the diffusion of the main mutations, reconstructing the migrations the
original area of the mutation has been identified: the eastern region of the Mediterranean
Basin. This mutation has been retained as a selective advantage, perhaps because of its ability

56
to trigger a greater inflammatory response as
a form of defence against certain pathogens
such as Yersinia Pestis (aetiological agent of
plague, a flea-borne zoonosis. The bacillus is
phagocytosed by monocytes, which cannot
degrade it because of its antiphagocytic
power, and by neutrophils, which are the only
ones who can degrade it. It has an incubation
period of 2-7 days and can manifest as
bubonic, pulmonary and septicaemic plague).

Clinical manifestations:
- Fever present in 97% of cases, with a
value of 38-40° C. In 30% of cases it is
preceded by chills. The fever lasts a
maximum of three days with recurrence every 7-30 days.
- Abdominal pain of the colic type, acute enough to simulate an appendicitis attack (95%
of cases). It is not uncommon in these patients for pain to be mistaken for acute
appendicitis (high fever, abdominal colic pain and high inflammatory indexes with
leukocytosis and increased PCR) before receiving an accurate diagnosis.
- Sterile and not bacterial serositis, peritonitis presents with a peritoneal fluid rich in
neutrophil granulocytes.
- Arthritis (75%).
- Chest pain (45%), due to pleurisy or pericarditis.
- Psudo-erisipela: it looks like erysipelas, but it is not
due to an infectious cause (7-40%).
- Restitutio ad integrum after the attack (between
recurrences).
- Amyloidosis AA, develops over time and is a very
high risk for these patients. It is the element that
most characterises the prognosis.

Tel-Hashomer Diagnostic Criteria

57
The criteria are divided into minor and major and 2 major or 1 major and 2 minor criteria are
required to make a definitive diagnosis.

Higher criteria:
- Recurring febrile episodes associated with serositis
- Type A amyloidosis in the absence of other correlated pathologies
- Response to daily colchicine administration (concept shown below).
Minor criteria:
- Febrile episodes without serum
- Pseudo-erisipela
- Positive FMF familiarity.

Genetics is not reported in these criteria because it is not available in all laboratories and there
are FMF clinical pictures that have negative genetics (it is believed that there is not a single
gene involved in this pathology). Genetics alone is not a diagnostic criterion.
Among the major criteria is the response to a drug, the ex-adjuvantibus response: if there is a
suspicion of FMF and after administration of colchicine it is shown that there is a good
response, the diagnosis can be confirmed because colchicine acts very selectively in this
pathology.
The MEFV gene is shown in
the picture on the side and
you can see the exons where
most mutations are collected.
Knowledge changes every
month and there are public
databases with all these
mutations with their multiples.

II. MEVALONATE
KINASE DEFICIENCY OR HYPER-IGD SYNDROME.
It is an early onset, within the first year of life, autosomal recessive transmission disease.

58
It was first defined as Hyper-IgD syndrome: before identifying the responsible gene, an increase
in IgD in patients was noted. In 1999 MVK was identified on chromosome 12 as the gene
responsible for the disease.
This mutation reduces the functionality of the enzyme with more or less severe pictures. In the
most severe manifestation the pathology becomes incompatible with life: mevalonic aciduria
(MVA), in which the gene is completely knocked out, the enzyme does not work and there are
very serious pictures that lead to death within a few months 2.
There are other situations where there is only a reduction in enzyme activity, such as in
hyperimmunoglobulinemia D syndrome (HIDS),
mutation v3771 followed by reduced enzyme
capacity in the biosynthesis of cholesterol and
isoprenoids.

Clinical manifestations:
- Febrile attacks preceded by recurring and
self-limiting chills
- Laterocervical lymphadenopathy (94%)
- Abdominal pain with vomiting and diarrhea
- Skin lesions (maculae, purple)
- Oral and genital aphthosis
- Polyarthralgies (80%)
- Symmetrical arthritis
On average these attacks last 4-6 days and repeat
every 6 weeks or so.

Many of the manifestations overlap with those listed for other auto inflammatory diseases. The
mechanism by which the deficit of this enzyme leads to pathological manifestations is not yet
completely clear, but again, interleukin-1β is a key cytokine. The enzyme involved in the
cholesterol synthesis pathway via isoprenols increases the activation of caspase 1 and the
release of IL-1β.

III. TNF RECEPTOR ASSOCIATED PERIODIC SYNDROME (TRAPS)

TRAPS is an autosomal dominant disease, linked to mutations of the super family 1° of the
soluble TNF receptor (TNFRS1A) on chromosome 12p13.

Clinical manifestations:
- Variable feverish episodes (they can last for weeks or months).
- Abdominal pain
- Skin manifestations in 75% of cases
- Psudocellulite
2
From Orphanet: MVA is characterized by psychomotor and growth retardation, progressive cerebellar ataxia,
dysmorphisms, progressive vision deficit and recurrent fever crises. Febrile episodes are usually accompanied by
hepato-splenomegaly, lymphadenopathy, abdominal symptoms, arthralgia and rashes. Life expectancy is always
shortened.

59
 - Very painful myalgia
- Sacroiliitis
- Neurological interest
The main difference with the other pathologies is the
duration of the febrile episodes: in TRAPS they last even 6
months in a row, in other pathologies they last only a few
days.
When these patients have acute attacks, the joint
component can be very important: a scintigram during an
attack shows the greatest capture of the radioactive
contrast medium in some skeletal areas under active
reshaping. Hyperacute collection at the level of a joint (in
this case the right knee) can lead to the suspicion of septic
arthritis, confirmed by arthrocentesis which will show sterile or non-sterile inflammation. An
MRI can also be performed to detect the presence of edema. Phlogistic inflammation recedes
completely with an anti-inflammatory drug.

Manifestations can be caused by different types of TNF receptor mutation, there are three
hypotheses:

1. Shedding hypotesis
Physiological mechanism: the TNF receptor has an extracellular and an intracellular
portion and the physiological mechanism of the inflammation process involves
shedding, i.e. the cleavage of the extracellular portion of the receptor. The extracellular
portion, separated from the intracellular portion, is no longer able to transmit the signal,
but still binds the cytokine TNF-α and works as a scavenger by blocking the signal of the
TNFR itself.
Pathogenetic mechanism: the mutated TNFR does not undergo the proteolytic cut so
the serum concentration, normally reduced by the cleaved extracellular portion, is not
reduced.

2. NF-kB Hypotesis
It increases the activity of the various subunits of NF-kB and the pro-inflammatory
response induced by the binding of TNFα to its mutated receptor, in this case there is a
mutation of the intracellular portion of the receptor and consequently a continuous
transduction of the signal even in the absence of the receptor binding.

3. Misfolding Hypotesis
In order to be exposed on the cell membrane and perform their function, proteins must
assume a certain three-dimensional configuration. If there are mutations affecting
particularly sensitive areas (with disorphous bridges that allow the protein to fold), the
protein does not fold properly and is not transported to the cell surface, but
accumulates within the endoplasmic reticulum of the cell.

60
 The mutated TNF receptor remains within the endoplasmic reticulum as oligomers.
These can form trimesters that induce a stress/inflammatory response by the lattice
itself and the NF-kB pathway is activated at the cytoplasmic level and blocking the
apoptotic pathway.
In fact, all these mechanisms converge in an altered inflammatory response, with a marked
production of IL-1β.

COMPARISON TABLE
The first three diseases are classified as
periodic fevers and the last three as
cryopyrinopathies.
There is a comparison between the
duration of the feverish episodes and
the main manifestations.

THERAPY
There are drugs that are able to
selectively block IL-1β. There are
currently two of them available in
Europe:

1. Interleukin1 receptor
antagonist, Anakinra: it binds to the receptor preventing cytokine from binding and
initiating signal transduction.
2. Monoclonal antibody directed against interleukin 1-β: they bind directly to cytokine.
Both drugs are so effective in these diseases that if diseases such as CINCA/NOMID are
recognized early and therapy with these drugs is established, patients have a completely
normal development, no symptoms and no damage (equally for Muckle-Wells syndrome, FCAS,
FMF, Hyper-IgD syndrome and TRAPS).
The first therapeutic attempt to treat TRAPS was to block TNF thinking that it was the main
mechanism responsible for the pathology, in fact, these drugs act in a minimal percentage, so
the IL-1β inhibitor drug is more suitable.
Selectively blocking IL-1β is extremely significant to prevent the very serious damage that
could occur in these diseases. These diseases are grouped together because they have IL-1β
as a common mediator.

61
GRANULOMATOUS SYNDROMES
BLAU SYNDROME
Among the granulomatous syndromes, the Blau syndrome, also
called juvenile familial systemic granulomatosis, a rare autosomal
dominant disease, is worthy of note.
It is an inflammatory pathology characterized by non-caseoid
granulomatous inflammation with a symptomatological triad
affecting joints (inflammation of the synovial membrane), skin
(papular reactions) and the ocular district.
Of these, the greatest effort is the ocular one: the progressive
inflammation can affect all the components of the eye causing panophthalmitis, with
progressive decrease in vision until blindness.
Other clinical manifestations may be persistent or intermittent fever, liver and kidney failure,
granulomatous arteritis with CNS involvement, hearing loss and cerebral infarction.
The gene causing the disease is NOD2, also implicated in the pathogenesis of Crohn's disease
(both diseases are characterized by granulomas). NOD2 is, in fact, a cellular sensor that leads to
the production of a granulomatous inflammatory response.
There is no data about a therapeutic strategy that is certainly effective in all patients: IL-1β has
been proposed as a possible mediator of inflammation, but only a small proportion of patients
treated with interleukin inhibitors had benefits.

PYOGENIC SYNDROMES
Hereditary pyogenic disorders are characterized by the presence of sterile pyogenic abscesses,
so in the absence of elements that suggest an infectious cause there is an abscess of neutrophil
granulocytes, which mainly affect skin, joints and bones.
They're in this group:
 PAPA syndrome (Pyogenic sterile Arthritis, Pyoderma gangrenosum, and Acne
syndrome)
 Majeed syndrome
 Deficiency of interleukin-1 receptor antagonist (DIRA)
 Deficiency of interleukin-36 receptor antagonist (DITRA)

PAPA
PAPA syndrome is an autosomal dominant disease linked to the
mutation of the PSTPIP1 gene encoding CD2-binding protein1.
CD2-binding protein1 binds the pyrin and stimulates the
inflammatory response, if the protein has changed it binds the pyrin
more easily.
From a pathological point of view it generally begins in children as
arthritis or dermatitis.

62
Arthritis, defined as sterile pyogenic, can affect 2 or 3 joints and enters into differential
diagnosis with septic arthritis, as both are characterized by purulent intra-articular effusion and
frequent development of erosions.
Skin manifestations often begin later, typically in the second decade of life.
Cultural examinations, both skin and joint, are always negative. From a pharmacological point
of view it responds variably to steroids, while it responds more to IL-1 and TNFα inhibitors.

MAJEED SYNDROME3
Majeed syndrome is an autosomal recessive disease linked to the mutation of the lipin 2
encoding gene LPIN2, whose role is not yet precisely clarified.
The disease is characterized by chronic recurrent multifocal chronic sterile osteomyelitis
associated with anaemia and chronic neutrophilic dermatosis and generally occurs in the first 2
years of life.
It is treated with corticosteroids and NSAIDs, although excellent results have been obtained
with IL-1 receptor antagonists and monoclonal anti-IL1 antibodies.

DIRA SYNDROME AND DITRA SYNDROME

DIRA syndrome (deficiency of the Interleukin-1-
receptor Antagonist) is an autosomal recessive
disease linked to the mutation of the IL1RN gene,
coding for the IL-1 receptor antagonist. In this case
we see what happens if IL-1 is not controlled leading
to major bone deformities and inflammation. It
generally begins at birth and is characterized by
bone lesions (given by multifocal osteomyelitis and
periostitis), skin manifestations (diffuse pustular
rash) and persistent increase in inflammatory
indexes.
This pathology, if recognized, is easily curable
because it has as drug the IL-1 receptor antagonist (Anakinra), equal to the physiological, if
administered in time there is no development of deformities and damage.

DITRA Syndrome is an autosomal recessive disease linked to the IL36RN gene mutation, coding
for the IL-36 receptor antagonist that inhibits the activation of NF-kB. It is always an
autoinflammatory pathology that begins in childhood and manifests itself with recurrent acute

3
Majeed's syndrome is characterized by chronic recurrent multifocal osteomyelitis (CRMO), congenital
dyserythropoietic anemia (CDA) and inflammatory dermtosis. CRMO in this pathology is characterized by more
frequent episodes and shorter remissions that can last a lifetime leading to growth retardation and joint
contractures. CDA is characterized by peripheral and bone marrow microcytosis. It can have variable severity, from
mild asymptomatic anemia to a transfusion-dependent form. Inflammatory dermatosis is usually Sweet's
syndrome, but it can also be pustular.

63
fever, erythematous and pustular rash, asthenia, leukocytosis and increased inflammatory
indexes.
The therapeutic approach is not defined, but corticosteroids, immunosuppressants, TNFα and
IL-1 drugs are used.

The pathologies treated so far are genetic

pathologies and above all monogenic
pathologies, but despite this they are not
pathologies exclusively of paediatric interest:

 The mutations can be post-zigothic,

therefore arise de novo, without
familiarity even if they are autosomal
dominant; in the adult it will be
possible to create a picture of
mosaicism where not all the cells of
his body will be carriers of mutation.
Mosaicism is important in
determining the phenotype of the
disease and in causing some of these
manifestations to occur at an older
age, sometimes even in the elderly given the increase in the percentage of cells with
that mutation with age.
 There are some low-penetrating mutations that are not associated with a complete
phenotype of disease; there may be completely healthy subjects that, however, in some
cases and even only in adulthood, can determine some of the typical manifestations of
these diseases.
 There may be a misdiagnosis/bad diagnosis even if the disease already occurs in
childhood; if the correct diagnosis is not made until years later the situation may lead to
very serious problems because we are faced with a picture of an advanced disease that
may have caused amyloidosis or developed significant damage to eyesight/hearing. The
misdiagnosis is because the diseases are not yet well known.
 Moreover, a major problem is with forms of focal mosaicism, so that mutations could
be localized only in certain districts not considered by genetic testing (performed by
blood sampling, isolating monocytes and extracting DNA from them). In this case, tests
should be carried out by taking samples from different tissues, such as skin and saliva. In
literature there are mosaicism paintings for most of the pathologies treated so far.

UNDIFFERENTIATED AUTOINFLAMMATORY FORMS

There may be undifferentiated forms: a clinical picture that orients towards an
autoinflammatory pathology (recurrent fevers, increased rash, atralgia, increased inflammatory
indexes), but there is an absence of a genetic mutation and therefore an absence of a specific
diagnosis.
64
These forms represent 10-20% of autoinflammatory diseases and are still considered as such
even in the absence of genetic confirmation as they respond to therapies set on drugs such as
colchicine, steroids and IL-1 inhibitors. Depending on the pharmacological response you can
then also address more to the diagnosis (a response to colchicine will direct me to FMF).

Considering these aspects, the professor is keen to make a consideration in the context of
family Mediterranean fever. There are several phenotypes of this one:
- Phenotype with FMF and typical 1-2-day fever attacks once a month;
- Phenotype with amyloidosis, but without the patient ever having the typical febrile
attacks, the diagnosis is made after the discovery of amyloidosis;
- Phenotype where you have mutation but no clinical disease.
There are late onset cryopyrinopathies for a progressive increase in somatic mutation carrier
cells. There is therefore a poor genotype-phenotype correlation, with an onset that can also
occur after the age of 20 in 14% of cases and after 40 in 1% of cases. In adult centres it is late
onset in 50 % of cases.

SCHNITZLER SYNDROME
In this context of autoinflammatory diseases to which no genetic mutation has been linked and
there is no familiarity, one must consider Schnitzler's syndrome (described by a dermatologist
in 1972).
It is a pathology considered a late onset cryopyrinopathy, typical of adulthood, characterized
by:
- Chronic non-itchy chronic urticarioid-like rash
- Slight monoclonal gammopathy IgM
- Intermittent periodic fever
- Arthritis and/or arthromyalgia
- Lymphadenopathy
- Splenomegalia
- Possibility of evolution towards a
lymphoproliferative disorder

Most of the symptoms are typical of autoinflammatory

diseases, but the characteristic element indispensable
for diagnosis is the monoclonal IgM gammopathy,
although its role is unknown.
The pathology has a clear-cut response to IL-1β
inhibition. But IL-1β inhibition does not affect the
monoclonal gammopathy that follows its development
and should be kept under control.
In the photo it is possible to observe the skin manifestation of hives that is accompanied by
very high fever. The patient in the photo to control the symptoms has taken for years very high
doses of oral cortisone that managed to keep the fever moderate and reduce the intensity of
skin manifestations, but with all the damage caused by continuous intake.

65
Starting therapy with IL-1β receptor antagonist, one dose every 24h, both fever and skin
manifestations disappeared. On several occasions then the pz tried to lengthen the time
between the administration of the drug (from one to two days), but each time you had the
reappearance of symptoms.

Genetic background
The diagram shows the
acronyms of specific mutations
of certain genes:
- In blue are those related to
FMF
- In green are those related to
TRAPS
- In red related to MVK deficit
- In orange related to
cryopyrinopathies and the
NLRP3 gene.

It can be observed that there is

an overlap of mutations in
autoinflammatory diseases,
where some mutations are
more frequent than others: for
example, R92Q for TRAPS or
E148Q for FMF12.
These overlaps may complicate the picture a bit and the pathology may then be more difficult
to identify clinically.
Another thing that can be inferred from these superimpositions is that these mutations can be
also find associated with other diseases, not just autoinflammatory.
For example, there are patients with rheumatoid arthritis who are positive for rheumatoid
arthritis.
M694V mutation of FMF and in these cases the pathology takes on different characteristics:
increases the phlogistic component, adds fever and
has a greater tendency to develop
amyloidosis13.

ADULT STILL'S DISEASE

Still's disease in adults is a polygenic
autoinflammatory disease, characterized by
recurrent acute febrile attacks with a temperature
>39°C and an average duration of less than 4
hours; generally there are 1-2 daily febrile peaks.

66
In the presence of the febrile attack usually there are other symptoms such as atralgia,
evanescent rash, pharyngodinia, serusitis, lymphadenopathy.
- Arthralgies, usually bilateral;
- Evanescent rash, which can disappear and reappear together with fever; typically it is
called "salmon colour", but can also have different skin manifestations, hives or forms of
dermatography;
- Pharynx, a very constant element, usually precedes a febrile attack of 10-14 days.
- Serious complications, such as pleuritis and pericarditis, can cause cardiac tamponade;
- Lymphadenopathy and splenomegaly which must lead to a differential diagnosis with
lymphoproliferative type diseases in young subjects (makes diagnosis difficult)
- Hepatopathy
- Arthralgia up to arthritis which can become chronic and evolve into destructive arthritis

His name is due to the pediatrician George Still, who identified these manifestations in children
(1897), then Bywaters identified in a group of adult women an overlapping symptomatology
(1971), then spoke of Still's disease in adults.
In fact, it is believed to be the same pathology, but it begins at different times in life:
 In the child, it's called systemic juvenile idiopathic arthritis.
 In the adult has retained the name Still's disease of the adult

The picture of manifestations is very non-specific and consequently the diagnosis of Still's
disease is very difficult: one enters into differential diagnosis with many pathologies, from very
mild (such as a flu syndrome, bacterial pharyngitis, ...) to more severe.

EPIDEMIOLOGY
It is a rare pathology widespread throughout the world, although its incidence is probably
underestimated.
It has an incidence of 0.1 to 0.4 cases per 100,000 people.
It has a prevalence of 1-34/1'000'000 and, in 75% of cases, it occurs between 16 and 35 years
old.

EZIOPATOGENESIS
The etiology is unknown: it is not known what the triggers are, even if it is considered an
autoinflammatory pathology.
Several hypotheses have been made about the triggering factors of the pathology:
 Genetic predisposition: it is possible that the pathology derives from a predisposition
to an exuberant inflammatory response to triggers of a different nature. The HLA
predisposition is quite variable and even in this case no HLA has been identified that is
strongly associated with the pathology.
 Infectious trigger, although there is no microorganism associated with the pathology
with certainty, but it is believed to be different from person to person.
 Altered cytokine production: we know that there are some cytokines that are altered
in this pathology (IL-18, IL-6 and IL-1β but also other cytokines such as TNFα).

67
This scheme summarizes the known pathogenetic mechanisms of the pathology: the stimulus
by a trigger, probably of infectious nature, determines the release of IL-18 and IL-1β which can
then activate an amplification cascade downstream of IL-6 and TNFα.
Macrophages play a particular role in this pathology: if activated in an excessively high way in
10% of patients they can cause Macrophagic Activation Syndrome (MAS), a hyperacute
situation in which macrophages also phagocyte healthy cells; this happens especially at the
level of the marrow, so that there is a very rapid drop in all the stem cells of the marrow in a
picture that can lead the patient to death in a short time. The onset of pancytopenia may be
the first tool to direct the diagnosis of this syndrome.

LABORATORY PARAMETERS
From the lab's point of view, we have signs of inflammation:
- High ESR/PCR
- Neutrophil leukocytosis
- Platelets
- Signs of liver commitment, with high liver enzymes in 73% of cases
- High IgG
- ANA absent (there are no signs of autoimmunity)
- FR absent
- Increase Ferritin five times over the limits (>1000 ng/ml)

68
Again, this is a largely non-specific picture. What
helps most in the diagnosis is the increase in
ferritin, which is normal during inflammation, but
in the case of adult Still's disease this is absolutely
disproportionate (values of 20000-50'000 ng/ml).

CLINICAL
 Fever: high, even above 39° C, with
continuous peaks that resolve after the
administration of cortisonics (next to a
thermal curve of a patient then treated with
cortisone).
 Skin rash: typically evanescent, present with fever and then disappears, defined as
salmon pink. There may also be other skin manifestations beyond this as forms similar
to dermatography, linear urticaria or hives.
 Pharyngitis: a constant element (which can lead to misdiagnosis), any exacerbation is
preceded by pharyngitis.
 Arthritis and Atralgia: Atralgia is always present, arthritis can appear and it progresses
becoming chronic and destructive.
 Lymphadenopathy and splenomegaly: in young people can lead to think of
lymphoproliferative type diseases
 Serositis: typically pleuritis and pericarditis (if important they can give cardiac
tamponade).
 Hepatosplenomegaly
The pathology, in addition to the symptoms listed above and the Macrophagic Activation
Syndrome, can give another series of complications, summarized in the slide. Cardiac
involvement can lead to myocarditis, which is very important. Neurological manifestations can
lead to meningoencephalitis. Pulmonary distress can complicate onset with pulmonary distress.
Macrophageal iactivation syndrome can develop in 10-15% of patients with very high mortality.

DIAGNOSIS
The diagnosis is
clinical: there are
criteria (by
Yamaguchi and
Fautrei) that help
in directing the
diagnosis, but in
the end we will
always proceed
to a diagnosis of
exclusion,
excluding
pathologies with

69
 similar patterns, therefore
infectious and
lymphoproliferative.

CLINICAL DEVELOPMENT
The course can be variable:
- Unicyclic forms; all
manifestations with all
possible complications are
exhausted within a few
weeks and the patient
heals.
- Polycyclic form; all
manifestations tend to
regress to a complete well-
being that can last for a
variable period (up to 2
years), but then reoccur.
- Chronic joint form; recurrent episodes of systemic manifestations are associated with
joint damage, with progressive joint erosion.

Different cytokines are differently involved in different course types, but in all cases (especially
in systemic form) IL-1β plays a fundamental role.

THERAPY
Level one therapy is based on Prednisolone.
If the disease does not respond adequately to
this therapy within a few weeks, either an IL-
1β receptor antagonist or a monoclonal
antibody against IL-1β is used.
LA GOTTA
Gout has been known for a long time and is
considered an autoinflammatory disease of
polygenic origin, leading to microcrystal
arthritis.
Gout is a clinical disease linked to a metabolic
disorder, with increased uric acid, which
causes precipitation of monosodium urate
crystals (UMS), which trigger an
autoinflammatory mechanism (arthritis), linked to the activation of NLRP-3 inflammosome
(often involved in autoinflammatory diseases) and therefore to a mechanism of innate
immunity.

70
The metabolic disorder underlying gout is hyperuricemia, which can be determined by genetic,
environmental and nutritional factors. Usually there is a basic genetic predisposition, which is
also affected by factors such as lifestyle or diet.
Hyperuricemia is often associated with other forms of dysmetabolism (such as diabetes
mellitus, dyslipidemia) and also with obesity and hypertension, a multimetabolic syndrome.

It is necessary to distinguish between hyperuricemia and gout: in an acute gout attack

hyperuricemia is not always present, on the contrary a normal uricemia is detected. The dosage
of uric acid is not a determining factor, but it is likely that hyperuricemia is pre-existing in
patients with acute gout attacks. The increased pool of persistent uric acid allows the
precipitation of monosodium urate crystals at the joint tissue level.
The likelihood of developing gout increases with an increase in the concentration of uric acid in
the blood and usually many years of hyperurukaemia elapses before developing an acute gout
attack. In any case, if hyperuricemia is found in a patient, even without signs of gout, treatment
is advisable.

SOLUBILITY OF URIC ACID

The solubility of monosodium urate in plasma is linked to physical factors: it is reduced as the
temperature and pH drop. The concentration of UMS saturation in plasma is 7 mg/dl, while the
solubility in urine is decreased by the acidification state: there is a higher risk that UMS
precipitates in the form of uric acid crystals in the urinary excretory system. The kidney is a
possible target organ of gout due to the high excretion of uric acid through urine.

EPIDEMIOLOGY AND AETIOLOGY

Hyperuricemia (>7 mg/dl in males and >6 mg/dl in females) is prevalent in males, in fact in the
Italian population between 20 and 59 years of age the prevalence is 4.3% in males against 0.9%
in females. There is a gender difference, but in any case the prevalence of gout increases with
age and hyperuricemia (in case of high uricemia, >9mg/dl, 80% of patients have joint
manifestations of gout). Gout affects 1-2% of adults of all sexes, but in subjects over 80 years
old it affects 5% of males and 2% of females, after menopause the risk of gout increases.
In women of childbearing age, before menopause, there is a low prevalence of hyperuricemia.
With menopause the percentages become similar to the prevalence in the male sex. Women
under 30 do not usually have gout, except in special situations where the acid increase is linked
to metabolic factors and certain therapies such as diuretics (cases of women who abused
diuretics and developed an acute gout attack have been described).
Until not many years ago it was believed that gout was exclusively due to nutritional factors, so
much so that it was historically considered the disease of the rich, because these were the ones
who could afford abundant meals (particularly rich in meat, rich in purines), in fact now it is
known that the major etiological component for the pathogenesis of hyperuricemia is genetic.
At the base of hyperuricemia there is therefore a genetic predisposition with an alteration in
the metabolism of purines that leads to an accumulation of uric acid, which, once the threshold
of solubility in the blood is exceeded, precipitates in the form of crystals.
There are local factors that determine the precipitation of the crystal in a specific articulation.

71
HYPERURICEMIA
There are primary forms of hyperuricemia (30% of cases), and secondary forms of
hyperuricemia (70%).
The role of diet in the development of uricemia has always been considered (a few centuries
ago gout was the disease of the rich), but nowadays the role of diet is not considered
determinant, as is genetic predisposition.
Common causes of hyperuricemia:
 Nephropathies with renal insufficiency: renal excretion of uric acid is eliminated.
 Drugs (diuretics, NSAIDs): may act on renal excretion.
 Lympho-proliferative diseases (lymphomas) and hemolytic and polyglobule anaemia:
in these diseases there is a high cell turnover and large amounts of uric acid are
released. In addition, if they undergo chemotherapy they can develop a gout attack as
the cell death of a large number of cells causes the release of various substances into
the circulation, including uric acid, derived from nucleic acids.
Rare causes of hyperuricemia:
 Enzymatic abnormalities
 Lactic acidosis
 Extensive psoriasis: you have large areas of skin affected by an inflammatory process
that leads to a continuous exchange that leads to the release of large amounts of uric
acid.

The picture opposite shows where the uric acid

pool in the body comes from: 1/3 from food
intake and 2/3 from physiological cell turnover,
i.e. catabolism of nucleotides and
nucleoproteins, both producing adenine and
guanine.
Uric acid is excreted mainly (2/3) by the kidney,
the rest by the intestine (1/3).

The image describes the enzymatic processes

that lead to the production of uric acid within
the purine metabolism. The most important
enzymatic pathway is that of

Hypoxanthin/Xanthine oxidase which,

when oxidized to Xanthine, transforms it into
Uric Acid. Xanthine can no longer be
reused and re-enter the purine synthesis
cycle, but becomes a waste product, uric acid,
which will be eliminated.

72
Once the solubility threshold of uric acid is exceeded, UMS crystals are formed and precipitate.
The crystals are picked up by the cells and activate the NLRP3 inflammosome, which in turn
activates the caspase 1 with the consequent production of IL-1, which is why the disease is
called auto-inflammatory: the effector mechanism is the production of IL-1.
The uric acid crystal is indispensable, but it is not sufficient to activate this mechanism: an
additional stimulus is needed to activate the inflammosome. A second stimulus can be given by
oxidized lipoproteins or fatty acids or presence of alcohol in the blood. This means that the
precipitation of uric acid crystals does not
cause an acute attack, which will only occur
with the presence of a costimulus. The attack is
an extremely marked inflammatory response,
linked to the production of IL-1.

ACUTE GOUT
The acute attack mainly affects middle-aged
male subjects and results in an inflammatory
response that typically affects the
metatarsophalangeal joint (MTF) of the first
finger, with swelling, redness, heat and marked
pain (gout was called podagra: foot in the
leghold trap). The pain is extremely acute,
suddenly onset, of very high intensity, so much
so that it is believed to be the strongest
inflammation our body can experience.
Swelling and pain are extremely rapid: within a few hours a normal joint becomes extremely
inflamed. The pain and swelling may be preceded by a period of irritability. Pain and swelling
occur mainly at night: the patient wakes up during the night with very important pain in the
foot, hot and reddened, the pain is so intense that even just the sheet resting on the foot
becomes extremely annoying (and even walking is difficult). The onset at night is usually due to
a dinner, the night before, with excessive alcohol and food. There may be other factors that
determine the attack such as cold, micro-trauma or sports activity.
In addition to MTF, other joints, such as tibio-tarsus, or other lower limb joints may be involved.
Acute gout attacks evolve in a positive sense: after the first attack you have a spontaneous
resolution (or with the help of NSAIDs or corticosteroids) within a few days. Spontaneous
resolution of the gout attack should not underestimate the disease: the patient is not cured,
but after the first one, the chances of further attacks, increasingly frequent and painful,
increase and slowly the response to anti-inflammatory drugs will decrease. Therefore, after the
first attack it is important to start preventive therapy.
Gout is an expression of lasting hyperuricemia followed by a deposition of crystals that have
encrusted the joint and the surface of the articular cartilage, when the second stimulus arrives,
the acute attack occurs.

73
The period between one acute attack and another, the so-called intercritical period, is initially
very long (even a few years), but if the patient is not treated properly, it tends to get shorter
and shorter, and the attacks will become more and more annoying.

Triggering an acute gout attack:

• Abundant meal
• High alcohol intake
• Dehydration
• Fever (stressful event for the body)
• surgeries (on second day)
• Joint trauma
• Chemotherapy: The death of large amounts of cells leads to massive release of uric acid.
When a patient is undergoing chemotherapy (especially if haematological diseases) he
also receives a hypouricemic drug.
• Intense exercise

As can be seen from the image, the extent

of inflammation can reach very marked
levels. Not only the metatarsophalangeal
joint may be affected, but it seems that the
whole foot is oedematous: a lymphatic
engorgement is established which causes a
diffuse oedema (the inflammation is
localized), swelling. There is a superficial
flaking similar to erysipelas and it is
accompanied by extremely marked painful
symptoms.

The pain generally is:

• Urente, the patient generally appreciates it as unbearable burning
• It interrupts sleep,
• Doesn't allow walking and induces limp
• It is accompanied by redness, swelling, heat and imbibition of the subcutaneous tissue,
which may suggest an inflammatory or even infectious appearance, similar to cellulite.
In the patient with acute attack, the inflammation
indexes are increased (ESR, PCR, neutrophil
leukocytosis) so that it can enter into differential
diagnosis with an infectious disease. The diagnosis is
made by examination of synovial fluid, with vision of
intracellular and extracellular crystals. Inflammation
can be quantified by white blood cell count, if septic
arthritis is suspected the microbiology is asked. In
the synovial fluid of a patient with gout you can see
mono sodium urate crystals: large and needle-

74
shaped, with typical birefringence, depending on the orientation with respect to polarized light
they can be blue or orange.
UMS crystals determine the death of the cell that tries to phagocyte them, resulting in the
release of additional cytokines and enzymes that recall other inflammatory cells. This IL-1-
mediated amplification mechanism is responsible for the significant inflammation at the joint
level during the acute gout attack: the activation of inflammosome attracts neutrophils who try
to phagocyte crystals but die and by dying they release cytokines that attract additional
neutrophils.
NATURAL HISTORY OF GOUT
Gout takes place in stages that include:
 Asymptomatic hyperuricemia (years): for years there are high levels of uric acid
without symptoms
 Acute arthritis attacks: typically on the
first toe, they initially resolve
spontaneously but continue to reoccur.
 Intercritical intervals: they are getting
shorter and shorter until they have
incoming attacks.
 Chronic tofacea gout with polyarthritis
and nephropathy. When chronic gout is
established, it changes from a
monoarticular form with spontaneous
resolution to a poilarticular form
(differential diagnosis with rheumatoid
arthritis when it becomes polyarthritis)
and the presence of tofacee (or tofi).
Tofi are accumulations of monosodium
urate that accumulate at the
subcutaneous (ear helix), para-articular,
articular level, can accumulate at the
renal level leading to nephropathy due
to increased excretion of uric acid with
urine and subsequent precipitation in the kidney that can lead to nephropathy and then
renal failure.
The local inflammation caused by the accumulation of crystals near the bone can cause
significant damage with joint destruction, deformities and alterations evident on X-rays.
You can see the sign of the halberd: the damage of erosion and bone resorption looks
as if it was caused by a removal made by a halberd.
After the involvement of the MTF joint, the tibio-tarsal joints, elbows, hands and wrists
are involved with the incoming attacks.

The possible polyarticular involvement of the hands is similar to rheumatoid arthritis (with
which it enters into differential diagnosis): all the small joints of the hands may be involved,

75
with more and more evident joint destruction and the presence
of swelling in the joints caused by deposits (and inflammation
leads to reabsorption).

The crystals of monosodium urate are radiotransparent, do not

contain calcium, so they are not visible on the X-ray, instead in
chondrocalcinosis the crystals of calcium pyrophosphate are
calcium-based, therefore radio-opaque and visible on the X-ray,
allowing the differential diagnosis.

Chronic tofacea gout is characterized by the appearance of tofi,

clusters of crystals that deposit:
 in the soft tissue (at the fingertip level),
 around the joints (fingers, knees, olecranon, bags),
 in the tendons (achilles),
 at the level of the helix (often the first tofi gottosi site is
precisely the ear cup)
 at the level of other para-articular and/or visceral tissues.
The tofi manifest themselves as small yellowish subcutaneous
patches of crystal accumulation. The first tofo appears about ten
years after the first gout attack (there is plenty of time to do
prevention).
It is important to assess the presence of tofi at the objective
examination, they are quite hard on palpation due to the presence
of crystals. Depending on where they are located, they can cause
different damage: if they are located on the bone surface, they cause
large areas of bone resorption, if they are more superficial they can
ulcerate.

The professor illustrates a series of characteristic images related to

the presence of tofi and increasingly marked and advanced
situations. Bone erosion can be very important, gout is not a disease to be underestimated.
Gout leads to major joint deformities. In chronic gout, permanent deformations occur due to
the deposition of permanent crystals in the soft tissue.
If we do not know the patient's medical history we can think, in front of pictures similar to
those shown in the pictures, of a differential diagnosis with psoriatic arthropathy, rheumatoid
arthritis with primary erosive arthrosis of the hands.
There is always the possibility to take a small amount of material from a tofo (hard-elastic
substance for crystal aggregates) and have the confirmation, analyzing it under the microscope,
of the presence of an accumulation of crystals and inflammatory cells.
In the image on the side the tofo has ulcerated, leaving whitish material, which can be
analyzed. In some situations it may not be necessary to take the sample because the clinical
picture is very evident.

76
If the disease is left on its own and
is not treated with adequate
hypouricemic therapy, the
evolution can be dramatic, with
tofi that can increase out of all
proportion to give particularly
serious pictures with joint
destruction and radiotransparent
swelling.

Question: "Is it true that tofo is

spared from inflammation because
he surrounds himself with IL-10?"
Answer: "The areas of great bone
resorption are related to the
presence of tofi, which have a
great capacity to stimulate
inflammation, there are also
physiological mechanisms that counterbalance it, since the attack also resolves spontaneously,
such as the type 2 receptor of IL-1, other mechanisms of motion sickness, or IL-10. These
mechanisms are partially effective because, in any case, damage is created in the area where
there is the tofo".

VISCERAL GOUT
Chronic gout is associated with visceral gout: crystals can be deposited in the eyes, heart,
nerves and kidneys. At renal level they lead to the development of uratic nephropathy (gouty
kidney) in which there is proteinuria, reduced urine concentration and nephrolithiasis. Slowly it
can lead to terminal failure and dialysis.

DIAGNOSIS
It is quite easy to have the clinical suspicion of gout because the acute attack has typical
characteristics: it occurs sharply, during the night, usually affects the first metatarsophalangeal
joint, the subject is more likely male and of average age, which may have exceeded with
drinking and eating. Often the patient does not present himself to the doctor at the first attack,
but during a subsequent one: it is easy to reconstruct anamnestically the natural history of the
disease. However, a diagnosis of certainty can only be made by analysing the synovial fluid
under the microscope for UMS crystals (removal of the fluid from the affected joint).
From the laboratory point of view in general hyperuricemia is found, but during the acute
attack, it may happen to find a normal uricemia value due to the precipitation at the joint level
of the present WHU.
There is a marked increase in phlogosis indices (ESR, PCR, etc.). In gout we have signs of
systemic inflammation, with neutrophil leukocytosis and increased PCR, which enters into
differential diagnosis with infectious forms. To resolve the doubt between the two forms, a
microscopic analysis of the synovial fluid, taken from the affected joint, is performed.

77
Whenever there is a suspicion of monoarthritis it is necessary to carry out this analysis and to
check for the presence of micro-crystals of UMS to confirm the diagnostic suspicion; it is also
possible to determine the degree of inflammation and the number of neutrophils, and send the
liquid to the microbiology laboratory to exclude that there is an infection in progress.

TREATMENT
Gout is a disease that can be treated beyond the acute attack, often underestimated both by
the patient and the doctor, as it can be resolved in a few days maybe only with the help of
some anti-inflammatory or corticosteroids. What interests us is not so much to treat the acute
attack, but to reduce the levels of uric acid in the blood, prevent precipitation in the form of
crystals, prevent an evolution from gout in the acute phase to gout in the chronic phase and
that this does not become tofacea and therefore more difficult to treat.

Treatment for acute attack:

 NSAIDs: not preferable in case of IBD, better to use corticosteroids.
 Corticosteroids: not preferable in case of diabetes, better to use NSAIDs. Corticosteroids
and NSAIDs are equally effective in acute attacks.
 Colchicine: it was considered a drug of choice for the treatment of gout but, at the
dosages usually given, it was poorly tolerated from a gastrointestinal point of view
(abdominal pain and diarrhea with up to 15 discharges per day). While in the past the
dosage was 1mg of colchicine every 8 hours, now we try to administer lower dosages
and rather associate it with an anti-
inflammatory or steroid. However, the
administration of this drug is no longer used as a
first approach.

Allopurinol should not be administered in the acute

phase because its ability to mobilise uric acid deposits
can worsen the acute phase.
When the acute phase has been resolved, colchicine is
kept in association with the hypo-uricemic therapy, to
prevent possible relapse and then after a certain time
the pz can only be treated with the uricostatic.

Treatment in the prevention of recidivism:

 First line with hypo-cure (must start one to two
weeks after acute attack)
o Uricostats: Allopurinol is the best known and used, Febuxostat can be a valid
substitute. Both act by reducing uric acid levels in the blood. Both are xanthine
oxidase inhibitors blocking the transition from hypoxanthin/xanthine to uric acid
and allow hypoxanthine to be reused for purine synthesis. In this way the de
novo synthesis of purines is inhibited by a feedback mechanism. They must be
used chronically.

78
 o Uricosurics: drugs that increase renal excretion of uric acid. They should be used
with care because they can increase the risk of precipitation in the kidney,
causing uratic nephropathy. To avoid this, the urine should be alkalinated (an
acidic pH promotes precipitation). The use of uricosurics should always be in
association with uricostats when these are not sufficient to control
hyperuricemia.
 Colchicine: maintained by the acute attack and used at low doses, especially at the
beginning of therapy to prevent further acute attacks. At the beginning of therapy with
hypouricemics, acute attacks of gout may develop because the drugs slowly modify the
balance between uric acid deposited in crystals and uric acid in solution, slowly leading
to a decrease in joint deposits and freeing the joints.

For an acute attack to occur it is necessary that the pz has had hyperuricemia for years, during
which time the UMS is deposited in the articular cartilage in the form of crystals, but this does
not immediately determine the acute episode. The joint fills up with crystals, ready to cause
damage. The hypo-uricemic therapy shifts the balance, reducing uric acid levels in the blood so
that even the initial uric acid deposits, little by little, are solubilized; for this reason, using this
therapy both prevents the formation of new deposits of UMS crystals at the joint level and
frees the joint from already present deposits. Therefore, the cornerstone of gout therapy to
prevent the damage is to start in the pz therapy with hypo-uricemics, which is a therapy for
life, despite the normalization of uricemia except in some particular forms such as
chemotherapy or excessive intake of diuretics. In some cases, if uricemia levels are good, the
dosage can be reduced. In fact, a possible suspension of the therapy would lead to a
resumption of the process that leads to the deposition of crystals and therefore the pz would
return to the risk of developing an acute attack.

Q: Is probenecid used?
A: No, not at the moment. The only drug used today is Adenuric (Nesulid) which has a
uricosurgical function, always associated with the uricostatic.
Q: If pz has hyperuricemia but has not yet had an acute attack is it pharmacologically treated?
A: In addition to a certain level should be treated, even if it does not have the acute attack
because it is a high risk factor for developing the acute attack and also for cardiovascular
events. In fact, uric acid is an inflammatory agent for the vasal endothelium and increases the
risk of cardiovascular events. The guidelines suggest to treat asymptomatic people with
hypouricemics also because an acute attack occurs years after the beginning of the crystals
deposit.

CHONDROCALCINOSIS/PSEUDOGOUT
It is an arthritis caused by microcrystals determined by calcium-based crystals: calcium
pyrophosphate dihydrate (CPPD) or basic calcium phosphate (BCP). It is important to make
terminological distinctions:

79
 • CHONDROCALCINOSIS: is a radiographic picture given by the calcification of articular
cartilage, visible because calcium crystals are radiopaque. These crystals can settle
without giving clinical inflammatory manifestations.
• PSEUDOGOTTA: Identifies the acute attack. It is an acute synovitis, usually
monoarticular, associated with intra-articular deposition of calcium pyrophosphate
crystals (CPPD). It's similar to gout. It is either a replacement (one joint synovitis is
replaced by another) or a chronic rheumatoid-like pattern (at the same joint level).
• CPPD ARTHROPATHY: characterized by cartilaginous structural alterations that can
cause a picture of aggressive arthrosis and a picture of chronic polyarticular synovitis.
These paintings can look like rheumatoid arthritis.
• HYDROSSIAPATITE CHONDROCHALCINOSIS : linked to the deposition of basic calcium
phosphate (CBP).

EPIDEMIOLOGY and EZIOLOGY

Chondrocalcinosis and pseudogotchaemia are more frequent in adults and the elderly. The
increase in prevalence is age-related, it tends to manifest itself after a certain age, so it is also
associated with arthrosis, which can complicate it. The frequency of chondrocalcinosis,
according to radiological surveys, would be 10% after age 60, 20% after age 70 and even 30%
after age 80.

The causes of
chondrocalcinosis can be
idiopathic (prevalent) forms,
forms linked to family
predisposition, forms linked to
metabolic alterations with
altered calcium and bone
metabolism.
Chondrocalcinosis is an
association of metabolic diseases such as hemochromatosis, hyperparathyroidism,
hypophosphatemia and hypomagnesemia, all factors that influence calcium metabolism.

The predisposing factors are: age, family predisposition, metabolic changes and degenerative
and post-traumatic arthropathies.

The professor hastily names the

existence of nucleation factors
and inhibition factors, most of
which are unknown, whose
imbalance can lead to the
deposition of CPPD crystals.
Unlike gout, however, we do not
have a specific way to intervene.

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FACTORS THAT CAN TRIGGER THE ACUTE ATTACK OF PSEUDO GOUT
 Trauma
 Surgical interventions or transfusions
 Situations that put the body
under stress as infectious
diseases
 Acute disease events such as
heart attack, pneumonia, renal
colic, etc.
 Introduction of thyroxine
therapy
As far as the localization is concerned,
surely the most involved joint is that of
the knee, both as regards asymptomatic
chondrocalcinosis and the acute attack
of pseudo gout arthritis. In smaller
percentages there is also involvement of
the wrist, shoulder, ankle and
metacarpophalangeal joint.

DIAGNOSIS
The diagnosis is based on viewing calcifications on X-ray and demonstrating the presence of
calcium pyrophosphate crystals in the synovial fluid
of the involved joint. The crystals have
birefringence and must be intracellular to be
meaningful, since the presence of non-intracellular
calcium crystals is quite frequent after a certain
age, while if they are inside the cell they are
probably responsible for inflammation.
Typical aspects of synovial fluid taken from the
pseudo-joint joint are its citrine yellow colour and
whitish flocculations (rice bodies given by
aggregations of fibrin and calcium crystals).

For a diagnosis of certainty, both criteria must be

met:
1. Parallelepiped-shaped crystals (smaller than
urate crystals) birefringent to polarized light
in synovial fluid. Birefringence is the
opposite of urate crystals.

81
 2. Typical calcifications in intra-articular,
synovial, capsular, meniscal, discal and
ligamentary soft parts on conventional
radiography. The X-rays show the
calcifications of the joints, they appear
as a double contour. The most
characteristic calcifications are at the
knee and wrist (where it is important to
assess the triangular ligament of the
carpus). The X-ray of the right shoulder
shows this double contour. Normally
the articular cartilage is
radiotransparent because it is not
composed of calcium, but 70-80%
water (the articular rhyme between
two bones is normally transparent. When calcium crystals are encrusted on the cartilage
then you are able to see the outline.

DIFFERENTIAL DIAGNOSIS
There may be situations of chondrocalcinosis that require a differential diagnosis, as in the case
of the image in which crystal deposits have generated swelling at the interphalangeal joints that
may be similar to gouty tofi.
In any case, the differentiation can be made
with an X-ray for the radioopacity of calcium
crystals.
Pseudo gout can lead to some diagnostic
doubts as the presence of hydroxyapatite
crystals can be associated with other
rheumatic manifestations:
 Calcific Periarthritis
 Tendinitis and calcification bursitis
 Arthropathy, and in this case it may
be:
 Acute (a form of
arthrosis with
Hebert's nodules
involving the distal interphalanges but with acute development, it is
similar to an attack of pseudo gout with increased rates of
inflammation in the blood)
 Erosive form (calcium phosphate is often found as a cofactor of
arthrosis)
 Osteoarthritis

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  Destructive form, it is the most frequent and is the Milwaukee
shoulder/knee syndrome, a very aggressive form of acute arthritis that
typically occurs in the elderly, usually monoarticular and is associated
with blood effusion. Analyzing the effusion we find a very inflamed
synovial fluid, with white blood cells, with a large blood content and
hydroxyapatite crystals that can be highlighted with particular colours
(they appear reddish). The crystals can also be recognized directly by
electron microscopy, even if it is not a routine examination. This
pathology is also called hemorrhagic shoulder of the elderly and is
generally linked to the formation of these crystals of basic calcium
phosphate.
The analysis of synovial fluid for monoarthritis is important to evaluate the differential
diagnosis.

THERAPY
We don't have drugs like gout to prevent crystals from forming. The acute phases are treated in
a similar way to gout (anti-inflammatory and corticosteroids). It also uses the unique colchicine
drug with prophylactic function to prevent acute attack. We cannot therefore avoid the
deposition of crystals, but we can limit the attacks and prevent inflammation.
Pseudo gout attacks last longer than gout attacks (even several weeks), but unlike gout they are
not so destructive and the damage is not chronic but acute (that's why it is important to treat
acuity).

It is not yet known with certainty what the relationship between arthrosis and calcium crystal
pathology is: whether arthrosis favours the deposition of crystals or the latter worsens the
arthrosis itself. But surely there is an association.
In general, microcrystal arthritis affects the diarthroid joints. One of these is often ignored: it is
the articulation between C1 and C2, between the arch of the atlas and the tooth of the
epistrophy. In calcium pyrophosphate arthritis this can be affected and lead to "crowned tooth
syndrome" because radiographically the tooth of the epistropheus has around it a deposition of
crystals that looks like a crown. This pathology gives acute pain pictures at the nuchal, cervical
and scapular cingulate level, fever and increased inflammatory indexes that are often
misinterpreted as rheumatic polymyalgia.

Resuming the previous lesson on connective tissue.

83
CONNECTIVITIES
 LES
 Systemic Sclerosis
 Idiopathic inflammatory
myopathies
 Sjogren's syndrome
 Undifferentiated connectivity
 Overlap syndromes

Connective diseases are diseases

characterized by inflammation of
organs and apparatuses, they have in
common the genetic predisposition,
partly similar and partly different. For
this reason we can find both overlap
syndromes: conditions in which
different diseases are added together in the same patient and different autoimmune diseases in
different members of a family with the same genetic predisposition.
The connective tissue is characterized by common clinical pictures (often the first
manifestations) and by specific elements of a given disease. Among the diversification events
we have mainly skin manifestations or specific anti-nuclear antibodies.
Table useful for the review of the various diseases with the summary of clinical pictures. In red the most
frequent features of diseases

84
SYSTEMIC LUPUS ERYTHROMATOSIS
EPIDEMIOLOGY
The prevalence of lupus is given by some Italian epidemiological studies. These studies are time-
consuming and expensive, the fact that there are also some in Italy is a valuable fact, despite
the suboptimal quality of the research (they are studies made with telephone interviews). The
best study is the one made in Brescia with a prevalence of 40:100,000 inhabitants.
In general, the prevalence of the disease in Italy varies between 1/2000 and 1/5000 inhabitants,
or between 11 and 25,000 patients throughout the country. In Veneto there are between 1000
and 2000 affections.
It mainly affects the female sex (9:1) in fertile age.
Female prevalence is partly due to genetics and partly to hormones: female sex hormones
stimulate the immune system while male sex hormones are immunosuppressive.
The natural history of the disease starts from a genetic predisposition, then there are
environmental factors such as infectious agents, especially EBV. Viruses induce an activation of
innate immunity, in particular the interferon 1 pathway that stimulates the whole immune
system, both innate and acquired immunity. The stimulus of acquired immunity induces the
production of anti-nuclear autoantibodies.
Anti-nuclear autoantibodies can bind to autoantigens and create immunocomplexes that
contain nuclear material (DNA and RNA). They are internalized by plasmocytoid dendritic cells
and induce the TLR to produce NFI 1.

85
A feedbak loop is created that brings autoantibody production to self-sustainability.
Autoantibodies appear before clinical manifestations, there is a second stimulus and then there
will be manifestations of the disease, with increased levels of autoantibodies. If the disease is
not recognized and treated there is an amplification of the pathways of the disease with
irreversible damage.
Autoantibodies appear first and increase progressively before the disease develops.
But do autoantibodies in lupus play a pathogenic role or are they just spectators?
Some have a proven pathogenetic role:
• They can join autoantigens and give immunocomplexes that precipitate in the tissues
and create severe tissue inflammation (skin or viscera).
• They can bind to antigens present on the
surface of blood cells (white blood cells,
corpuscles and platelets) and induce cellular
damage leading to apoptosis and subsequent
cytopenia that characterizes the disease.
• They can penetrate through the blood-brain
barrier, in case of increased rupture due to
different factors (infections, smoke, stressors,
trauma) and come into contact with some
antigens expressed on the surface of
neurons, in particular from calcium channels.
Once bound to the channels, they lead to a
massive release of calcium into the cell,
leading to apoptosis and neurological and
cognitive damage. It's mainly P-ribosomal
antibodies that are responsible.
• They can also bind to substances present in the plasma and can cause in vitro
thrombosis, thus leading to the formation of thrombi and ischemic damage
downstream. The latter are mainly represented by antiphospholipid antibodies present
in diseases such as lupus, or alone as a disease by primary antiphospholipid antibodies.

CLINICAL MANIFESTATIONS
Lupus is an extremely heterogeneous disease, over 150
reactivities for different autoantibodies have been described
from a serological point of
view, but only a few have
clinical and pathogenetic
significance.
There is no organ or tissue
that is not affected by the
pathology, making the clinical
manifestations heterogeneous
("he who knows lupus knows
medicine", "internal medicine

86
is a branch of lupology").
There are more specific and frequent
manifestations of the disease, they are divided
into 6 groups:
1. Osteoarticular apparatus interest
(arthritis and arthritis)
2. Haematological interest (various forms
of cytopenia), in 70% of cases.
3. Dermatitis
4. Nephritis
5. Commitment of serous
6. Brain involvement: Many
manifestations are non-specific, such as migraine. If we consider the specific
involvement of the disease in the central nervous system then it is 10-15% of the cases,
if we consider it extensively we reach even 50%.

1. MUSCULOSKELETAL MANIFESTATIONS
They can affect all districts (joints, tendons and muscles), mainly concerning the joints. The
most common manifestations are:
 Symmetrical non-erosive polyarthritis is a joint inflammation that unlike rheumatoid
arthritis does not erode the bone and therefore is more fleeting and better treatable.
It affects the small joints of the hands and wrists, it can only be erosive in a small
percentage of patients (7-8%).
 We can also note another form of arthritis called
Jaccoud's syndrome, characterized by major joint
deformities in the absence of erosive lesions. As
we can see from the image, there are articular
misalignments due to periarticular engagement
and not of the bone. In the initial stages,
extending your hand on a cot can reduce
misalignment. In more advanced stages, synaecia
develop at the level of the joint capsule, which no
longer allow the joints to be realigned. Jaccoud's arthritis can also be seen at foot level.

2. HAEMATOLOGICAL MANIFESTATIONS
The haematological manifestations of lupus can be multiple,
with all the different cytopenias. One of the main features of
Lupus is non-haemolytic anemia, usually iron deficiency anemia
characteristic of chronic diseases (50-60%).
There may also be anaemia due to ineffective erythropoiesis or
chronic renal failure.
Hemolytic anemia, i.e. due to anti-GB or anti-erythrocyte
antibodies, also present in lupus, but in a minority of patients
(5%).

87
We also have at the haematological level leukopenia
(60%), lymphopenia (70%) and platelets (25-30%) of
almost always moderate degree (70,000 platelets),
therefore without evident clinical manifestations.

3. SKIN MANIFESTATIONS
 Non-specific (also present in other
autoimmune and connective diseases):
o Photosensitivity: it is not an exclusive
manifestation of patients who have lupus,
it is also present in other diseases and also
in the general population;
o Vasculitis
o Hives
o Alopecia
o Livedo reticularis (present in antiphospholipid antibody syndrome).

 Specifications (characteristics of lupus and distinct in acute, subacute or chronic lupus):

o Acute skin lupus: always in the context of the
disease in systemic form. He shows up
frequently with:
◦ Butterfly Erythema: specific of lupus in active
form or a relapse, present especially in young
women. The erythema is not always the same
and is distinguished by prevalence of edema,
skin hyperparacheratosis or inflammatory
infiltration. It never involves the naso-labial folds
and goes into differential diagnosis with
seborrheic dermatitis or rosacea.
◦ Mucositis: in the most severe pictures it can reach the
mucosa ulcer. It looks like interface mucositis.
o Subacute skin lupus: can be present both as a skin-only
form (60%) and in the systemic form (40%). The skin
manifestations mainly affect the face, extensor surface
of the limbs, anterior and posterior trunk (the photo-
exposed areas) and may be:
◦ Polycyclic ring finger with map lesions
◦ Papulo-squamose-like psoriasiform
o Chronic skin lupus: usually observed in isolated
form, i.e. cutaneous and not in the systemic form
of the disease. Only 5% of it is systemically
shaped. Another possible trigger of lupus, besides
sun and viral diseases, is cigarette smoking:

88
 smokers more frequently have a subacute or chronic skin involvement.
In chronic skin lupus, inflammatory infiltration, skin flaking and inflammation prevail.
It has typical discoid lesions.

The systemic form of lupus is identified by the presence of anti-SSA antibodies.4

It is difficult to differentiate the morphology of a chronic lupus from a subacute or acute lupus:
the major differences are histopathologically noted, depending on the extent of the lesion (the
lesion is always the same):
• In acute skin lupus, colliquatory necrosis prevails at the
epidermis level, lymphocytic infiltrate and oedema at
the dermis level. There are no scars
• In chronic skin lupus, hyperkeratosis prevails in the
epidermis, lymphocytic infiltrates and telegianctasias in
the dermis. The skin annexes are also involved and
there is never restitutio ad integrum, with the presence
of scars.
• Subacute lupus: it's a middle ground between chronic
and acute. Along with the acute tend to heal
completely without scarring.

Lupus Band Test: direct immunofluorescence test performed on a biopsy taken from healthy,
non-photoexposed skin (normally taken from the skin of the
buttock). Evidence the deposition of immunoglobulins,
immunocomplexes and complement at the dermo-epidermal
junction. If the test is positive even in the non-photo-exposed
area then you have a systemic form of lupus (it is positive even in
a photo-exposed area).
The lupus band test was used when autoantibodies were not yet
available and was used to determine whether the manifestation
of lupus was only cutaneous or even systemic: positivity in a
biopsy of non-photoexposed skin indicated systemic disease.

The image shows a patient who makes ice cream, in summer she sold ice cream
with the truck, and developed a lesion only on the left side, therefore only on the
window part (a subacute lesion); this is a classic sun-induced lupine skin

4
Typical test question is the explanation for anti-SSA antibodies:
1. They can be present in all connective tissue with different frequency, especially in Sjogren's syndrome.
2. They're associated with subacute or acute lupus.
3. They can cross the placenta and be responsible for the baby's ventricular atrial blockage. They pass
between the 13th-15th week and the 25th week, if they determine a third degree block is irreversible.
Autoantibodies remain in the child until the 8-9th month and can give skin manifestations similar to subacute
lupus if the child is exposed to the sun.

89
manifestation. In most cases photosensitivity manifests itself with skin lesions, but not always.
Prolonged exposure to the sun may cause a recurrence of glomerulonephritis, or fever.
Therefore, although in most cases photosensitivity is manifested by the induction of specific
skin lesions, sometimes it can also occur with systemic alterations.

4. LUPINE NEPHRITIS
Nephritis is the most common chronic
manifestation of the disease (50%), in
particular one of the most common serious
manifestations. The development of
glomerulonephritis indicates a worse
prognosis and the need to use more
aggressive therapies leading to lower
survival.
All facilities may be involved in nephritis. The
classification is based on 6 histological
classes:
- I: Mesangial GN, characterized by the
proliferation of the mesangium;
- II: GN mesangioproliferative;
- III: Focal proliferative GN, affecting less than
50% of glomerules;
- IV: Diffuse proliferative GN, affecting more
than 50% of glomerules; it manifests itself in
two ways that are histopathologically different
but have no difference in prognosis or
treatment:
or IV-S Segmental, which affects less than
50% of the glomerular skein;
or Global IV-G, which affects more than
50% of the glomerular skein;
- V: membranous GN, characterized by a
thickening of the basal membrane and a
epithelial proliferation;
- VI: GN scleroialina, where the glomerule has
now become hyaline;

You then have 6 clinical presentation pictures:

• Asymptomatic hematuria;
• Asymptomatic proteinuria;
• Nephrotic syndrome: protein loss with urine (>3.5g/day), lipodisprotidemia and edema;
• Nephritic syndrome: loss of protein, an active urinary sediment (hematuria, leukocituria
and cylinders) hypertension and creatininemia.

90
 • Chronic kidney failure;
• GN rapidly progressive, is a
particularly acute nephritic
syndrome that evolves into
terminal renal failure within a
few months. It is a form that
manifests itself in ANCA-
associated vasculitis.

There is no match between histological

and clinical pictures, the only way to
identify the histological class is to do
renal biopsy.
It is important to know the histological
class of nephritis because different prognoses and therapies are associated. In proliferative
classes the disease, and therefore the therapy, is more aggressive. The graph above shows the
survival curves of patients with the various forms of gomerulonephritis lupica (they are patients
treated in the 50s and 60s), currently, with the new treatments the curves are flattened and
more similar to each other, especially in the short to medium term.
Now, biopsies are also performed to assess possible signs of chronicity or disease activity, which
are predictive of prognosis more accurately than histology.

5. NEUROPSYCHIATRIC MANIFESTATIONS
Neuropsychiatric manifestations are heterogeneous and difficult to classify as due to lupus.
There are some common manifestations:
• Epilepsy
• Cerebrovascular disease.
Other rarer ones:
• Acute confusion
• Major Depression
• Peripheral neuropathy.
More serious ones:
• Psychosis
• Korea
• Aseptic meningitis
• Cranial nerve neuropathy
From a clinical and therapeutic point of view it is
important to distinguish them in forms:
• Focals: vasculopathy and anti-phospholipid
antibodies prevail. They occur mainly with
strokes and require anti-aggregant and
anticoagulant therapy.
• Widespread: they have vasculopathy and
different types of autoantibodies, such as ribosomal P antibodies that can bind to

91
 neurons or cytokines themselves. The main clinical manifestation is dementia or
psychosis and requires the use of immunosuppressive therapy.

6. CARDIAC MANIFESTATIONS
 Pericarditis (20-30%) is one of the most common cardiac manifestations, it is a serositis.
Other manifestations are rarer, but can involve all cardiac leaflets leading to myocarditis
and endocarditis.
 The characteristic endocarditis is Libman-Sacks endocarditis (3-4%), an atypical warty
endocarditis (initially it was thought to be present only in the atrioventricular valves of
the right heart, then it was seen to occur in the left heart). Some time ago it was only
seen on the autopsy table because it does not give clinical manifestations (usually an
endocarditis from an objective point of view gives the sign of the breath). Injuries may
not be at the edges of the valve leaflets and therefore do not deform the valve closure
and do not cause blows. The warts are located on the atrioventricular side at the foot of
the valve leaflet attachment and do not give puffs because they do not cause alterations
to the rhyme of the valvular host. Today, on the other hand, two-dimensional
ultrasound or trans-esophageal echocardiography can also be used to diagnose in life.
Libman-Sacks endocarditis is characterized by the deposition of fibrous material: it is
associated in SLE patients with antiphospholipid antibodies and this type of endocarditis
has also been described in patients with primitive antiphospholipid antibody syndrome.
The genesis may be different: inflammatory in the case of lupus and exclusively
thrombotic in antiphospholipid antibody syndrome, but the clinical picture of the heart
is the same.
 Another characteristic manifestation is ischemic heart disease (rare) which may be due
to:
o Coronary vasculitis or coronaritis in younger patients (rare).
o Thrombosis in healthy coronary artery disease in patients with antiphospholipid
antibodies syndrome.
o Accelerated atherosclerosis in older patients. Women with lupus and the 40/50 age
group have myocardial infarction with a frequency 50 times higher than normal.

7. LUNG MANIFESTATIONS
Among the most common manifestations is pleurisy (30%), while other forms of parenchymal
involvement are rarer. In lupus, acute interstitial pneumonia (4%) is more frequent than chronic
interstitial pneumonia (2-3%) typical of scleroderma, idiopathic inflammatory myopathy and Sjogren's
syndrome.

8. SERUMIMMUNOLOGICAL ALTERATIONS
 Increased gammaglobulin, polyclonal expression of
B lymphocyte activation.
 ANA antibody positivity, they are a screening test.
 Specific antinuclear antibody positivity:
o Native anti-DNA antibodies;

92
 o Anti-Sm antibodies and anti-U1 RNP antibodies also found in mixed connectivitis;
o Anti-Ro/SSA antibodies;
o Ribosomal P-protein antibodies that are associated with neurological manifestations
because they pass the blood-brain barrier and bind to proteins present on the
neuronal surface and mediate neuronal damage.
 Positive antiphospholipid antibodies, present not only in lupus but also in other connective
tissue:
o Anti-cardiolipin antibodies;
o Anti-2 glycoprotein I antibodies;
o Lupus anticoagulant5, is an immunoglobulin that binds to phospholipids and proteins
placed on the cell membrane. It is a hemocoagulation test that is required both
internally and obstetrically because these antibodies are associated with both
thrombosis and obstetric complications.
 Complement reduction (C3, C4, C1q) is not always linked to consumption, sometimes there
is a reduction for a genetic effect.
 As far as inflammation indexes are concerned, the most reliable is ESR while PCR increases
little. Even in the most inflammatory manifestations of lupus, such as arthritis or sererositis,
the increase is always more modest than in rheumatoid arthritis. However, PCR is often
used to distinguish an infectious fever, characterized by high levels, from lupus fever.

CRITERIA
They are not criteria for diagnosis, but for classification.
These are recently adopted criteria, composed of clinical and immunological domains. Each one
is assigned a specific weight according to the importance it plays in making a diagnosis of lupus
(they are useful to understand which are the most relevant manifestations).
The overall final score must be ≥ 10.
There is also a discriminatory entry criterion, which is the positivity of ANA antibodies to the
immunofluorescence test ≥ 1:80.
For example, in a patient who is already antibody positive, the fact that he also has
glomerulonephritis with class III or IV biopsy (10) allows him to be immediately classified as
having lupus. If you have only a class II or V biopsy the final score is insufficient (8) and if you
have only proteinuria the final score is even lower (4). Pleuritis (5), synovitis (6), acute skin
lupus (6) and subacute (4) are all insufficient on their own for diagnosis. Among the
immunological criteria are Anti-DNA and Anti-Sm antibodies which are among the most specific
(6).

These ranking criteria therefore allow us to see which manifestations weigh the most in the
diagnosis of lupus. These criteria have been developed recently and have shown a better
performance than previous ones.

5
Lupine anticoagulant is a misnomer as it is actually a prothrombotic agent. The term "anticoagulant"
accurately describes its function in vitro. However, in vivo, it works as a pro-coagulant. In vivo, it is believed
that it can interact with platelet membrane phospholipids, increase platelet adhesion and aggregation and
thus promote the formation of clots.

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 NOTE: Previously there were 11 clinical criteria and 6 laboratory criteria. To be affected by lupus, a
patient had to have at least 4 lupus, including at least one clinical and one immunological, or a renal
biopsy that was suggestive of the disease, with a positive ANA or anti-dsDNA. Analyzing the
performance of these criteria, it can be seen that it is good, but there are still 6% false negatives and
8% false positives; this means that there are some patients who do not have the disease even though
they meet the criteria. This is due to the fact that these criteria serve to identify a well-defined
disease and not its early stages, so they do not allow an early diagnosis. For these reasons they have
been replaced.

Therapy

The therapy is based on the use of:

• Non-steroidal anti-inflammatories to control joint pain and fever.

94
 • Cortisone, sometimes used even at very high dosages, in intravenous boluses, up to 1
gram per day for 4-5 days. In view of the numerous side effects of chronic therapy, an
attempt is made to use the minimum possible dose or to suspend it in case of remission
and during the maintenance phase of the disease.
• Antimalarial drugs (chloroquine and hydroxychloroquine), are recommended in all
patients with SLE, drugs that give an important immunomodulation, also have a
protective effect on chronic damage by lowering cholesterol and blood pressure and an
antithrombotic effect (they were once used after hip replacement surgery to reduce the
thrombotic risk post-operatively).
• Immunosuppressants/immunomodulants:
◦ Cyclophosphamide,
◦ Azathioprine,
◦ Mycophenolate mofetil,
◦ Cyclosporine A,
◦ Methotrexate,
◦ Tacrolimus, calcineurin inhibitor.
• Monoclonal anti-BLyS antibodies (Belimumab). It is a completely human monoclonal
antibody that inhibits the B lymphocyte stimulator (BLyS), inhibiting the family TNF
activation factor (BAFF).
• Monoclonal anti-CD20 antibodies (Retuximab) already seen in rheumatoid arthritis but
not yet approved for lupus and used off-label.

PROGNOSIS
This graph shows a
comparison of the cohort
survival curve thirty years
later; it can be seen that
the short-term prognosis
has improved, but the
long-term prognosis is still
unsatisfactory. This may be
due to the effects of the
disease but also to those
given by the complications
of the therapy. In fact, only
1/3 of patients die of aggravated lupus, while the remaining 2/3 die either from cardiovascular
or cerebrovascular complications, infections, or neoplasms (especially lymphoproliferative
ones).

Q: Lupic nephritis therapy should be done on the basis of the histological picture. Should a kidney biopsy
be done in other cases?

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A: Usually it is done when there is a persistent proteinuria, i.e. assessed several times, more than 0.5 g
per day, especially in the presence of hematuria. If the values are the same or higher, a class I or II biopsy
is more likely to be found.

Q:Why do you no longer use the lupus band test to distinguish between the skin shape and the systemic
shape?
A: In the past when there were no antinuclear antibodies, in the presence of a chronic skin picture this
test was used to distinguish between skin case and systemic case. Nowadays it can still be used to
determine whether a skin manifestation is actually lupus, doing it directly on the lesion to see if there is
deposition of immunoglobulins. In this case it is very likely to be, although this is a shared picture with
dermatomyositis, which is also an interface dermatitis.

IDIOPATHIC INFLAMMATORY MYOPATHY (MII)

Idiopathic inflammatory myopathies are a group of acquired diseases characterized by skeletal muscle
inflammation. They are called idiopaths because their cause is not yet fully known. If inflammation of
the muscle is not recognized and treated it leads to loss of muscle function.

CLASSIFICATION
They are divided into four main forms:
• Polymyositis (PM),
inflammation of several
muscles.
• Dermatomyositis (DM),
inflammation that affects both
muscle and skin.
• Necrotizing myositis or
autoimmune necrotizing
myopathy (NAM), in which
necrosis prevails over
inflammation.
• Myositis from including bodies
(IBM), in which inflammation is
accompanied by important degenerative phenomena. It is seen more by neurologists than
by rheumatologists because, unlike the other forms, it mainly affects the muscles of the
extremities of the limbs, placing itself in differential diagnosis with neuropathy.

These forms can occur in particular subgroups of patients:

a. In young people dermatomyositis clearly prevails over polymyositis (DM >> PM).
b. In people with neoplasms dermatomyositis still prevails over polymyositis (DM >
PM). Typically about 1/3 of patients with myosites also have neoplasia, which is why
cancer screening is necessary.
c. In patients with associated other connective tissue, i.e. overlap or overlap connective
tissue syndromes, polymyositis prevails over dermatomyositis (PM > DM).

96
Then there are more rare and isolated forms whose diagnoses are made on a histological basis and not
on a clinical basis and for this reason they will not be treated. They understand:
1. Eosinophilic myositis,
2. Myositis granulomatosa,
3. Macrophagic myositis,
4. Myositis focal/nodulare.

EPIDEMIOLOGY
Idiopathic inflammatory myopathies are included in the list of rare diseases drawn up by the Istituto
Superiore di Sanità. Patients with myositis are therefore entitled to an exemption from the payment of
the rare disease ticket which covers both
the cost of examinations and treatments.
The incidence is 5-10 people per million,
while the prevalence is 1 in 10 thousand.
They are therefore much rarer than
rheumatoid arthritis and lupus. The
female/male ratio (F/M≈2-3:1) is variable
and depends on the clinical phenotype. In
general the disease prevails in women,
except in the case of myositis from bodies
including IBM where men are most
affected.
The age of onset also depends on the
type of illness:
- Polymyositis and dermatomyositis
have two peaks of onset, one in childhood (5-15 years) and one in adulthood (30-50 years).
- Myositis from included bodies is an exception and is more frequent after the age of 50.

ANATOMY AND STRUCTURE OF SKELETAL MUSCLE

The muscular fibrocell is wrapped by a band called endomysium; the file that collects the muscular
fibrocells is enclosed by the perimysium; while the whole muscle is then surrounded by the epimysium.
The main vessels are at perimysium level, while the smaller capillaries are at endomysium level.

PATHOGENESIS
- In polymyositis there is an expansion of CD8+
lymphocytes both peripherally and muscularly.
The expansion is due to a not yet fully known
antigen that engages the class I MHC molecules
expressed on the muscle fibrocell. The muscle
fibrocell behaves like a cell of the immune system.
The lymphocyte CD8+ establishes an
immunological synapse and exerts its destructive
action, cytokines are produced to amplify the
inflammatory process. Lymphocytes can also
transfer perforin to the cell and induce necrosis.
Cytokines such as IL-1, TGF beta and TNF are

97
 produced that amplify the
inflammatory process. B cells
and plasmocytoid dendritic cells
are also present in the tissue.
Local production of antibodies
has also been shown to be lower
than in dermatomyositis.

- In body myositis including the

pathogenetic mechanisms are
very similar to those of
polymyositis, but there are more
important degenerative
alterations. There is a response to stress in the reticulo-endothelial system with protein
misfolding and accumulation of beta amyloid precursors. This painting therefore partly
resembles that of Alzheimer's.

- In dermatomyositis the pathogenesis is completely different. The binding of an

autoantibody with an autoantigen expressed on the endothelial cell causes cascading
activation of the complement. The activation of C3 thus attracts other inflammatory
cells, while C3b and the MAC
membrane attachment
complex attack the
endothelial cell. The small
vessels of the capillaries go
thus to ischemia, in particular
in the periphery of the
muscle files, causing a peri-
fascicular atrophy. Again,
dendritic plasmocytoid
dendritic cells, B lymphocytes
and local antibody production
are present in the tissue.

HISTOPATOGENSIS
 In polymyositis we have an
inflammatory infiltrate at the endomysium level, as the lymphocytes penetrate inside each
muscle cell. There is an over-expression of the class I MHC complex and the inflammatory
trigger, i.e. the target of inflammation is the muscle fibrocell.
 In myositis from included bodies you see included bodies containing beta amyloid
substance.
 In the necrotizing form there are not so much lymphocytes as macrophages, even if the
inflammatory picture is scarce and necrosis phenomena prevail.

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Both the included body myositis and necrotizing myositis have many aspects in common with
polymyositis, while all three are distinctly different from dermatomyositis.
 In dermatomyositis the inflammatory picture is distributed around the vessels and in the
atrophic peripheries. Here we have the overexpression of the MAC, the membrane attack
complex, and the target of the inflammation is the endothelial cell. The histopathological
picture is that of a complementary mediated micro-angiopathy, as the vessels of the
microcirculation are affected.

CLINICAL ASPECTS
From a clinical point of view, the distinction is not so clear: certainly in dermatomyositis there is skin
involvement and in polymyositis there is not, but in both pathologies the major effort is borne by the
muscles.
Symptoms:
1. Muscular commitment: it is important to point out that, unlike what you might think,
the main symptom of patients is not muscle pain, but muscle weakness (asthenia).
These patients feel tired and weak when they have to make even slight efforts (lifting a
bottle, holding the phone, drying their hair with a hairdryer, getting up from the chair...).
There can also be pain, similar to that experienced by anyone who has done intense
exercises without proper training. The muscles most affected are the flexor muscles of
the neck, the proximal muscles of the scapular and pelvic cingulate, while the
oculomotor muscles are always spared. This difference makes it possible to make a
differential diagnosis with myasthenia gravis in which the oculomotor muscles are
always compromised (palpebral ptosis). The long-term outcome is in any case muscular
atrophy, which is irreversible: it is very difficult to have restitutio ad integrum. Patients
who maintain mild atrophy with therapy can already be considered a therapeutic
success.
2. Articular commitment: not very common, if arthritis is present it is not important
anyway.

99
 3. Esophageal engagement: reflux or oropharyngeal dysphagia, especially of the
pharyngeal muscles. Patients are at risk of pneumonia ab ingestis: to prevent it, it is
important to change their diet to a parenteral one (prob or PEG).
4. Pulmonary commitment: in addition to pneumonia ab ingestis, there are 2
characteristic pictures:
a. Restrictive respiratory failure due to the commitment of the respiratory bellows
with a Reduction in Vital Capacity due to the decrease in the strength of the
respiratory muscles, i.e. deficit of the bellows (restrictiveness, diagnosed with
spirometry).
b. Chronic interstitial pneumonia (diagnosis with DLCO and high resolution CT scan). In
idiopathic inflammatory diseases it is very frequent. It is evaluated by respiratory
tests, CO diffusion or high definition CT (it is the gold standard and allows the
definition of the type of interstitial pneumonia). Characteristically there is a
reduction in the diffusion of DLCO, which can also be present if there is a reduced
vital capacity for bellows reduction. In order to assess the interstitial commitment,
therefore, the CV/DLCO report, which is the KCO, is used.
5. Cardiac involvement: less frequent than lung involvement. Arrhythmias, left ventricular
dysfunction and congestive heart failure are not frequent manifestations.
6. Kidney involvement: myoglobinuria and renal failure from myoglobinuria. It occurs
especially in patients with very aggressive disease, in order to avoid the renal
consequences it is important to hydrate the patient abundantly.
Q: Can the diaphragm be hit?
A: It is not frequent, but as skeletal
muscle can be affected. There is a
picture of increased diaphragm
elevation or dyspnea due to
inspiratory or expiratory
insufficiency.

OBJECTIVITY
Muscle pain on palpation is not
frequent (20%).
Muscle hypoasthenia is evaluated
with the Manual Muscle Test, a
sensitive and reproducible
examination that allows you to
explore strength in 8 muscle
districts. Each muscle group is
assigned a score depending on the
strength demonstrated and at the end an overall score is obtained which indicates the general state of
muscle strength in the patient. Following therapy, the asthenia picture may improve, while a worsening
of atrophy may occur. This is an inevitable outcome that can be improved with kinesiotherapy. Muscular
atrophy rarely occurs at the onset because it usually appears only in advanced stages or in extremely
severe and aggressive cases.

100
SKIN MANIFESTATIONS
The skin manifestations are divided into
pathognomonic, characteristic and
compatible:
Pathognomonic signs:
They are only present in patients with
dermatomyositis and their detection
already makes it possible to make a
diagnosis. These are papulo-eritematous
signs on the extensor surface of the small
joints of the hands (phalangeal
metacarpals, proximal and distal
interphalanges), on the ankles of the
ankles or on the extensor surface of the
knees. The papule is called "Gottron's
papules" and the erythema is called
"Gottron's sign".

Characteristic signs:
 Periorbital heliotropic rash. The heliotrope is a flower whose characteristic lilac-violet
colour gives its name to the rash. It is not pathognomonic because it can also be observed in
case of Trichinella Spiralis infection6 or in case of sarcoidosis.
 Symmetrical purplish erythema or
symmetrical erythematous areas on the
cheeks. Dermatomyositis erythema of
dermatomyositis is very similar to the
butterfly erythema of SLE but unlike this it
also involves the naso-labial folds. Both are
photosensitive and present as interface
dermatitis on histological examination.
However, differential diagnosis is not a
problem and is made on the basis of the other
characteristic signs of Lupus. Injuries are
possible on the forehead, face, upper,
anterior and posterior thorax, and on the
extensor surface of the arms, with typical
disposition of photosensitive erythema.

6 2The
professor talks about Trichinella Canis, who does not exist. There are Trichinella Spiralis and Toxocara
Canis. There are two species of nematodes: at dermatological level, the first causes periorbital edema; the
second rashes. So, it's more likely he's referring to Trichinella Spiralis.

101
 Skin teleangectasias, visible to the naked eye, often at periungueal level. They can be seen
with the capillaroscope.
 Dystrophy of the cuticles, very common, even in the absence of telangiectasia.

Compatible signs:
 Poichilodermatomyositis, in which inflammatory areas
alternate with atrophic hypopigmented areas.
 Calcium deposition is the deposition of calcium at the level
of the bands or subcutaneously in the most exposed photo
areas. It is characteristic a little of all the connective tissue
in particular of scleroderma. In this case it is an outcome of
the inflammatory process, while in scleroderma it is an
outcome of the ischemic process. Pseudo-cancer calcinosis
is observed similar to renal failure and is very difficult to
treat.

The clinical spectrum of Dermatomyositis is very broad:

1. Dermatomyositis sine
dermatitis, therefore with
only muscular effort: the
diagnosis is by histology.
2. Classic dermatomyositis, with
both muscle and skin
components.
3. Hypomyopathic
dermatomyositis with little
muscle involvement.
4. Amyopathic dermatomyositis,
no muscle involvement.

Q: Is the pericarditis picture exudative or

fibrotic?
A: Initially it is exudative, but then, in the advanced stages it has the fibrotic aspect and the possible
thickening of the pericardial leaflets.
Q: Is there a risk of embolization of material in Libman-sacks endocarditis?
A: Yes, you have to be careful because it is warty material.
Q: Can cyclosporine administration worsen nephritis?
A: Yes, as cyclosporine can cause renal failure, it should be used with care especially in patients with
nephrotic syndrome. From this point of view Tacrolimus is better, which gives less side effects at
metabolic level (kidney failure, diabetes, hypercholesterolemia).

ARTROSIS
It is a chronically evolving joint pathology characterized by degenerative and productive
injuries to the cartilage of the diarthrodial joints: these are the mobile joints with joint

102
cartilage, synovial membrane and synovial fluid. The main target is cartilage but can extend to
all other joint structures.
It should also be noted that, since the target tissue of the disease is the articular cartilage, the
initial stages of the disease are asymptomatic because the articular cartilage is not innervated;
pain occurs when the damage has already involved other structures or when the cartilage is
already damaged.

CLASSIFICATION
The pathology is defined as degenerative, in the context of rheumatic joint diseases, where an
attempt is made to distinguish inflammatory or arthritic forms from degenerative or arthrosis.
In fact, the mechanisms underlying the damage of cartilage in arthrosis involve pro-
inflammatory substances, but it is minimal inflammation at the tissue level and nothing at the
systemic level. They are therefore considered degenerations and not inflammatory forms.
The classification currently in force is not recently published (1999) and refers to the one drawn
up by the Italian Rheumatology Society, but a new classification is underway, which has not yet
been completed.
It stands out:
1) Primary arthrosis: forms in which there is no element that can clarify the etiology. It
includes:
 Localized forms: mainly related to arthrosis of the hands (distal, proximal and
rhizarthrosis of the thumb);
 Generalized form (polydirectal arthrosis without a trigger cause);
 Erosive finger arthrosis (detail).
2) Secondary arthrosis: there are elements that can be recognized as related to the
development of the disease. They're secondary to:
 Trauma;
 Developmental abnormalities;
 Biomechanical turbulence;
 To alterations in bone structure;
 Metabolic/endocrine diseases (congenital or acquired) that affect the structure and
consistency of the ligaments or the cartilage itself;
 Inherited connective tissue diseases (e.g. collagen mutations) that result in a more
fragile and more easily damaged cartilage;
 Hematological diseases;
 Arthritis and endemic arthrosis: due to damage to the early articular cartilage (septic
arthritis, rheumatoid arthritis, psoriatic arthritis) which triggers subsequent
degeneration, even in the absence of inflammatory stimulation and even if the
arthritic episode is properly treated.
Basically, these are all situations that compromise either the structure of the cartilage itself or
the load to which the cartilage is subjected (e.g. valgism or varus stress on one side of the joint
more than the other, or a fracture that does not reposition according to the correct articular
axis).

103
EPIDEMIOLOGY
It is an extremely widespread and extremely frequent disease.
It is linked to the ageing process, it is a chronic disease and represents a considerable burden in
terms of costs for both the health system and society, the statistics are dramatic given the
further ageing of the population. Example: USA estimated cost in 2020 of $ 100 billion.
The fact is that there is no therapy, unlike the progress made for therapies of arthritis
(rheumatoid, psoriatic) and connective tissue.
The therapeutic progress for arthrosis is very limited, as it is not yet possible to prevent the
disease or slow down its course, so as to limit the damage that the pathology can lead to.
It represents an important problem both for the frequency and for the great level of handicap
that results from it.
Framingham's study shows that: 11% of women and 7% of men between 63/75 years of age
have symptomatic gonarthrosis, and an even higher percentage (around 30%) still have
gonarthrosis, which is evident on X-rays but does not correspond to the expected symptoms.
It can be seen that there is no absolute correspondence between symptomatology and
radiography. X-rays with particularly important arthrosis can be found in paucysymptomatic or
completely asymptomatic patients. This suggests that there is some other undeciphered
element that explains the symptoms of arthrosis.
A more recent study in Veneto (PROVE)
investigates the prevalence of
symptomatic arthrosis and its location:
hand, knee and hip, both male and
female over 65 years of age. It has
emerged that after a certain age the
female sex is more involved in the
arthrosis procedure. If the research is
extended to younger age groups, the
ratio is unbalanced against the male
population, which is more affected.
It can therefore be deduced that until
before the age of 50 (average age of
menopause in women) the process is
more frequent in males, after the age of 50 (with the onset of menopause in women) is more
frequent in females, while the average prevalence is the same for all age groups.

PATHOGENESIS
Arthrosis results from an imbalance in the relationship between articular cartilage, load and
its distribution.
Articular cartilage is a delicate structure whose function is to cushion and distribute the load to
which the joint is subjected. In normality there is a physiological balance between load and
weight, if this is unbalanced the cartilage damage is established.
It affects the development of osteoarthrosis:
 Age: with increasing age there has been an increase in the prevalence of joint
cartilage chondrocytes (as with all other tissues).

104
 It has a particular structure with a relatively low cell concentration, there are
chondrocytes that are metabolically active, but have very poor regeneration
capacity, if they suffer damage with death of the chondrocyte is not repaired or
replaced, but is lost.
 Genetic factors: There are some forms of arthrosis with remarkable familiarity, such
as primary arthrosis of the hands. Or rarer forms related to defects in one of the
collagen genes where the articular cartilage has an altered structure and is more
sensitive.
 Systemic factors: may affect the good health of articular cartilage.
 Local biomechanical factors, where cartilage is healthy,
but loads are unbalanced (greater in a district),
excessive, repeated, not physiological: knee valgism,
congenital hip dysplasia, arthritis outcomes, joint
misalignment.
These are all cases where the load is not evenly
distributed.
Or in the case of very obese people, overloading the joint itself.

The components of the cartilage are:

Chondrocytes: they are 2-10% of the total volume, they are endowed with considerable
metabolic activity which is linked to the production of the MEC and the control of their spatial
arrangement. They lack cell-cell contact, have a rich lysosomal kit and have little mitotic activity,
go into senescence but are not replaced.
The Extracellular Matrix: formed by an amorphous substance and structural macromolecules
that give the tissue shape and stability; the amorphous substance is composed of water (60-
80%, for this reason the healthy cartilage is radiotransparent), gas, small proteins, metabolites
and cations. Structural macromolecules account for 20-40% of cartilage composition and are
Proteoglycans, Gllicoproteins and Collagen (type 2 mainly).
The proteoglycans are formed by a core-protein to which they bind, forming branches, the
Glycosaminoglycans; the various core-proteins then bind in succession to hyaluronic acid
molecules forming a glyco-protein skein. GAGs, having exposed negative charges, repel each
other and recall H2O molecules, consequently this macromolecule, if not subjected to
compression, has an expanded structure filled with water (similar to a sponge). When, on the
other hand, the cartilage is subjected to compression, the meshes of this net expel the water
they have inside, when the articulation returns to the drain, they regain the lost water.
Consequently, the substance formed by PG and GAG is capable of absorbing the compressive
forces.
Collagen types II (90-95%), VI, IX and XI form crossed fibrils that support the cartilage and are
able to release the tensile forces; collagen type X
intervenes in the cartilage maturation processes.
The function of chondrocytes is to produce and
maintain in good condition the cartilage and the
surrounding tissue (forming the so-called
chondrocyte-matrix unit) also producing different

105
types of proteinases involved in the remodeling of the structure (Metalloproteinase,
Cysteinaproteinase, Aspartatoproteinase, Serinproteinase).
When there is a minimal inflammatory process, the catabolic processes in the cartilage increase
and the cartilage weakens, the collagen and proteoglycan scaffold is defibrated until the death
of the chondrocytes (electron microscope gaps in the image below).

At the base of the cartilage damage and chondrocyte death are pro-inflammatory cytokines:
IL1 and TNFα, which have considerable capacity to induce a catabolic type program in
chondrocyte: the chondrocyte, like the bone cells that must maintain the balance between
bone formation and degradation, degrades and reforms the surrounding matrix.
During arthrosis the pro-inflammatory cytokines, although present in minimal amounts,
therefore in a mild inflammatory state (not comparable to that present in arthritis, rheumatoid
or septic), but continuous, shifts the chondrocyte towards the catabolic type program with
constant matrix degradation and indirectly causes further inflammation.
If the cartilage is suffering, fissures begin to form and debris comes off.
Debris and fissures amplify the damage:
 The debris also induce inflammation in the synovial
membrane, i.e. in the cells circulating in the synovial
fluid.
 The fissures, given the pressure inside the cavity,
soon widen and deepen.

If there is a degenerative phenomenon, the articular cartilage is

partly thinned and partly degraded, another element can be
seen: bone protuberance.
(histological image)
In arthrosis there is therefore both cartilage degradation and
bone hyperproduction with formation of osteophytes. They
represent an attempt of the bone to regain a certain equilibrium, they have a predominantly
horizontal course to try to increase the joint surface in order to redistribute the joint load. But it
is completely ineffective, in fact they are an element that worsens the functionality of the joint
and contribute to the symptomatology of arthrosis: pain, because they can go to compress the
surrounding nociceptive structures and hinder movement.

CLINICAL
Pain is the main representation of arthrosis, with different causes and components.
1) Increased pressure of the subchondral bone, with a friction component between the
two bone heads when the cartilage is drastically eroded.
2) Synovitis: because however the detaching cartilage fragments give a certain degree of
synovitis (less than rheumatoid arthritis) and the synovial membrane is well innervated,
contributing to pain.
3) Sprain of the capsule and ligaments: a considerable amount of liquid can form inside the
joint, which is poorly inflammatory (<2000 white x mmc), which expands the capsule
with compression of the surrounding nociceptive structures, ligaments and tendons.

106
 4) Muscular and entesitic commitment: they depend on the position, even of an analgesic
nature, that the patient assumes as the pain is accentuated with the load and
movement. This is mechanical pain (appears with the load), unlike arthritis pain which is
greater at rest. There is therefore an imbalance in the musculature, resulting in muscle
contractures and irritation of the insertions with accompanying enthesitis. 7

SYMPTOMS
Osteoarthritis therefore essentially presents itself with mechanical pain and short-term
stiffness, while inflammatory pain of arthritis leads to post-activity stiffness, the maximum
expression of which is in the morning resulting in morning stickness lasting over an hour. In
arthrosis it is short-lived, never over 30 min even in the morning, it "unlocks" quickly, but as the
day progresses and if the load on the joints increases, the pain also increases, at rest there is no
pain. (on the other hand, inflammatory pain, arthritic, is a pain present even at rest, it is also
present during the night and is accompanied by a long lasting morning stiffness). This helps to
guide the diagnosis.
The functional limitation is progressive, linked to the damage of the joint that, by losing
articular cartilage and due to the formation of osteophytes, affects the joint itself, causing it to
lose functionality, also the muscular aspects contribute to the loss of functionality: the subject
stands more and more stationary, he performs antalgic positions, with the appearance of
contractures that progressively limit him.

SIGNS
As far as objectivity is concerned:
 There may be a non-inflammatory or poorly inflammatory joint effusion, so not hot
or flushed (at most a little hot and flushed),
 Hard tumefaction due to deformity, or elastic if there is spillage.
 Crackles or Rattles, not tendinous, but due to friction that occurs in articular surfaces
that are no longer congruent.
Radiographically speaking:
 Reduction of the articular rhyme , radiographically you can see an empty space, but
in reality it is occupied by articular cartilage that is radiotransparent because it is
composed for 60/65% of its weight by water. A reduction in rhyme means that there
is a reduction in cartilage, i.e. it is disappearing. It is also reduced in arthritis,
however, but is usually uniform in all parts of the joint (homogeneous reduction); in
arthrosis, on the other hand, it is prevalent in the compartment subjected to the
greatest load.

7
Enthesitis is an inflammation that affects the area of insertion of the tendon on the bone. Often, this condition is caused by
wear and functional overload that occurs during sports and work activities (degenerative enteritis). The inflammatory process
can also occur following trauma and in the context of more complex diseases, such as ankylosing spondylitis and some forms of
arthritis.

107
  Subchondral sclerosis. In arthritis a characteristic and early radiographic sign is iuxta-
articular osteoporosis: bone is more osteoporotic near the joint with bone
resorption until erosion due to inflammatory mediators. In arthrosis, however, it is
the opposite: there is an increase in the density of the subchondral bone.
 Osteophytosis i.e. the tendentially horizontal bone deformations described above
 Pseudocyst or subchondral geodi, for micro-fractures and synovial fluid pressure,
with formation of articular cartilage in ectopic position inside the bone.

HEADQUARTERS
All diarthrodial joints can be affected. The most frequent are:
 Hip: coxofemoral (10%),
 Knees (30%),
 Small joints of the hands: not the metacarpophalangeal joints, which are rarely
affected, but the distal (40%) and proximal (15%) interphalangeal joints and the
trapezio-metacarpal joint of the thumb (30%). The thing that differentiates them
from other joints is that they are not usually subjected to particular loads, so the
arthrosis that develops is a primary arthrosis.
 Rachide, especially the lumbar and cervical tracts,
 Metatarsophalangea 1° (big toe).

Heberden's nodules form in the distal interphalanges of the

hand, which can enter into differential diagnosis with other
types of distal arthritis (psoriatic). They manifest themselves
with inflammation of the 2nd to 3rd finger which lasts for
weeks/months, when it goes off the nodules remain. The
radiographic equivalent shows that there is no erosion, but
there is the disappearance of the articular rhyme and the
enlargement of the bone.
Proximal interphalanges are rarer and can involve all joints,
you may suspect arthritis but then radiology clarifies the
picture (no presence of erosions, but Bouchard's nodules).

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Trapezio-metacarpal arthrosis of the thumb is more frequent
and very disabling because it can greatly reduce the opposition
capacity of the thumb, it is called rhizoarthrosis.
Distal interphalangeal arthrosis is also less tolerated due to an
aesthetic factor, it is more frequent in women starting in
adulthood (50 years) immediately after menopause.

These manifestations are linked to the proliferative component

of osteoarthritis, which causes deformities and functional
limitations.
In this image on the right, instead, we see the disappearance of
the articular rhyme in an IFD with osteophyte formation; there is
also a flange misalignment that contributes to the appearance of
deformity and nodularity.

EROSIVA ARTROSIS - hands

We distinguish a more aggressive form of arthrosis of the hands,
called Erosive Arthrosis. This form of arthrosis can also more rarely affect other joints.
It is clinically distinguished by its aggressiveness, the degree of severity of the joints with
erosive aspects that sometimes lead to ankylosis.
From a biohumoral point of view, there are generally no signs of systemic inflammation in
arthrosis. In erosive arthrosis, on the other hand, there may be slightly high levels of PCR,
evaluated with ultra-sensitive methods.

On the radiographic aspect, there are pictures of

 Pseudocyst
 Erosions
 Osteophytosis
 Reduction of joint rhyme
 Ankylosis
 Subluxation
 Periostite
Seagull wing erosions, specific to erosive arthrosis,
form in the central portion of the joint and cause a
collapse of the central surface of the bone
(osteophytosis and sclerosis in the distal phalanx
and erosion in the proximal phalanx). There's also
crumbly erosion where the bone looks a little
crumbled. One can also see the complete
disappearance of the articular rhyme with the
typical sawtooth shape, which most frequently
affects VFP and can evolve into ankylosis.

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 The diagnosis
of this
pathology is
not always
immediate
because the
commitment
of VET and
FHD is also found in psoriatic arthritis; on the contrary, in rheumatoid arthritis the commitment
is of MF (metacarpophalangeal phalanx) and VET so the differential diagnosis is easier. In any
case, psoriasis has a generic context in which the etiological meaning of a specific district is
more easily framed. The radiographic aspects are, however, discriminating and characteristic,
except for some cases of uncertainty. The therapy of the various forms is different so the
diagnosis must be clear.

GONARTROSIS or GINOCCHIO'S ARTROSIS

Arthrosis of the knee mainly involves the female sex.
Gonarthrosis is more often bilateral and all three compartments can be involved in the knee:
lateral tibial femur, medial tibial femur and patellar femur. It can bring important diassemblies
with valgism but above all, more commonly, varus. The misalignments are a consequence of
arthrosis but, in any case, they in turn amplify it due to the resulting altered load distribution
which accelerates the process.
The clinical criteria for gonarthrosis, in addition to pain, are:
 Adult age: >40 years
 Brevity morning stiffness: <30 min
 Non inflammatory synovial fluid: there may be GB but with value <2000/mm3
 Presence of osteophytes
 Crackles
In the picture you can see specifically the pathogenetic process affecting the knee.
In short: from a normal joint there is cartilage damage, dilatation of the synovial membrane
and capsule, formation of osteophytes and degradation of cartilage, first ipsilateral and then
contralateral.

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The radiographic image above shows reduction in medial rhyme, varus and osteophyte
formation. In the patellofemoral joint, the patella appears as one with the femur. You can also
see sclerosis with thickening of the subchondral bone.

Clinically there are the same symptoms listed above, there are no particular qualities. It is,
however, important to stress that the pain is mechanical. You may have painful contracture
and post-activity stiffness, the latter usually lasting less than 30 min, and functional impotence
related to the progressive diassembly of the joint. The signs are also the same: hard swelling,
soft swelling with effusion, roars and misalignment.

The image below shows the evolution. At first the rhymes are well preserved, after four years
the medial compartment is reduced and the sharp spines, after seven years the articular rhyme
at medial level has disappeared; here there is friction between the two bone heads because the
cartilage has disappeared.
The time span increases and the damage gradually increases to a very important disability
picture. In the clinic, therefore, one must certainly take into account the pain but also the
functional damage with the related disability.
From a therapeutic point of view, to date we have no way of significantly interfering with this
degenerative process other than to intervene in the causes of secondary arthrosis. The only
prospect of surgery is prosthetic implant surgery.
There are no drugs capable of repairing any cartilage lesion but there are chondroprotective
drugs that should strengthen it: chondroitin sulphate, glucosamine, hyaluronic acid, etc.. These
are substances normally present in articular cartilage and it is thought that using them as
supplements may help, but some clinical studies have shown that intensive use only delays the
prosthetic procedure by a couple of years.
In addition to medications, hyaluronic acid infiltrations are also practiced locally, which have,
however, more of a physical-mechanical effect: both functions as a lubricant and facilitates
cushioning. In this case the patient enjoys a real benefit but does not slow down the
degenerative process.
The most concrete perspective is the use of stem cells, since chondrocytes are not able to
regenerate. There are studies underway, it's not yet discussed in the clinical context.

HIP ARTROSIS
This type of arthrosis is characterized by pain mainly located in the gluteal and posterolateral
region of the thigh up to the knee or even in the groin and in the front part of the thigh up to
the knee.

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X-ray shows an effusion; usually the thickness of the joint rhyme is measured and an indication
of surgery can be given. This joint is easy to replace surgically and this translates into more
successful surgery.
There are different degrees:
 Grade I: joint involvement with subchondral bone sclerosis
 Degree II: advancement of the pathology with rhyme reduction, sclerosis and
osteophytosis
 Grade III: even more advanced with femoral head ovalization, subchondral bone
thickening, osteophyte formation and disappearance of the articular rhyme. Here the
patient feels severe pain and has an important functional limitation.
The classification criteria for osteoarthritis or osteoarthritis indicate:
 Pain: is the pivotal symptom, to which at least two of the following symptoms must be
associated
 Radiographically visible joint space reduction
 Presence of osteophytes
 ESR (or ESR in English) normal then <20mm/hour

The therapy of arthrosis disease, in

the hip but in general, sees pain as
the main point on which to act.
The functional limitation may be
related to the pain itself, i.e. defined
as analgesic, or is due to the
complete destruction of the joint.
In concomitance you have a related
muscle weakness.
Solving only the pain does not limit
the progression of the pathology and
thus we move from disease to
functional damage. One arrives at disability, characterized
by difficulty in performing daily actions, and ends up with
dependence on others,
frustration, depression and
social isolation that establish a real state of disability.
There is not much the doctor can do except try to control the pain
and, at the right time, give the indication for surgery. The timing of
the surgery is important. The prosthesis should be done when the
tissue is not too compromised because, otherwise, you are going
against a surgical failure (applies to knee and hip).

ARTROSIS of the VERTEBRAL COLUMN

In this image there are osteophytes of the spine with the appearance of hooks, a typical picture
of arthrosis. In this case scoliosis probably contributed to the development of the disease with
the formation of horizontal osteophytes that try to compensate for the incorrect distribution of

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the cute. In addition, it denotes the usual thickening of the subchondral bone, clearly especially
in the area where the load is greatest.

In this other image on the right there is the anatomical counterpart of the radiographic image
in which the proliferation of the bone is seen starting from the horizontally oriented edge
(osteophyte).

RHEUMATIC POLYMYALGIA - PMR

PMR is a disease that presents epidemiological, etiopathogenic, clinical and therapeutic
elements in common with Gigantocellular Arteritis, with which it is associated in about 30% of
cases. Also, they both affect people over 50. The Polimialgia Reumatica is characterized by
intense muscular pain and rigidity of the tracks, both scapular and pelvic. These symptoms
come with an inflammatory picture.

EPIDEMIOLOGY
The incidence of PMR is 10-100:100.00 inhabitants, it increases with age but the typical starting
age is around 70 years. The prevalence is higher in women (2:1).

EZIOPATOGENESIS
Often this pathology is not recognized. The aetiology is unknown but several concausal factors
have been hypothesised. Probably hormonal factors play a role, this is due to the prevalence in
the female sex, genetic factors, referring to the higher prevalence in the white race and the
association with HLA-DR4, and environmental factors, especially infectious given the seasonal
prevalence of the winter-spring period so it is thought that the trigger is likely to be infectious
with a flu-like onset.

CLINICAL
The painting is characterized by
 Muscle pain that appears in acute within a few hours, intense and continuous,
accentuated by attempts at movement and associated with marked and persistent
stiffness. The people most affected are the elderly in whom these pains are often
underestimated or perhaps confused as symptoms of arthrosis. It should be stressed
that the onset is acute, it is not a pain present for a year or two, the day before it is not
there and a few hours later it is. The pain is linked to inflammation, especially of
tendons and bursa.

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  Interest of tracks but also neck, trunk and root of limbs
 Possible systemic accompanying symptoms (40% of cases): fever, asthenia, weight loss,
apathy. If we do not intervene early these symptoms become very marked because we
are in the presence of an inflammatory pathology.
 Possible concomitance of asymmetrical peripheral arthritis in which knees and small
joints of hands and feet are affected (it is a non-erosive form) but it is however rare
 Possible presence of swelling of the distal extremities with imprinting edema, especially
in the hands that are called "puffy hands" but also in the feet
 Possible association of carpal tunnel syndrome.

Pain and functional limitation involve global movements such as turning around, getting out of
the chair or getting out of bed. Passive mobility and muscle strength are preserved.
It is therefore necessary to consider some clinical aspects for the differential diagnosis: if the
pathology was linked to muscle inflammation there would be no pain. That's because myositis
gives little pain. PRM pain is linked to inflammation of tendons and bags.
DIAGNOSIS
Clinical, laboratory and instrumental parameters are taken into consideration for diagnosis.
The clinical elements taken into account:
 Age > 50 years
 Increase in inflammatory indexes and systemic manifestations of disease
 Pain typically distributed to the tracks, with abrupt onset and generalized rigidity
 Drastic response to corticosteroids: an important criterion for the diagnosis is the
brilliant response to low-medium dosage of corticosteroids; this is an ex adjuvantibus
criteria
Biohumoral tests are indicative of systemic inflammation:
 ESR and PCR are always greatly increased but so are other acute phase proteins such as,
for example, a1-globulins, a2-globulins and fibrinogen.
 There may be sideripenic anemia, leukocytosis, platelets as a sign of inflammation.
 It is important to note that muscle enzymes have not increased despite the patient's
report of severe pain and difficulty in movement.
With regard to imaging and instrumental analysis
 Joint ultrasound usually shows a slight synovitis in the proximal joints, but above all
tendonitis and bursitis occur.
 You can also proceed with MRI and bone scintigraphy
 Muscle biopsy and electromyogram are not altered in the same way as muscle enzymes.

DIFFERENTIAL DIAGNOSIS
Differential diagnosis needs to be done with:
 Polymyositis: there is no difficulty of differential diagnosis because in this, being an
inflammatory pathology of the muscular fibre, a clear muscular damage manifests itself;
 Fibromyalgia: more benign pathology linked to the altered perception of pain; the
differential diagnosis is simple because in this case the inflammation indexes are not
increased and there is no organic alteration.

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  Myalgia in progress of viral infections
 Rheumatoid arthritis with senile onset: this sometimes begins with a polymalgic picture
so sometimes these symptoms can be the first manifestation of rheumatoid arthritis.
The AR with senile onset is usually not particularly aggressive (NdS: compared to
juvenile AR) and is rarely seropositive for rheumatoid factor and anti-citrulline
antibodies; it mainly involves the joints of the hands, but can also involve the feet, with
the usual tendency to deform.
 Spondyloarthritis in senile onset: same speech as AR but more rarely
 Pseudogrugus: more critical because it can also involve the C1-C2 latero-epistrophic
joint causing a picture of acute pain at cervical level that radiates to the shoulders so the
scapular cingulate could be involved; moreover in the pseudogrugus there is an increase
in the inflammatory indexes.
 Bilateral Periarthritis of the shoulders or cervical spine and shoulder arthrosis: in this
case, however, we do not have the increase in systemic inflammatory disease indices.
 Paraneoplastic syndrome (leukemias, lymphomas): it is the most important element to
keep in mind because rheumatic polymyalgia secondary to neoplastic forms is described
in a good percentage of cases. Let us remember that we are in an older population
group where the incidence of neoplasms is increasing.

THERAPY
Corticosteroids, particularly Prednisone, are the drugs of choice. They are taken with a
medium-low dosage (10-30 mg/day) in a single morning dose and very quickly, within a few
days, the symptoms disappear completely. Phlogosis indices that were particularly high also
normalize.
Once ESR normalization has been achieved, the steroid dose is reduced (by 5 mg/day every 10-
15 days) to the minimum dose necessary to keep the patient asymptomatic without altering the
inflammatory indexes.
In cases of resistance to therapy or in those where it is necessary to decrease the dose,
cortisonics are associated with the same drugs used in Rheumatoid Arthritis, first of all
Methotrexate.
In conjunction with the continued use of corticosteroids, particular attention should be paid to
monitoring certain aspects such as:
 Induction / aggravation of diabetes
 Osteoporosis
 Hypertension
 Gastrointestinal disorders
This clarification should be made
because the therapy, despite its
rapid effectiveness, should be
maintained chronically for at least 8
months, sometimes even longer up
to a few years. So, in general, you
have to keep in mind all the
possible side effects of cortisone.
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We must also always bear in mind that we are talking about elderly patients with comorbidities,
perhaps already osteoporosis and diabetes.
In order to limit the side effects some indications must be given to the patient
 Take the medicine in the morning, to respect the circadian cycle of the hormone by the
adrenal glands, and then on a full stomach after breakfast.
 Use the lowest detectable dosage and discontinue the medication at least once or twice
a week, as soon as this becomes possible.
 Drink plenty of water, reduce the consumption of sugar (including fruit), avoid eating
out of meals; generally follow a diet low in calories and rich in vegetables. Diet control
aims to reduce the risk of diabetes
 Check blood pressure
 Absolutely additional the patient with Calcium and Vitamin D; in these prolonged
therapies there is also the indication for anti-absorption drugs such as bisphosphonates.
This is an attempt to prevent osteoporosis.

IDIOPATHIC INFLAMMATORY
MYOPATHIES
The lesson starts with a review of the latest topics,
i.e. polymyositis and dermatomyositis, in the field
of inflammatory idiopathic diseases (IIM). This is a
heterogeneous group of acquired muscle diseases
characterized by an inflammatory process in the
skeletal muscles.
The classification is divided into 4 main classes:
 Polymyositis PM
 Dermatomyositis (DM)
 Necrotizing myositis (NAM)
 Myositis from bodies included (IBM)

There are other, less frequent pathologies that can be found in specific categories of patients:
 Juvenile myositis, under the age of 16 (DM>>PM)
 Myositis associated with cancer (DM>PM)
 Myositis associated with other connective tissue disease (CTD) (DM<PM)

The pathogenesis and histological

picture of polymyositis, including body
myositis and dermatomyositis are
different.
In PM the biological target is the muscle
fibre (the lymphocytes penetrate inside
the fibre itself) while in DM the

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inflammatory infiltrate is peripheral, around the vessels, indicating that the biological target in
this case is the blood vessel.

Clinical manifestations are expected:

 Muscle engagement with hypotonia, hypostenia, muscle asthenia: the muscles most
affected are the neck flexors or the proximal limbs, with the only exception of myositis
from included bodies affecting the distal muscles.
 In the pulmonary area:
o Respiratory muscle engagement with restrictive respiratory failure
o Pharyngeal interest with difficulty in swallowing and possible development of
ingestis pneumonia
o Commitment to the crevice, as in all other connective tissue, with chronic
interstitial pneumonia.
The symptoms and signs:
 Pathognomonic are:
o The papules of Gottron and the Gottron sign
 Characteristic are:
o Rush heliotropic on the upper eyelid surface
o Purplish erythematous areas, symmetrical in the photo-exposed areas (interface
dermatitis, similar to that observable in lupus)
o Periungueal teleangectasias, dystrophic cuticles
 Compatible (outcome of the inflammatory process) are:
o Poichilodermatomyositis
o Chalcinosis (may be pseudotumoral, as observed in other conditions such as
scleroderma)

Spectrum of clinical manifestations of DM:

 DM sine dermatitis: muscle effort and histopathological characteristics of DM without
having a skin picture.
 Classic form: both the skin and muscular effort are present and variably distributed.
 Hypomyopathic forms
 Amyopathic forms

(end of the review: if the teacher asked you in general about idiopathic inflammatory myopathies and you
answered with a similar summary "you would certainly get a good grade")

LABORATORY AND INSTRUMENTAL INVESTIGATIONS

The useful laboratory and instrumental investigations are:
 Increased muscle indexes of cytolysis (myocytolysis)
o Creatinphosphokinase CPK: is the main enzyme, if muscle asthenia and high CPK
are detected there is a likelihood of MII.
o Aldolasi

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 o AST: If AST>>ALT probably indicates muscle involvement (AST can increase by up
to twice as much as ALT). It is an important fact, if not considered it can lead to
invasive investigations such as a liver biopsy to look for the cause of increased
transaminases. If you have a picture with AST >> ALT you need to investigate the
CPK for the high probability of myopathy.
o LDH
o Myoglobin: is a non-enzymatic muscle protein. In case of muscular necrosis it can
be discharged into the circulation and when it is massive it causes myoglobinuria
and renal failure.
 Electromyographic alterations
o Increased add-on activity (muscle irritations)
o Potential alterations in action: polyphasic, small, short (loss of muscle fibre
tracts)
o Spontaneous activity of muscle fibres, fibrillation
This cortege of alterations is strictly neurological, but generally indicate a myopathy
situation in which the muscle is suffering.
Sometimes there is a mixed-
myneuropathic commitment. The latter
case is frequent in the subgroup of
myositis by bodies included. The latter
differs not only from the demographic
point of view, but also from the clinical
point of view: in fact, unlike DM or PM
necrotizing, the most affected muscles
are the distal ones, i.e. the muscles of
the hands, feet; often patients are men
>50 aa, who fall accidentally because
they lose the dorsiflexion movement of the foot. Patients with accidental falls 2-3 times
must immediately think of peripheral neuropathy or myositis (in this case from bodies
included).
 Muscle biopsy
o Evaluable: histopathological picture, infiltration and inflammatory distribution
(which allows to distinguish DM from PM), staining for MHC I or MAC. In
doubtful cases histology is direct.

The information that can be deduced from laboratory surveys is the basis for the classification
criteria of MIIs, developed many years ago. Currently they have been updated. These are very
complex criteria that are not taken into consideration; the one presented is simpler and more
meaningful.

Until recently these elements were guidelines for the classification and diagnosis of disease;
more recently the ICM laboratory has been enriched with other useful elements, especially to

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differentiate ICM from other myopathies, responsible for muscle hypostenia and increased CPK,
such as:
 Toxic myopathies: alcohol, medication (statins can give myalgia and actual myopathy)
 Endocrine Myopathy (Hyper/Pothyroidism)
 Metabolic myopathy
 Mitochondrial Myopathies
 Muscular dystrophies: normally they are non inflammatory myopathies but some of
them can also have an inflammatory streak and manifest themselves with increased
CPK, entering into differential diagnosis. Muscle dystrophies occur mainly in children but
there are some forms that can occur in adults such as dyspherline or myopathies of the
caterpillars.
 Infectious miosis
 Neurological neuropathy/syndrome. Myositis from included bodies, affecting the distal
muscles, enters into differential diagnosis with neurological pathologies (myopathic
myopathic streaks with increased CPK may also be present in neurological pathologies
as a symptom of muscle suffering).
 Paraneoplastic syndrome
 Other connective tissue disorders
 Miscellany: amyloidosis and sarcoidosis

The new investigations that have entered the clinical routine are:
 MRI muscle
 Muscle ultrasonography
 Specific myositis antibodies and myositis specific and myositis associated with you
MRI
It's an examination that's part of the diagnostic work up routine.
 In the T1 weighted sequences, hyperintensity indicates adipose substitution, therefore a
non-active picture: it manifests itself in the image with areas of greater clarity. The
weighed T1 sequences allow a better view of the anatomy of the muscle.
 In T2 STIR sequences with fat subtraction, hyperintensity demonstrates muscle oedema,
the presence of water. T2 sequences are less anatomically clear but visualize well the
inflammatory activity of the disease.

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MRI is useful in early stages to assess muscle involvement and as a guide for biopsy; it may be
useful in cases where the patient has muscle hyposthenia, but it is not possible to distinguish
whether it is due to disease activity or the outcome of a chronic disease. If there is oedema and
inflammation, the picture is active and should be treated; if there is only fibrotic involvement
(chronic involvement), the picture should not be treated with immunosuppressants and
cortisone because it is useless (the same reasoning made for glomerulonephritis, such as gn.
lupica: in the active phase of the disease,
immunosuppressive treatment is done; in the
chronic phase, with sclerosis already occurred,
there is no rationality in treating it).

ULTRASONOGRAPHY
In expert hands it provides very useful
information.
 Hyperecogenicity is present in the case
of fibrotic outcome or fibroadipose
substitution (chronic process).
 Hypoecogenicity is a sign of acute
inflammation.
The US is certainly an inexpensive but difficult
examination because it is a dependent operator; MRI is more laborious but less dependent
operator.
AUTOANTIBODIES IN MYOSITIS (60-80%)
In recent years they have acquired considerable importance: there is even talk of classifying
diseases no longer on clinical-histological evidence (as is currently done), but to use a clinical-
serological criterion. Serology is less invasive than biopsy, so if these antibodies would allow
with good accuracy to predict the histopathological picture you could avoid doing histology,
and do only serology. They exist:
 Specific myositis antibodies (they are NOT specific muscle, but specific myositis,
directed against cellular constituents common to cells, not only concerning the muscle
cell):
o Anti-Mi2
o Anti-SRP (anti-signal recognition particle)
o Anti-aminoacyl tRNA synthetase
 These three are the most important, to know absolutely.
o Anti TIF 1 (biomarker
associated with neoplasia)
o Anti-NXP2 (associated with a
form of dermatomyositis,
rather severe; a possible
association with neoplasms
discussed)

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 o Anti-MDA5 (it is associated with amyopathic dermatomyositis and especially
with very severe acute interstitial pneumonia that quickly leads to exitus)
 These are more
recently identified
but already entered
into clinical practice
and dosed in
central laboratories
and other
peripheral
hospitals.

 Associated myositis antibodies

(both in patients with IMM but
also in other connective tissue and
overlap syndrome)
o Anti- PM/Scl (overlap with
scleroderma)
o Anti-Ro/SSA (antibody present in various connective tissue, including
undifferentiated. Responsible for neonatal lupus. It is often the subject of a
QUESTION FOR EXAMINATION!!)
o Anti-U1 snRNP (overlap syndrome called mixed connectivitis)
o Anti-Ku (p70/p80) (overlap shape)

Clinical significance:
 Anti-Mi2: dermatomyositis (skin rush), acute onset but good prognosis, response to
therapy. They're usually young patients.
 Anti-SRP: severe polymyositis, necrotizing myopathy, acute onset and resistant to
steroid therapy; cardiac commitment. Poor inflammatory infiltrate, consisting mainly of
macrophages, with important muscle necrosis. Clinically acute form, with very high CPK
values.
 Anti tRNA synthetase: antibodies against enzymes that catalyze the union between
each amino acid and its transport RNA.
o There are at least 9 autoantibodies, but the best known and dosed is the anti-
istidiltRNA synthetase (Jo1). This antibody, along with others, is associated with
an overlap anti-synthetic clinical syndrome (Jo1 antibody syndrome)
characterized by:
 Myositis (histopathologically similar to PM)
 Arthritis (non-erosive)
 Raynaud's phenomenon (very common in connective tissue)
 Pulmonary Fibrosis
 Mechanical hands (hyperkeratosis of the fingertips in patients who are
not mechanical and therefore have no physiological reason for the
hyperproliferative process)
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  Poor response to therapy.

CANCER FREQUENCY IN POLYDERMATOMYOSITIS AND POLYMYOSITIS

In a patient with MII it is always necessary to suspect the presence of a neoplasm, perhaps
occult, and therefore must be investigated in this sense. DM presents a higher risk than PM.

Screening for occult neoplasms involves a very wide range of tests to be performed, to be
chosen according to the risk of the presence of the neoplasm.
 If the risk is high: total body CT, PET/TC
 If the risk is moderate: Enlarged abdominal ultrasound, chest x-ray
Neoplasms are mainly solid neoplasms: in this case, there is a difference compared to Sjögren's
syndrome or other connective tissue, which more often give tumors of the lymphoproliferative
system.

MII THERAPY
 Cortisone: glucocorticoids are the first therapeutic step. Some patients respond very
well and then it will be possible to reduce the dosage quickly afterwards. In others the
response is less brilliant: an immunosuppressant is inserted instead of continuing with
very high dosages of
cortisone.
 Immunosuppressants /
immunomodulants
o Methotrexate: first
choice as for
rheumatoid arthritis,
among
immunosuppressants
is the one with the
highest anti-
inflammatory activity.
o Azathioprine
o Mycophenolate mofetil
o Cyclosporine A
o Cyclophosphamide: used in resistant cases.
In patients with MII when choosing immunosuppressant therapy there may be some
doubt depending on the pathology the patient has, particularly if the patient has only
myositis or also chronic interstitial pneumonia. Methotrexate is excellent for myosysitis,
but it can give pulmonary interstitiopathy on an allergic basis: if the patient also has a
previous interstitiopathy, methotrexate can be risky because hypersensitivity
interstitiopathy will mask an even more difficult picture to interpret. In these cases it will
be more appropriate to use cyclophosphamide or mycophenthalate, which have an anti-
fibrous effect.
 Intravenous immunoglobulin (in cases resistant to standard cortisone +
immunosuppressant)

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  Biological drugs (Rituximab, Abatacept
used off-label)
 Rehabilitation therapy: must be started
early to prevent muscle contractures due
to inactivity. Sometimes patients in severe
and acute forms cannot move any muscle
and are clinically confused with ALS. If
treated properly, unlike ALS, patients can
improve. In the advanced stages it is used
for muscle strengthening: once the
inflammation is resolved, the muscle
remains atrophic or hypotrophic and needs to be exercised.

In the case of skin involvement:

 Antimalarial drugs (Chloroquine, Hydroxychloroquine): they are the pivotal therapy of
lupus, they are used in the skin manifestations of DM which can resemble lupus for
interface dermatitis and photosensitivity.
 Topical therapy (Cortisone, Tacrolimus, Photoprotectors) also used in lupus.

SJÖGREN SYNDROME
Sjogren's syndrome is defined as a chronic autoimmune epithelitis, characterized by infiltrated
lymphocytes at the level of the exocrine glands (all of them are affected, the most affected are
the tear and salivary glands).
It is possible to make a good parallelism with autoimmune thyroiditis because they have a
similar pathogenetic mechanism. In addition, autoimmune thyroiditis is very much associated
with autoimmune rheumatic diseases such as rheumatoid arthritis and connective tissue.
Autoimmune thyroiditis presents a lymphocytic infiltrate of the thyroid endocrine gland, which
destroys the gland and causes the thyroid hormones to disappear. The therapy of the pathology
involves the administration of replacement hormones only at the time of total destruction of
the gland. Sjögren's syndrome is very similar and involves an inflammatory lymphocytic
infiltrate of the exocrine glands, which therefore no longer produce their secretion: dry eyes
and mouth are the resulting symptoms (depending on the gland involved, the symptomatology
varies).
The difference between the two syndromes is not only the location of the inflammatory
infiltrate (exocrine or endocrine glands), but also the extent of the disease: Sjögren is a systemic
disease and can involve other organs or viscera besides the exocrine glands.
EPIDEMIOLOGY
 From an epidemiological point of view it is not very rare: the frequency is superimposed
on rheumatoid arthritis, although it is probably overestimated because not all the
causes of eye and oral dryness are attributable to Sjögren's syndrome, but may be due
to other different causes. The prevalence can also be overestimated.
 Distribution: the ratio women:men is 9:1

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  Age of onset: >40 years (Lupus begins at a younger age)
 Sjögren's syndrome
o Primary, insulated (HLA DR3) 40%
o Associated with other autoimmune diseases, overlap 60% (it is the one most
frequently associated with other connective tissue diseases).

PATHOGENESIS
From a pathogenetic point of view it follows the typical autoimmune processes.
1. There is a hypothetical environmental trigger, often viral.
2. The trigger induces the stimulation of both epithelial cells and dental cells.
3. Dendritic cells, especially plasmocytoids, produce INF α (type 1) and IL-12.
4. IL-12 stimulates both NK cells and Th1 lymphocytes, which in turn can produce INFγ
(type two).
5. Interferons α and γ can stimulate the
BAFF
a. Belimumab is the monoclonal
antibody used in lupus directed
against BLyS, B Lymphocyte
Stimulator, alternatively called
BAFF, B Activating Factor: it is
the same cytokine, which
stimulates lymphocytic B
proliferation.
b. At the level of the gland, the
expansion of B lymphocytes
occurs, first polyclonal, then monoclonal.
As a consequence of this clonal expansion,
the risk of developing lymphoproliferative
disease rises in patients with S. di Sjögren's disease.
6. In the presence of this hyperstimulation of the immune system (and humoral response)
and in the presence of epithelial damage there is release of autoantigens, specific
autoantigen response and formation of immune complexes that stimulate:
a. Plasmocytoid cells to produce more INF (hyperstimulation picture)
b. Formation of additional specific autoantibodies (anti-SSA, anti-SSB, rheumatoid
factor).
i. Rheumatoid factor is an autoantibody directed against a human IgG,
more frequent in patients with Sjögren's syndrome than in patients with
rheumatoid arthritis.

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CLINICAL MANIFESTATIONS
The main clinical manifestations are
borne by the exocrine glands: the
most affected are the glands of the
eye and oral mucosa with dryness of
the mucous membranes called
xerophthalmia and xerostomia
respectively.

Extra glandular manifestations

include, on the other hand:
 Arthralgia-arthritis joint
involvement
 Raynaud's phenomenon
present in all the connective
tissue
 Interstitial pneumonia: there
may be a NSIP (Non Specific Interstitial Pneumonia, typical of all connective tissue) or a
LIP (Lymphocytic interstitial pneumonia) pattern, the latter typical of Sjögren's
syndrome, in which lymphocytes not only infiltrate the exocrine glands but also infiltrate
the interstice of the lung. Keep in mind that in other connective tissue the typical
pattern is NSIP with the exception of rheumatoid arthritis which has a typical UIP
pattern.
 Renal interstitial nephritis due to lymphocytic infiltrate with tubolopathy. There may be
renal tubular acidosis, determined by tubulopathy, or neurogenic diabetes insipidus.
 Membranous or proliferative membranous glomerulonephritis (rarer case).
 Small vessels vasculitis that can affect both the nervous system and the skin. At the skin
level there is a different picture of palpable purpura compared to thrombocytopenic
purpura, or in more serious cases where the affected vessels are larger there are
manifestations of vasculitic urticaria which is different from allergic urticaria because
the pompoms in this case last longer (1-2 days) and give pain and burning rather than
itching.
 Multiple mononeuritis from involvement of SNP vasa nervorum. CNS involvement is
rare.

THE SICCA SYNDROME

Sicca syndrome occurs mainly in the eye with xerophthalmia and in the oral mucosa with
xerostomia.
Eye symptoms:
- Feeling of dryness or xerophthalmia
- Foreign body sensation or "sand in the eyes"...
- There may be photophobia
Oral symptoms:
- Dry mouth or xerostomia
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 - Difficulty swallowing especially for dry food
- Early and widespread caries
- Difficulties with prolonged speech
- Taste alterations.
Symptoms of exocrine glands other than tear and
salivary glands:
- Vaginals: dryness and dyspareunia
- Respiratory paths: dryness of the nasal mucous
membranes, trachea, bronchi, oropharynx and
larynx. You can have endonasal crustiness,
nosebleeds, alterations of the sense of smell, if
the lower respiratory tract is affected coughing and bronchitis.
- An involvement of the stomach glands can cause atrophic chronic gastritis which can
give dyspepsia
- At the skin level in case of involvement of the sweat glands there may be a skin xerosis
that causes itching.

Sicca syndrome can be linked to causes other than Sjögren's syndrome as can also be a
functional disorder reported by the patient and therefore
it must be documented whether or not dryness is present
at the level of these glands.

EYE DRYNESS TEST




 Schirmer test: Apply an absorbent
map to the fornix of the eye and
wait five minutes. If the absorbent
paper wets less than 5 mm in 5
minutes the test indicates the
presence of hypolacrimation, if the
absorbent paper wets more than 5
mm the test can be considered
normal.
 Method with dyes, such as Rose Bengal and Lissamine Green: These are used to
assess whether areas of corneal distress are present.
Rose Bengal and Lissamine Green are dyes that dye damaged cells at the corneal level,
highlighting hyposecretion. Positivity to the dye test is validated if the score, according to Van
Bijstervald's scoring system, is greater than or equal to 4.

TEST FOR SALIVARY DRYNESS

It is more difficult to assess saliva secretion, various tests are used:

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  Scialometry: it is a fairly invasive
functional test that is mainly
used in randomized trials but
little in clinical practice. The test
involves intubation of the ducts
of the salivary glands (Stenone's
duct for the parotid) and the
secretion is measured in basal
condition and after stimulation.
It's not an easy test to run so they're used
more today:
 Salivary glands ultrasound: it is a frequently used examination. You can see parotids
and minor salivary glands. The ultrasound picture is characterized by
inhomogeneous ultrasound density and glandular volume reduction, with
characteristics similar to those seen in autoimmune thyroiditis.
 Salivary glands biopsy: it is a simple procedure that can also be performed on an
outpatient basis by a rheumatologist. A cut
is made on the outside of the lip with a
scalpel and then the minor salivary glands
are extracted. It is an invasive test and
sometimes the patient after the operation
may report a feeling of paresthesia that can
last a long time. It allows to see the
histology or the lymphocyte infiltrate
around the ducts and any lymphocyte
aggregates where the larger ones may have a germination centre.

SIEROLOGY
The characteristic serological picture presents:
-Leucopenia
-Increase of ESR
-Hypergammaglobulinemia polyclonal
-• ANA positivity
-• Positivity of the Rheumatoid Factor which is frequently detected in Sjögren's syndrome
-Anti-Ro/SSA
-Anti-La/SSB

One can make a definite diagnosis of Sjogren's syndrome in case there is Sicca syndrome
associated with a characteristic serological picture. If the serological picture is missing,
however, the diagnosis may be more uncertain. The literature on this subject reports conflicting
opinions: those who argue that in the absence of serology a diagnosis cannot be reached and
those who argue that in the presence of a histological predisposing picture one can still speak
of Sjögren.

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In all cases it is certain that in the presence of such a characteristic histological picture it may be
useless to biopsy the salivary glands.
However, biopsy has its role and is useful since Sjögren's syndrome is frequently associated
with the development of neoplasms, especially B lymphomas (especially MALTomas).
The risk of developing lymphoma in these patients is 5 to 44 times higher than in the general
population (recent studies show a probability closer to 5 than 44).
Lymphomas are mostly extranodal. As far as localization is concerned, in 58% of cases they are
located at the level of the salivary glands and in 13% at the level of the stomach.
There are clinical risk factors that need to be monitored, that is:
 Persistent parotid tumefaction
 Splenomegaly and/or lymphadenomegaly
 Vasculitis of small vessels, both skin and Peripheral Nervous System
 Presence of a monoclonal electrophoresis component
 Presence of cryoglobulinemias
 Reduction of complement factor C4
 Similar germination centre structures at the level of the minor salivary glands at biopsy
examination. This is why it seems important to perform a biopsy anyway, regardless of
serology, particularly in young patients.

CRITERIA FOR CLASSIFICATION

They're considering it:
 Eye symptoms
 Oral symptoms
 Eye tests: Schirmer test and Rose Bengal
test
 Histological alterations of salivary glands
 Some Salivary Tests: Salivary Scintigraphy,
Parotideal Scialography, Unstimulated
Scialometry
 Positivity Anti-Ro (SS-A) and/or Anti- La
(SS-B) Antibodies

In order to make a diagnosis of primitive Sjögren's syndrome, it must be excluded that there are
no other associated connective tissue.
Four of these criteria are enough to define a patient with Sjogren's syndrome.
However, these are classification criteria and not diagnosis. So they have a high performance if
an advanced stage of disease is assessed, while they have poorer results in the case of early
stages of disease.

SYNDROME SICK
There are numerous conditions that can be considered responsible for a sicca syndrome.
Among them, they remember:
 Weathering and environmental agents (very dry and poorly humidified environment)

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 Some drugs such as anticholinergics, anxiolytics, antidepressants, beta-blockers, diuretics,
especially in the elderly, since depending on age there may already be atrophy of the
exocrine glands.
 Patient with previous cancer of the neck region who underwent radiotherapy may have
developed salivary gland atrophy and xerostomia;
 Viral infections such as HCV, AIDS or local oral and conjunctiva infections (blepharitis);
 Lymphomas
 Sarcoidosis
 GvHD
 Diabetes
 Recently identified IgG4 syndrome. This syndrome is characterized by the presence of an
infiltrate of plasma cells expressing on their IgG4 surface. These often increase in the
peripheral blood (but it does not always happen), to make a diagnosis it is useful to use
histological or histopathological examination that shows the presence of infiltrate (to make
a diagnosis the percentage of infiltration of the organ/tissue must be more than 40% of
plasma cells expressing IgG1) and the presence of fibrosis.
Clinical pictures associated with this syndrome are:
 Infiltration of
the salivary
and tear
glands, once
called Mikulicz
syndrome.
 Frameworks of
fibrosis such as

retroperitoneal fibrosis, characteristic of the syndrome, and mediastinal fibrosis

 Periaortitis and periarteritis also features
 Riedel's thyroiditis is also associated with this syndrome...
 The syndrome is also often associated with autoimmune pancreatitis.

IgG4 syndrome responds very well to cortisone in most cases, especially in the early
stages of the disease. However, some cases may not respond, such as cases that are
treated too late.

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 This image presents a picture of Heerfordt's sarcoidosis
syndrome with parotid swelling (remember that sarcoidosis is a
potential cause of sicca syndrome).

Q: Can the alteration of the sweat glands affect the

thermoregulation process?
A: Yes, although other glands are mainly affected (lacrimal and
salivary) and therefore it is not one of the symptoms mainly
reported by the patient.

Q: Treatment of Sjögren's syndrome?

A: There are not many treatments from a medical point of view, the therapy is the symptomatic
one for which artificial tears are used for dry eyes while for oral dryness there are no equally
effective substitutes even if a pilocarpine therapy can be used. As far as medical therapy is
concerned, if there are visceral interests, immunosuppressants can be used, otherwise there is
no clear indication for the therapy, but in case of a characteristic serological picture, anti-
malarial drugs can be used.

Q: Risk associated with the use of immunosuppressants in the treatment of a syndrome that
may give rise to neoplasms?
Immunosuppressants are dangerous drugs, but they must be used as these patients may
experience even very serious manifestations of the disease.

ANTIPHOSPHOLIPID ANTIBODY SYNDROME

Antiphospholipid-APL antibody syndrome is a transversal syndrome of rheumatological interest
as it was first described in Lupus patients.
This syndrome is characterized by the positivity to antiphospholipid antibodies directed against
proteins associated with phospholipids and in particular 2 Glycoprotein 1.
APL are the main risk factors for thromboembolic events in patients with autoimmune
rheumatic diseases and also in the general population especially in young subjects (in fact there
is a primitive form of the syndrome not associated with other connective tissue). These
antibodies can be demonstrated by numerous tests (the first three are the main ones):
 Test for Lupus anticoagulant. It is a hemocoagulative test that results positive for Ab Anti-
phospholipids;
 Anti-cardiolipin antibody test;
 Test for Anti 2 Glycoprotein 1;
 Test for Ab Anti-Prothrombin
 Test for Ab Anti-ethanolamine

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 Test for Ab Anti-annexin
 Test for Ab Anti-phospholipids

The most important antigen in phospholipid antibodies syndrome is 2 Glycoprotein 1, a

polypeptide chain formed by 5 different domains. It is a circulating anticoagulant that exists in
two forms: one open and one circular, present in a circle in which the domain D5 and D1 are
bound. Under particular conditions, such as endothelium activation, there is exposure to

negatively charged amino acids such as phosphatidylserine, which allow the binding to the
endothelium of the glycoprotein that opens by exposing cryptic antigens present at D1 level. In
genetically predisposed subjects antibodies to 2 GP1 are formed that can bind to two
molecules of 2 GP1 and stimulate an effect depending on the tissue where the 2 GP1 is
attached. In fact, 2 GP1 complexed with autoantibody can adhere to various cell receptors
expressed on different cell types (in endothelium cells, monocytes, platelets, trophoblast cells,
deciduous cells, neurons, fibroblasts) as reported in the table.

The thrombotic event (very frequent) is precisely related to the binding of autoantibodies on
receptors present on monocytes, platelets and endothelial cells and that can induce a
prothrombotic cell phenotype. This, however, is not sufficient to trigger thrombosis or
thromboembolism but represents a risk factor (other risk factors that may add up are cigarette
smoke, hypercholesterolemia or predisposing genetic factors such as S and C protein

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polymorphisms). The thromboembolic event occurs when a second "hit" is added: a patient
immobilized by fracture with circulating antiphospholipid antibodies, a young woman with
antibodies taking oral contraceptives or in case of pregnancy.

The thrombotic (or internist) phenotype is the first clinical phenotype associated with this
syndrome and differs from the obstetrical phenotype due to the action of antibodies on the
placenta, in particular on trophoblast and decidua. Antibodies can bind these cells and induce a
prothrombotic phenotype and/or microthrombosis in the placental vessels which results in
intrauterine loss or complications during pregnancy.

ANTIPHOSPHOLIPID ANTIBODY SYNDROME

Like other syndromes in rheumatology (mixed connectivitis characterized by the anti U1RNP
antibody, the anti-synthetase syndrome) this syndrome is characterized by antiphospholipid
antibodies (aPL) that recognize proteins associated with phospholipids, the most important of
which is 2 Glycoprotein 1, a chain of 5 protein domains. The protein in circulation is present in
closed (circular) form, under certain conditions of endothelium activation it opens and
discovers cryptic domains, which in predisposed patients can lead to the formation of
antibodies. Antibodies linked to 2GPI can act on some receptors present on the surface of
endothelial cells, platelets, monocytes by mediating thrombophilic effects; they can also bind
syncytiotrophoblast and deciduous cells by mediating obstetrical alterations; they can also act
on other types of cells, such as neurons and fibroblasts by mediating other manifestations,
which are not considered as classification criteria.

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In the internal phenotype a thrombophilic state is created which, if precipitating factors occur
(second hit), causes the thrombotic event
The obstetric phenotype is due to alteration of the activity of deciduous and trophoblast cells
and thrombotic events at the placental level.

CRITERIA
In order to classify a patient as suffering from
antiphospholipid antibody syndrome we have two
clinical criteria and three laboratory criteria. The clinical
criteria are the presence of arterial or venous
thrombosis (i.e. the internal phenotype) and obstetrical
problems. The laboratory criteria are the tests to
demonstrate the presence of antibodies:
 Lupus Anticoagulant
 IgG and/or IgM anti-cardiolipin antibodies
 Anti-2 glycoprotein 1 IgG and/or IgM
antibodies.
The patient must have at least one clinical criterion and
at least one positive test to be classified as suffering from the syndrome.

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CLINICAL CRITERIA
Internalist phenotype: provides at least one
episode of arterial, venous or small circle
thrombosis in any district; thrombosis must be
confirmed by an imaging method, e.g. ecodoppler,
or histopathology (which must show signs of
thrombosis without signs of inflammation).
Clinical case: patient with positive for anti-nucleus
antibodies, facial erythema that suggested lupus.
However, on histological examination it turned out to be
a thrombosis with very little inflammatory infiltrate. With
the demonstration of positivity to all three tests for
antiphospholipid antibodies, it was classified as a
primitive antiphospholipid antibody syndrome, not
associated with lupus because it had no other
manifestations.

Obstetrical complications: one or more fetal deaths (loss

of the fetus after the tenth week, therefore late, with morphologically healthy fetus); or one or
more preterm births of morphologically normal
newborns during or before the 34th week for
eclampsia, severe preeclampsia, placental
insufficiency; or three consecutive miscarriages, i.e.
early fetal loss (before the tenth week), after
excluding hormonal or genetic causes.

In addition to these clinical manifestations typical of

internist and obstetric phenotypes, there are many
other possible manifestations that are not considered
classification criteria: they are frequently found in
patients, but do not allow them to be classified as
part of the disease. Among these we have
thrombocytopenia (very frequent); livedo
reticularis (skin manifestation that can be
a manifestation of vasculitis or
vascuolpatia, therefore inflammatory or
not, thrombotic or microthrombotic);
valve warts (Libman-Sachs encocarditis,
which may also be present in lupus
associated with antiphospholipid
antibodies); epilepsy (due to the
involvement of small vessels of the central
nervous system); nephropathy with

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modest proteinuria (histological examination does not see signs of glomerular inflammation, it
is an alteration of the tubules).

Livedo reticularis: erythematous rosette-like manifestations due to the involvement of the vase
from depth to surface. When the contour is not regular it is called livedo racemosa. In
phospholipid antibodies syndrome the acral form is more typical.

CATASTROPHIC ANTIPHOSPHOLIPID ANTIBODY SYNDROME

Catastrophic aPL syndrome presents a multi organ engagement (at
least 3 in a few days) on a microthrombotic basis with organ failure. It
is a severe and fattening form, with high mortality (50%). It is
precipitated by external factors such as infections, surgical maneuvers,
suspension of anticoagulants. May lead to respiratory failure due to
respiratory distress syndrome; formation of microthrombi in the heart
and CNS. The therapy must be rapid and involves plasmapheresis,
which eliminates antibodies and reduces the risk of further ischemic
events.

LABORATORY CRITERIA
We have three tests available: lupus
anticoagulant, cardiolipin antibodies of IgG or
IgM types at medium to high titer (more than
40 GPL) andanti-2 glycoprotein1 IgG or IgM
antibodies (they must be at a titer greater
than the 99th percentile for that laboratory).
To classify the patient it is not enough to have
a positive determination, you must have at
least two determinations after 12 weeks.

EPIDEMIOLOGY
The frequency of the syndrome is different
from the frequency of antibody positivity.
Antibodies to cardiolipin are present in 2-4% of the general population, 5-10% of children and
the elderly, 30-40% of patients with lupus (patients with connectivitis and polyclonal activation
of B lymphocytes).

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Lupus anticoagulant is much less
frequent, it is present in less than 1% of
the general population and in 15% of
patients with lupus. It is a higher risk
factor than anti cardiolipin, even when
present alone.
There are not many epidemiological
data from a 2002 study: 1000 patients
with antiphospholipid antibody
syndrome were collected at European
level, about half of them with primary
syndrome, half with secondary
syndrome to other connective tissue
(more frequently lupus).
Risk of developing thrombotic events:
 Subject without other
connective tissue diseases and
positive aPL antibodies: risk
<1% per year.
 Women with recurring fetal
losses, even without
thrombosis in the past: 10%
risk per year.
 Subject with a history of
venous thrombosis who has
discontinued anticoagulant
therapy: risk >10% per year.
Based on this observation, the
use of anticoagulant has been
recommended for a lifetime. It
must be borne in mind that
these are young patients, so the impact of the therapy is important, but this is based
on the high risk of thrombotic recurrence after suspension.
 If the patient has lupus the thrombophilic risk is higher, due to the presence of
nephrotic syndrome and general endothelial activation (2-5%).
A prospective study done in Padua on 100 patients showed a risk of 1% per year. The risk is
higher depending on the number of positive tests.
Those with triple positivity risk more. This observation
is especially true for the internalistic phenotype, for
the obstetric phenotype the proportionality of the risk
is less evident. Certainly triple positivity leads to a
higher risk of fetal loss, but this does not decrease
much with one or two positives.
PRIMARY PROPHYLAXIS

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If a subject has only antiphospholipid antibodies but no connective tissue, first of all it is
necessary to stratify the risk: then evaluate how many tests he is positive and at what level. The
patient should also be advised to avoid the modifiable risk factors: smoking, hypertension,
dyslipidemia, estroprogestin pill, obesity. The possible presence of genetic thrombophilia must
be assessed.
We have no data available regarding the primary prevention of abortion and obstetric
complications.
A randomized trial in antibody positive patients evaluated the effectiveness of cardioaspirin
prophylaxis compared to a placebo control group. The result showed that patients with
cardioaspirin showed more thrombotic events than those receiving placebo. It's an evidence-
based study the professor doesn't believe. Evidently the study was poorly designed by not
stratifying patients according to risk.
Positivity to the lupus anticoagulant test is the highest risk factor, high titers of anti cardiolipin
are also dangerous, IgG determine more risk than IgM; the persistence of positivity over time
must also be taken into account. A positive aPL should be carefully evaluated according to risk
in order to decide on a possible therapy: a patient with triple positivity should receive
antithrombotic prophylaxis (cardioaspirin). Cardioaspirin protects especially on the arterial side,
an arterial thrombosis is more dangerous than a venous one.

SECONDARY PROPHYLAXIS
Secondary prophylaxis concerns prophylaxis for patients who have already had thrombosis or
obstetric complications, it serves to prevent a future event of the same or another type.
If a patient has had a first venous event it is recommended to anticoagulate with a
dichumarolic, keeping an INR between 2 and 3. If he has had an arterial event, the INR should
be held between 3 and 4, or between 2 and 3 by combining a platelet antiplatelet.

137
If the patient has a recurrence of
a venous event despite warfarin,
the intensity of anticoagulation
should be increased, bringing
the INR between 3 and 4, or low
molecular weight heparin can be
used.
If the patient has had a
thromboembolic event but has
only one low titer positivity, he is
not treated for life but only for 6
months, then he is suspended.
So also in the case of an arterial
event but with single and low
titre positivity (this type of
positivity has little clinical
significance).
New oral anticoagulants were
studied, the most complete study was done on Rivaroxaban by Prof. Pengo. Subjects with triple
positivity were randomized between Rivaroxaban and dichumarolic: the study was suspended
because patients treated with Rivaroxaban had more thrombotic recurrences, especially on the
arterial side. The Rivaroxaban, in fact, protects mainly for events on the venous side and does
not protect on the arterial side. Therefore, patients cannot use the new oral anticoagulants but
must continue with dichumarolics.
The prophylaxis of fetal loss has been a very important achievement: without therapy, women
with this syndrome experience fetal loss in 70-80% of cases. With therapy, pregnancy failures
have become 20-30%.
Patients who have had a thrombosis are being treated with dichumarol: if they want to have a
pregnancy, the teratogenicity of dichumarol must be taken into account, which acts between
the sixth/week and eleventh week. As soon as the woman has a positive pregnancy test, she
switches to low molecular weight heparin (subcutaneous, twice a day). Add low-dose aspirin if
she had previously had fetal discharge. Warfarin can be summed up from the 14th week up to
the 35th week, it is not done often but it can be useful in case of very serious forms with a
tendency to thrombinate also with heparin.
If the patient has a certain obstetrical syndrome she will take cardioaspirin before conception
(it does not give problems during pregnancy), when she gets pregnant she will switch to low
molecular weight heparin, first to prophylactic dose and then therapeutic. After the birth you
have to continue to protect the patient for 6 weeks, because it is still a situation at risk.

Q: "During an internship, a diagnosis of antiphospholipid antibody negative syndrome was

made: is it possible to make a diagnosis in the absence of antibody positivity?
It is possible (or at least some people are convinced of it) that there are situations that are part
of the syndrome, with thrombosis and associated manifestations indicative of a characteristic
picture, but that have antibodies different from those we demonstrate with our tests (e.g. anti-

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prothrombin, antiphosphatidylcholine). It would therefore be a seronegative phospholipid
antibodies syndrome (similar to seronegative rheumatoid arthritis). The therapy is the same.
Q: "In a patient who is positive for antibodies but hasn't had an event yet, do I do prophylaxis
anyway?"
Yes, it's primary prophylaxis. In this case the patient does not fall within the classification
criteria because the clinical criteria are missing, but this does not exclude the possibility of
making a diagnosis: for example in the example treated in the previous question, the diagnosis
was made in the absence of antibody positivity. In the case of antibody positivity alone it is
difficult to make a diagnosis, because the diagnosis presupposes clinical manifestations;
however, it can be said that the patient has a thrombophilic risk and prophylaxis (cardioaspirin)
can be indicated if the risk is high, as in a triple positivity. It is reiterated that the classification
criteria are not used to make a diagnosis, but to include patients in studies with a unique
criterion that makes them comparable. The diagnosis is based on clinical judgment. For
example, a convincing positivity with thrombocytopenia (and perhaps a livedo reticularis)
makes it possible to make a diagnosis, but not to classify the patient as affected and therefore
include him/her in the studies.

SCLERODERMY
The term scleroderma identifies some morbid forms characterized by fibrosis, i.e. accumulation
of collagen, in the skin and internal organs (scleroderma means hardening of the dermis).
Scleroderma is a less frequent form compared to lupus, but more severe. Classification of
scleroderma syndromes (to be learned correctly, the professor says that 90% of students fail on
this question):
 Circumscribed scleroderma (involves only the skin, dermatological expertise):
 Linear;
 Morphea (plaque or generalized);
 Systemic sclerosis (involves skin, locomotor system and viscera), classified on the basis
of the extent of skin involvement:
 Limited cutaneous (affects the distal parts of the limbs and the face);
 Diffuse cutaneous (affects the whole body);
 Scleroderma associated with other connective tissue (overlap syndromes);
 Scleroderma induced by toxic substances:
 Vinyl chloride;
 Organic solvents (benzene, toluene);
 Silicone (breast implants);
 Drugs (bleomycin, pentazocin).

CIRCUMSCRIBED SCLERODERMA
Circumscribed scleroderma affects only the skin and can be distinguished in:
 Plaque morphea: patches of skin
sclerosis

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  Generalized morphea, which, unlike diffuse systemic sclerosis, does not affect the
hands, feet and face, affecting only the limbs and trunk.
 Linear shape, which, if it hits the face, determines lesions called sabre-shaped.
The circumscribed forms are of dermatological relevance and can be treated with
corticosteroids or immunosuppressants.
Eosinophilic fasciitis is not a real scleroderma, but it becomes part of the schlerodermic-like
forms because the inflammation of the muscle fascia causes a hardening of the skin.

SYSTEMIC SCLEROSIS
Systemic sclerosis is less frequent than lupus, Sjogren's syndrome or rheumatoid arthritis; it has
a frequency more similar to that of idiopathic inflammatory myopathies. It has a prevalence of
5-30/100.000 people and an incidence of 10-20/1.000.000 people. It has been recognised as a
rare disease and, therefore, provides the right to an exemption for affected patients.
The age of onset is between the 3rd and 5th decade, affects women most frequently (ratio of 3-
9:1) and survival is 60% at 5 years, a significantly reduced survival.
Systemic sclerosis is divided into limited form and diffuse form exclusively on the basis of the
extent of skin involvement: the limited form is acrolocalized, while the diffuse form involves the
whole body. The limited shape is more frequent than the widespread one, with a 3:1/4:1 ratio.
Systemic sclerosis is characterized by involvement:
 cutaneous (scleroderma);
 vascular: small vessels are one of the main targets of the disease;
 musculoskeletal (muscular-articular-tendinous);
 visceral (digestive, lung, heart, kidney).

PATHOGENESIS
The vascular damage represents the primum movens: the Raynaud's phenomenon, which
causes vasospastic manifestations in the peripheral circulation with perfusion ischemia, is
present in all connective tissue,
in particular in all scleroderma;
it is a particularly serious
phenomenon that can occur not
only at the peripheral
circulation level, but also at the
visceral level. These ischemic
phenomena can induce
oxidative stress and therefore
endothelial damage at the
vascular level. As a result of this
endothelial damage there is a
reduction in vasodilator
substances (such as
prostacyclines and NO), while
there is an increase in
vasoconstrictive substances

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(such as Endothelin-1 and Thromboxano-A2). This leads to ischemia and activation of free
oxygen radicals, resulting in oxidative stress that causes platelet and immune system activation
(B and T lymphocytes). Therefore, as a consequence of endothelial damage, platelet and
immune system activation there is stimulation of fibroblasts, which produce collagen fibers
causing fibrosis. With regard to autoimmunity, the B cells that are activated produce different
types of antibodies, some of them with a pathogenic role. An example is the anti-PDGFR
autoantibody, which, by binding to this receptor, stimulates the transcription of genes coding
for collagen and TGFβ, with a profibrotic effect.
From a clinical point of view there are two phases of the disease:
 prescleroderma
 disease

PRESCLERODERMA
In the prescleroderma phase, which can last for many years (later the professor contradicts
himself by claiming that this phase lasts little for fast progression), the patient presents:
 Raynaud's phenomenon, which can occur in all its phases or
only one of them (ischemic, cyanotic, hyperemic phase) and
can involve one or more fingers, usually triggered by cold but
sometimes also by emotions;
 Diffuse tumefaction of the hands (puffy hands) and face,
expression of oedema that may precede the fibrotic phase;
 Esophageal interest (distal hypotonia, altered peristalsis and
potential gastroesophageal reflux).
In the case of a patient with Raynaud's phenomenon, two specific tests are performed:
 Anti-nucleus antibody (ANA) assay: in case of positive ANA assay, a second level test is
performed, i.e. native and anti-ENA antibody assay.
 Capillaroscopy
Capillaroscopy (right, non-pathological nail beds) consists in the
analysis of the nail bed by means of a microscope, through which
different parameters are evaluated:
 visibility;
 morphology and orientation of the loops;
 capillary density;
 length of the loops;
 diameter of the loops.
The abnormalities that can be found are:
 Tortuosity of the loops, not necessarily an
expression of pathology and found in
numerous situations as a phenomenon of
primitive Raynaud, undifferentiated
connective tissue, acrosciosis or SLE;
 Ectasias and microaneurisms;
 Megacapillari;

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  Avascular areas;
 Neoangiogenesis;
 Microhemorrhages.
If both tests are negative, the presence of
connectivitis can be ruled out. If only one of them
tests positive, the patient should be monitored.
The positivity of both, even in the absence of
other signs and symptoms, makes it possible to
strongly suspect the presence of the pathology.

DISEASE
In the second phase, that of concomitant
scleroderma, the patient presents:
 Skin sclerosis;
 Raynaud's phenomenon, with
necrotic lesions and reabsorption
of the distal phalanges;
 Teleangectasias on face (perioral
species), neck and upper chest;
 Soft part calcifications;
 Arthralgias (rarely arthritis) and
tendonitis (tendon roars);
 Lung: pleurisy and chronic
interstitial pneumonia;
 Kidney: malignant hypertension
with renal failure due to
pathology of intralobular arteries
and efferent arterioles (nephro-
vascular hypertension);
 Digestive system:
 oesophagus: altered peristalsis, dilation, slow transit, reflux esophagitis;
 stomach, duodenum, fasting: contour stiffness, hypomotility, dilation, bacterial
growth;
 colon: rigid, dilated, pseudodiverticular;
 Heart: cardiomegaly, pulmonary hypertension.

SKIN SCLEROSIS
Characteristics of skin sclerosis:
 thick, rigid, inelastic, adherent to deep structures,
skin dyschromia;
 thin, atrophic, shiny skin;
 disappearance of wrinkles, reduction of
perspiration and skin attachments.

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Typical sites of skin sclerosis are the fingers (sclerodactyly), face, forearms and trunk.
Scleroderma facies has the following characteristics:
 friend;
 forehead flattened;
 microchemistry;
 microstomy;
 perioral folds with radial arrangement;
 sharp nose;
 telangiectasia.
The scleroderma hand is, instead, characterized by:
 pitting scares, puncture wounds on fingertips;
 rounding off the fingertips;
 contracture in flexion;
 shortening the distal phalanges;
 periungueal necrosis.

Ischemia caused by Raynaud's phenomenon can cause periungueal necrosis (below image on
the left) or, in more serious cases, amputation of the distal phalanges (below image on the
right).

CALCIFICATION OF SOFT PARTS

The calcifications of the soft parts, also
present in idiopathic inflammatory
myopathies, are caused by
accumulations of carbonate and
calcium phosphate; they can also
fistulize. This situation can very rarely
evolve into universal calcinosis, which
consists in the formation of large
calcifications in different parts of the
body; there is no therapy, the only
solution is the surgical removal of the
masses.

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POLMON
Scleroderma is one of those diseases in which
chronic interstitial pneumonia is most frequently
observed. In most cases it is NSIP (nonspecific
interstitial pneumonia), more rarely UIP (usual
interstitial pneumonia), which has a much worse
prognosis.

RENE
With regard to renal involvement, systemic
sclerosis can cause renal scleroderma, obliterative vasculopathy due to hyperplasia of muscle
cells at the level of interlobular archerioles and afferent to renal glomerules with consequent
activation of the renin-angiotensin system. This results in severe malignant hypertension
associated with a rapid increase in creatininemia and/or microangiopathic hemolytic anemia.
This picture may lead to hemodynamic consequences such as heart failure, cerebrovascular
accidents, acute pulmonary edema and hypertensive retinopathy.
Scleroderma kidney crisis is associated with a specific scleroderma antibody, the anti-RNA
polymerase III, and is treated with ACE-inhibitor, a drug usually not used in renal failure.
The professor very often asks the examination which are the rheumatological pathologies with
renal involvement, i.e. SLE (glomerulonephritis lupica), scleroderma (scleroderma renal crisis),
idiopathic inflammatory myopathies (possible renal failure due to massive myoglobinuria),
Sjogren's syndrome (interstitial nephropathy due to lymphocyte accumulation).

DIGESTIVE SYSTEM
At the level of the digestive system, the oesophagus, stomach and intestines can be site of:
 Esophageal dilation resulting in
dysphagia (affecting the lower
third of the oesophagus);
 Gastroesophageal reflux disorder;
 Dyspeptic disorders (nausea, early
satiety);
 Pseudo- intestinal obstruction;
 Diarrhea;
 Malabsorption;
 Fecal incontinence;
 Pseudo-diverticals.

HEART
Cardiac scleroderma can cause scleroderma:
 restrictive myocardial disease with:
 conduction disorders,
 arrhythmias (mainly ventricular),
144
  heart failure;
 pericarditis;
 pulmonary hypertension.
Pulmonary hypertension is one of the most formidable manifestations of scleroderma. Also in
this case it is an obliterating vasculopathy of the pulmonary arterioles which causes an increase
in pulmonary resistance, with consequent decompensation of the right heart. It can lead to
arrhythmias and sudden death.
Definition of pulmonary hypertension:
 increase in mean pressure at rest >25 mmHg, under stress >30 mmHg with normal left
atrial pressure (PCWP <15 mmHg);
 calculated systolic pressure increase >35-40 mmHg, transmitral gradient velocity >3.4
m/s.
Pulmonary hypertension in scleroderma involves 5-50% of patients and, in the absence of
treatment, is characterized by a mortality rate of 50% to one year.
In scleroderma there can be, therefore, two types of pulmonary hypertension: a post-capillary
caused by chronic interstitial pneumonia and a pre-capillary, very similar to a primitive
pulmonary hypertension, due to obliterative vasculopathy of the pulmonary arterioles.

LABORATORY TESTS
 Increased ESR (less PCR) in active phase;
 Hypergammaglobulinemia;
 Positivity of rheumatoid factor (20-30% of cases);
 ANA positivity (98% of cases);
 centromeric pattern: anti-centromeric (already visible at immunofluorescence),
 pattern speckled: anti-topoisomerasi/Scl70,
 nucleolar pattern: anti-nucleolus, anti-RNA polymerase III.
The anti-RNA polymerase III antibody is associated with scleroderma renal crisis and, according
to recent studies, also with ongoing scleroderma neoplasms. Both anti-Scl70 and anti-RNA
polymerase III are associated with diffuse skin scleroderma, anti-centromere is associated with
limited skin scleroderma.

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CLASSIFICATION CRITERIA (ACR/EULAR 2013)
For the diagnosis of scleroderma,
the patient must achieve at least
a score of 9. It should be noted
that proximal skin sclerosis of the
metacarpophalangeal joints is, on
its own, sufficient for the
diagnosis of systemic sclerosis
(circumscribed scleroderma can
be excluded because the latter
does not affect the hands).
The professor states that these
are criteria of classification and
not of diagnosis, despite
contradicting what has just been
said above.

DIFFERENCES BETWEEN LIMITED AND DIFFUSE SKIN SCLEROSIS

Apart from the extent of skin involvement, there are differences between these two forms in
the frequency of involvement of the different
viscera. As for the limited form, calcinosis,
telangiectasia and pre-capillary pulmonary
hypertension are more frequent. On the other
hand, arthralgia, myopathy, pulmonary fibrosis
(post-capillary pulmonary hypertension), heart
failure and renal failure are more frequent.
The biggest difference between the two forms
is, however, the different speed progression of
the disease: for the limited form the
progression is very slow (even tens of years
after the appearance of the Raynaud
phenomenon), while for the widespread form
the progression is much faster (a few months
after the appearance of the Raynaud
phenomenon).

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 Trick question: A patient
has scleroderma with
distal limb and facial
involvement and has
anti-Scl70 antibody, is it
a diffuse or limited form?
It is a limited form
because the only thing
that matters is the skin
extension. What we
cannot know is whether
this limited form will
evolve into a diffuse form
due to the presence of
the anti-Scl70 antibody.
Survival is better in the
limited form than in the
diffuse form; even in the diffuse forms survival depends very much on organ effort: the greater
the number of organs involved, the worse the prognosis.

CIRCUMSCRIBED SCLERODERMA
The professor shows a series of photographs of the various types of circumscribed scleroderma.

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THERAPY
Scleroderma therapy is less satisfactory than other diseases already seen as rheumatoid
arthritis or SLE. Since the disease affects small vessels, vasoactive drugs are used:
 calcium channel blockers (nifedipine);
 ACE inhibitors;
 tailors;

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  prostanoids (Iloprost, which probably also improves endothelial function);
 Bosentan, endothelin receptor inhibitor;
 phosphodiesterase-5 inhibitors (sildenafil, tadanafil).
In addition, immunosuppressive drugs are also used:
 Methotrexate;
 Azathioprine;
 Mycophenolate mofetil;
 Cyclophosphamide.
Recently the antifibrotic drug Nintedanib has been approved for the treatment of interstitial
pneumonia.
Another therapy used mainly in scleroderma kidney crisis is plasmapheresis.

Question: Why are anti-malarial drugs used in the treatment of certain rheumatological
diseases?
Answer: Antimalarial drugs are particularly
concentrated within the endosomes and increase
their pH. This prevents TLR-immunocomplex binding
and the resulting release of interferon II, which is
necessary for the production of antibodies and the
maintenance of autoimmunity.

SPONDYLARTHRITIS
Different clinical phenotypes of spondyloarthritis
(SpA) can be distinguished:
 Ankylosing spondylitis
 Psoriatic Arthropathy (PsA)
 Reactive arthritis
 Arthritis associated with IBD (Crohn's disease, ulcerative colitis)
 SAPHO syndrome (synovitis, pustular acne, hyperostosis, osteomyelitis)
 Undifferentiated spondyloarthritis: diseases with characteristics that suggest
spondyloarthritis, but which do not present any element that allows to frame these
forms within one of the previous phenotypes. It takes up the concept of
undifferentiated connectivitis.

Spondyloarthritis is a particularly complex group, and recently it has been proposed to consider
these diseases as a single disease with common characteristics but also different clinical
phenotypes, therefore with different clinical and pathological aspects. Two main groups have
been identified:
 Spondyloarthritis with prevalent axial involvement: mainly skeletal structures of the

149
 spine and sacroiliacs are involved. They mainly involve patients with ankylosing
spondylitis and undifferentiated spondyloarthritis, some patients with psoriatic arthritis
and enteropathic arthritis.
 Spondyloarthritis with prevalent peripheral involvement: patients present with
enthesitis, arthritis, tendonitis, dactylitis. They mainly involve patients with psoriatic
arthritis and enteropathic arthritis, all patients with reactive arthritis and a small
proportion of patients with undifferentiated spondylarthritis.

DEFINITION
Group of inflammatory diseases of the musculoskeletal system characterized by the
preferential involvement of entheses and synovial membrane of the rachis and peripheral
joints and affecting mainly genetically predisposed subjects (HLA-B27 positive).
The first to consider these diseases as a single one were V. Wright and J. Moll in 1976 who
noted that these diseases have a similar involvement of the musculoskeletal system
(oligoarthritis, spondylitis, sacroiliitis, enthesitis) to which is added a frequent involvement of
the skin (psoriasis) and mucous membranes (intestinal, urethral, conjunctival, uveal). Both the
skin and the muscles are structures that separate the inside of the organism from the outside
and this suggests that in addition to genetic predisposition there are environmental factors that
interact for the development of this pathology.

While once there was talk of seronegative spondyloarthritis to emphasize the fact that in all
these diseases there was the absence of the rheumatoid factor, in reality now we have seen
that it is not so much the seronegative rheumatoid arthritis that characterizes them (in fact,
there are both seronegative rheumatoid arthritis and spondyloarthritis with FR dosable), but
the fact that they affect entesis.

Enthesions are anatomical structures in which tendons or ligaments are

inserted into the bone: they are transitional tissues at the level of which
the collagen fibers as they approach the bone, first they become
fibrocartilaginous tissue, then they are ossified.
One can distinguish between extra-articular entheses (especially those of
the tendons), articular (of the joint capsules) and intra-articular
(especially those of the cruciate ligaments at knee level).
Examples of enthesitis are: elbow
epicondylitis, epitroclitis, shoulder and hip
periarthritis, trochanteritis, yarrow
tendinopathy.

The professor shows an image

comparing a normal insertion at the
bone level and one affected by
enthesitis.

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PATHOGENESIS
The main factors are:
 Genetic predisposition: the most important genetic factor is HLA-B27, present in all
these diseases but with different frequency. It is mainly associated with ankylosing
spondylitis (90%), but is also present in reactive arthritis (40-80%), juvenile
spondylarthritis (70%), enteropathic spondylarthritis (35-75%), psoriatic arthritis (40-
50%), undifferentiated spondylarthritis (70%). You have association with HLA-B27
especially if the commitment is axial. Less strong associations are with HLA B06,07 and
Cw6 in case of skin psoriasis and with HLAB 38 and 39 in case of psoriatic arthropathy.
Genes for ERAP (Endoplasmatic Reticulum Aminopeptidase) and the IL-23 receptor are
also considered important in pathogenesis.

Genetic factors are not enough,

triggers are needed to trigger the
disease:
 Infections: germs enter at the
level of the different altered
mucous and skin barriers and are
a relevant factor in the
development of these diseases
(e.g. psoriasis is a typical skin
alteration that allows the entry
of germs).
At the moment the microbiome
is being studied a lot, especially
at intestinal level, but also
cutaneous, oral, in general any
mucosa, and in these diseases there is a lot of evidence of microbiome alteration.
 Mechanical stress at the entesis level: fundamental mechanism for the development of
the disease both by triggering and maintaining the inflammatory process. Mechanical
stress leads to the induction of an inflammatory process with two activation pathways:
one via TNF and one with the
increase of IL23 and IL17, more
specific than spondylarthritis. It is not
known whether the processes are
simultaneous or one before the other.
The two pathways lead to the
differentiation of lymphocytes from
TH0 to TH17. In rheumatoid arthritis
this axis of activation of interleukins
and lymphocytes is much less
involved.
Another important aspect is

151
 osteoproduction after inflammation, as a restorative process (unlike rheumatoid
arthritis). Osteoproduction has BMP (bone morphogenetic protein) and WNT as
markers. TNF acts by stimulating BMP and simultaneously stimulates DKK1 which is the
WNT inhibitor. The final effect is the balance between these mediators, which may or
may not lead to osteoproduction.

Then the pathogenetic process can recognize a first inflammatory moment with inflammatory
cell infiltrate, mediated by TNF and IL23 and IL17, followed by erosion formation, mediated by
cathepsin and metalloproteases, and finally a moment of osteoproduction, mediated by BMP
and WNT.

This process is a peculiarity of these diseases (it is in fact absent in rheumatoid arthritis) and
represents a reparative process, an attempt of the organism to restore homeostasis after the
formation of erosion, which, however, is evidently unbalanced and ends up with excess bone.
From the anatomo-pathological point of view we
can distinguish an inflammation with bone
resorption and phlogistic infiltrate, and then a
reparative phase with reactive bone formation and
osteoproduction.

The difference between arthritis present in

rheumatoid arthritis and that characterizing
spondylarthritis is the fact that:
 In rheumatoid arthritis the main target of the immunophlogistic process is the synovial
membrane, with subsequent involvement of tendons and entesis
 In spondylarthritis, the process is the opposite: the disease starts with entheses and
tendons, and only in the second instance does it also involve the joint

EPIDEMIOLOGY
 Beginning peak: III decade of life (young adult age)
 M/F ratio
o Ankylosing spondylitis 2-3:1 (as opposed to the majority of rheumatic diseases
where there is prevalence in the female gender).
o Axial spondylarthritis 1:1
 Prevalence:
o HLA-B27 in the European population: 8% (with a higher prevalence among
Sardinians)
o Ankylosing spondylitis: 0.5% (so there is a large percentage of subjects who have
HLA-B27 but never develop the disease)
o Axial spondylarthritis: 0.3-1.4%
o SpA in Italy: 1.06% (it is in the middle of the range, with a frequency similar to
rheumatoid arthritis).

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 CLINICAL FRAMEWORK
1. AXIAL COMMITMENT
 Spondylitis (spinal involvement): characteristics of inflammatory
pain:
o Debuting before the age of 40
o Insidious debut
o Persistence for at least 3 months
o More intense at night or at rest: due to the fact that the
patient stays still. Often subjects wake up in the second part of the night in pain
and have to get up and move (important feature). If the pain was mechanical, it
would be present during the day.
o Associated with morning
stiffness, usually long lasting
o Improves with movement
(without overloading)

 Sacroiliitis (first symptom of axial

involvement): topography of pain:
o Low lumbar: especially in
the gluteal area, with
inflammatory pain
characteristics
o Irradiation to the posterior
region of the thigh and can
reach the popliteal cavity:
'severed sciatica' (in fact,
sciatica due to protrusion or
disc herniation radiates up
to the heel).
o More often unilateral (asymmetric) or tendency to recur alternately left and
right: 'alternating sciatica' (herniated disc sciatica is monolateral).

SEMEIOTICS of the SpA: manoeuvres that detect a commitment at the level of the axial
skeleton.
 INSPECTION
o Early signs: loss of lumbar lordosis
o Late signs:
 Dorsal kyphosis and cervical lordosis inversion
 Abdominal distension from diaphragmatic breath
 Hip flexion contracture with compensatory knee flexion
Patients take an increasingly curved position as the disease progresses.
 PALMING

153
 o Diffuse pain and symmetrical tension of the paravertebral muscles
o Painfulness of sacroiliac joints, iliac ridges, ischial tuberosities and pubic
symphysis

The sacroiliac joint is difficult to palpate because it is in a deep seat, the available maneuvers
basically consist of acupressure on the iliac crests or right on the seat of the sacroiliac. As for
the spine, palpation is simpler and consists of the pressure of the spinous processes of the
dorsal, lumbar and cervical vertebrae.

Main semeiological mobilization maneuvers:

 Early signs:
o Sacroiliac pains awakened by hyperextension of the lumbosacral rachis
(Mennel's sign).
o Reduced lateral flexion of the lumbar spine.
 Late signs:
o Reduced anterior flexion of the lumbar spine (<40°).
o Schober's test: in upright bending, the point placed at 10 cm cranially on the
perpendicular joining the posterior iliac spines has a reduced excursion (<3cm,
while normally it is 5cm). Final distance will be less than 13 cm total.
o Reduction of chest expansion (<2.5 cm at IV intercostal space level).
o Reduction of the global rachis extension (<20°)
o Reduction of cervical spine flexion: chin-to-exterior distance.
o Reduction of Forestier's arrow: wall to eye distance in upright station. The
patient is obviously unable to extend the back of the neck.

2. PERIPHERAL ARTHRITIS
 Involvement of one or more peripheral joints in 30-50% of cases.
 Articular involvement: mono-oligus asymmetrical arthritis,
therefore a maximum of 4 joints are involved (it differs from
rheumatoid arthritis because the latter is a symmetrical
polyarthritis).
 More often involved the large joints of the lower limbs: knees,
ankles (because from a pathogenetic point of view one of the
triggers is the mechanical stress at the level of entesis, clearly
greater at this level).
 Pain, swelling, joint effusion with redness and heat in the
overlying skin, functional impotence.
 Frequently associated: tenosynovititis, enthesitis, dactylitis.
1. Enthesitis: the basis of all these pathologies, but
clinically evident in 40% of SpA patients. Not always
observable because they can be deep (like those at
the column). If superficial, I can also have signs of
inflammation such as redness and heat. There's not

154
 always pain. Enthesitis can be calcific, leading to the formation of spurs
(typical calcaneal spur for Achilles tendon enthesitis) which are not always
symptomatic.
2. Dactylitis: clinical finding of easy identification, with involvement of flexor
tendons of the fingers (especially the feet), do not present bone edema. At
diagnosis about 7% of patients with axial joint scan and 30% of patients with
PsA are affected by dactylitis.

3. EXTRA-MUSCULOSKELETAL ENGAGEMENT
 Grapesite:
o It is the most frequent extra-articular manifestation of the SpAs
o In the forms associated with the axial joint stock is an anterior
uveitis usually monolateral and acute onset, with a tendency to recur in the
contralateral eye.
o In the forms associated with PsA it is characterized by a more insidious beginning
and is often bilateral from the beginning.

 Psoriasis:
o At the time of diagnosis it is present in 8% of the pcs with axial SpA and in 90% of
the pcs with PsA (there is a 10% of patients with PsA who do not have skin or nail
psoriasis: in this case to make the diagnosis it is sufficient that, in addition to the
characteristic picture of SpA, there is a first degree family member suffering from
psoriasis. These patients may subsequently develop psoriasis).
o Skin psoriasis: prevalence of 2-5% of the population.
o Most frequent localizations: extensor surface of arms (elbows) and legs (knees),
retroauricular region, scalp, periombelical area, nails, intragluteal fold. It may be
unrecognized if it is located in areas that are not easy to control.
o Ask the patient in history if he or she has any family members with psoriasis, and
then examine them carefully (pay attention to the retroauricular area,
intergluteal fold and nails).

 Pustulous palm-plantar: characteristic picture of

the SAPHO syndrome.

 Nail involvement:
o Present up to 50% of pcs with
uncomplicated psoriasis, but can reach up
to 83% of patients
with PsA (psoriatic
onychopathy).
o The nails are
intimately related to

155
 entheses by the extensor tendon of the distal interphalangeal joints, so when
there is a psoriatic onychopathy there is almost always an involvement of the
distal interphalangeal joints (usually not affected in rheumatoid arthritis, while
they are affected in osteoarthritis, with the formation of Heberden's nodules).
o The alteration leads to the formation of 'pierced' nails (nail pitting). To observe
these irregularities, a tangential nail should be observed.

 Pitting edema: in patients with psoriatic arthropathy and RS3PE (Remitting seronegative
symmetric synovitis pitting edema). Characterized by the fact that the fovea remains as
a result of pressure on the extensor surface of the limbs. It is present in SpAs, in
particular in PsA, but can also be found in patients with rheumatic polymyalgia, or in
paraneoplastic syndromes.

 Osteitis: frequent manifestation of the SAPHO syndrome (characterized by pustular

palmar and plantar, acne and osteitis). It is often mistaken for infectious osteomyelitis
and/or bone cancer. It affects the clavicle very frequently, at bone scintigraphy it shows
an important inflammation of the bone.

BIOHUMORAL ALTERATIONS
1. Increased inflammation indexes, in particular ESR and PCR: they are more frequently
increased when there is peripheral arthropathy than axial involvement, because at the
peripheral level there is inflammatory involvement of the synovial membrane, with tissue
rich in inflammatory markers; while at the axial level, inflammation concerns entheses,
which are fibrocartilaginous structures, where there is rarely an accumulation of
inflammatory cytokines. The increase in inflammation rates is of great help in the case of
rheumatoid arthritis, while it is less so in the case of spondylarthritis, as they are more
subtle inflammations even though they can still be serious and disabling. It is also important
to stress that the process is slower and therefore there is more time to make a diagnosis
than rheumatoid arthritis, where in 1-2 years, in the absence of a diagnosis, the patient gets
worse quickly with joint erosions.
 ESR high in 80% of cases at an early stage, with a return to normal at a late stage;
 ESR and PCR correlate more with peripheral than axial involvement;
 A normal ESR or PCR does not rule out the presence or activity of the disease.

2. HLA-B27 typing: it is an important genetic marker but from a practical point of view it is not
always useful: for example, in a patient with axial involvement
symptoms and imaging evidence, the search for HLA-B27 is useless;
at the same time, however, without imaging evidence, it can help in
case of doubt. Its positivity, in the absence of imaging, can make us
support the diagnosis in a patient to whom biological drugs are to
be administered (being very expensive, they are given in selected
cases with specific profiles).
 Useful in selected cases, such as patients with inflammatory

156
 lumbago, asymmetric peripheral arthritis or enthesitis, where radiographic changes and
MRI do not allow diagnosis;
 It does not distinguish between SA (ankylosing spondylitis) and SpA (spondylarthritis);
 It is present in 8-10% of the population: only 5% of positive subjects will develop an SA,
so not all subjects will develop the disease.

3. Absence of rheumatoid factor and anti-CCP antibodies: however, there is an exception in

the form of psoriatic arthropathy with a rheumatoid-like phenotype in which there may be
joint erosion and there may be positivity for rheumatoid factor and anti-CCP antibodies.

4. Synovial fluid of inflammatory type: especially relevant in the case of mono/oligo-arthritis.

The leukocyte count allows to direct to an arthritis, excluding a non-inflammatory effusion.

If a person is not positive for HLA-B27, can they still develop ankylosing spondylitis? Of course.
In 90% of cases patients have HLA-B27, in 10% there are other genes, such as ERAP or IL-23R,
that can predispose to the development of the disease.

IMAGING
It is a very important aspect in these diseases. Various tests can be
performed including:
 RX: it should always be the first examination to be done in
these patients, even if it does not always help at an early
stage (unless there is already a serious picture). Radiographic
examination of the affected column, pelvis and peripheral
joint sites is the commonly used tool to support the diagnosis
of ankylosing spondylitis (SA).

 MRI: it is the most sensitive examination in the early stages,

you look at the STIR (fat subtraction) sequences that highlight
inflammation, and the T1 sequences, where you see the
results (sclerosis and adipose replacement). In early SA,
before the appearance of radiographic evidence, MRI is
useful to demonstrate the
presence of active inflammation in
the sacroiliac and/or vertebral
joints.

 CT: it is not a first choice technique

and should be reserved as a
supplement to the Rx examination
in cases of doubtful interpretation.
It highlights any structural damage
to the bone. It has the
disadvantage of emitting radiation

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 (whereas MRI does not), and since the subjects studied are usually
young, with the sacroiliac and therefore the pelvis area being studied,
it is clear that therefore this examination should not be of first level.

 Bone scintigraphy: is performed with the use of marked technetium,

which accumulates in areas that are
rapidly regenerating, as in the case of
bone inflammation, but there may be
areas of regeneration even without
inflammation, as in osteoarthrosis.
It does not add anything useful from a diagnostic point of
view, considering that in the suspicion of spondylarthritis
scintigraphy is characterized by low sensitivity and
specificity. It is used for example in a patient with
fibromyalgia, therefore with hyperalgesia which makes it
very difficult to examine, which can develop
spondylarthritis. If the scintigraphy gives a negative
result, an inflammatory picture can be more reliably
excluded, while if it is positive it detects an inflammatory
picture that must be confirmed by other tests.
The side scintigraphy shows hyperaccumulation of the
tracer at the level of the lower limbs and sacroiliac
(which should be analyzed anteriorly not posteriorly). The hyperaccumulation in the
anterior part attests the inflammation of the two sacroiliac in the inferior third.

 Articular ultrasound: it is a useful examination for the evaluation of peripheral

involvement in the form of arthritis, tendonitis and enthesitis. In addition to seeing the
swelling, you can perform Power Doppler to see the perfusion of these tissues,
indicative of inflammation.
In rheumatoid arthritis it is very useful because it detects the effusion, the hypertrophic
synovial membrane (while in patients with SpA the hypertrophy of the membrane is not
so evident).

GRADING OF SACROILIITIS: NEW YORK RADIOLOGICAL CRITERIA

The parameters to be evaluated are:
1. Regularity and definition of joint margins (erosions);
2. The width of the articular rhyme;
3. Bone sclerosis;
4. The fusion of the sacroiliac.

Grade 1: possible sacroiliitis (doubtful); minimal involvement of sacroiliac joints with pseudo
widening of the rhyme.
Grade 2: minimal but certain, ileus and sacral bone sclerosis.
Grade 3: evolved (moderate-severe), increases thickening and bone erosion is formed.

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Grade 4: partial or complete fusion of sacroiliac (ankylosis).

Far more important, especially in the early stages, is the MRI: these are STIR (fat subtraction)
sequences you can see areas of hyperintensity that correspond to subchondral bone edema
suggestive of sacroiliitis. These early lesions are seen three to four months after the onset of
symptoms.
Synovitis, capsulite or enthesitis, without subchondral bone oedema, are compatible with
sacroiliitis, but not sufficient for diagnosis.

RADIOLOGICAL ALTERATIONS OF VERTEBRAL BODIES DURING SPAS

a) Sign of Romanus: it is an erosion of the vertebral bodies anteriorly (anterior spondylitis)
b) Squaring: loss of normal concavity of vertebral bodies
c) Spondyloditis: inflammatory involvement of the intervertebral disc

DIFFERENTIAL ASPECTS OF INTERVERTEBRAL OSSIFICATIONS

a) Ankylosing spondylitis: characteristic are syndesophytes,

i.e. the formation of fine bridges at the anterior or
posterior longitudinal ligament level;
b) Spondyloarthrosis: Osteophytes are coarser and tend to
go outwards, widening the surface of the vertebral body
so as to provide greater stability to the joint;
c) Vertebral hyperostostic disease: formation of real
vertebral bridges due to calcification and ossification of
the anterolateral ligaments of the rachis, is characteristic
of the DISH (Diffuse Idiopathic Skeletal Hyperostosis) form;
d) Reiter's disease: less coarse bridge, it starts from the centre of the vertebra and joins
the two centres of the vertebra above and below;
e) Psoriatic arthropathy: more regular ossification.

RADIOLOGICAL PROGRESSION
1. It starts with osteitis: Romanus sign, Squaring and Shiny
corner;
2. They will then form syndesmophytes, with very subtle
calcification;
3. The most characteristic picture is when you have a complete
calcification of the column, bamboo cane, a late and
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 characteristic aspect of the disease,
typical of the advanced form of
ankylosing spondylitis;
4. Finally, there is bilateral ankylosis of
the interapophyseal joints (binary
sign) and interspinous ligaments.
MRI at column level: arrows highlight shiny
corners at erosion. In order to have an
indication of sero-negative spondylarthritis
the MRI must show the alteration of at least
three vertebral bodies, the greater the number of bodies involved, the greater the specificity of
the diagnosis.

CLASSIFICATION AND DIAGNOSIS

Recently, the classification of these pathologies has been reviewed by introducing a very
important concept: there is radiographic spondylarthritis and non-radiographic spondylarthritis.
1. Non-radiographic: it is an early stage of the disease, the characteristic symptoms of
spondylarthritis and sacroiliitis are present but there are alterations only on MRI and not
on X-ray.

2. Radiographic: it is the later stage, sacroiliac and spinal lesions are also visible on the X-
ray.
The risk that a patient with a non-radiographic form will evolve into a radiographic form is very
high, especially in the presence of HLA-B27 and high PCR. If a patient has the non-radiographic
form is low PCR, the risk is lower.
It is very important to distinguish between these two forms because some biological drugs are
indicated only for the radiographic form.

ASAS CRITERIA FOR CLASSIFICATION

As for the diagnosis of the axial form:
If the patient has had back pain for more than three months and is less than 45 years old, he or
she should have sacro-iliitis at imaging and one of the following characteristics:
- Arthritis - Entesite

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 - Dactylite - HLA-B27
- Grapes - Family history for SpA
- Psoriasis - high PCR
- IBD - Good response to NSAIDs
The patient may not have X-ray evidence but in this case must be HLA-B27 positive and have
two or more of the listed features.

In the peripheral form only, for diagnosis, the patient must have arthritis or enthesitis or

dactylitis, and one of the more specific characteristics (uveitis, psoriasis, IBD, HLA-B27,
sacroiliitis on imaging, previous infections) or two of the less specific ones (arthritis, enthesitis,
dactylitis, back pain and family history for PLC).
The prof. recalls that they are always classification criteria and not diagnostic (not all
classification criteria are needed for the diagnosis).

Nomenclature of the joint stock companies according to ASAS criteria: we can distinguish the
spondyloarthritis in:
- Spondylartriti mainly axial (axSpA):
1. Non-radiographic (nr-axSpA)
2. Radiographic = Ankylosing Spondylitis (AS)
3. undifferentiated SpA (uSpA)
Both can be associated with psoriasis and IBD.
- Mainly peripheral spondylartritis (pSpA):
1. Psoriatic arthritis (PsA) associated or not with spondylarthritis
2. Shapes associated with IBD: type I and II
3. Reactive Arthritis (ReA)
4. undifferentiated SpA (uSpA)

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Therefore it is important to consider that there
are clinical phenotypes in this group of
pathologies that have common characteristics
and can therefore be seen as a whole, both from
a pathogenetic point of view and as clinical
characteristics.

ANKYLOSING SPONDYLITIS
It is the most severe clinical phenotype in the
spondyloarthritis spectrum that mainly affects
men (F:M=1:2) at a young age and has a very high
association with HLA-B27. It electively affects the
axial skeleton in the insertion sites of tendons and ligaments, resulting in diffuse stiffness and
progressive ankylosis. In the final stages, involvement of the sterno-clavicular and costo-sternal
joints is possible and patients may have respiratory failure due to ankylosis in the ribcage. In
association, there may be more frequent anterior uveitis and aspecific colitis-enteritis also due
to dysbiosis in the GI system (up to 40% of patients have enteritis).

PSORIATIC ARTHRITIS
It is the form associated with skin psoriasis (it can also be diagnosed in patients without
psoriasis but with familiarity). It has a prevalence of 0.2-0.5% of the population, 15-30% of
patients with psoriasis. It has some characteristic associations according to the HLA:
- Psoriatic arthritis in axial form: HLA-B27
- Psoriatic arthropathy: HLA-B38, HLA-B39
- Skin psoriasis: HLA- Cw6, HLA-Cw7, HLA-B07, HLA-B08
Psoriatic arthropathy has five clinical phenotypes:
1. Predominant interest of distal interphalanges (5%): classical form;
2. Mutilating arthritis of the distal phalanges (rare);
3. Systemic polyarthritis (15%): similar to rheumatoid arthritis, where we can sometimes
find rheumatoid factor and anti-CCP antibodies. Within these clinical phenotypes, it is
one of the most erosive forms along with mutilating arthritis;
4. Asymmetric oligoarthritis (70%): it is the most common form with involvement of distal,
proximal and metacarpal phalangeal FUs;
5. Axial shape (5%): ankylosing spondylitis-like.

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In the case of distal interphalangeal interphalanges,
differential diagnosis with osteoarthritis can be difficult.
Arthrosis mainly affects the distal (Heberden's nodules) and
proximal (Bouchard's nodules) interphalanges, while it
generally spares the metacarpophalanges and wrists. In these
cases the swelling is not as soft as when there is joint
inflammation but it is harder (in rheumatoid arthritis, for
example, it is softer). At the radiological level, differential
diagnosis can be difficult. In the picture above you can also
see the uneven pitting.

On the side you can see an X-ray of a case of mutilating arthritis: it is rarely found in patients
with psoriatic arthritis, it is characterized on the Rx by acroosteolysis of the distal phalanges.

REACTIVE ARTHRITIS
It is a sterile arthritis that develops after 7-10 days from an infection that has affected the body
away from the joint. There are no germs in the affected joint, the process is immunomediated.
A typical example of reactive arthritis is acute joint rheumatism that manifests itself after
tonsillitis from Streptococcus beta-haemolytic type A with manifestations affecting the joints,
heart (valvulopathies), kidneys (glomerulonephritis) and also CNS.
Another form is Reiter's Syndrome with the characteristic triad of urethritis-arthritis-junctivitis,
the initial trigger is a urethral infection by intracellular germs (Chlamydia and Mycoplasms).
Reactive arthritis can also be triggered by intestinal infections by Shigella, Salmonella, Yersinia
and Campylobacter.
It is important in this case to treat infections: if the patient has a urogenital infection with
Chlamydia and Mycoplasms, which are transmitted sexually, the partner should also be treated.
Disease picture:
- Artralgie
- Arthritis especially in the lower limbs
- Dactylite
- Entered, frequent to the Achilles tendon
- Tenosinoviti
- Rare axial interest.

ARTHRITIS ASSOCIATED WITH IBD

It's arthritis associated with ulcerative rectocolitis and Crohn's disease. At diagnosis, about 4%
of patients with ankylosing spondylarthritis have IBD. The prevalence of joint manifestations is
slightly higher in patients with Crohn's disease than in patients with CCU: peripheral arthritis is
usually more frequent than ankylosing spondylitis.
Disease picture:
- Recurring arthritis: usually follows the course of enteritis
- Entered
- Asymmetrical oligoarthritis/polyarthritis of the lower limbs

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- Spondylitis and chronic sacroiliitis: they have a course independent of enteritis.

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SAPHO SYNDROME (SYNOVITIS, ACNE, PUSTOLOSIS, HYPEROSTOSIS, OSTEITIS)

There is association with HLA-B27 in 30% of cases, with possible involvement of peripheral
(usually asymmetrical arthritis) and axial (sacroiliac) joints. It is frequent the involvement of
the anterior thoracic district, in the territory of entesis or bone (mainly clavicle) with osteitis
(chronic recurrent multifocal osteomyelitis). It is associated with acne conglobate, acne
fulminans, suppurative hydroadenitis, pustulous palm-plantar

THERAPY
The therapy depends on the prevailing manifestation, in particular the therapies are
differentiated by axial and peripheral manifestations.
First-line therapy is the same for both axial and peripheral manifestations: NSAIDs are
administered associated with kinesiotherapy, i.e. muscle stretching, which stretches and
relaxes the muscle, allows the tendon to be released and reduces the stress of the enthesis.

1. In peripheral manifestations, especially in the case of monoarthritis, local injections of

cortisone (one or two infiltrations) can also be used, which can sometimes be resolutive and
the drugs used for rheumatoid arthritis can also be used: methotrexate, sufasalazine,
DMARDs. In patients with axial forms there is no point in using this therapeutic approach,
especially with DMARDs (Disease modifying antirheumatics drugs: a class of chemically
unrelated drugs that reduce the progression of rheumatoid arthritis including Etanercept,
azathioprine, chloroquine, cyclosporine, etc.).

2. In axial forms, and in peripheral forms that do not respond to DMARDs, biologicals are used
as second line drugs. These include 5 different anti-TNF preparations and their biosimilars,

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and drugs directed against IL17 or blocking the axis of IL23. Ustekinumab, for example,
intervenes on a p40 subunit common to IL12 and IL23.

TAKE HOME MESSAGES

 The SpAs are among the most frequent inflammatory diseases of the locomotor system
seen in rheumatology clinics;
 They are a group of diseases characterized by common genetic, pathogenetic and
clinical aspects;
 The most important distinguishing feature is the involvement of the entesi;
 The new acquisitions have allowed the development of more accurate classification
criteria and diagnostic algorithms;
 The management of these diseases is improved through the use of new therapeutic
strategies and new biological drugs.

Can these drugs stop the progression of the disease?

TNF acts on WNT and BMP responsible for osteoproduction and calcifications that lead to
functional impairment of the joint, so antiTNF drugs, when used in non-advanced stages, can
lead to a slowing of disease progression by reducing abnormal osteoproduction.
Spondyloarthritis, also psoriatic, tend to go into remission, induced by therapy or even
spontaneously, while ankylosing spondyloarthritis has a slowdown of manifestations, but there
is no remission. If you were diagnosed with ankylosing spondylitis, it would be better to use
biological drugs right away.

Does the surgical treatment of IBD prevent the progression of the SpA?
Peripheral arthropathies, the most common in IBD, are synchronous with the intestinal
commitment, if the inflammatory disease worsens it also worsens the SpA. The axial forms, on
the other hand, are untied from the intestinal course. Therefore, the frequency of attacks after
surgery is significantly reduced if the SpA is not axial, but does not disappear completely. It
should also be considered that anti-TNF drugs are used in Crohn's and CCU, which improves
joint engagement.

NEOPLASMS AND RHEUMATIC DISEASES

Autoimmune diseases are the result of an interaction between genetic and
environmental factors (e.g. microorganisms, viruses, cigarette smoke, other
toxicants, ...) that induce a dysregulation of the Immune System that, at
least initially, is caused by the loss of immune tolerance to the body's own
Ag, with the formation of auto-Ac.

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The ability to distinguish self from non self (i.e. immune tolerance) is maintained in immuno-
competent B and T cells through central and peripheral
mechanisms; in these mechanisms important receptors present on
the surface of Ag-presenting-cells and lymphocytes play an
important role. The receptors can be inhibitory or activator; one of
the important receptor families is the B7:CD28 family, which
includes both activator and inhibitor receptors (shown in the image
opposite).
 Activator receptors include: CD28, expressed on naïve T
cells; ICOS, expressed on follicular T cells;
 Inhibitory receptors include CTLA4 and PD1, expressed on
the surface of T cells.
Inhibitory receptors have recently become the target of anti-
neoplastic therapies; CTLA4 and PD1, along with all other inhibitors,
are in fact called check point inhibitors and play an important role because they control the
immune response, in particular they control the balance between induction and inhibition of
the immune response itself.
The balance of the immune response is fundamental to maintain the health of the individual; if
the immune and inflammatory responses are weak there is the risk that infectious diseases
may develop but also neoplasms; on the other hand, if the immune and inflammatory
responses are strong there is the risk that autoimmune or immune-mediated diseases may
develop.
 Stimulating inhibitory receptors results in reduced antibody production, reduced NFI
production and therefore immunosuppressive action;
 By blocking the inhibitory receptors instead there is a reduction in regulatory T cells, an
increase in cytotoxic T lymphocytes that infiltrate the neoplastic mass with a reduction
in tumor size and therefore the action is immunostimulation.
However, immunosuppression increases the risk of developing cancer, immunostimulation
increases the risk of developing autoimmune or immune-mediated disease.
One of the inhibitory receptors is CTLA4, in neoplastic therapy Ab anti-CTLA4 is born that block
the receptor itself; on the contrary, in rheumatoid arthritis CTLA4 Ig Abatacept is used, a drug
that stimulates the CTLA4 pathway to induce an inhibition of the autoimmune response.
In clinical practice we try to understand if the use of biotechnological drugs for the treatment of
autoimmune rheumatic diseases leads to the development of neoplasms; a Swedish study
collected information on biological and conventional drugs from 2006 to 2015, and found that
the use of biotechnological drugs does not seem to lead to an increased risk of neoplasms,
including Abatacept, so in clinical practice, at the pharmacological dosages used,
biotechnological drugs even if they suppress the immune and inflammatory response do not
seem to increase the risk of neoplasms.

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Patients treated for cancer (with Ab anti-CTLA4 and anti-PD1) instead have developed
numerous autoimmune manifestations, i.e. arthritis, sicca syndrome, vasculitic manifestations,
rheumatic polymyalgia, lupic nephritis, psoriasis, scleroderma, etc. Therefore biotechnological
antineoplastic drugs that stimulate the immune response can induce rheumatic
manifestations on an autoimmune and immunomediated basis.
This is a new chapter in medicine that has opened with the use of these drugs.
It must be understood, however, whether or not patients with rheumatic or autoimmune
diseases who have a hyper-reactive immune system are protected from cancer. In reality there
is a balance sheet: on the one hand there is a strong immuno-flogistic response, which protects
against neoplasia, on the other hand there are two factors that can predispose to the
development of neoplasia:
o The polyclonal proliferation of lymphocytes is important in these patients; under these
conditions it is more likely that a lymphocyte clone releases itself from control and gives
rise to monoclonal neoplasia;
o Chronic inflammation is one of the main factors predisposing to the development of
neoplasms.
The balance of these factors gives the final result, i.e. the development or otherwise of
neoplasia in the patient with rheumatic disease.
Three different conditions can be distinguished:
1. The tumor develops in patients with long-term rheumatic disease after years of
rheumatic disease
2. The tumor develops concomitantly with the rheumatic pathology (paraneoplastic
syndrome).
3. There are rheumatic manifestations due to the invasion of the skeletal muscle
apparatus, in particular the joints, by tumors.

CANCER THAT DEVELOPS IN PATIENTS WITH LONGSTANDING RHEUMATIC DISEASE

In this case there are two additional options:
 Rheumatic diseases in which the development of neoplasia is related to the
pathogenetic mechanism of rheumatic disease (Sjogren, SLE, AR, Systemic Scelrosis,
Paget)
 Drugs used against the disease may pose a risk of developing neoplasia
(Cyclophosphamide, cyclosporine, biological drugs).

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SJOGREN'S SYNDROME
In the picture opposite: risk of neoplasia in
Sjogren's syndrome over the years, according
to several studies. The red box shows how
much the risk increases compared to the
general population: it can be seen how it has
decreased over the years and is currently 4-9
times higher.
Sjogren's syndrome is part of the first case,
i.e. it is a rheumatic disease whose
pathogenic mechanism can lead to the
development of neoplasms, in particular increases the risk of lymphoma.
The risk, in fact, varies: in recent work the risk is lower than in past studies; it is 4 to 10 times
higher in these patients than in the general population.
The most frequent tumor is MALToma, which develops because in the ectopic germination
centers of Sjogren's syndrome there can be important production of auto-Ab anti-Rho (or anti-
SSa) and anti-Sb, with formation of immune complexes; the production of antibodies and the
formation of immune complexes further stimulate the immune response, in particular the
population of B lymphocytes to produce IgM (the rheumatoid factor). In this polyclonal
stimulation, a clone can release itself and become neoplastic, with the development of
lymphoma that mainly affects mucosa-associated lymphoid tissue (MALT). Most MALTomas
develop in the salivary glands, but they can also develop outside of them, such as in the eye
sockets, nose-farines, thyroid glands, lungs and stomach.
Other tumors are lymphoplasmacytoid lymphoma and large cell lymphoma, which are rarer
but also more severe.
Faced with parotid swelling, a differential diagnosis must be made between an increase in
volume due to a maltoma with benign
hyperplasia (see table opposite).
o Clinical presentation: swelling is
bilateral and soft in benign
hyperplasia, while it is unilateral
and hard in MALToma.
o Ultrasound with Doppler: benign
hypertrophy shows parenchyma is
inhomogeneous, the tumor is
hypoecogenic.

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o In MRI: there is diffuse enlargement of honeycomb-like parotids in benign hyperplasia,

while the tumor is a solid or cystic-solid solitary node in the protein itself.
MALTomas in Sjogren's syndrome are low in malignancy, have an asymptomatic course and in
particular there are no typical B symptoms of lymphoma; subjects feel well, have normal levels
of LDH and 2microglobulin; marrow is rarely affected. The course is very slow and
asymptomatic.

It is important to assess the risk factors (summarized in the picture opposite)

o Some are clinical, such as the persistence of
parotid swelling, the persistence of
lymphadenopathy, the presence of purpura
(vasculitic manifestation);
o Other risk factors are biohumoral, such as
cryoglobulinemia, lymphopenia, reduction of
the C4 complement fraction, presence of
monoclonal compound;
o Another element is the finding that the
biopsy of the salivary glands has a
germination centre, which represents a risk
factor for the development of lymphoma.
There is no consensus on the timing of patient
monitoring and in recent years researchers'
attention has focused mainly on two aspects that
could be the drivers of lymphoma development in this disease.
a. Chronic antigenic stimulation
b. Disease activity, therefore it is very important to treat patients properly, not so much for
the sicca syndrome, but rather for the treatment of potential extra-ghiandular
manifestations, which are then found in the risk factors (lymphopenia, vasculitis,
cryoglobulinemia).

Usually when the disease is inactive, an annual or bi-annual check-up is sufficient; if the disease
is active with many risk factors the check-up should be more frequent every 6 months.
However, an important aspect to consider is the number of risk factors present: the greater the
number of risk factors, the more frequent must be the monitoring of the disease to
demonstrate the development of lymphoma.

LES

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In the picture opposite: risk of development of various neoplasms in SLE. Underlined with
continuous line tumours with increased risk (NH lymphoma, vulva tumour, thyroid tumour);
underlined with dotted line tumours with reduced risk (breast and endometrium)
An American study with a multicentre cohort involved 16,000 patients and indicated that the
risk of cancer increased in SLE patients, but the increase is modest and mainly concerns
haematological neoplasms (in particular non-Hodgkin's lymphoma with risk 4 higher than the
general population), vulva and thyroid; It has also been shown that these patients appear to be
protected from the development of other neoplasms, in particular breast and endometrial
neoplasms, and this could be due to the fact that patients experience early menopause (due to
the therapies performed) which could protect them from female sex hormone sensitive
neoplasms (such as breast and endometrium).
In SLE patients, there are risk factors for the development of neoplasms that mainly concern
therapy.
Cyclophosphamide is one of the most powerful drugs used in autoimmune rheumatic diseases
and involves an increased risk of neoplasms; however, it is a drug that is used less and less
today as there are more specific and effective immunosuppressive drugs and less toxic.
Hydroxychloroquine, on the other hand, has a protective effect on the tumor, the mechanisms
involved to explain this antineoplastic effect are multiple:
o It is a DNA intercalating agent: it is able to prevent mutations in rapidly growing cells.
o May inhibit the telomerase enzyme involved in the unlimited replication of cancer cells.
o It increases the synthesis of TP53 which protects the cell of the genotoxic stimulus;
o It improves the repair mechanisms, especially in those patients undergoing alkylating
therapy;
o Stabilizes p53 which induces cell apoptosis and thus blocks the development of
neoplasms.
o It has an inhibitory effect on the mechanism of autophagy: autophagy is the mechanism
by which rapidly proliferating cells eliminate cellular debris and reuse it in terms of AA
and proteins for development and survival; autophagy is a mechanism that uses
neoplastic cells that must proliferate actively, so by inhibiting autophagy the drug
inhibits tumor proliferation. Clinical data also confirm this effect.
Chloroquine has therefore been added to standard antineoplastic therapy in patients with
glioblastoma multiforme (very severe CNS tumour) and the survival of these patients has been
seen to increase; this result is combined
with another study in SLE patients which
showed that hydroxychloroquine in
these patients leads to a lower
frequency of neoplasms.
If on the one hand the use of this
famraco, associated with

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antineoplastics, can be useful against cancer, on the other hand the association with some
antineoplastics (such as cisplatin) is dangerous, in fact hydroxychloroquine can increase the
sensitivity of other cells in the body to the toxic mechanism of cisplatin.
So from the point of view of the mechanism of action it can help and protect the patient, it is
used in patients with autoimmune diseases and can protect them from the risk of developing
neoplasms, but if associated with antineoplastics such as cisplatin it can also have a toxic effect
on other cells in the body.

RHEUMATOID ARTHRITIS
In the picture opposite: risk of cancer
in rheumatoid arthritis according to
several studies. In red it is highlighted
that the risk is 1.05 higher than in the
general population.
The situation is similar to SLE, so the
risk of neoplasia has slightly increased
compared to the general population,
but is still very low. The risk is
increased for lymphomas (both
Hodgkin's and non-Hodgkin's), and for
lung cancer; instead, there is a
reduced risk for breast cancer (for
treatment-induced early menopause)
and colorectal cancer (because these patients take NSAIDs as a protective factor).
Among the drugs used in the treatment of rheumatoid arthritis is methotrexate, which does
not seem to increase the risk of neoplasms, except for non-melanoma skin cancer, whose risk
is also increased by cyclosporine.
For biotechnological drugs there are no data that indicate an effective increase in the risk of
neoplasia; in fact, everything depends on a balance: these drugs are effective in reducing
inflammation and immuno-flogistic response in patients who present an imbalance of the
same; this effect could instead encourage the development of neoplasms in subjects who do
not have basic immunological alterations.

SCLERODERMY
An increased risk has been observed for lung cancer (especially in patients with
interstitiopathy), breast cancer (unlike the previous ones), and Hodgkin's lymphoma.
Among the diseases seen, haematological neoplasms are the tumors that can develop more
frequently, particularly Hodgkin's and not Hodgkin's lymphomas; this is explained by the fact

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that in autoimmune rheumatic diseases there is a polyclonal proliferation of B lymphocytes that

can lead to the development of a
lymphomatous clone.
There is a scleroderma antibody clearly
associated with the risk of neoplasia, i.e.
Ab anti-polymerase III, which is therefore
associated with scleroderma kidney crisis,
diffuse forms of scleroderma and also the
development of neoplasia.

TUMOR CONCOMITANT TO RHEUMATIC PATHOLOGY: PARANEOPLASTIC SYNDROMES

The paraneoplastic syndrome derives from a substance produced by the tumor and induces
manifestations in any location in the body. The most frequent paraneoplastic syndromes in
rheumatology are various such as osteoarthropathy (osteoarticular hypertrophy), polyarthritis,
RS3PE, PFPAS, CAM (Cancer Associated Myosite), osteomalacia. Paraneoplastic myositis (CAM)
is one of the main manifestations, therefore it is important to screen patients with myosites for
frequent association with neoplasms
(dermatomyositis is associated in 30% of
cases, polymyositis in 15%).
The pathogenesis of CAM seems to derive
not from the production of a substance
by the tumor, but from the production of
autoantigens of the tumor tissue. The
antigens that the tumor produces are the
same as those expressed by muscle tissue
in the case of myositis and are antigens
normally not expressed by healthy tissue.
Therefore, in a genetically predisposed
patient, exposure of these autoantigens
on neoplastic tissue leads to the production of an antigen-specific immune response and, in
conjunction with muscle stress, may induce myositis.
The tumor risk is different in myosites and there are factors that can increase the risk: advanced
age, male sex, patients with severe skin manifestations with ulcerations, more severe muscle

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manifestations (patients with more severe disease are those most at risk), patients with a poor
response to therapy, patients with antiTIF1 antibody (typical in dermatomyositis).
In patients with MII it is important to have screening for occult diseases. It is important to do an
accurate anamnesis, an objective examination with palpation of the testicles in the man and the
breasts in the woman, the gynaecological examination, the search for fecal occult blood. In
patients with low risk, chest X-rays and abdominal echoes are sufficient, in patients with high
risk it is better to proceed with more advanced examinations such as CT-total body, PET-TC and
also endoscopies. Most myosites are associated with adenocarcinomas (70%), the proportion
associated with lymphomas is much lower.
In particular, for paraneoplastic syndromes we observe:
 Dermatomyositis: predominantly associated with lung cancer, ovarian cancer, cervical
cancer, gastrointestinal cancer and non-Hodgkin's lymphoma.
 Polymyositis: predominantly associated with bladder cancer, Hodgikin's lymphoma and
non-Hodgkin's lymphoma.
 Chronic polyarthritis: often polyarticular, it is more frequently associated with solid
tumors, in some cases a positive rheumatoid factor can be found and usually occurs
within 2-3 months after the development of the neoplasm.
 RS3PE syndrome (Remitting seronegative symmetrical synovitis with pitting edema): it
has a pathogenesis involving metalloproteases that may therefore share a role in the
development of neoplasia.
It is a rare disease that can arise as a paraneoplastic form and when it is found, the
association between this and other non-neoplastic
causes such as rheumatic polymyalgia, psoriatic
arthropathy or spondylarthritis must be excluded.
 PFPAS syndrome (Palmar fasciitis with
polyarthritis). In the final stages can have a very
marked clinical picture with progressive retraction
of the fingers with tension contracture of the fingers
with considerable functional limitation.
 Another neoplasm that can occur in patients
suffering from rheumatic diseases is osteosarcoma
in patients with Paget's disease (a disease
characterized by bone tissue disruption); it is a rare form that affects 1-2% of Paget's
patients and should be taken into account in the general evaluation of these patients.

RHEUMATIC MANIFESTATIONS DUE TO NEOPLASTIC JOINT INVASION

They may be due to:

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 Malignant neoplasms such as acute leukemia, synovial sarcoma, epithelioid

sarcoma or clear cell sarcoma. They're of orthopedic interest because the
therapy is surgical.
 Benign forms such as villonodular synovitis, in which there is a large hypertrophy
of the villi and the treatment is local. Other benign forms are synovial
hemangioma, synovial chondromatosis.
In case of tumor infiltration we are faced with a joint that does not show all the signs of
acute inflammation characteristic of rheumatic pathology, but we will find a swollen,
painful and functionally limited joint that can lead us even wrongly to think of an
arthritic phenomenon.

Question: Are rheumatic diseases more associated with haematological neoplasms? While the
drugs used for these diseases induce more solid tumors?
The drugs used in autoimmune diseases induce immunodepression, thus losing control over the
onset of neoplastic cells, leading to an increase in both solid and liquid tumors. Invec, and in
autoimmune diseases, characterized by greater lymphocytic proliferation, immune
dysregulation is characterized by less apoptosis, leading to the development of mainly
haematological neoplasms.

BIOTECHNOLOGICAL DRUGS IN RHEUMATOLOGY

From the point of view of the therapeutic approach in patients with rheumatological diseases,
biological (or biotechnological) drugs have had great importance. A biotechnological drug is a
therapeutic substance produced by the use of living organisms.

RECOMBINANT DNA TECHNIQUE

In most cases these products are proteins that
are manufactured in the pharmaceutical industry
using recombinant DNA. Initially the monoclonal
antibodies, whose amino acid sequence is well
known, were produced by the animal. Nowadays,
however, monoclonal antibodies are also
produced through molecular biology techniques,
i.e. through recombinant DNA.
It is a matter of transferring the plasmid that
contains the gene to be replicated, into a
structure, such as a bacterium, that is able to
reproduce this vector. The vector is then
transferred to a further system where the
protein to be produced is synthesized in large

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quantities. It is a very complex process that requires purification steps in addition to a control of
what is the finished product. For this reason the production of such drugs is very expensive, and
therefore biotechnological drugs are much more expensive than synthetic drugs. Cost is one of
the main limitations of the use of biotechnological drugs.

THERAPEUTIC ANTIBODIES
Initially, monoclonal antibodies entirely of
murine origin were used. Subsequently,
chimeric antibodies composed of the human
variable region and the constant murine region
began to be used. Then humanized antibodies
took over where the
murine sequences were
only complementary
regions. In the end, the all-
human antibody was used.
With the improvement of
the techniques we have
moved from a completely
murine monoclonal
antibody to a completely
human one. The transition
from murine to human has
had important advantages
for the function of the
product: human antibodies
are better tolerated and
determine less frequently
the development of an
immune reaction of the
organism towards unrecognized antibodies, obviously the production of antibodies against
monoclonal antibodies leads to their inactivation.
Looking at the suffix of the names, you can tell if a monoclonal antibody is of murine (-mab),
chimeric (-ximab), humanized (-zumab), human (-mumab) or fusion protein (-cept) origin. Some
examples can be seen in the table opposite.

BIOSIMILAR DRUGS

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As already mentioned, the main problem with biological drugs is their high cost. Of all the drugs
that are used in rheumatology, those that have resulted in the highest cost for the treatment of
patients can be seen in the table below. The first of all is the Humira (adalimumab).
The positive news is that biosimilar drugs have been on the market for two years. Once the
patent for biological drugs expires, like generic drugs that are produced as a substitute for
synthetic drugs at much lower cost, biosimilar drugs are produced that are not completely
identical to the corresponding biological drugs precisely because they are not synthesized.
Biosimilar drugs are not manufactured using the same type of cultures but their equivalence is
clinically tested against the original biological drug (originator). Biosimilar drugs are much
cheaper than originator drugs, so administrators recommend their use, but they can only be
used with certainty in patients who have never taken any biological drug.
On the other hand, there is some reluctance to replace (switch) a biological drug already in use

by the patient with a biosimilar one, because the two drugs are not identical. When you switch,
there may be either a loss of effectiveness of the medication or some side effects. The change
should be made in patients who are well, i.e. who have already achieved remission with the use
of the originator drug, bearing in mind that this may lead to a loss of efficacy in the patient's
therapy or a side effect. The switch, therefore, cannot be made automatically by the pharmacist
as is done with synthetic drugs. It has been declared by EMA and AIFA that biological and
biosimilar drugs are interchangeable but not substitutable. In the concept of interchangeability,
the doctor's judgment comes into play, which means that they can be changed, but the decision
and responsibility lies with the doctor. This is why the switch is not being used on all patients, at
least for the time being.

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The advent of biosimilars, however, has led to a great benefit as it has calmed prices in the
market. All originator drugs have been lowered in order to stay on the market. New biological
drugs, which came out after the advent of biosimilars, were also launched at a lower price than
the original price in order to align themselves with the price of biosimilars.

THE MAIN TARGETS OF BIOLOGICAL REPUTATIONS IN AUTOIMMUNE RHEUMATIC DISEASES

The main targets of biological drugs are cell receptors that transmit signals between cell and
cell and cytokines that mediate the signal between cell and cell and recognize cell receptors.
Recently, new synthetic drugs have been released that act, instead, on the intracellular signal
following the binding of cytokine to the cell receptor. An example are the inhibitors of JAK
kinases: intracellular enzymes responsible for signal transmission.

CITOCHINE
They are hormone-like protein substances used to transport information between cells.
Cytokines guide biological processes such as inflammation, immunity, cell growth and fibrosis.
They are produced by different cells that possess specific receptors and act essentially at the
production site. They have similar molecular structures and can be grouped into families.
Advantages of hitting cytokine as a therapeutic target:
 Small amounts of inhibitors are required to neutralize cytokine
 Many cytokines are up-regulated at the site of damage, such as at the site of
inflammation.
 They act as a cascade: by blocking a certain cytokine, the entire downstream process is
neutralized.
 They are accessible as extracellular and can be targeted with monoclonal antibodies or
soluble receptors.

Disadvantages of hitting cytokine as a therapeutic target:

 There is a potential or real redundancy between the various cytokines so that the
pathological function of a blocked cytokine can also be performed by other cytokines
having the same pathological function
 They cannot be blocked by small molecules, monoclonal antibodies and fusion proteins
are needed to block them, i.e. rather large molecules that cannot be taken orally, for
this reason all the biological drugs available must be administered by parenteral route:
initially the first biological drugs were administered by infusion and then gradually move
to the subcutaneous route that is easier to practice for the patient.

CYTOKINE-RECEPTOR INTERACTION

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The action of cytokine on the receptor results in the triggering of an intracellular signal that
causes a transcription factor to penetrate the nucleus to lead to the production of a pro or anti-
inflammatory substance.

CYTOKINES AS TARGET
One way to block the cytokine is to
administer a soluble receptor to
neutralize the target cytokine (soluble
receptors already exist in nature that
antagonize the cytokine receptors
acting as regulators of the cytokines).
The other way to neutralize the
cytokine is to use a monoclonal
antibody directed towards the
cytokine. The neutralizing antibody
binds the cytokine and prevents it
from acting on the receptor.

RECEPTOR AS TARGET
An antagonist receptor can be used
to block the receptor by binding it
and preventing cytokine-receptor
binding.
Or you can use a monoclonal
antibody directed towards the
receptor you want to target.
Anti-inflammatory cytokines are less
used for therapeutic purposes, a
possible application for lupus has
been seen but is still in the
experimental phase.

BIOLOGICAL AGENTS IN RHEUMATOLOGICAL DISEASES

The drugs currently available are TNF-α inhibitors, the first monoclonal antibodies to be
introduced: the first of all was Infliximab, followed by Etanercept and then Adalimumab, for
which biosimilars exist. There are five in all (see table).

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All five are indicated for the treatment of

rheumatoid arthritis. Etarnecept,
Infliximab and Adalilumab are indicated
for ankylosing spondylitis and psoriatic
arthritis. Etanercept is also approved for
the juvenile form of rheumatoid arthritis.
None of the TNF-α inhibitors are
approved for connective tissue.

For each of these biological drugs, there

are one, two or three biosimilar drugs
that compete with each other by entering
the market at ever lower prices. The fact
that there is more than one corresponding biosimilar drug complicates the question of the
therapeutic switch. If you want to change a patient's therapy using the cheapest biosimilar
drug, you go to multiple switches, i.e. over time you switch from one cheap biosimilar to
another cheaper one. This additional aspect complicates the concept of the switch between
originator and biosimilar and has not yet been studied. Competitions between biosimilars are
won depending on who offers the lowest price and in different regions of Italy, these can be
won by different drugs. This leads to the use of different biosimilar drugs in different regions.

Other biological drugs other than TNF-α inhibitors are, are:

 Anakinra (IL1-R) approved for rheumatoid arthritis
 Rituximab (anti-CD20) approved for rheumatoid arthritis, recently also for ANCA-
associated vasculitis
 Abatacept (anti-CTLA4-Ig) approved for rheumatoid arthritis and juvenile rheumatoid
arthritis
 Tocilizumab (anti-IL6R) approved for rheumatoid arthritis and juvenile rheumatoid
arthritis
 Belimumab (anti-Blys) currently approved only for lupus.
There are also more recent biological drugs:
 Secukinumab (Anti-IL17)
 Ustekinumab (Anti-IL12/23)
Both these drugs are currently approved in
patients with psoriatic arthropathy and
ankylosing spondylitis.
ANTI-NF DRUGS

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Synthesis and action TNF-α

TNF-α is one of the main pro-
inflammatory cytokines, it is very
present at the sites of inflammation. It
exists both in membrane related and
soluble form acting on two different
receptor types expressed on the
target cell: p75 and p55.
This cytokine performs a key task in
all inflammatory processes. It is
found in inflamed tissues, in
rheumatological diseases it is abundantly expressed in the synovial membrane of patients with
rheumatoid arthritis.
TNF activities are:
 Action in lymphoid organogenesis as it guides the development of secondary lymphoid
organs.
 Role in the regulation of the immune system as it controls the maturation of T, B and
dendritic cells and their interactions. It is able to inhibit the production of IFN-α which is
one of those cytokines of innate immunity that intervene in the early stages of systemic
autoimmune diseases. In patients with a particular genetic background, blocking TNF-α
may act as a trigger for the induction of autoimmune disease.
 It has a proapoptotic effect on apoptosis. If the TNF-α value is lowered, there is a
potential risk of an increased incidence of neoplasms.

By blocking these biological mechanisms, the lymphoid tissue organization, immunoregulation

and apoptosis are affected at the peripheral level with beneficial effects for inflammatory
disease.
However, at a central level this block can result in some unwanted effects, including:
 Autoimmune phenomena
 Infections
 Increased risk of cancer
Anti-TNFα drugs are not used in patients with
autoimmune rheumatic diseases. For example,
peripheral arthritis that can develop in lupus is
not treated at the peripheral level with an anti-
TNFα drug (although there may be a potential
local beneficial effect) because there is a risk of
worsening the systemic autoimmune process as
the anti-TNF unleashes the immune system.

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MEDICINES AGAINST
AMPHΑ
The image opposite shows
the five monoclonal anti-
TNFα antibodies:
 Adalimumab
(Human Ab)
 Golimumab (Human
Ab)
 Infliximab (Ab
chimeric)
 Etanercept (fusion
protein with human
Fc fragment and two
variable receptor
portions)
 Certolizumab pegol: pegylated construct consisting of a Fab fragment with a
polyethylene glycol support, making the molecule much smaller and less heavy.
While Etanercept binds only soluble TNF, monoclonal antibodies bind both soluble and
membrane bound TNF.

The five drugs have different molecular characteristics: molecular weight (Certolizumab has a
lower PM than monoclonal antibodies), pharmacokinetics, bioavailability, half-life. This

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justifies that the intervals of administration are different: Infliximab every 4 weeks,
Adalimumab every 2 weeks, Certolizumab pegol and Etanercept every week.
The only one to be administered intravenously is Infliximab, all the others are administered
subcutaneously.

ANTI-IL1 DRUGS
IL-1 is a key cytokine in the inflammatory process against which there are natural inhibitors, i.e.
naturally soluble receptors that have a regulatory role in the inflammatory process. IL-1 has
local effects in the tissue where it is produced and at systemic level, in fact it is one of the main
mediators of fever and intervenes in all general manifestations: myalgia, asthenia, neutrophilia,
headache. IL-1 is involved in the rheumatoid process having an effect on both inflammatory and
synovial cloth development, cartilage damage and bone resorption.
IL1 is involved in joint
inflammation, however the
first IL-1 inhibitor to be
introduced, Anakinra (receptor
antagonist occupying the
cytokine receptor site) has not
been very successful in
rheumatoid arthritis: it has the
effect of stopping the
radiological progression of
damage but is not very
effective on clinical
manifestations (pain, swelling).
Anakinra is used successfully in
systemic rheumatoid arthritis,
i.e. in systemic juvenile
rheumatoid arthritis and adult Still's disease, or in periodic fevers (autoinflammatory diseases
where inflammosome, the intracellular system leading to IL1 formation, is involved).
Canakinumab, the latest release of the three IL1 inhibitor drugs, is a monoclonal antibody
directed to the IL-1 receptor, indicated in patients with adult Still's disease, juvenile rheumatoid
arthritis or certain autoimmune diseases (TRAPS).
Rilonacept, released for second, has never been used much. It's a soluble receptor.

ANAKINRA: DOSAGE AND METHOD OF

ADMINISTRATION
A disadvantage of Anakinra, compared to antiTNF, is
that it should be administered subcutaneously once a

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day (100mg vials s.c.) with the frequent risk of local lesions appearing at the infusion site. These
local reactions are less frequent with new drugs because they depend on non-pharmacological
substances used and which have been tried to be eliminated in new drugs. To prevent injuries,
it is important to change the place of administration every day (different points on the belly,
arm, thigh, etc.). When these injuries appear, you should discontinue or change the medication.
If there are particularly marked lesions, you can try administering cortisone.
Local injuries are less frequent with Canakinumab because it is administered every three
months.
The fact that a drug has a short half-life gives the possibility to stop it abruptly in case of side
effects. If the half-life is very long, as in the case of Canakinumab, you have to wait for the drug
to be disposed of once it has been administered in case of side effects.

ANTI-IL6 DRUGS
IL-6 is the third major cytokine, after TNF and IL-1, involved in the inflammatory process. Recent
data suggest that IL-6 is the first to intervene, among the pro-inflammatory cytokines, taking on
the role of initiating the inflammatory process, determining:
 A local or systemic inflammatory effect (acute and chronic inflammation)
 A systemic effect: fever, asthenia, weight loss
 A marrow effect: stimulates hematopoietic cells
 An immune effect: stimulates B and T lymphocytes

Tocilizumab is a humanized antibody directed towards

the IL-6 receptor. It was initially produced to be
administered by intravenous infusion (8mg/kg e. v.)
once every four weeks. Subsequently, the
subcutaneous to be administered (162mg) once a
week also came out. Subcutaneous administration is
much more convenient as it does not require access to
the hospital, unlike intravenous administration which
costs the hospital and disadvantages the patient. More
recently another monoclonal antibody directed against
IL-6 has been introduced: Salimumab.
Abatacept does not block IL-1 but
intervenes in the regulation of the immune
system, in particular in the activation of T
cells.
In the interaction between T cell and APC
for T cell activation it is important that
there is:

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1) Interaction between TCR and Class II MHC

2) Bond between CD28 and CD80/CD86
3) Signal given by cytokines

Abatacept is a construct formed by:

 Fc portion of a human Ig
 Extracellular domain of CTLA4-Ig
(the transmembrane part is removed):
usually CTLA-4 is present inside T
lymphocytes; when these are activated,
CTLA-4 is expressed on the surface of the T
cell to limit its increase and perpetuation of
activation by blocking the link between
CD28 and CD80 because it has a much
higher affinity than CD28; this procedure
blocks the activation of the T cell.
Abatacept therefore goes to block the
costimulation process between lymphocyte and APC.
Abatacept was initially introduced intravenously (10mg/kg per day 1, 15, 29 and then every 4
weeks), now it is switched to the subcutaneous route (125mg) once a week.

NEW PHARMACIES
Anti-IL17
 Secukinumab is a monoclonal antibody that inhibits IL-17, produced by Th17
lymphocytes and other cells. IL-17 plays an important role in the development of
inflammation in many tissues and in the pathogenesis of many diseases, such as skin
psoriasis with psoriatic arthropathy, spondylarthritis, rheumatoid arthritis,
glomerulonephritis lupica. So far it has been more clearly identified in psoriatic
arthropathy and spondylarthritis. Blocking IL-17 has proven useful in all these diseases.
Secukinumab is administered at a dosage of 150mg in naïve patients to biological drugs.
If you are treating a patient who has not responded to a previous biological drug,
administer the 300mg dose of Secukinumab. This has economic implications as the
300mg dose costs twice as much as the 150mg dose is competitive with biosimilars. This
is an invitation to use Secukinumab at the forefront of organic farming.

 Ustekinumab: recent medication indicated for psoriasis and spondylarthritis. It is

directed against the p40 subunit, common to both IL-12 (for the development of

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cytotoxic T Th1 lymphocytes) and IL-23 (for the differentiation of T into Th17 with
production of IL-17).
It is currently indicated for the same diseases for which Secukinumab is indicated, but
with new studies it seems to be usable in other diseases, such as lupus.

In summary, there was talk of drugs directed towards cytokines, drugs directed towards T-
lymphocyte stimulation and activation such as Abetacept, oriented in the T-lymphocyte
blockade.

B-CELL APPROACH
The B cell produces minimal antibodies and is a precursor to plasma cells.
Plasma cells produce more antibodies than the lymphocyte B: they have a higher weight in
antibody production.
The B lymphocyte is also involved in antigen presentation and cytokine production, making it an
ideal target for intervention.

There are several ways to limit this cell:

 Acting on the CD20 receptor
 Block BLyS (or BAFF) with the administration of Belimumab, which acts on three
receptors present on the lymphocyte.
 Block CD22, receptor involved in homing through administration of Epratuzumab (drug
tested but without activation yet).

RITUXIMIMAB
The simplest approach is to use a chimeric monoclonal antibody directed towards CD20, a
receptor present on the surface, considered a calcium channel specific for B lymphocytes.
The binding between the monoclonal antibody and this channel can, through different
mechanisms, induce a calcium flow within the cell and the apoptosis of the lymphocyte itself.
Besides Rituximab there are other humanized monoclonal antibodies that bind CD20 such as
Atumunab, Ocrelizumab, and Veltuzumab.
The final effect is the depletion of all B
lymphocytes expressing CD20, i.e. all
stages of maturation from pro-B cells
to memory cells, only stem cells and
plasma cells are spared.
The use of mAb against CD20
preserves the regenerative capacity of
the marrow and the immune memory,
determining both positive and

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negative effects, since saving the immune memory means not eradicating the autoantibody
induced disease maintained by plasma cells with long survival.
If you do not have a drug to block these cells you can intervene on the disease, improve it and
heal it: to completely solve the disease you should find a system to destroy the memory cells.
In general, anti-CD20 drugs have advantages because they do not affect plasma cells that
produce protective antibodies.
Long-lived plasma cells are those that guarantee immune memory, they survive for 10-20 years.
It has been calculated that after a vaccine, general plasma cells can live for many years.
Long survival plasma cells are present in two settings:
 Traditionally they are present at the level of the niches of the marrow
 In inflamed tissues: if a patient has lupic nephritis or rheumatoid synovitis, these cells
are formed on the synovial membrane of the niches where these cells are present and
continue to produce autoantibodies: if this membrane is defused, the niches are
destroyed and the plasma cells go into apoptosis.
They can only be eliminated in inflamed tissues and not in the marrow because, at this level,
very toxic drugs, such as those used in multiple myeloma, should be used.
It has not yet been possible to find a drug that only eliminates plasma cells that produce
autoantibodies.
So far, only peripheral lymphocytes expressing CD20 with reduced plasma cell formation thrust
have been eliminated (supplies are removed).
It is a limited intervention because, after lymphocytic depletion following the use of Rituximab,
the marrow gradually repopulates and these CD20 lymphocytes reappear in the bloodstream.

When going to treat the patient there are two modes of administration:
o Scheme used for lymphoma: 375 mg/m2 once a week for 4 weeks
o Diagram used for rheumatoid arthritis and most frequently used in
rheumatology: two 1g infusions two weeks apart
After this cycle you have a complete depletion of CD20 lymphocytes.
CD20 lymphocytes in the peripheral circulation are present in 5-6 % of lymphocytes, after
treatment the percentage drops to 0%.
This depletion lasts on average 5-7 months, in some subjects it can last up to 12 months.
At one time Rituximab was used every six months redoing the cycle, now it tends to be used as
needed when symptoms of disease appear or when you have the repopulation of b cd20
lymphocytes.

BELIMUMAB

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Another mode of intervention is

represented by Belimumab, a
monoclonal antibody directed against
BLyS, a survival factor that acts on
certain receptors expressed in
different phenotypes of B
lymphocytes during lymphocyte
development.
They play a key role especially at the
level of some checkpoints, the most
important being at the level of the T1
type B lymphocyte. At this stage the
lymphocyte that recognizes the
antigen with high affinity goes into
apoptosis while the one that
recognizes the antigen weakly has time to express the receptor for the Blys and then pass the
check point.
In subjects who express a lot of BLys, protective B lymphocytes specific for antibodies directed
to both germs and self-reactive antibodies may pass these check-points.
Reducing Blys levels restores peripheral immune tolerance mechanisms.
The drug is administered intravenously at a dose of 10 mg/kg on days 1, 15, 29, and then every
4 weeks.
The subcutaneous form, which is administered once a week, has recently been placed on the
market.

All the drugs shown so far are medicinal products that have been indicated for a specific
disease because they have been found to be effective: a drug needs an articulated pathway to
be approved by AIFA or EMA and must be effective in at least two phase III randomized
controlled trials.

SIDE EFFECTS
Generally these drugs, given their selectivity in their mechanism of action, are better tolerated
than traditional synthetic drugs.
Immunosuppressants such as Methotrexate are drugs that act on all cells of the body which can
therefore give liver, kidney, gastric, hematological toxicity.
Biological drugs have a more targeted action, have less variable side effects, but going to block
specific mechanisms can give rise to side effects due to a specific intervention.
They can be verified:

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1. Infusion reactions at the injection site, or local reactions such as subcutaneous

administration
2. Infections: it is a complication since these drugs act on the immune system by limiting
inflammation and thus reducing a defense mechanism against germs.
Long-term studies have observed a recurrence of latent tuberculosis during treatment
with antiTNF, with fatal or very serious cases. This is because TNF contributes to the
production of the granuloma that forms around the mycobacterium of tuberculosis, the
use of anti-TNF drugs leads to the destruction of the granuloma.
Therefore, before starting therapy with these drugs it is appropriate to do:
 An accurate history to identify patients who may have had contact with
mycobacterium
 Chest x-ray screening and a Quantiferon test.
If the patient has a latent tubercular infection, antitubercular prophylaxis is mandatory
before biological therapy.
These drugs can induce opportunistic infections because these patients often take an
underlying drug such as Metatrexate or cortisone in combination with the biological
drug.
They are all medicines that have an effect on the immune system and can therefore
contribute to the development of these infections.
Rituximab, in the long run, can induce a reduction of immunoglobulins and in some
cases, an acquired immunodeficiency.
It is important to evaluate the number of blood cells over time, such as neutrophils,
lymphocytes but also IgG-IgM to understand if the immune system is intact.
They can also reactivate or worsen viral infections such as HCV or HBV: hepatitis
markers must be performed before treating these patients with biological drugs.
If the patient has active hepatitis B and you still want to use one of these medications,
you should also treat this disease.
Now the dynamics for the treatment of HCV have changed, you have drugs that induce
healing: this is something to take into account.
3. Lymphomas and solid tumors: official epidemiological studies have not shown a real
increase in patients treated with these drugs, partly due to the difficulty of
demonstrating such an event because the disease itself involves an increased risk of
certain types of neoplasms or even probably, when we use these drugs, we do not
completely suppress cytokines.
If we administer anti-TNF drugs to these patients we do not completely eliminate this
molecule at the circulating or inflamed tissue level, but we down-regulate it and also for
this reason the real risk of developing neoplasms is not a phenomenon that can be
identified with great certainty.

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Obviously the inhibition of the immune response is not such as to cause tumours; it is
necessary to assess on a case-by-case basis, paying attention to the possible presence of
additional risk factors.
4. Haematological disorders: more common with anti-IL6 that act on the maturation of
haematopoietic cells. IL-6 is an important regulator of the development and maturation
of hematopoietic cells and blocking this cytokine can lead to anaemia, reduction in the
number of white blood cells and lymphocytes.
5. Cardiovascular manifestations: more have been observed with the use of anti-TNF that
were initially used for the treatment of heart failure.
It was then seen that the use worsened the regulation in the development of the heart
muscle.
These drugs can have a protective effect against accelerated atherosclerosis because
they reduce the inflammatory state.
In some studies, a reduction in cardiovascular events was observed with the single use
of Metatrexate or in combination with biological drugs to reduce the inflammatory
process at the atheroma level.
Hypertensive crises can rarely be present.
6. Alterations in liver function: not very significant and infrequent
7. Psoriasis: paradoxical effect of antiTNF; infrequent
8. Neurological disorders: anti-TNFs rarely induce demyelinating peripheral neuropathy.
TNF is involved, in fact, in the myelination of nerve fibres.
9. Autoimmune disorders: Increasing INF stimulates the immune system and in the
predisposed subject can lead to the production of autoantibodies.
10. Vasculiti
11. AntiTNF-induced chronic interstitial pneumonia: it is a rare event

These are the main effects, some are very rare, on average this class of drugs is well tolerated.
The type of action requires special attention from the doctor especially for certain effects.
SMALL MOLECULE INHIBITORS
These drugs have recently entered the market in Italy.
They inhibit the molecules that are involved in signal transmission within the cell.
In this process the receptor is activated by the cytokine, there is a cascade of events until the
activation of the transcription factors and the transcription of some proteins or cytokines.
The molecules involved in the signal are protein kinases: enzymes responsible for transferring a
phosphate molecule from ATP to a target molecule, a dormant protein, which is activated after
receiving this phosphate molecule.
There are two ways to intervene on protein kinases from a pharmacological point of view:
1. Competitive inhibitors: drugs go to block the pocket for ATP, it is the most used.
2. Allosteric inhibition: drugs that bind to kinase, change its form and ATP cannot bind.

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In the picture you can see the numerous

signal paths, each characterized by
different types of kinases.
The most studied are the Jak-chinasi, on
which the available drugs have been
produced and approved. The JAK family
includes four different isoforms: JAK1,
JAK2, JAK3 and tyrosine kinase 2; they are
targeted by STAT.
The number of drugs studied is numerous:
the most used are Tofacitinib and
Baricitinib which go to block certain
members of the JAK family.
Tofacitinib inhibits Jak3, Jak1 and Jak2,
Baricitinib Jak1-2.
These differences translate into small
differences in the biological effect of these
inhibitions.
These drugs have a similar clinical effect, but
there may be differences in side effects.
These are drugs that intervene on numerous
isoforms: the situation will be different when
selective inhibitors that only inhibit a specific
isoform will come on the market.
Although there are small differences between
the various drugs, the effects are basically quite
overlapping.
These drugs have the advantage of being
administered orally and have characteristics
and clinical efficacy that are quite comparable to biological drugs.
They are preferably used in association with Methotrexate in rheumatoid arthritis and psoriatic
arthropathy.
In patients who do not tolerate Methotrexate they can also be used in monotherapy.

The side effects of small molecule inhibitors are non-specific as they have a diffuse intracellular
action and cannot be traced back to a single transduction pathway. For example, many inhibit
INF-1 and therefore may give a higher frequency of cases of Herpes Zoster.

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DIFFERENCES BETWEEN SMALL MOLECULES AND BIOTECHNOLOGICAL INHIBITORS

 Inhibitors small molecules: they are small molecules, stable at T environment, also
administered orally, good efficacy, intracellular action mechanism acting on several
pathways
 Biotechnological drugs: they are large molecules, unstable to T environment (must be
stored in the fridge), have a complex structure, are administered by EV or SC, good
efficacy, have a specific mechanism of action.

FIBROMYALOGY
Fibromyalgia, or fibromyalgia syndrome, is a very frequent rheumatological pathology
characterized by chronic musculoskeletal pain spread throughout the body that is accompanied
by a large number of other symptoms (sleep disorders, anxiety, depression, intestinal disorders,
...), but no organic disorders.
The pain is due to an altered perception of the peripheral stimuli it causes:
- Hyperalgesia, increased pain sensitivity with reduced pain threshold.
- Allodynia, altered tolerance to many non-painful stimuli such as pressure, temperature
changes, cold and heat.

All accompanying symptoms are listed in this slide.

What they all have in common is the fact that, if one goes to investigate with analysis in search
of the nature of these manifestations, one does not find any organic alteration.

EPIDEMIOLOGY
It is a frequent disease and is the most common cause of chronic diffuse pain.
It has an estimated prevalence of 2-5% worldwide.
However, there are substantial differences according to gender and age:
- the female sex is much more impressed, with a 10:1 ratio than the male.

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- the age of greatest onset is 35-60 years, working age (the disease can be debilitating
and lead to a significant loss of working days due to the high prevalence).

The graph analyses the distribution of pain sensitivity

in the general population: while the general
population (in grey) shows a Gaussian, in fibromyalgia
there is an unbalanced distribution towards
hyperalgesia (which then translates into allodynia).

EZIOPATOGENESIS
Alterations in the perception and interpretation of
stimuli could find a cause both at the
receptor level and at the medullary or
central level; in fibromyalgia the cause is
to be found at the central level, where
there is hypothalamic-pituitary
hyperactivity with alteration of
neurotransmitters (substance P
increases, serotonin decreases); this
results in central hyperalgesia.
Various stimuli act on this mechanism as
predisposing factors:
 physical or psychological stress
 traumas
 infections
 hormonal factors, which explains the imbalance for the female gender
 familiarity, there may in fact be genetic predisposition

Moreover, this alteration clearly leads to mood disorders, but mood disorders in turn can
promote hyperalgesia.
Similarly, these alterations lead to sleep disturbances that are a predisposing factor for
hyperalgesia.
This creates a vicious circle between hyperalgesia, sleep disorders and mood disorders.
Hyperalgesia results in increased fatigue, poor physical activity and reduced endorphin
production; consequently, muscle alterations such as contracture and sensitization of
nociceptors can be seen, which further amplify central hyperalgesia.

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The main manifestations of fibromyalgia are therefore:

 Diffuse, chronic pain, described by the patients as a "burning/sensation of needles
piercing the skin" or in any case with very extreme adjectives that imply a real suffering;
there is also the presence of 18 tender points, areas where the pressure evokes a
particular pain that does not radiate but remains well localized at the point of pressure
 Sleep disorders, mainly characterized by non-restorative sleep, but also nocturnal
awakenings and difficulty in falling asleep; these disorders can be objectified by means
of a polysomnography
 Muscle rigidity/asthenia, present throughout the day, with extreme fatigue at
minimum physical effort.

On a cognitive level, there can be several symptoms, the most characteristic of which is the
"fibro fog": the patient feels his mind muffled and has difficulty concentrating, generally
describing him with the feeling of feeling "empty head".
In this slide some of the characteristic symptoms of fibromyalgia are again summarized.

Clearly not all these symptoms occur at the same time, but all of them are likely to appear
during the patient's lifetime.

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This complex symptomatological picture is affected by several external factors that can both
attenuate and worsen some of the symptoms:
 Pejorative factors:
- Stressful events (the fibromyalgic patient generally has a particularly
uncomfortable family, work, social situation, often they are people who have
suffered psychological or physical trauma)
- Atmospheric variations (cold, heat, humidity, rain, ...)
- Inactivity/Operative
- Anxiety, depression
 Improvement factors:
- Atmospheric variations (sun, mild temperature, ...)
- Moderate physical activity (so as to reduce muscle contracture and produce
endorphins)
- Sleep well
- Caloric applications (such as mud therapy cycles).

CLASSIFICATION
A distinction is made between primitive fibromyalgia (60%) and associated fibromyalgia (40%).
Associated fibromyalgia can be associated with other rheumatic diseases (rheumatoid arthritis,
systemic connective tissue, osteoarthritis) or other morbid conditions (thyroid disease,
psychiatric diseases, diabetes or others).
In these associated forms, if the underlying pathology is adequately treated, the fibromyalgic
component is most often resolved.

LABORATORY AND INSTRUMENTAL TESTS

The reported clinical manifestations are not matched by instrumental or laboratory tests:
 Indexes of systemic inflammation in the norm
 No signs of autoimmunity (FR, gamma-globulins, C3 and C4 in the norm)
 Normal muscle enzymes despite muscle weakness and pain
 Muscle biopsy within limits
 Electromyography shows nothing
 All radiological examinations in the norm
Sometimes it is found positive for antinuclear antibodies, but at a low titre and therefore
without specificity.
The enormous gap between the magnitude of symptoms reported and the results of the
investigations leads on the one hand to the frustration of the physician who, failing to find a

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match for the symptoms, risks underestimating what has been reported and releasing patients
who actually suffer from the disease, and on the other hand to frustration of the patient who
does not feel that he is taken seriously by the doctor.
At the same time, however, there is a risk of overdiagnosis of fibromyalgia: the patient who
goes to the doctor 2-3 times complaining of pain is often labeled as fibromyalgia, especially if
they are female or have some mood alterations.
It is therefore a difficult diagnosis and classification criteria have been developed on which to
base a correct diagnosis.

DIAGNOSIS
The ACR (American College of Rheumatology) classification criteria of 1990 are in fact based on
the exclusion of the presence of other underlying diseases when in fact these could be present
and fibromyalgia is associated with them.
To formulate the diagnosis of fibromyalgia with these criteria it is therefore necessary that:
 diffuse pain has lasted for at least 3 months (it must be bilateral, above and below the
waist and there must be axial skeletal pain in at least one site)
 you have acupressure pain of at least 11 out of 18 tender points.
The ACR 1990 criteria have 86% sensitivity and 81% specificity, therefore not brilliant.

The tender points have the distribution

shown in the slide and require
acupressure with a force of about 4
kg/cm². This can be measured either
with special digital algometers (small
machines that apply pressure by means
of a piston) or, as is typically done in
clinical practice, it is squeezed with the
thumb until the nail bed becomes pale.
With the new 2016 diagnostic criteria,
however, the tender points, which were
fundamental for diagnosis according to
the 1990 criteria, have lost much of
their importance.

The RTA 2016 classification criteria are

met if there are at least 3 of the following 4 conditions:
1. Index WPI ≥ 7 and score SSS ≥ 5 or WPI of 4-6 and score SSS ≥ 9.
2. Diffuse pain in at least 4 of 5 body regions (axial, upper left, upper right, lower left,
lower right).

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3. The symptoms have been present for at

least 3 months.
4. The diagnosis of fibromyalgia is valid
regardless of other diagnoses. A diagnosis
of fibromyalgia does not exclude the
presence of other clinically important
diseases.
The WPI (Widespread Pain Index) is a value that
identifies the number of regions in which the
patient has had pain during the last week. It has a
value between 0 and 19, depending on how many
areas are sore. It includes:
1. Upper left region: left jaw, left shoulder, left arm, left forearm.
2. Left lower left region: left hip, left thigh, left leg.
3. Upper right region: right jaw, right shoulder, right arm, right forearm.
4. Lower right region: right hip, right thigh, right leg.
5. Axial region: neck, upper back, lumbar part of the back, chest, abdomen.

The SSS (symptom severity scale) score is a score that considers fatigue, asthenia and cognitive
symptoms. Each of these is assigned a score between 0 and 3 depending on the magnitude of
the symptoms; to this is then added another point for the presence of each of the symptoms
between headache, abdominal pain and depression. A final value between 0 and 12 is thus
reached.

The ACR 2016 criteria have therefore been used to make the assessment of pain more
objective. It is important that the diagnosis, if these conditions are met, is still feasible
regardless of other underlying diseases. It is therefore no longer a predominantly exclusionary
diagnosis.
When compared, the new
classification criteria are able to gain
considerably in sensitivity compared
to those of 1990.

However, differential diagnostics

remains a very important aspect when
talking about Fibromyalgia.
The first distinction should be made
for the presence or absence of
structural alterations highlighted by

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examinations. Excluding the presence of structural alterations, the differential diagnosis is

mainly with psychological/psychiatric disorders (major depression, OCD, bipolarism, post-
traumatic stress disorder, generalized anxiety disorder, panic attacks), syndromes with loco-
regional pain (IBS, interstitial cystitis, temporomandibular joint dysfunction, idiopathic lumbar
pain, tension headache, vulvodinia) and chronic fatigue syndrome, which has many features in
common with fibromyalgia.

In this area there may be significant overlaps between fibromyalgia and other disorders that do
not result in obvious tissue damage, but rather an amplification of sensory and pain.

Fibromyalgia, as already mentioned, is very often associated with psychiatric disorders.

You have comorbidity with:

 eating disorders (odds ratio 2.4)
 anxiety disorders (odds ratio 6.7)
 substance abuse (odds ratio 3.3)
 major depression (odds ratio 2.7).
It is not really clear whether it is the psychological disorders that predispose to fibromyalgia or
vice versa.

CHRONIC FATIGUE SYNDROME (CFS)

It is not a rare disease and differs from fibromyalgia syndrome primarily because what prevails
is not so much pain as persistent fatigue (lasts more than 6 months). It has a certain degree of
overlap with fibromyalgia since it is associated with symptoms that could place it in differential
diagnosis with it as:
- Cervical or axillary lymphadenopathy;
- Joint pain (in CFS it is more localized than in fibromyalgia);
- Non-restorative sleep;
- Headache;
- Malaise after exercise;
- Throat inflamed;
- Short-term memory loss.
The causes are not known for CFS either, but there is more evidence that it has an organic
substrate and is likely to be linked to some kind of viral infection, not by a specific virus. It is
probably determined by an abnormal response of the immune system because very often it
appears a few months after a clear viral infection. It seems that the administration of
intravenous immunoglobulins may be beneficial, in contrast to fibromyalgia, a condition for
which they are ineffective.

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MYOFASCIAL PAIN SYNDROME (MPS)

It is another pathology that can enter into differential diagnosis with fibromyalgia. In this case
we are not talking about Tender points but about Trigger points located at the muscle or fascia
level, whose compression evokes a pain that is not limited to the point where pressure is
exerted but spread to the whole muscle. Myofascial trigger points are more frequent in FM
patients than in the general population. Hyperalgesia of MPS is regional and in this it differs
greatly from fibromyalgia. Usually it is possible to identify a possible cause such as direct muscle
trauma or muscle overload. The prevalence of somatic symptoms is low. MPS generally resolves
in a few weeks without the need for any intervention by the doctor.

APPROACH TO THE FIBROMYALGIC PATIENT

The fibromyalgic patient has nothing organic altered so the approach consists of:
- Human and temporal availability because you might often think that the patient invents
symptoms that complain to get attention;
- Information on the reality of the pathology and reassurance on its benignity because
often the patient is anxious and agitated considering the disease very serious,
irreversible and completely invalidating. This is true to a certain extent because in the
absence of organic alterations if the disease is well controlled there is no long-term
consequence;
- Attention should be paid to lifestyle habits, family or occupational environment since
the external environment, youth trauma and stress can be a trigger for the disease;
- Insistence on the need for prolonged treatment because one cannot think of helping the
patient by limiting the treatment to one or two months.
First of all, it is important to educate the patient: he or she must be informed about his or her
condition and possible methods of treatment. The actual treatment is both pharmacological
and non-pharmacological.
As far as pharmacological treatment is concerned, there is no drug for fibromyalgia and there
is hardly any patient who benefits from a single drug, very often the therapy is combined with a
"step-up/step-down" mechanism (one drug is added at a time or many drugs are administered
at the same time which are then scaled down as a result is obtained). There are no specific
guidelines, much depends on the patient's acceptance of the treatment.
The drugs for which we have strong evidence of effectiveness are basically those that act on the
central nervous system at the level of pain but also the mechanisms of amplification of pain
sensation, tricyclic antidepressants, serotonin and noradrenaline (duloxetine) re-uptake
inhibitors and some antiepileptic drugs (gabapentin, pregabalin). Myorelaxants are widely
used especially in the evening because they relax the muscles during the night and increase the
duration and quality of sleep.
There is little evidence of effectiveness with analgesics and some selective serotonin re-uptake
inhibitors.

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There is no or weak evidence for opioids, corticosteroids, NSAIDs, hypnotics, thyroxine, DHEA,
melatonin, calcitonin. Cannabis has also started to be used, with which there is a fair amount
of benefit.
The non-pharmacological treatment consists of kinesiotherapy (aerobic exercise and
stretching) and cognitive-behavioural psychotherapy, especially in patients with psychiatric
comorbidities.
Alternative therapies such as acupuncture are also possible. It can be said that each of these
practices works as long as the patient is convinced, because of the placebo effect (statistically it
works in 20% of cases of any disease).
These different types of treatment should not be understood as successive levels because the
correct approach is to act on all these aspects simultaneously. Clearly the patient must first of
all be treated, but drug therapy must be combined with kinesiotherapy and psychotherapy.
The following figure gives a brief summary of the main differences between fibromyalgia,
polymyositis and polymyalgia. In fibromyalgia it is the symptom that prevails, muscle pain and
weakness, but there are no positive inflammatory indexes or markers of hypothetical damage
to the muscle fiber, which is not the case in polymyositis. In polymyalgia there is no muscle
damage but there is inflammation. It is important to be familiar with these distinctions so as not
to make a hasty (and probably wrong) diagnosis by labelling the patient as fibromyalgic.

SEPTIC ARTHRITIS (AS)

Septic arthritis is the inflammation
of the joint due to the location of
a microorganism (bacteria,
viruses, fungi) within the joint. It
should not be confused with
reactive arthritis in which the

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infectious agent leads to an extra-articular infection resulting in an inflammatory response in

the joint, but which remains sterile.
It is a pathology capable of causing rapid onset of serious and permanent damage if not
recognised and properly treated. In addition to local damage, which is permanent damage
because the joint is destroyed, it can be associated with increased mortality because the germ
can enter the bloodstream and give sepsis. It can also happen that septic arthritis is the
expression of unrecognized sepsis. It is considered an emergency situation. It can affect any
joint.

EPIDEMIOLOGY
The incidence in Europe is 4-10 cases/100000 subjects/year. It can affect any age even if the
groups most affected are children (<15 years) and adults over 55 years. In subjects with
rheumatoid arthritis the incidence is higher than in the general population, 30-70 cases/100000
subjects with AR/year, because of the therapies to which these subjects are subjected
(immunosuppressive and immunomodulatory drugs, cortisone, methotrexate, biological drugs)
but also because these patients often undergo intra-articular procedures such as infiltrations,
arthrocentesis that can create doors of entry for the various microorganisms.

RISK FACTORS
These are risk factors:
- Age;
- Rheumatoid arthritis and osteoarticular diseases;
- Joint prosthetic procedures, although we try to minimize the risk of infection in the
operating room;
- Low socio-economic rate;

- Alcoholism;
- Drug addiction;
- Diabetes: In diabetics, ulcers that are difficult to heal are possible entry routes for
microbes;
- Skin ulcers;
- Immunodepression;
- Dialysis therapy;
- Intra-articular injections.

ETIOPATHOGENESIS
The iatrogenic pathway as a result of diagnostic or therapeutic procedures is one of the most
frequent ways of accessing infectious agents within the joint. Microbes frequently enter the

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joint as a result of penetrating trauma. Spread from an infectious outbreak located in the
periarticular soft tissue (for contiguity) or from an adjacent osteomyelitis (for continuity) is also
possible. In an elderly subject with sepsis, microorganisms can enter the joint hematogenously
from a distant outbreak. In 20-30% of cases the etiopathogenesis is unknown.
The professor lists the microorganisms most frequently involved in septic arthritis related to the
age group.

These microorganisms trigger a very important local immune response with the production of a
series of cytokines and other mediators that result in indirect damage to bone in addition to the
direct damage of microbes.

JOINT IMPLANT INFECTION

It is a particular case of septic arthritis that almost always involves the need to remove the
prosthesis because the adhesion of microorganisms to it is facilitated by the presence of
fibronectin and fibrinogen, reduced vascularization and the ability of these to form biofilms that
increase resistance to defense mechanisms and antibiotic therapy. If the prosthesis were left in
place, beyond the possibility of spreading germs, there would be a real risk of
evolution into osteomyelitis. It concerns the hip and shoulder prostheses in 1% of cases, the
knee in 2% of cases and the elbow in 9%.

CLINICAL FRAMEWORK
Generally septic arthritis presents as acute monoarthritis with involvement of large joints,
however polyarticular involvement (more severe form) is possible in case of pathogenic
dissemination, usually in immunodepressed subjects. In patients with rheumatoid arthritis
septic arthritis is more frequent and in the case of well-controlled AR when there is a relapse
affecting a single joint in which a therapeutic procedure may have been performed recently,
septic arthritis must be immediately suspected.
It can occur in 60% of cases with a fever generally below 38°C.

LABORATORY TESTS
Septic arthritis is accompanied by an increase in phlogosis indices (ESR, PCR) but not
necessarily. Procalcitonin, which normally helps to identify infectious pictures, in septic arthritis
has an uncertain meaning, sometimes it is increased, sometimes it is not. By far more useful is
the analysis of synovial fluid: greenish-yellow colour, turbid appearance, GB> 50000/mmc with
PMN>95% are indicative parameters of infection and septic arthritis. It is then essential to send
the liquid into culture, also to decide the therapy in a targeted way, but unfortunately in 33% of
cases the result can be negative, so a negative culture does not allow to exclude AS.

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Verosimilarly without waiting for the cultures of the liquid in the presence of these
characteristics of synovial fluid you start to treat the patient.

IMAGING
Instrumental examinations (X-ray, CT, scintigraphy, MRI) are not helpful in confirming the
diagnosis. FDG-PET is used a lot in case of suspected prosthesis infections. The association of
PET with FDG and CT/RMN is used because it allows to highlight collections of periprosthetic
inflammatory fluid and to monitor the response to therapy over time.

DIFFERENTIAL DIAGNOSIS
Septic arthritis goes into differential diagnosis with:
- Rheumatoid arthritis: we must be able to discriminate against the exacerbation of the
underlying disease,
involving a single articulation from an overlapping infectious picture, the analysis of the
synovial fluid is indispensable;
- Psoriatic arthritis: it is often a mono-oligo arthritis, and can also lead to a major spill,
especially at the knee level, which can be misleading;
- Trauma;
- Hemophilia;
- Osteomyelitis;
- Lyme disease;
- Arthritis caused by microcrystals, especially monosodium urate arthritis, which evokes
an acute inflammatory picture (redness, edema, flaky skin). Sometimes doing
arthrocentesis can be found microcrystals in the course of septic arthritis, the features
clinics and the liquid, beyond the presence of the crystals, should suggest sending the
liquid
in culture.

THERAPY
The patient should be treated as early as possible because septic arthritis evolves very quickly,
over the course of days the joint can be irreparably compromised. While waiting for the culture,
an empirical therapy based on the patient's characteristics (age, comorbidity, allergies) is
started depending on the severity of the clinical picture.
The classic choices are:
- amoxicillin/ac.clavulanic + quinolonic;
- third-generation cephalosporins;
- vancomycin;
- dapotomycin or linezolid (inf. nosocomial).

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Antibiotic therapy is prolonged, initially administered in an inpatient for 3 weeks to achieve

adequate joint concentrations. Afterwards, oral therapy is continued for another 3 weeks, but
the timing may be even longer depending on the patient's response. Even if after the first 3
weeks the patient is clinically well, the therapy should be continued to avoid the risk of a
relapse or an evolution towards osteomyelitis.
In addition to antibiotic therapy it is very important to drain the joint by arthrocentesis because
the synovial fluid is colonized by bacteria and phlogistic substances, thus reducing the microbial
load. The operation must be repeated daily in a serious manner because the speed at which
synovial fluid is formed is extremely high (the day after drainage the fluid is almost completely
reformed).

PROGNOSIS
If antibiotic therapy is not adequate or the infection is not promptly treated (within 24-48 h)
the patient may present residual permanent damage with loss of joint function in 25-40% of
cases. If the cartilage part of the joint is affected, this results in early arthrosis. The mortality
rate is 0.7%, but reaches 9.5% in the elderly.

We would like to remind you of the Rheumatology integrative didactics meetings, which will not be an
examination subject but are highly recommended.

ALGODISTROPHY
Algodystrophy is a complex pathology characterized mainly by severe pain, soft tissue swelling
and autonomic vasomotor dysfunction, associated with trophic disorders and functional
impotence of the involved joint. The initial picture is therefore characterized by intense pain
that evolves to the point of functional impotence. The peculiarity of this pathology is that it is
not a picture of inflammatory nature, as rheumatoid arthritis is.
Many syndromes have been identified that are included in algodystrophy, so there are many
synonyms: causalgia, acute bone atrophy, Steinbrocker syndrome, Sudeck's disease,
sympathetic reflex dystrophy, etc..
The term algodystrophy is losing importance as it is defined by international classification as
Complex Regional Pain Syndrome (CRPS) type 1; there are two types of CRPS:
 Type 1. Algodystrophic syndrome (in European literature), resulting from local
muscular/skeletal trauma. In overseas literature it is defined as sympathetic - reflex
dystrophy.
 Type 2. It's the result of trauma to a nerve fiber, a nerve.
In fact, they are painful syndromes that arise after a traumatic event but are disproportionate
to the event that causes them, which can also be minor, causing a regional painful syndrome
that persists over time.

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EPIDEMIOLOGY
It's an infrequent disease.
There's two bands of insurgency:
 Pediatric age: it is not uncommon to find pictures of algodystrophy especially in women.
 Adult age: 40-60 years, more in the male sex.
The incidence is not known exactly because of the diagnostic inaccuracy: in some cases the
manifestations may be overestimated, while in others it is underdiagnosed because the clinical
picture may be blurred or resolve spontaneously over time.

EZIOLOGY
The precise aetiology is not known, but in 50% of cases these painful regional syndromes arise
after a traumatic event; however, it is not possible to identify the trauma really triggering
because they are of variable severity: from fracture to repeated micro-traumatisms. This
damage can involve skeletal and articular structures as well as nerve branches and soft tissue.
The problem is that a trauma of the same entity with apparently the same consequences only
in some cases is responsible for the triggering of algodystrophy: evidently there are genetic and
congenital associated factors that have not yet been identified.

In addition to marked pain, algodystrophy is

characterized by dysfunction of the
autonomic nervous system, which causes a
cyanosis (in this case of the foot) that is not
related to occlusive factors of the vessels,
but simply to a reflex motor vessel that leads
to the appearance of venous stasis, bluish
color and cooling of the skin, paresthesias.

In addition to direct trauma, there are other

factors associated with impatience with the
disease:
 Immobilization (Sudec's syndrome, situation of algodistriphy appearing after
immobilization by plaster cast, after removing the plaster the limb is atrophied with very
serious autonomic neuropathy problems)
 CNS and SNP disease
 Cardiovascular diseases, in particular thrombophlebitis and coronary thrombosis
 Endocrine metabolic disorders (diabetes, hyperthyroidism, hypertriglyceridemia)
 Neoplasms

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 Non-traumatic diseases of the locomotor system (inflammatory, metabolic, infectious

and neoplastic diseases)
 Algodystrophy in the 3 trimester of pregnancy and postpartum
 Surgical interventions
 Intra-articular maneuvers
 Antitubercular and barbiturate drugs
 Patients with a tendency to anxiety and depression may experience algodystrophic
manifestations.

PATHOGENESIS
We don't exactly know the pathogenesis. A reflex mechanism
seems to be involved, whereby, starting from a peripheral
stimulus, the interpretation of the pain occurs at central level and
the activation of the SNA is reflexively induced; this leads to the
symptomatological procession, given mainly by intense
neuropathic pain reported as burning, which limits the movement
of the affected segment, in addition to the cyanotic
manifestations on the skin caused by the vascular spasm. A vicious
circle is formed in which the pain stimulates the activation of a
second autonomic response that is maintained over time.
Although there are several situations associated with the onset of
algodystrophy in about 1/3 of cases are idiopathic forms usually
involving the lower limb (43%), especially the coxo-femoral joint,
and in 27% the upper limbs.
In the image on the side you can see the typical
swelling that is diffuse and not localized on a
single joint, but above all it is NOT inflammatory
in nature: for example at the EO in fact it is not
appreciated increase of heat to the
thermotatto, so it is defined as diffuse swelling
of non-inflammatory nature.

LOCALIZATION
- It is frequently referred to an entire
distal segment (hand-foot)
- Usually it is monolateral and rarely
manifests as bilateral
- If involved in a trauma or immobilized, the location of the pathology is that of the
damaged district.

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- It is not uncommon to involve the shoulders and knees while it is not uncommon to
have the parcel involvement of one or more metacarpophalangeal radii, or a single
femoral condyle.
- There is a form called transient hip osteoporosis or regional migrant osteoporosis that
affects the coxo-femoral district, whose manifestation is right-left migrant.

CLINICAL
Clinically there is a certain variability from patient to patient, and it depends on the location,
intensity and duration of the symptomatology; as a consequence sometimes the diagnosis can
be delayed, imprecise, until it is not formulated in time (therefore it is possible to make a
diagnosis only when there are irreversible alterations).
The affected district shows a change in skin colour due to autonomic activation, associated with
alteration of the skin annexes with loss of the hair annexes, hypersurination and pain
accompanied by significant functional impotence: the affected segment is disabled due to
severe pain.

STAGES OF THE DISEASE

There are classically three phases that cannot always be found because they can blur one over
the other resulting in incomplete or modified forms of therapy.
1. Inflammatory phase. It is the first stage of the disease and is characterized by:
- Intense pain of the neuropathic, stabbing/extractive type described as burning
- Continuous pain, exacerbated by loading and movement, even at night; the patient
tends to take analgesic positions to avoid loading the limb concerned
- Allodynia and hyperpathy (just touching the skin with mild or moderate stimuli evokes
intense pain. The patient does not want to be examined for the intensity of the pain. )
- Reduced tactile and thermal sensitivity ('glove' or 'stocking')
- Anti-inflammatories and analgesics are not very effective
- Tumefaction variable from modest to pseudophlegmose
- Vasomotor disorders (subcyanosis, erythema, paleness) are the ones that orient
towards differential diagnosis.
- Skin alterations (subungueal dystrophy and related hair dystrophy)
In the initial phase a differential diagnosis can be made with arthritis for the presence of pain
that increases at night, however in the case of algodystrophy there are no characteristics of
local inflammation as in arthritis (the joint will not be warm to the touch).

2. Dystrophic phase. It typically appears after 3-6 months.

There are further alterations of the skin that becomes cold, shiny, loses elasticity and a
functional deficit of the joint begins to appear due to the loss of elasticity; the loss of
joint functionality is therefore no longer only functional (i.e. due to an analgesic attitude

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of the patient), but it is also structural: it creates a thickening of the joint capsule that
causes a physical block to mobility.
This picture is accompanied by muscle mass contracture and hypotrophy resulting from
both the antalgic attitude of immobility and the lack of afferences to the SNA and the
alteration of the vascularization processes.
There is a thickening of the fascia at the palm and plantar level.
In general, therefore, there is the evolution towards a restorative framework towards
the district concerned which, however, increasingly limits the functionality.

3. Atrophic phase. It is the final stage of the disease in which a picture of skin and
subcutaneous atrophy prevails associated with progressive fascial and capsular
contractures that become irreversible. There is an evolution towards loss of function
due to impairment of the para-articular structures and the joint capsule itself without
erosive damage as in the case of arthritis.

According to Steinbrocker's staging, you have division in:

- Stage 1: major pain and hearing, swelling, hyperhidrosis, increased skin temperature,
erythema
- Stage 2: pain, cyanosis, initial skin atrophy, cold skin, initial joint stiffness
- Stage 3: atrophic and cold skin, joint stiffness, modest or absent pain: what dominates is
the joint disability, preventing any movement of the affected joint segment.

LABORATORY TESTS
Phlogosis indices and phospho-calcium metabolism are normal. Since there is no effusion, the
joint is not pricked (unless a possible differential diagnosis with monoarticular arthritis), but if it
were to be done, a non-inflammatory and basically normal synovial fluid would be found;
The histological examination is not performed, if it were done a synovial hypervascularisation
without inflammatory cellular infiltrate would be observed, and in the bone there would be
variable aspects from osteoclastic resorption to neoapposition, to normality depending on the
various stages of evolution; basically there are histological non-specific alterations.

IMAGING
To help with the diagnosis so you need diagnostic imaging.
 RX: X-ray alterations appear after weeks or months; damage is only seen in late stages:
spotted osteoporosis, a characteristic but not early sign, particularly marked in the
subchondral site. It is important to perform bilateral X-rays to compare with the
contralateral joint.
Unlike arthritis, bone demineralization is not only subchondral.

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The reduction of joint rhyme (cartilage is not

affected) or pictures of bone sclerosis are never
observed.
X-ray alterations are not specific and can also be
observed in other conditions where increased bone
turnover is present.
The image on the side allows the left hand to observe
areas of diffuse radiotransparency compared to the
contralateral, which indicate spotted osteoporosis.

In this image you can see a

radiotransparent line that may
look like a fracture line but is actually an area of osteoporosis.

The Rx is therefore an examination that is used but is not useful in

making an early diagnosis, while it is more functional in the follow-up
of the patient.

 Bone scintigraphy: very sensitive but not very specific examination because it captures
all the areas where there is a bone reshaping without distinction of cause. It can be
exploited in the diagnostic suspicion of algodystrophy, so in a patient with pain,
swelling, there is a widespread hypercapture much earlier than
radiological changes.

The triphasic study that provides information on circulatory alterations is

useful:
1. The immediate phase corresponds to the local blood flow,
2. The early stage to interstitial diffusion
3. The late stage to bone fixation.
In contrast to arthritis where there is a localized catchment, in the image on
the side (algodystrophy) there is a
picture of diffuse catchment.
Scintigraphy is also a useful test in the
early stages of illness.

 MRI: an examination that is used a lot, of

election, because it allows to catch early
changes in the signal preceding the ostroporosis:

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you can observe bone marrow edema, which precedes the visible damage to the X-ray,
only after a few weeks. Edema is displayed as a hypointensity zone in T1 and
hyperintensity zone in T2.
There may be other non-specific abnormalities indicating micro-fractures of the trabecular
bone, such as epiphyseal contour deformities and low signal intensity intra-epiphyseal striae in
T1 and T2: these are signs that may help to orient towards a picture of algodystrophy.
MRI is therefore a useful examination, but it should be noted that none of these findings are
specific to algodystrophy: bone marrow oedema is also seen in case of joint overload, in case of
arthritis (bone on MRI in case of arthritis is oedematous because the cytokines released in the
joint cavity also act at the level of the bone determining a phlogistic-edematous state);
MRI with spinal cord oedema of the entire thalus;
anterior tibiotarsaltherefore
and subtalarthe
jointinformation
effusion that can be obtained from MRI should always be compared with
the clinic.
It happens that sometimes a radiological diagnosis of algodystrophy is made: the radiologist
sees a bone oedema and reports an algodystrophy when it is perhaps a picture of
monoarticular arthritis, psoriatic... one cannot make a purely instrumental diagnosis of
algodystrophy.

DIFFERENTIAL DIAGNOSIS
- Inflammatory, septic, microcrystalline arthritis: these are monoarticular forms with the
presence of swelling and significant pain on acute onset. Differential diagnosis can also
be made with psoriatic arthritis and seronegative spondyloarthritis.
- Fractures
- Osteonecrosis
- TVP
- Arterial Ischemia
- Osteomyelitis
- Tenosynoviti and septic fasciitis
- Scleroderma, for the tendency of the skin to lose elasticity starting from the dystrophic
phase, associated with stiffening due to tissue sclerosis
- Dupuytren's disease, for the thickening of the bands

THERAPY
It is important to make a diagnosis as early as possible because in the first few months the main
symptom is pain, but as time goes by, irreversible tissue stiffening damage is established; the
treatment is therefore as effective as it is early. Action must be taken to reduce pain, avoid
capsular retractions and contractures, and control the anxious depressive state of the patients,
which can also appear as a result of irreversible damage.

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The drugs used mainly are bisphosphonates, which are indicated for the treatment of
algodystrophy. In particular, the intravenous nerhydronate, 100mg for 4 infusions spaced 2
days apart has an important effect that allows to block the evolution of the disease.
You then have to go and control the pain for which anti-inflammatory drugs are generally not
used, but corticosteroids because they are more effective.
Another fundamental therapeutic element to start early is functional rehabilitation: the initially
passive and then active movement is able to maintain the patient's physiological articular
excursion and to prevent the evolution to the atrophic phase of algodystrophy. It is important
to associate rehabilitation with steroid therapy because by controlling the pain you can move
the patient earlier, allowing better control over the pathology.

OSTEOPOROSIS
Osteoporosis is a systemic skeletal disease characterized by a reduction in bone mass and an
alteration in microarchitecture of bone tissue, resulting in increased bone fragility and risk of
fracture.
It is asymptomatic until the onset of the fracture, after which the symptoms begin.

Bone anatomy: the image compares the trabecular component of

an individual with normal bone with that of a subject with
osteoporosis: the trabecular scaffold is thinned, both in the number
of trabeculae and in their thickness. The problem is primarily about
bone mass, not mineralization.

Physiology: The bone undergoes reshaping as a result of loading

and for the maintenance of homeostasis of the lime. It is a
metabolically active organ, in particular osteoclasts and osteoblasts
work together to resorb and form new bone. The two cell types
communicate with each other through cytokines and membrane
receptors.
In osteoporosis this process is unbalanced in favour of reabsorption
(osteoclastic activity), to the detriment of bone neoposition. There are various types of
osteoporosis that converge towards this final mechanism of increased bone turnover,
dependent on hormonal factors that are in turn controlled on a genetic basis.

GENETIC PREDISPOSITION1
Genetic predisposition is based on the presence of:
 Polymorphisms of the gene expressing collagen I, associated with bone mass and able
to predict bone loss with age;

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 Allele variants of the vitamin D receptor gene (VDR) or the estrogen receptor gene (ER),
which could represent markers of bone mineral density;
 Allelic polymorphism of the IL-6 gene, which correlates with bone mineral density;

 Allele T of the gene expressing the calcitonin receptor, associated with low bone mass
levels;
 Association of the allelic variant of the TGF-b gene with bone turnover, BMD and
incidence of osteoporotic fractures.
The different variants predispose to shapes of different gravity.

COURSE OF BONE MASS DEVELOPMENT

The peak (highest point of bone mass) is reached
around 30-35 years of age, from then on it will be
reduced by 0.5-1% per year. If you start from a
very high level, it is more difficult to fall below a
threshold at risk of osteoporosis.
Reaching a high peak depends on:
 Genetic factors
 Environmental factors: nutrition and
physical activity
 Function of gonads producing hormones
that affect bone mass accumulation
(hypogonadism results in reduced bone
mass) S T U D IO E S O P O
After menopause, due to an estrogen deficiency, bone mass
loss in women is much faster than in men (2-5% per year
compared to 0.5-1% in the absence of other F E M M IN E 2 2 ,8 % 4 2 ,3 % 3 4 ,9 %
( > 4 5 a n n i)
predisposing factors).

The ESOPO study, an Italian study highlights how MASCHI 1 4 ,5 % 3 4 ,3 % 5 1 ,2 %

( > 6 0 a n n i)
women over 45 years of age have a higher risk than
men over 60 for both osteoporosis and osteopenia. 0% 20% 40% 60% 80% 100%

o s te o p o r o t ic i o s te o p e n ic i n o r m a li

Q U S d e l c a lc a g n o in 1 1 .0 0 0 d o n n e e 6 0 0 0 u o m in i it a lia n i ( 2 0 0 0 )
CLASSIFICATION:
- Primary forms: post menopausal (type I), senile (type II), idiopathic.
- Secondary forms: related to hyperparathyroidism, hypogonadism, drugs
(corticosteroids, antiepileptic drugs, heparin, oral anticoagulants, loop diuretics),

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reduced intestinal absorption, prolonged immobilization, primitive bone diseases (eg

osteogenesis imperfecta), COPD, celiac disease, neoplasms.
Often there are several factors associated with each other that contribute to the pathogenesis
of osteoporosis, for example in an elderly woman (post-menopausal) with COPD, bedded down
and treated with cortisone.
The professor now reads a list of conditions associated with osteoporosis in the slide below. He
dwells mainly on rheumatic diseases, explaining that they are associated with osteoporosis
because:
- Inflammation facilitates bone resorption by osteoclastic stimulation;
- The drugs used (especially cortisone) play a decisive role in this respect.

PREDISPOSING FACTORS:
 Not modifiable: female gender, age (post-menopausal), genetics (slim constitution
)
 Modifiable: poor diet, sedentariness, poor physical activity, drugs (especially
corticosteroids and heparin), thinness.

SYMPTOMATOLOGY

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From a clinical point of view, the progressive loss of bone mass is asymptomatic, so early
diagnosis can be difficult; symptoms appear when bone mass has been reduced to such an
extent that the bone fractures due to minimal and trivial trauma. Only then does the pain
appear.

DIAGNOSIS
- Clinic/anamnestic is based on the search for risk factors: age, sex, amenorrhea, early
menopause, familiarity with fractures, previous fractures, smoking, medication (even
just 10 mg/day of prednisone for more than 2 weeks increase the risk in predisposed
people), lifestyle (smoking increases the risk of osteoporosis).
- Laboratory investigation: there are no significant alterations.
- Instrumental investigations: the most significant is the bone densitometry, able to
evaluate the bone mass, classifiable according to the site (lumbar, femoral, whole body)
or the method used (DEXA: double energy X-ray absorbimetry, is the gold standard, is
the most used and sensitive; QCT: quantitative computed tomography; QUS:
quantitative bone ultrasonometry, is less sensitive, used for example for the calcaneus,
phalanges, tibia).
When performing bone densitometry, certain precautions must be taken: for example,
in a woman with rheumatoid arthritis, avoid the sites involved, because they will clearly
be characterized by marked iuxtaarticular osteoporosis which does not necessarily
reflect the general picture.
- Radiography: can detect paucisymptomatic or sometimes asymptomatic fractures. The
demineralisation picture, on the other hand, is hardly detectable.

Based on the number of fewer standard deviations than healthy people of the same age, DEXA
stratifies patients into four categories with different bone mass thresholds:

COMPLICATIONS/CONSEQUENCES OF OSTEOPOROSIS

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The most frequent complication of osteoporosis are fractures: the most frequent are the
vertebral, femur, wrist, humerus, ribs and pelvis fractures. Sometimes they're spontaneous,
especially the vertebral ones.
Probability of fracture for a woman: 40%.
Probability of femur fracture: 17%.
Probability of fracture for a man: 1/3 compared to a
woman.

Spinal fractures:
The image shows a cuneization of the
vertebra and its different structure. The
vertebra may have a biconcave or wedge-like
appearance due to the collapse of the
anterior wall of the vertebral body. Usually
when the vertebrae give way, the back wall
rarely collapses, the more often the front
wall is involved. For this reason there is rarely
a neurological impairment, given by the
posterior collapse and involvement of the
nerve roots that emerge posteriorly.
In the X-ray on the right we can see the
evolution in 2 years, particularly at the
anterior level, as well as the involvement of
new vertebrae due to domino effect (these
fractures tend to be associated with each
other, i.e. to the single vertebral collapse we
often add collapses of the vertebrae above
and below).
It is possible to strengthen the vertebral body
by injecting substances that cement it, but
since this type of fracture has a domino effect, the most effective strategy remains prevention
rather than treatment.
The risk of vertebral fracture in women aged 50 is 20%, 65 years old is over 25%, 80 years old is
over 30%.
A vertebral fracture increases the risk of a new vertebral fracture by 5 times within one year of
the event; moreover, a vertebral fracture after the age of 50 doubles the risk of a femur
fracture.
The consequences of multiple vertebral collapses are long-term back pain (up to 3-4 months),
reduced height with back kyphosis, reduced lung volumes and abdominal protrusion, which in

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turn lead to dependence on analgesics, distortion of one's body image, loss of self-esteem and
independence and depression.

Femur fracture:
The most frequent femur fractures are those of the neck
of the femur and the trochanteric.
The risk of fracture is double in women compared to men.
With increasing age the risk of falling increases
exponentially, which is often the cause of the fracture.
The risk of mortality from femur fracture is very high, in a
50-year-old woman it is equal to the lifetime risk of dying
from breast cancer and higher than for endometrial
cancer, this is also due to complications related to post-
traumatic trauma bedding.
The consequences of femur fracture in patients with osteoporosis are disability (50%), death
(20%), 2.3-fold increase in the risk of contralateral femur fracture within one year.
The femur prosthesis is an operation that usually gives excellent results, although it depends on
several factors: age of the patient, comorbidity, degree of osteoporosis (if the bone does not
support the prosthesis due to excess osteoporosis, the operation is not effective).

Rib fractures:
occur for trivial situations, like leaning your chest on a parapet.

Colles' wrist fracture:

F r a t t u r e c o s t a li
PREVENTION:
- Primary: prevention of osteoporosis and
addressing patients at risk to bone
densitometry;
- Secondary: prevention of disease progression
and fractures.

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Primary prevention should start very early in childhood. Although bone growth is genetically
regulated, 20% of skeletal development is modifiable. You'll have to act on the bone mass peak
through:
- Lifestyle (physical activity);
- Nutrition: administration of calcium, vitamin D and proteins.
The picture on the right shows the recommended
daily calcium intake, broken down by age group and
particular risk categories.
The effects of the treatment are an improvement in
bone mineralization, prevalent in the first year.
You try to get to 1500mg total per day. Quantities
above the recommended amounts are not harmful in
the normal individual.
Kidney stones can occur in individuals who are
predisposed or already have them. In these cases the
calcium supplement should be more moderate and
associated with hydropinic therapy and possible
thiazide diuretics.
In the image on the right you can see the extent to
which the incidence of fractures in the elderly
following the administration of vitamin D and calcium
is reduced compared to placebo.

Foods containing vitamin D are mainly fish (salmon,

mackerel, tuna) whole grains, orange juice, egg, milk,
butter, cheese, cod liver oil, porcini mushrooms and
shiitake.
The amount of Vitamin D normally taken through the
diet is only a small part of what is needed, sun
exposure is very important for its synthesis and
activation in the skin. Vitamin D is essential in elderly or at-risk individuals because any diet in
these cases is insufficient.
Prolonged and severe hypovitaminosis D involves osteomalacia, with which osteoporosis is
often associated, but these are two very distinct conditions:

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OSTEOMALACY
Osteomalacia is a metabolic osteopathy characterized by a normal bone mass volume, but with
a low mineral content due to a bone mineralization defect.
This osteopathy, which can be present in various pathological conditions, is usually caused by
reduced availability or altered vitamin D metabolism. If present in childhood, the disease takes
the name "rickets" and presents a characteristic clinical picture.

The main causes of osteomalacia are summarized in the table below:

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CLINICAL
Unlike osteoporosis (asymptomatic up to the fracture), there is often a symptomatology
characterized by bone pain (widespread, mainly on the tracks, at the beginning insidious and
ingravescent) and deep asthenia (it can be so deep that it prevents walking or keeping the
station erect).

RADIOLOGICAL FRAMEWORK
In addition to generalized decalcification (resembles an osteoporotic picture), the peculiarities
of Rx osteomalacia are the fracture or pseudo-fracture lines of Looser-Milkman, which can
contribute to skeletal deformities such as coxa vara, flattening of the chest and dorsal kyphosis.
These fractures are spontaneous, perpendicular to the surface of the bone, and they never see
the formation of a callus around them.

LABORATORY INVESTIGATION
Laboratory investigations are not always the same but depend on the cause of osteomalacia. In
general, there is a decrease in lime, phosphoremia and calciuria with normal or slightly reduced
phosphaturia. It increases alkaline phosphatase, hydroxyprolinuria and parathormone, while
vitamin D is reduced.

DIAGNOSIS
The diagnosis is suspected on the basis of the clinical and radiological picture
and biohumoral abnormalities; bone scintigraphy can reveal pseudo-fractures
(Looser-Milkman fractures can be detected by scintigraphy), which can then
be studied in more detail with a CT scan or MRI. Histological confirmation is
useful (increase in the number and thickness of osteoid orlets and rarefaction
of the calcification front), but bone biopsy is not part of routine investigations.

THERAPY
The therapy involves administration of vitamin D or its metabolites,
depending on the type of osteomalacia. In the deficiency form (main cause)
dosages of 2000-4000 IU/day are used for at least 12 weeks; improvement is rapid and
complete healing can be achieved within 6 months.
If, on the other hand, there is a malabsorption problem at the base, the necessary dosages are
higher, 40,000-100,000 IU/day, and a calcium supplement is also required.

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To complete the topic of osteoporosis 8, the professor presents some useful tools to calculate
the risk of fracture, in order to decide if and when to do preventive therapy. Osteoporosis is an
asymptomatic disease until a fracture occurs (the aim of preventive therapy is to avoid the
appearance of the "symptom").
In order to identify subjects at
risk of developing osteoporosis,
WHO has created an algorithm
that takes into account several
variables (both quantitative and
qualitative) and calculates in
percentage the risk that a given
subject develops a fracture from
that moment to ten years. This
program is called FRAX and you
can find it online. Among the
parameters taken into
consideration are: sex, age,
weight, height, familiarity with
osteoporosis, previous fracture, rheumatoid arthritis, steroid intake, alcohol abuse, smoking
and sedentariness.
In Italy an attempt has been made to make the algorithm even more sensitive: in Verona a
slightly different one (DeFRA) has been designed, which takes into account some variables in a
different way, for example with regard to smoking stratifies the risk according to the number of
cigarettes. This is also calculable online, and has recently been considered useful for the
prescription of anti-osteoporotic
drugs, in particular
bisphosphonates, according to
note 79 (for this category of
drugs reimbursement is granted
according to note 79, and the
DeFRA allows to identify patients
who can access this therapy for
preventive purposes). In the
picture we see the risk card,
which puts on paper the risk of a
subject with osteoporosis to
fracture.

8
See lesson 13 of 16.12

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The compilation of the interface of these programs is very simple, but the result is a really
sensitive risk quantification. It is therefore important that specialists and general practitioners
make use of these algorithms.
DEAD OF PAGET
Paget's disease is a pathology characterized by focal alterations of bone remodeling, due to
incorrect functioning of osteoclasts and osteoblasts; there is therefore a subversion of bone
architecture, normal bone tissue is replaced by non-organized tissue with a tendency to
deformity. It is an infrequent disease in Italy and Mediterranean countries (about 0.1%), almost
absent in Africa and Asia, while it reaches 5% in English-speaking countries and the USA.
It is a pathology that mainly affects men over 50 years of age. Often the pathology is
asymptomatic for a long time, therefore it is not diagnosed, so much so that the diagnosis often
occurs due to the accidental finding of characteristic findings in radiographic examinations
performed for other reasons.
The etiology is unknown, a possible multifactorial origin
is recognized with several factors:
 Cytoplasmic inclusions in osteoclasts containing
viral capsides of paramyxovirus (measles virus; in
the image we see under the electron microscope
the nucleus of an osteoclast with a granulation
with the appearance of inclusion by
paramyxovirus, indicated by the arrow)
 Mutations to the SQSTM1 gene encoding for p62
protein, implicated in the induction of osteoclast
growth and proliferation
 Morphologically altered osteoclasts: they
normally contain 3 to 20 nuclei, but in Paget's
disease they contain many more and their
precursors are much more sensitive to vitamin D
and RANKL (promoters of proliferation and activation).

The pathology is characterized by a greater resorption and osteoproductive activity but the
newly formed bone is abnormal, with collagen fibers arranged in an irregular way, the bone
turnover is very high.
The SQSTM1 gene mutation is
found in 30% of cases. There
are alterations in other loci
(see image) that predispose to
the development of Paget's
disease, coding for proteins

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involved in the activation of

osteoclasts.

In the anatomo-pathological
finding alongside we see,
indicated by the arrows,
multi-nucleated osteoclasts.
(ob means osteoblasts, TB
means trabecular bone).

The measles virus is considered to be implicated in the genesis of Paget's disease for two
reasons: the presence of the characteristic inclusions and the decline in the incidence of Paget's
disease following the initiation of measles vaccinations; this could be a trigger mechanism in
some patients.
Other pathogenetic hypotheses include those related to exposure to environmental factors. In
England the incidence of the disease reached 5% and, following some studies, it was thought to
be related to environmental pollution from arsenic (coming from industrial plants). Following
the closure of the industries there has been a reduction in the incidence of the disease, so a
correlation is possible. Similarly, a possible correlation with environmental lead poisoning has
been found in the USA. It is likely that there are several environmental factors that contribute
to the manifestation of the disease in individuals genetically predisposed to various types of
polymorphisms or mutations in certain genes that control the activity of osteoclasts.

PATHOGENESIS
From a clinical point of view, there are three phases of evolution of Paget's disease lesions,
which can coexist with each other:
 Osteolytic or destructive phase: increased bone resorption (initial phase)
 Intermediate stage: high turnover of both reform and reabsorption
 Osteoplasty or osteosclerotic phase: bone apposition prevails

CLINICAL FRAMEWORK
The symptoms are related to the location of the lesions. Bone involvement can be localized
(monoostotic, i.e. only one bone involved) or polyostotic (several bones involved). More
frequently the pelvic bones, long limb bones, skull and spine are involved. The clinical
manifestations and symptomatology depend on the bone segments involved. The main
symptom is pain, probably caused by increased pressure inside the bone due to abnormal
bone growth and also by the compression of nearby structures. Irregular bone attachment is

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accompanied by a deformation of
the bone itself, which in practice
results in an important functional
limitation.

In the image we see two tibias, on

the right a normal one and on the
left a saber tibia, typically present
in patients with Paget's disease.
Such a situation is found in
patients who have never been
treated before, if an appropriate therapy is set up at
an early stage these consequences can be avoided.
Always in the same image we notice a particularly
thickened bone cortical (whiter part at the edges of
the bone).
In this other image we see a bone scan. In this case
the patient has polyostotic Paget's disease. The
darkest area inside the pelvis is the bladder, where
the contrast medium physiologically accumulates.
Bone captures are instead due to Paget's disease
localization (in this case in several bone segments).
The scintigraphic representation of the Paget is very
characteristic, because it highlights the parts of the
bone involved. Sometimes it happens to make a
diagnosis in totally asymptomatic patients, because
in the early stages the symptomatology is very blurred: I can have aspecific pain, for example
limb pain, but without objectivity. When the skull is involved, in addition to headache, I may
have neurological disorders, such as hearing loss due to compression of the auditory nerve by
narrowing of the auditory foramen (due to changes in bone structure), or compression of the
brain or cerebellar or cranial nerves. When the vertebrae are involved we have lumbago
sometimes irradiated to the lower limbs; in these patients it is frequent to encounter
secondary arthrosis or compressions of the marrow that can cause tetra paresis.

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The professor reports the case of a patient who had only a ptosis in his right eye, without any
other symptoms, not even a headache. When X-rays were performed on the skull (shown on
the side), a Paget of the skull was found that caused a nerve compression and therefore a
deficit of the eyelid.

COMPLICATIONS
 Neuropathy: compression of cranial or vertebral nerves
 High range heart failure secondary to arteriovenous venous anastomosis of pagetic
bone; appears in Paget polyostotic when more than one third of the skeleton is involved
 Anomalous bone fragility especially in the osteolytic phase when the activity of the
osteoclasts prevails; it can happen that there are fractures, even spontaneous ones,
that repair themselves in a difficult way because the bone structure is reformed in an
altered way.
 Neoplastic degeneration in sarcoma (it happens in 1% of the cases); it is to be
suspected when we have important changes in the symptomatology, with a large and
sudden increase in painful symptoms, increase in the volume of the affected bone and
rapid increase in alkaline phosphatase (bone isoenzyme). Sarcomatous degeneration
has a severe prognosis, as it has a great tendency to metastasize.

IMAGING
In the phase of bone destruction, areas of osteolysis appear in the epiphyseal portion,
especially in the long bones, which progress towards the extremity with an inverted V-shaped
front. This can be seen on the X-ray but not
prematurely. In the intermediate phase the lithic
zones are surrounded by sclerotic tissue and the
bone appears enlarged, with an irregularly
thickened cortical and alternating lithic and
sclerotic zones. In the sclerotic phase
we have a uniform increase in density
and volume; bone deformity also
becomes more evident.
Bone scintigraphy is considered the
method of choice. In this image we
see how the scintigraphy has a more
immediate response (here we see
mainly pelvis and femur which are the
most frequently affected areas).
The laboratory helps us to make
diagnosis: as a sensitive marker we

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have alkaline phosphatase (bone isoenzyme); there are other parameters that normally
express increased bone remodeling, such as urinary pyridinium cross-links, N-terminal portion
of type 1 pro collagen and urinary prolinuria hydroxy.
X-ray, scintigraphy and alkaline phosphatase are sufficient to diagnose and monitor the course
of the disease. In most cases, however, the diagnosis is linked to imaging, with evidence of
increased cortical thickness, loss of cortico-trabecular differentiation and overall bone
enlargement. The differential diagnosis arises with neoplasms that result in a mixed
appearance (osteolytic and osteoaddensing), such as prostate cancer, thyroid cancer,
mammary and bronchial neoplasms. Sometimes it may be necessary to have biopsy
confirmation of the pathology; in widespread polyostotic cases imaging is sufficient for
diagnosis.

TREATMENT
Bisphosphonates are used
as first choice drugs in the
treatment of Paget; they are
able to rapidly induce
normalization of bone
turnover, to determine a
persistent remission of
clinical symptoms and a
complete normalization of
parameters. The therapy
should be continued for
several months, but it is extremely effective especially if administered early; when there are
important deformities the pathology stops but the deformities clearly remain.
The markers should be monitored approximately every 3 months and after 6 months of therapy
it is evaluated whether to make another cycle in relation to the alkaline phosphatase levels
which are the most sensitive parameter.
Here we see two scintigraphies taken two years after the treatment; we notice a decrease in
the collection in the skull and pelvis, which shows a significant improvement, also from the
symptomatological point of view.

CLINICAL CASES
CLINICAL CASE 1

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22-year-old male patient, Caucasian. Admitted to gastroenterology on suspicion of

inflammatory bowel disease, during his stay he developed acute arthritis of the right elbow,
which brought him to the attention of the rheumatology clinic in February 2014. In anamnesis:

1) Family history: 36 year old sister and 32 year old brother reported in good health; no
pathologies in the aristocracy.
2) Physiological anamnesis: born from eutocytic birth, without complications, psychophysical
development in the norm. He marches regularly at 14 months, pronounces the first words
at 1 year and at 10 years neurological development is normal, as is the use of language.
3) Remote pathological history: at the age of 8 months he develops musculoskeletal pains in
the lower limbs, while from the age of 2 years he begins to show episodes of recurrent
fever resistant to antibiotic therapies. At the age of 3 he develops bilateral hearing loss,
which forces him to place a hearing aid. At 4 years of age she develops headache with
endocranial hypertension, associated with mild facial dysmorphism with zygomatic bone
hypotrophy and, in the laboratory, hypochromic anemia, leukocytosis and negative
antibody profile. At the age of 6 years the visus begins to deteriorate with consequent
narrowing of the visual field and the following year migrating atralgia develops with
recurrence every 2-3 months involving the shoulders, elbows, knees and frequently diffuse
erythematous rash lasting a few days.

The complexity of the picture in APR required the genetic counselling that proposed the
suspicion of Stickler syndrome9 Despite this, since 1995 he has been frequently hospitalized for
hyperpyrexia, increased inflammation indexes, headache, fluctuation in visual acuity,
atromialgia to which, in 2000, were added episodes of abdominal pain. From 1995 to 2004, the
elusive medical history led the patient to perform several tests, with negative or normal results:
cerebral angioRMN, cerebral angiography, ECG, ANA, ANCA, FR, immunoglobulins, regular bone
biopsy. At lumbar puncture evidence of proteinorrhagia with absence of oligoclonal bands.
Evoked lower limb potentials show some latency and central conduction delays at the cervical
and bulbar level. A brain MRI with mdc from 2008 shows, in the occipital, parietal and frontal
region bilaterally, hyperintense T2 halos with irregular contours.

The patient had already been treated (ex adjuvantibus) with:

1) 3 cycles of immunoglobulin ev (transitional benefit) in 2000;

9
Stickler syndrome is a vitreo-retinopathy characterized by the association between ocular signs, craniofacial
dimorphisms (glossoptosis, retrognathia and posterior-medial soft palate schises), skeletal alterations and
neurosensory deafness (10% of cases). The incidence is estimated at about 1 per 7,500 newborns. Eye disorders
include juvenile cataract, myopia, strabismus, vitreo-retinal or chorio-retinal degeneration, retinal detachment and
chronic uveitis. Early arthrosis and flattened facial bones can be associated. It is transmitted in AD form and is due
to mutation in collagen genes, COL2A1 (Stickler type 1) and COL11A1/A2 (Stickler 2).

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4) 3 cycles of methylprednisolone boluses with mild benefit, then prednisone per os without
results, so it returns to treatment per vein but without benefit (2001);
5) 3 administrations of cyclophosphamide always in 2001, always without benefit.

In 2013-2014 new symptoms appear and new investigations are carried out:
1) Abdominoalgia with high PCR, negative for ASCA, ANA, ENA, ANCA; CT scan, abdomen
ultrasound normal, chest x-ray normal;
6) Colonoscopy: Hyperemia of the ileum and sigma;
7) EGDS: hyperemic mucosa at the bottom of the stomach

The histological report concludes by suggestive picture of large intestine IBD of

indeterminate/unclassifiable type. Therapy with mesalazine, pantoprazole and prednisone is
recommended. Abdominal pain does not improve, it is associated with vomiting, asthenia and
lack of appetite and hence the admission to gastroenterology mentioned at the beginning. An
entero-RMN is performed that does not show ileo-colic thickening, no abnormal enhancement
after mdc, some enlarged lymph nodes along the mesenteric vessels and enlarged spleen (15
cm) with an accessory spleen of 2 cm.

Once in rheumatology due to the violent pain on the right elbow, an ultrasonography of the
soft parts is done, with abundant corpuscular liquid pouring of articular origin, with disposition
in the external periolecranial site where it reaches a thickness of about 1,5 cm. Biohumoral
tests show anemia, increased ESR, GB above 13000/mm3, increased PCR, increased protein
profile of inflammatory proteins and reduced albumin percentage, elevated amyloid serum
protein and faecal calprotectin over 20 times the cut-off. Synovial fluid examination is
compatible with septic arthritis (GB 61000/mmc, 92% PMN, no crystals, turbid appearance and
very low viscosity). However, on cultural examination, there is no evidence of bacterial growth
(which is not uncommon to be negative even in the case of severe septic arthritis). As part of an
in-depth diagnostic investigation, the patient undergoes a genetic investigation on suspicion of
autoinflammatory disease of the cryopyrinopathy group.
Genetic analysis shows mutation in CIAS1. The search for amyloid
with periomobelical fat biopsy is negative. The patient is diagnosed
with CINCA/NOMID10, a more serious form of cryopyrinopathy than
the various cryopirinopathies.

10
It is the most serious form of cryopyrinopathy, characterized by skin rush even permanent, fever,
lymphadenopathy, CNS impairment, chronic arthropathy up to bone erosion and dimorphisms typical of the face
(prominent frontal drafts, saddle nose, facial hypoplasia). In addition, patients also have overgrowth of the bone in
their knees, hands and feet. It is recalled that cryopironopathies also include MWS and FCAS and are due to
mutations in the NLRP3 (or CIAS1) gene, which encode for the NALP3 protein, implicated in the formation of
NALP3 inflammosome and therefore in the production of high levels of IL-1.

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The patient starts treatment with Kineret (Anakinra) 100mg/day and after 5 days the clinical
picture regresses almost completely, with disappearance of symptoms and apyrexia. After 12
months of therapy, the patient is in complete remission although drug treatment cannot be
suspended.

In the picture opposite, typical facies of patients with CINCA.

Although CINCA is a genetic and congenital disease, the patient was only diagnosed at the age
of 22, after a practically persistent state of disease. This underlines that in the case of complex
or doubtful pictures these diseases should be suspected, also because treatment with IL-1
antibodies is resolutive. Unfortunately, the visual and auditory damage, which was not properly
treated at first, is irreversible. So although cryopyrinopathies are paediatric diseases, they are
also suspect in adults because they are frequently undiagnosed.

CLINICAL CASE 2
34-year-old female, Caucasian, comes to the attention of the rheumatology clinic. The parents
are living, healthy, with a 32-year-old brother. Physiological history is mute.
In APR:
1) from 6 years atralgia periodically, retrosternal stabbing pain and posterior chest pain
associated with fever and rashes.
8) in 2006, when she was 27 years old, the patient developed exudative pericarditis treated
with steroids and since then periodic episodes of restrosternal constrictive pain.
9) in 2008 (29 years old), she was admitted to infectious diseases due to suspected bacterial
endocarditis, then unconfirmed
10) in 2009 rheumatological examination for febrile, atralgia, rashes, for which a therapy with
hydroxychloroquine is proposed in the suspicion of undifferentiated connectivitis (but FR,
anti-CCP, ANA, anti-ENA, anti PL were in the norm). Despite treatment, abdominal colic and
exacerbations with painful retrosternal symptoms and fever appear.
11) In 2010 oral aphthosis, one of the characteristic clinical signs of 11Behçet's syndrome, also
endorsed by the HLA typing that resulted B51+, a genotype associated with Behçet,
appeared. The treatment with colchicine 1mg/day is therefore started and in the following
six months the symptomatology recedes, but with the appearance of annoying side effects
of colchicine in the abdomen, including persistent diarrhea despite a reduction in dosage.
The patient suspends the colchicine, but the usual symptoms (febrile, atralgia, chest-
abdominal pain) resume.

11
Behçet's disease is a relapsing chronic multisystemic vasculitis with inflammation of the mucous membranes.
Common manifestations include recurrent oral ulcers, eye inflammation, genital ulcers and skin lesions. The most
severe manifestations include blindness, neurological or gastrointestinal manifestations, venous thrombosis and
arterial aneurysms. For more information, please refer to the following lessons on vasculitis.

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12) Since Behçet's diagnosis was not certain (since canker sores were not present, a typical
feature of the disease), the patient underwent genetic analysis in 2012 for
autoinflammatory diseases and the E148Q mutation (associated with others) of the12MEFV
gene was found. The diagnosis of familial Mediterranean fever is proven by a good
response to colchicine, reintroduced slowly and carefully. After two months of treatment
the picture was good.

In
the images, two mild rash, one facial and the
other on the patient's hand.

As can be seen from the clinical history, it is not a characteristic manifestation of FMF, because
the fever was quite low, with no recurrent spikes lasting 1-2 days and a periodicity of 30 days
and colic abdominal pain. The picture here is of thoracic pain and atrialgia, therefore more
nuanced, without a typical erysipelas-like picture. This is because the clinical manifestations
depend on the type of mutation involving the MEFV gene.

CLINICAL CASE 3
Female patient, 31 years old, Caucasian, who comes to observation for recurrent fever, arthritis
in hands and feet and papulonodular rashes. Family and
physiological history do not show any kind of significance.
As can be seen from the two images, the rash is nodular
and there is a fairly clear swelling of the VET joints and
some of the distal joints. However, the spillage was quite

12
the MEFV gene encodes for the protein marenostrine or pyrin, a protein responsible for the inactivation of pro-
inflammatory cytokines and therefore, if mutated, leads extrinsically to the increase of IL-1.

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evident and there were no typical inflammatory traits, so the skin was neither warm nor very
sore.
The first signs of the pathology emerged when the patient was 15 years old, with symmetrical
polyarthritis in her hands, wrists and feet and the appearance of diffuse papular eruptions and
subcutaneous nodules at the extremities. Since then intermittent manifestations with arthritis
well controlled by NSAIDs.
At 20 years of age, the patient manifested chronic bilateral uveitis, which forced her, four years
later, to have an iridectomy, which was followed, some time later, by cataract surgery
bilaterally. In more recent times the skin manifestations, the number of febrile episodes and
arthritis have worsened.

Clinically:
1) diffuse and asymptomatic brownish papules on the back
of the hands, feet and extensor surface of the legs;
13) swelling MCF, VMP, with low painfulness and without
redness or increased heat;
14) to the rx: perinatal enlargement of the bone, without
erosion;
15) biohumoral investigations within limits, especially
phlogosis indices within the norm;
16) forearm skin biopsy shows non-caseotic granulomas
with polypid histiocytes;

A low dose of steroid is prescribed which is very beneficial to

the patient.
From the Rx we can see that there is no erosion of the articular
bone heads, but only a widening of the bases of the proximal
phalanges.

A month later, the 5-year-old daughter also develops rash similar to

her mother, although less severe. No therapy is prescribed. Four
years later her daughter develops arthritis of the hands and the
dermatitis gets worse. The girl is hospitalized: the biohumoral tests
are within limits, the forearm biopsy confirms the diagnosis of
granulomas. At 12 years of age, arthritis worsens and a synovial
membrane biopsy shows granulomas. At 13 years of age, bilateral anterior uveitis appears,
treated with topical drugs.

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Granulomatous inflammation leads to the diagnosis of Blau syndrome, an autosomal

dominant disease, due to mutation in the NOD2 gene, the intracytoplasmic receptor of innate
immunity. The NOD2 gene has three different domains: one LRR, one NACHT and one CARD
domain. Mutations in the NACHT domain lead to Blau syndrome, which is a very rare disease,
while mutations in the LRR domain lead to Crohn's disease. NOD2 overactivation leads to
increased levels of NF-kB and therefore pro-inflammatory cytokines.

In Blau syndrome the most significant damage is panophthalmitis, which can lead to blindness,
while arthritis is not erosive and generally not very serious. Despite medical recommendations,
the woman's daughter had two other children, carriers of the mutation, although they still have
no symptoms at 9 and 12 years of age respectively. Being an AD disease, even heterozygosity is
sufficient for the onset of the disease. They are currently in follow-up, in the hope that new
drugs useful in this pathology will be discovered, 13especially for eye involvement, which greatly
affects the prognosis.

THE BASKETS
The vasculitis are a set of pathologies, altogether rare, characterized by inflammation of the wall of the
vessels.
The inflammation of the wall determines:
 Stenosis, with reduced vessel lumen
 Occlusion of the vase itself with consequent ischemic manifestations
 Greater fragility of the vessel with formation of aneurysms that can rupture with
manifestations of hemorrhagic nature.

The aetiology of vasculitis is unknown although in some cases an infectious agent, toxic or
pharmacological environmental factors and hormonal factors in some forms that have a higher
prevalence in the female sex may be suspected as a trigger. There is certainly a genetic predisposition:
vasculitis have a different prevalence and incidence in different ethnic groups, and therefore
geographical areas, each characterized by a different genetics.
It can affect subjects of all ages. However, there are forms that only affect children (Kawasaki's disease)
and others that are almost exclusively adult (giant cell arteritis).
The prognosis is very variable in relation to the extent of the vasculitic process and which vessels are
involved. In fact, there are purely cutaneous forms that can be very mild and spontaneously resolved,
unlike other forms in which large-calibre vessels are involved, which can cause extremely marked
damage such as ischemic or haemorrhagic events.
13
Daily therapy with low-moderate corticosteroids is effective in controlling uveitis and joint disease, but the side
effects of prolonged use can become untenable. Methotrexate at a dose of 10-15 mg/m2, once a week, is effective
in suppressing the activity of the disease and reduces the dose of corticosteroids. The introduction of monoclonal
anti-TNF antibodies (infliximab and adalimumab) represents a significant advance in the treatment of BS; however,
the effects on uveitis may be less effective.

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Vasculitis is a very large group of diseases that are also different from each other and this has made it
very difficult to classify them in a way that is shared by all. The first attempt at classification was made
by a rheumatology society in 1990 (ACR Classification 1990) and later in 2012 with the Chapel Hill
Consensus Conference, an attempt was made to find greater agreement on how to classify vasculitis by
defining them according to the size of the vessels concerned.

NOMENCLATURE AND CLASSIFICATION

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In the Chapel Hill nomenclature, the vases are subdivided according to the size of the convoluted vases
according to whether they are large, medium or small.
1. Vases of great caliber:
a. Takayasu's arteritis,
b. Giant cell arteritis.
2. Medium-sized vases:
a. Polyarteritis nodosa (PAN),
b. Kawasaki disease.
3. Among the vasculitis affecting small-calibre vessels it is necessary to make a distinction based on the
positivity to neutrophil cytoplasm autoantibodies (ANCA):
a. Associated ANCA vasculitis: microscopic polyangitis, granulomatosis with polyangitis (or
Wegener's syndrome) and eosinophilic granulomatosis with polyangitis (Churg-Strauss
syndrome). This type of vasculitis can actually also involve medium sized vessels.
b. Associated non-ANCA vasculitis: cryoglobulinemic vasculitis, vasculitis associated with IgA
(Henoch-Schonlein syndrome), hypocomplementemic vasculitic urticaria (due to anti-C1q
antibodies), Goodpasture syndrome (glomerular basal anti-membrane antibodies).

PATHOGENESIS
Vasculitis are inflammatory diseases of the vessel wall with involvement of the innate and adaptive
immune response. The main pathogenetic mechanisms that cause inflammation are due to:
1. Formation and deposition of immune complexes in the vessel wall
2. Formation of autoantibodies, in particular against lysosomal enzymes of neutrophils and monocytes
and against endothelial cells (less certain)
3. Cell activation with secretion of cytokines and adhesion molecules
4. Alteration of the cell-mediated immune response with formation of granulomas
5. Direct damage to endothelial cells from triggers of an infectious nature, drugs, toxic substances or
neoplasms.
There are many different pathogenetic mechanisms that can converge into vessel wall damage that will
lead to the development of different clinical forms.

PATHOGENETIC MECHANISMS
1. FORMATION AND DEPOSITION OF IMMUNE COMPLEXES
Immunocomplexes settle on the vessel wall where they activate the complement by the
classical route and the endothelial damage is mediated by C5a which induces the expression of
adhesion molecules with neutrophil recall and diapedesis. Neutrophils swallow immune
complexes and release proteolytic enzymes and cytokines that cause direct damage to the
endothelium. The endothelium, therefore, loses the barrier function so that neutrophils cross it
more easily, the anticoagulant and anti-inflammatory capacity of the endothelial cell is lost and
the damage is amplified.

2. FORMATION OF AUTOANTIBODIES
Anti-neutrophil cytoplasmic autoantibodies (ANCA) are directed against enzymes contained in
neutrophil granules such as serinprotease 3 (PR3), directed against monocyte myeloperoxidase

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(MPO) and lysosome membrane protein (Hlamp-2). There are also other antigens against which
autoantibodies can be developed but they are very rare and not as obvious as the previous
ones.
The target neutrophil antigens (PR3, MPO) are exposed on their surface after their pre-
activation by circulating TNF-a or, in case of neutrophil apoptosis, PR3 expression may occur
even without pre-activation With the recognition of these antigens, antibodies will be formed
that have an important pathogenetic role because they promote neutrophil adhesion to the
endothelium and their degranulation. This initiates the mechanism of amplification of damage at
the level of the endothelium, which promotes the transmigration of neutrophils, thus
inflammation of the entire wall and surrounding tissue.
Another group of autoantibodies involved in the pathogenesis of damage are endothelial cell
antibodies (AECA). It is a very heterogeneous group of antibodies involved in various
inflammatory pathologies but they are also found in healthy subjects, so their meaning is not yet
known (they could also form after endothelial damage). AECA are found in several systemic
primitive vasculitis such as Takayasu, giant cell arteritis, eosinophilic granulomatosis with
polyangitis, IgA vasculitis, polyarteritis nodosa, Behcet's syndrome, microscopic polyangitis and
Kawasaki's syndrome.

3. ALTERATION OF THE CELL-MEDIATED IMMUNE RESPONSE

In some vasculitis granulomatous lesions appear, ascribable to the activation of the cell-
mediated immunity. There are therefore antigens circulating or localized in the vessel wall that
can activate, directly or through dendritic cells, CD4+ T lymphocytes that in turn recall
monocytes. These are transformed, in the tissues, into macrophages that release cytokines such
as IL-6 and IL-1 that cause direct damage to endothelial cells, on the other hand they promote
the transformation of macrophages into giant multinucleated epithelial cells, with granuloma
formation. Granuloma consists of dendritic cells, neutrophils and T and B lymphocytes. The
latter are able to produce ANCA antibodies within the granulomas.

4. TRIGGER
Damage to the vessel wall can be caused by various triggers such as microorganisms (bacteria,
viruses, parasites), drugs and neoplastic forms.
Different microorganisms can induce the same type of vasculitis but the same microorganism
can cause different patterns of extension and severity. There is no unique correlation between a
specific microorganism and a specific vasculitis, they are quite aspecific triggers, so the damage
that is created is the sum of different factors, genetic and environmental, to which we add the
influence of the microorganism that according to the sensitivity of the patient can manifest itself
with one vasculitic form rather than another.
Some microorganisms can create direct damage to endothelial cells, can lead to the formation of
immunocomplexes that precipitate on the vessel walls or can lead to the formation of
autoantibodies (ANCA), therefore they are part of all pathogenic mechanisms.
The table shows the microorganisms most frequently associated with vasculitic manifestations.
We find different types of bacteria, some also particular as Brucella or Klebsiella, viruses (the

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most frequently associated are

HBV and HCV, HIV), fungi like
Aspergillus and parasites like
Toxoplasma gondii.
As far as drugs are concerned, many
are considered possible inducers of
vasculitis: hydralazine, sulfasalazine,
penicillamine, monocycline, allopurinol
and propylthiouracil.
Some of these drugs are
commonly used in
rheumatology: allopurinol is
used in the prevention of
chronic gout and in
hyperuricemic patients,
sulfasalazine is used in
seronegative spondylarthritis and rheumatoid arthritis. In drug-induced vasculitis the
pathogenesis is due to the formation of immunocomplexes, the formation of ANCA
autoantibodies due to drug-induced neutrophil apoptosis or due to the aggregation of the drug

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to neutrophil proteases, are then exposed on the cell surface going to trigger the vasculitic
process.

Chapel Hill's classification also includes vasculitis affecting vessels of various sizes such as Behcet's
disease (a disease on the borderline between vasculitis and spondylarthritis, treated in the last lesson)
and Cogan's syndrome. There are also forms limited to a single organ such as primitive CNS vasculitis, or
those associated with systemic diseases such as SLE and AR.

LARGE-CALIBER VASES
TAKAYASU ARTERITIS
Among the arthritis affecting large vessels is Takayasu's arteritis.
It is a chronic vasculitis, often granulomatous and affects the aorta and/or vessels that originate from it,
the pulmonary arteries and coronary vessels.
The pathology determines stenosis, occlusions and sometimes aneurysms. The particularity of this form
of vasculitis is that it mainly involves young people under 40 years of age, of the female sex, with a
greater prevalence in Asia (estimated cases 4.2/100,000 in Japan and 2.6/million in the USA). Female
male ratio declines from east to west.

PATHOLOGICAL ANATOMY
From an anatomical pathological point of
view we have a thickening of the aorta with a
fibrotic
process
that
involves
all layers
of the
vessel and
the

consequences of lumen reduction. There is inflammation of the

interstitial vas vasorum, fibrosis of the middle cassock and thickening
of the intimate cassock. In the chronic phase the entire wall is
fibrotic with destruction of the inner elastic membrane which can more easily lead to the formation of
an aneurysm.
In the picture you can see the appearance of an inflamed vessel with a reduced lumen and around it a
large sleeve of inflammatory cells, fibrous tissue and unsettling muscle and elastic cassock.

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CLASSIFICATION OF TAKAYASU ARTERITIS

Takayasu's arteritis is distinguished in

relation to the extent of involvement
of the aorta and large vessels. There
are different modes of presentation
and therefore gravity. The disease
may involve the aortic arch (I), the
ascending aorta, the aortic arch and
its branches (II), the ascending aorta,
the aortic arch and its branches and
the descending thoracic arch (IIb),
descending thoracic aorta, abdominal
aorta and/or renal arteries (III),
abdominal aorta and/or renal arteries
(IV), from the ascending aorta to the
abdominal aorta including all
branches (V).
CLINICAL
Clinically we distinguish between an acute inflammatory phase and a phase of vasal occlusion in which
the symptoms are the result of vessel obstruction.
The first phase is a sneaky phase that can last several weeks and months and is characterized by fever,
night sweats, asthenia, arthralgia, chest or neck pain, erythema nodosum, irites/episcleritis. Most of the
symptoms are quite generic so that often you get to the diagnosis late.
During the second phase the events depend on the district concerned. We can have:
 Acute aortic valve failure, angina pectoris, myocardial infarction.
 Visual disorders (amaurosis, blurred vision, blindness), headache, TIA, stroke, carotidodynia, upper
limb claudication, subclavian theft syndrome, arterial hypertension, Raynaud's phenomenon. The
symptoms depend on which district you are interested in.
 Chest pain.
 Angina abdominis, lower limb claudication and nephrovascular hypertension with mesangial,
proliferative or focal, membrano-proliferative glomerulonephritis.
 Dyspnea, hemoptysis, pulmonary hypertension.
The symptoms depend on the districts involved. The first stage of the disease being very non-specific, it
is difficult to diagnose. In fact, just over 50% of those affected have an increase in ESR and PCR.
Phlogosis indices do not correlate with disease activity and are not useful in identifying patients in the
subclinical phase.

DIAGNOSIS
To diagnose Takayasu's arteritis it is necessary to do targeted examinations such as angioresonance or
vessel wall resonance, which can highlight the presence of an inflammatory picture at the level of the
vessel wall. Often MR-angio can be preceded by a PET or PET-TC, as these are extremely sensitive tests

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that can tell us if there is an uptake of the vessel and confirm the inflammatory state. They're very useful
in cases of diagnostic suspicion.
There are also other exams such as CT angio and angiography, which used to be the standard exam, now
it is used much less because the exam is invasive and the contrast medium is potentially harmful.
In the picture there is an example of PET, with interest in the vertebral arteries and their respective
capture (marked by arrows) and a PET-RM that shows a thickening of the vessel wall. These images may
therefore confirm the diagnostic suspicion.

If in the acute phase the symptoms are very non-specific, in the chronic phase we find clinical signs of
strong suspicion like:
 Reduced pulsatility of the peripheral wrists or their complete absence (Takayasu's arthritis is
defined as "disease without wrists")
 Pressure asymmetry between the limbs or hypertension at a young age
 Auscultation blowing
It is important to make a differential diagnosis with giant cellular arteritis and atherosclerosis when the
disease is recognized after the age of 50.
These are all signs that should place a strong diagnostic suspicion and indication for more thorough
examinations.

THERAPY
The therapy is based on:
 Corticosteroids (1mg/kg/day) with very slow reduction to avoid a recovery of the disease.
 Immunosuppressants: methotrexate, azathioprine, cyclosporine, mycophenolate,
cyclophosphamide. They are used in cases where corticosteroids are not sufficient for treatment or
there is a recurrence of the disease.
 Biological: anti-TNF, anti-IL6, anti-CD20, are used in diseases that do not respond to first and
second line drugs.
The monitoring of the therapy is performed with PET or MRI, in order to have a reduction of disease
there must be a reduction of the catchment. Biohumoral tests (ESR or PCR) are not reliable.

PROGNOSIS
The pathology is characterized by phases of remission and exacerbation, with possible clinical
progression despite an apparent biohumoral remission. Survival at 5 years is excellent (about 96%), but
complications may arise, particularly heart failure, myocardial infarction, stroke, renal failure and
rupture of aneurysms.

GIANT CELL ARTERITIS

It is a chronic, often granulomatous
vasculitis that affects not only the
temporal arteries, but also the aorta
and/or the resulting branches. The onset

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usually occurs after the age of 50, with a ratio F:M=1.7:1 and is frequently (20-30% of cases) associated
with Rheumatic Polymyalgia. It is the most frequent vasculitis in Northern Europe and North America,
rare in Asia. The prevalence is 2 cases per 100 thousand inhabitants between 50 and 59 years, but
increases to 52 cases in the over-80s.

PATHOLOGICAL ANATOMY
The arteries most affected are temporal, vertebral,
ophthalmic, ciliary arteries, although any major artery can be
affected. From a histological point of view, the artery is
irregularly involved (this explains the negativity to biopsy in
15% of cases) and is characterized by an inflammatory
transmural infiltrate of lymphocytes and macrophages mainly
localized near the elastic membrane, moreover the intimate
is thickened and the lumen is reduced/occluded with
thrombosis.

CLINICAL
The pivotal symptom is mainly temporal, sudden, continuous
headache, sometimes associated with scalp pain. On
objective examination it is possible to appreciate a hard,
irregular, painful and pulsatile cord at the temporal artery
level. There is also chewing claudication, because the
masseterine artery is a collateral branch of the temporal
artery, so the patient after a while chewing must stop for pain.
The disease is accompanied by non-specific systemic symptoms (fever, general malaise, fatigue,
anorexia, weight loss) and the main complication is anterior ischemic opticopathy which can lead to
blindness due to retinal ischemia. It may be the initial symptom but is often preceded by transient
amaurosis, visual hallucinations, diplopia and blurred vision. It is important to set up corticosteroid
treatment early to prevent blindness from becoming bilateral.
Up to 22% of cases the pathology affects the thoracic or abdominal aorta leading to a clinical picture
indistinguishable from Takayasu.

EXAMINATIONS
ESR and PCR are positive in 90% of cases with a marked increase. There is normocytic normocytic
anemia and modest alteration of liver function. Microscopic hematuria is present in 10% of cases.
Usually the biopsy is not performed, because it is invasive and falsely negative in 15% (this depends on
the sample analyzed).
Very specific (97%) is the echocolordoppler of temporal arteries with halo sign demonstration
(hypoecogenic wall halo). Both MRI (shows thickening of the wall) and PET (to assess whether the effort
is limited to the temporal artery only or more extensive) are performed.

DIAGNOSIS

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In acute the diagnosis is difficult because the symptoms are non-specific, while in chronic phase the
diagnosis is faster and can be appreciated:
 Reduction or absence of peripheral wrists ("the disease without wrists")
 Pressure asymmetry between the limbs or hypertension at a young age.
 Auscultation can be appreciated blasts
It is necessary to make the differential diagnosis between giganto-cellular arteritis and atherosclerosis
when the disease arises after the age of 50.

THERAPY
The therapy is based on:
 Corticosteroids (1mg/kg/day) with reduction after one month, the therapy is prolonged for at least
8 months to avoid a recovery. In case of visual disturbances, 1000mg steroid boluses are required
for 3 consecutive days.
 In patients with high steroid threshold, immunosuppressants such as methotrexate, but also
biological drugs can be associated.
 Useful association with high doses of ASA against possible thrombosis.

PROGNOSIS
The prognosis depends on the location of the artery and the speed of diagnosis and treatment.
Cause of death is stroke and aortic dissection.
The most severe complication is blindness. In addition, there are risks due to prolonged steroid therapy,
so in these patients osteoporosis, hypertension and diabetes (diseases often present after the age of 50)
must be monitored.
We must remember the association (up to 30% of the cases) with Rheumatic Polymyalgia, a pathology
characterized by acute myalgia of the scapular and pelvic girdle. The reason for this association is not
clear, it is thought that rheumatic polymyalgia is an initial picture of Horton's Arteritis.

MEDIUM-CALIBER VASCULITIS
POLYARTERITIS NODOSA
It is a necrotizing vasculitis of the arterial vessels of medium and small size, i.e. arterioles, capillaries and
venules. Clinical manifestations are borne by the SNP, skin, kidney, gastrointestinal tract (never to the
lung). It is a very rare disease, further reduced by vaccination against HBV, with an incidence of 4-9 cases
per million. The average age of onset is 50-60 years, but can also appear in paediatric age. The ratio is
slightly unbalanced towards the male sex: M:F= 1.7:1.

EZIOPATOGENESIS The
disease is associated with numerous infections such as HIV, HZV, parvovirus B-19 and especially HBV.
The endothelial damage is due to the deposition of immune complexes and complement activation that
can lead to the formation of fibrinoid nodules with skin ulcerations. There are idiopathic forms of the
pathogenesis of which is unknown.

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PATHOLOGICAL ANATOMY
It is a focal and segmental necrotizing vasculitis of medium sized vessels, arterioles, capillaries, venules,
it presents with fibrinoid necrosis with infiltrate of neutrophils, eosinophils,
lymphocytes.
The vasal architecture is subverted, the elastic membrane is fragmented and
replaced by amorphous eosinophilic material (fibrinoid). The destruction of
the elastic membrane promotes the appearance of aneurysms and
thrombosis. The vessel is characterized by an alternation of traits with
aneurysmatic manifestations and others with fibrotic endoarteritis leading to
occlusion.

CLINICAL
The pathology is characterized by:
 Systemic symptoms: remitting or intermittent fever, weight loss in 2/3
of patients.
 Skin involvement, sometimes without systemic involvement: painful
subcutaneous nodules, petechiae, purpura, skin ulcers, livedo
reticularis, mainly in the lower limbs.
 SNP: multiple mononeuritis (hypoesthesia, paresthesia, pain, motor
deficits) usually in the lower limbs with acute onset. More rarely the
symptoms can be of simple mononeurite.
 CNS: encephalopathy with cognitive disorders, epilepsy, stroke, subarachnoid
haemorrhage.
 Kidney: parenchymal infarctions, nephrovascular hypertension.
 Arterial vessels: severe or malignant arterial hypertension.
 Heart: coronary artery disease, multiple coronary aneurysms, heart failure, heart
attack.
 Gastrointestinal tract (40-60% of cases): abdominal pain, gatsrointestinal bleeding of
the tenuous.
 Genital apparatus: orchitis, usually monolateral, for ischemia of the testicular artery.

ESR and PCR often increase

, leukocytosis and normocytic normocytic anemia occur. Always look for HBV infection (it may be that
polyarteritis nodosa occurs before HBV infection). In angio-RM it is possible to appreciate the presence
of microaneurysms and stenosis in the mesenteric, renal and hepatic arteries. The lesions can disappear
with therapy, even aneurysms, as they are inflammatory. A CT scan of the abdomen is performed in case
of visceral infarctions.
Electromyography can show axonal peripheral neuropathy.

DIAGNOSIS

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In 1990 the RAC proposed classification criteria and at least three out of ten criteria must be present to
classify the disease as polyateritis nodosa:
1. Weight loss of more than 4kg;
2. Livedo reticularis;
3. Testicular pain or tension;
4. Myalgia, weakness, or polyneuropathy;
5. Mononeuropathy or polyneuropathy;
6. Diastolic pressure >90 mmHg;
7. Increase BUN or creatinine;
8. HBV;
9. Arteriographic abnormalities;
10. Biopsy of small and medium caliber arteries.

A muscle biopsy in patients with myalgia can identify fibrinoid necrosis.

THERAPY
The therapy is based on:
 Corticosteroids(1mg/kg/day) with reduction in 9-12 months
 In the most demanding cases it is necessary to combine cyclophosphamide per os or in boluses to
induce remission. Azathioprine is used for maintenance.
 Plasmapheresis may be useful in HBV related forms.

PROGNOSIS
The disease does not tend to recur after healing and the prognosis depends on visceral involvement.
The five factor score is used to assess the prognosis and to orient the therapy:
 Proteinuria> 1g
 Renal insufficiency (creatinine >140 mol/L)
 Myocardial Disease
 Symptoms GI
 Involvement of the CNS

KAWASAKI DISEASE
It is a vasculitis of medium and small vessels that often involves coronary arteries leading to the
formation of aneurysms and thrombi. It is more common in Southeast Asia (220/100000) than the
Caucasian population (9.1/100000). The M:F ratio is 1.5:1.
In 70% of cases it affects children under 3 years old, it is rare in children over 10 years old, very rare in
adults.

EZIOPATOGENESIS

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It is a pathology caused by a pathogen directly or indirectly by triggering an autoimmune process. The

bacteria most often implicated are Staphylococcus Aureus, Yersinia pseudotubercular,
propionibacterium acne, EBV.
Within 8 days from the onset of the disease there is infiltration of the vessel wall by macrophages and
neutrophils; the process quickly involves the whole wall damaging the elastic membrane and the
smooth muscle cells of the average so that around the twelfth day aneurysms appear and then intra-
aneurysmatic thrombosis. After the twenty-fifth day the inflammatory process decreases, on the fortieth
day only scarring lesions remain.

PATHOLOGICAL ANATOMY
It is a necrotizing panarteritis with fibrinoid necrosis and inflammatory infiltrate consisting of
macrophages, lymphocytes, neutrophils that affects the entire wall of the vessel.

CLINICAL
The disease presents with fever for 5 or more days; cervical lymphadenopathy, nausea, vomiting,
abdominal pain, cough, rhinorrhoea, bilateral conjunctival
congestion, erythema of the lips, tongue in the form of a
rash,polymorphous rash, reddening of the palms of the hands
and feet with initial hardening oedema and subsequent
desquamation.
If left untreated, coronary aneurysms appear. In 30% of cases
pericarditis or valvular insufficiency also appears. Aneurysms of
other arteries are rare.

EXAMINATIONS
ESR and PCR are generally increased; thrombocytosis,
neutrophil leukocytosis, mild anemia are present.
The echocardium during the acute phase shows coronary
aneurysms and possible thrombosis, it is essential for follow-up.
The coronarography can be used for confirmation.

THERAPY
It's based on:
- In the acute phase: high-dose immunoglobulin(2g/kg)
and aspirin(80-100mg/kg/day).
- In convalescence: Low-dose ASA and possible
anticoagulants in patients with giant aneurysms. This therapy should continue for 1-2 years until
the lesions regress.
- In refractory forms (up to 20%) steroid boluses (30 mg/kg/day) for 3 days.
If you intervene in the acute phase often the pz heals.

PROGNOSIS

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The disease is potentially fatal if not recognized in time and treated, death occurs by myocardial
infarction; fortunately most patients respond to immunoglobulin therapy.

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