Pathogenesis – pre clinical stage

 Under genetic and environmental influence Break down in self tolerance occurs, leading to
formation of auto antibodies, seen many years before clinical disease.

 Auto antibodies include

1. Rheumatoid factor

2. ACPA
 Rheumatoid factor
 An autoantibody that binds to the Fc portion of IgG.

 RF can also fix and activate complement by the classic pathway.

 The RFs produced in RA differ from those produced by healthy individuals or from patients
with paraprotein..
 Anticitrullinated Protein Antibodies (ACPAs)
 Immunoglobulins that bind to citrullinated proteins.

 citrulline, derived from posttranslational modification of arginine by PADI

 Humans have four isoforms of PADI. PADI2 and PADI4 are especially abundant in synovium.

 ACPAs can activate the classical and the alternative complement pathways.

 IgE ACPAs from patients with RA can sensitize basophils and mast cells to degranulate.
 Anticitrullinated Protein Antibodies (ACPAs)
 One interesting subset involves antibodies that recognize mutant citrullinated vimentin (MCV).

 Anti-MCV antibodies might be more specific for RA in established disease and also might be more
predictive for radiographic progression than standard ACPA tests.
 Pathogenesis
Role of CD4 T cells :
 CD4 binds to invariant sites on MHC 2
with shared epitopes.
 CD4 memory T cells more in synovium
of RA patient.
 CD4 T cells showed initiation of
arthritis in animal modes.
 T Cell directed therapy has very good
clinical efficacy.

TH-17 sub set plays an important role in

promoting joint inflammation,
destroying cartilage and sub chondral
bone.
 Pathogenesis
Activated T helper cells activate B cells,
macrophages, fibroblast like synoviocytes by
Mechanism of:
 Cell to cell contact.
 Release of soluble mediators.

 Activated synovial fibroblasts produce MMP,

Proteases, IL1,6, TNF alpha.
 Pathogenesis
Role of TNF alpha:

 Up regulates adhesion molecules on endothelial cells

 Influx of leukocytes into synovium

 Activates synovial fibroblasts

 Stimulates angiogenesis

 Promotes pain receptor sensitizing pathways

 Drives osteoclastogenesis
 Clinical features – patterns of onset
Insidious Onset

 Seen in 55% to 65% of cases.

 Asymmetric initial presentations (often with increased symmetry developing later in the course of
disease) are common.

 The reason for the symmetry of joint involvement compared with other forms of arthritis, such as the
seronegative spondyloarthropathies, is unknown.

 Morning stiffness is a cardinal sign of inflammatory arthritis that can appear even before pain and may
be related to the accumulation of edema fluid within inflamed tissues during sleep.
 Clinical features – patterns of onset
 A subtle, early change in RA is the development of muscle atrophy around affected joints. Muscle
efficiency and strength become diminished.

 Depression and anxiety can accentuate symptoms.

 A small but significant weight loss is common and reflects the catabolic effects of cytokines and associated
anorexia.

Acute or Intermediate Onset:

 8% to 15% have an acute onset of symptoms that peak within a few days

 Acute-onset RA is difficult to diagnose and sepsis or vasculitis should be ruled out.

 An intermediate type of onset, in which symptoms develop over days or weeks, occurs in 15% to 20% of
patients.
 Clinical features - patterns of onset
Palindromic Pattern:
 usually begins with pain in one joint or in periarticular tissues; symptoms worsen for several hours
to a few days and are associated with swelling and erythema.
 Then, in reverse sequence, symptoms resolve, leaving no residua.
 Half of patients with palindromic rheumatism go on to develop RA, particularly those with HLA-
DR4.
Arthritis Robustus:
 Most patients are men whose disease is characterized by proliferative synovitis, often with
deformity, which seems to cause little pain and even less disability.
 Patients invariably keep working (often at physical labor).
 Periarticular osteopenia is unusual
 New bone proliferation.
 Bulky subcutaneous nodules develop.
 Subchondral cysts also develop, presumably from excessive pressure caused by synovial fluid within
a thick joint capsule during muscular effort.
Clinical features – articular manifestations
• The joint is normal 1 year prior to the development of rheumatoid arthritis.

11/9/20
• Six months following the onset of rheumatoid arthritis,there is a bony erosion adjacent to the joint and
joint space narrowing.

• After 3 years of the disease ,diffuse loss of articular cartilage has lead to marked joint space narrowing.
Clinical features – Articular Manifestations :

Swan Neck Deformity :

Boutainnere deformity :
Z shaped deformity Of thumb :
• Complete subluxation with marked deviation of the metacarpophalangeal joint.
• Shortening of intrinsic muscle causing tension in dorsal tendon sheath.
 Clinical features – articular manifestations
 Flexor tendon tenosynovitis is a frequent hallmark of
RA and leads to decreased range of motion, reduced
grip strength and “trigger” fingers.

 subluxation of the first MCP joint with

hyperextension of the first interphalangeal (IP) joint
results in Z-line deformity.

 Although metatarsophalangeal (MTP) joint

• Valgus of ankle, pes planus, forefoot varus
involvement in the feet is an early feature of disease, deformity of the left foot related to painful
synovitis of the ankle, forefoot, and
chronic inflammation of the ankle and mid tarsal
metatarsophalangeal joint
regions usually comes later and may lead to pes
planovalgus (“flat feet”).
Clinical features – articular manifestations

• Inflammation about the ulnar styloid and

tenosynovitis of the extensor carpi ulnaris may
cause subluxation of the distal ulna, resulting
in a “piano-key movement” of the ulnar
styloid.
 Clinical features – articular manifestations
 Atlantoaxial involvement of the cervical spine is clinically noteworthy because of its potential to cause
compressive myelopathy and neurologic dysfunction.
 Neurologic manifestations may evolve over time with progressive instability of C1 on C2.
 The prevalence of atlantoaxial subluxation has been declining in recent years, and occurs now in less than
10% of patients
Extra articular manifestations
 Rheumatoid nodules
 Subcutaneous nodules occur in 20–35% of patients with RA and are usually nontender, firm, fixed
or mobile
 Occur most frequently over pressure point areas but also can overlie joints

 Rheumatoid nodules are strongly associated with rheumatoid factor (positive in >95% of cases) and
in patients with RA who smoke.
 Rheumatoid nodules have characteristic histologic findings of central fibrinoid necrosis with a rim
of palisading fibroblasts
 Rheumatoid nodules
 A subset of rheumatoid patients, experience paradoxical accelerated nodulosis with methotrexate
therapy .
 Nodules in these patients can be frequently found over the extensor aspect of the MCP and PIP joints.
 Methotrexate should be discontinued.

 Rheumatoid nodules in the lung may be solitary or multiple, and some are necrotic and difficult to
distinguish from carcinoma.

Caplans syndrome:
 Caplan described multiple rheumatoid nodules, some with cavitation, in the lungs of Welsh coal
miners with RA. This pattern has also been reported in RA patients exposed to silica dust and
asbestos.
 SJÖGREN SYNDROME
 Approximately 30% of patients with RA have sicca symptoms due to secondary Sjögren syndrome.

 D/D :

1. Chronic hepatitis C infection can cause polyarthritis, sicca symptoms, and rheumatoid factor.

2. primary Sjögren syndrome with polyarthritis.

 SS-A/Ro and to SS-B/La are not prevalent in the secondary Sjögren syndrome associated with RA.

 Hypergammaglobulinemia, interstitial nephritis, and distal renal tubular acidosis uncommonly

develop in patients with RA and secondary Sjögren syndrome.
 PULMONARY INTERSTITIAL
 FIBROSIS
The prevalence of clinically evident pulmonary fibrosis among RA patients is approximately 2–3%.

 Virtually all patients with interstitial fibrosis are seropositive for rheumatoid factor and have anti-CCP
antibodies

 Risk factors: male, Smoking

 Nonspecific interstitial pneumonitis (NSIP) and usual interstitial pneumonitis (UIP) are the most
common pathologic types of fibrosis encountered.

 NSIP has a more uniform distribution on plain radiographs and a “ground glass” appearance on HRCT.

 UIP has a more basilar distribution of fibrosis; HRCT shows honeycomb patterns and, frequently,
traction bronchiectasis.
 PULMONARY INTERSTITIAL
 FIBROSIS
NSIP is often responsive to glucocorticoids, but there are no current treatments capable of halting the
progression of UIP.

 Trail of oral prednisone (1 mg/kg/d) regardless of the whether the pathology

 Prednisone is then tapered in accordance with the clinical picture and the results of serial pulmonary
function tests, especially the diffusing capacity.

 Little evidence for an ameliorative effect of anti-TNF agents on interstitial fibrosis.

 Patients with preexisting interstitial lung disease may be at increased risk for methotrexate-induced
pneumonitis—a hypersensitivity reaction to the drug

 Because of this concern, many clinicians obtain a pretreatment chest radiograph

 Other Pulmonary manifestations
 Cryptogenic organizing pneumonia produces a characteristic pattern of multiple patches of consolidation
in the sub pleural areas on HRCT and is often responsive to glucocorticoids.

Additional pulmonary complications of RA include :

 Bronchiectasis, which is present in approximately 3% of patients.

 Bronchiolitis obliterans, which is rare, is poorly responsive to therapy, frequently leads to severe
pulmonary compromise with hypoxia.

 Pulmonary hypertension.
 PLEURAL INVOLVEMENT
 Pleurisy or pleural effusion or both can be the initial manifestation of RA, preceding the onset of
articular disease.

 This occurs in approximately 1–3% of patients, most of whom are male.

 Analysis of pleural fluid is necessary to exclude malignancy, bacterial empyema, and infections with
Mycobacterium tuberculosis.

 Rheumatoid pleural fluid is exudative and characterized by an extremely low level of pleural-fluid
glucose, with the result frequently approaching zero.

 Low glucose is secondary to a defect in glucose transport across the pleural membrane.
 PLEURAL INVOLVEMENT
Treatment :
 Rheumatoid pleuritis consists of moderate- to high-dose prednisone tapered in accordance with
the clinical response.

 Pleurodesis or decortication may be required in unresponsive cases.

 Cardiac involvement
 Risk of premature death in RA is largely due to an increased incidence of cardiovascular disease,
primarily myocardial infarction and congestive heart failure

 It was reported that 70% of patients with nodular disease and 40% of those with non-nodular RA have
some cardiac involvement

 The most frequent site of cardiac involvement in RA is the pericardium.

 Clinical manifestations of pericarditis occur in less than 10% of patients with RA despite the fact that
pericardial involvement may be detected in nearly one-half of the these patients by echocardiogram or
autopsy studies.
 Cardiac involvement
 Cardiomyopathy, manifestation of RA, whose involvement may also be subclinical and only
identified by echocardiography or cardiac MRI.

1. Necrotizing or granulomatous myocarditis

2. Coronary artery disease

3. Diastolic dysfunction.

 Mitral regurgitation is the most common valvular abnormality in RA.

 Complete heart block usually is permanent and is caused by rheumatoid granulomas in or near the
atrioventricular node or bundle of His.

 Rarely, the heart muscle may contain rheumatoid nodules or be infiltrated with amyloid and
amyloidosis can also be responsible for heart block.
 HAEMATOLOGICAL

ABNORMALITIES
Most patients with active RA have a mild normocytic normochromic anemia that correlates with ESR
elevation and the activity of the disease.

 A useful guide is that three-quarters of rheumatoid patients with anemia have the anemia of chronic
disease, whereas one-quarter respond to iron therapy.

 Patients in both groups may have superimposed vitamin B12 or folate deficiency.

 Thrombocytosis is often associated with RA.

 A significant relationship has been noted between thrombocytosis and extra-articular manifestations of
rheumatoid disease.
 FELTY SYNDROME
 Felty syndrome develops in patients with longstanding (usually >10 years duration), erosive RA who are
seropositive for rheumatoid factor and have anti-CCP antibodies.

 Patients with Felty syndrome have synovitis that appears bland and “burnt out.”

 The hallmarks of the syndrome are leukopenia (<4000 white blood cells/mcL), neutropenia (<1500
neutrophils/mcL), and splenomegaly.

 About one-third have evidence of rheumatoid vasculitis with necrotic leg ulcers. Some are positive for P-
ANCA, anti-myeloperoxidase antibodies and cryoglobulins.

 Rarely, fibrosis develops in the hepatic portal system, which leads to portal hypertension, esophageal
varices, congestive splenomegaly, and ascites.
 T cell large granular lymphocyte leukemia (T-LGL)

 Patients have increased numbers of large granular lymphocytes in the peripheral blood, bone marrow, and
liver.

 These lymphocytes contain many azurophilic granules in the cytoplasm and may account for more than
90% of mononuclear cells in blood.

 This syndrome is characterized by a chronic, indolent clonal growth of LGL cells, leading to neutropenia
and splenomegaly.

 The large granular lymphocyte syndrome in patients with RA has the same HLA-DR4 association as seen
in Felty’s syndrome.
 HAEMATOLOGICAL

ABNORMALITIES
Hence a proposal has been made that Felty’s syndrome and large granular lymphocyte syndrome
represent different variants of a broader syndrome comprising

1. RA

2. neutropenia

3. large granular lymphocyte expansions

4. HLA-DR4 positivity

5. variable splenomegaly
 There is a fourfold increased risk of lymphoma in RA patients compared with the general population.
 The most common histopathologic type of lymphoma is a diffuse large B cell lymphoma.
 RHEUMATOID VASCULITIS
 Develops after 10–15 years of disease.
 Almost exclusively in patients who are seropositive for RF & anti-CCP antibodies.
 Approximately 1–3% of patients affected.

Nail fold infarcts,typically are

associated with rheumatoid
factor positivity and active
joint disease

 The pathologic finding in rheumatoid vasculitis is a pan arteritis. All layers of the vessel wall are
infiltrated with mononuclear cells.
 RHEUMATOID VASCULITIS
 The most common form of rheumatoid vasculitis is a smoldering small-vessel vasculitis that produces
painless nailbed infarctions.

 Less often, RA causes a medium-vessel vasculitis which clinical manifests as necrotic leg ulcers, digital
gangrene, and mononeuritis multiplex.

 Rarely, a systemic necrotizing arteritis develops, which is indistinguishable from polyarteritis nodosum
and can lead to infarction of small or large bowel.

 ANCAs, cryoglobulinemia and hypo complementemia are sometimes present.

 Initial treatment consists of high doses of glucocorticoids and, often, cyclophosphamide.

 NEUROLOGIC MANIFESTATIONS
 The most common neurologic complications of RA are compression neuropathies (carpal tunnel
syndrome).

 Rheumatoid vasculitis can cause mononeuritis multiplex a mixed motor-sensory peripheral neuropathy.

 Atlantoaxial subluxation and basilar invagination can produce cervical myelopathy and brainstem
compression.

 Unusual complication of RA is pachymeningitis—inflammation and thickening of dura mater.

 Presents as Clouded sensorium, cranial nerve abnormalities, and retardation of motor activity.

 Once an infectious etiology has been excluded, pachymeningitis is treated vigorously with
glucocorticoids and appropriate DMARDs.
 DIAGNOSIS
 In 2010, a collaborative effort between the American College of Rheumatology (ACR) and the
European League Against Rheumatism (EULAR) revised the 1987 ACR classification criteria for RA
in an effort to improve early diagnosis.
 Differential diagnosis
 Rheumatoid arthritis
 Viral arthritis
Positive test
for  Tuberculous arthritis
 Rheumatic fever
rheumatoid  Bacterial endocarditis
 Gonococcemia
 SLE
 Meningococcemia factor
Migratory  Sarcoidosis
 Viral arthritis
arthritis  Systemic vasculitis
 SLE
 Acute leukemia  Rheumatoid arthritis
 Whipple’s disease Morning  Polymyalgia rheumatica
stiffness  Still’s disease
Effusion  Tuberculous arthritis  Some viral and reactive arthritides
disproportionat  Bacterial endocarditis
ely  Inflammatory bowel disease Symmetric  Rheumatoid arthritis
greater than  Giant cell arteritis small joint  SLE
pain
 Lyme disease synovitis  Viral arthritis

 Rheumatic fever  Lyme disease

Pain  Familial Mediterranean fever  Crystal-induced arthritis
disproportionately  Acute leukemia  Inflammatory bowel disease
greater than effusion
 Acquired immunodeficiency Episodic
 Whipple’s disease
syndrome recurrences
 Mediterranean fever
 Still’s disease
 SLE
 CLINICAL COURSE
 Natural history of RA affected by a number of factors including age of onset, gender, genotype,
phenotype and comorbid conditions.

 As many as 10% of patients with inflammatory arthritis fulfilling ACR classification criteria for RA will
undergo a spontaneous remission within 6 months (particularly seronegative patients).

 The overall mortality rate in RA is two times greater than the general population, with ischemic heart
disease being the most common cause of death followed by infection.

 Median life expectancy is shortened by an average of 7 years for men and 3 years for women compared to
control populations.

 Patients at higher risk for shortened survival are those with systemic extra articular involvement, low
functional capacity, low socioeconomic status, low education, and chronic prednisone use.
 Treatment
 challenges in treatment :

1. Identifying markers that predict in a differential fashion who will respond to treatment or have side
effects from the treatment.

2. Developing methods that will allow to measure the amount of immunosuppression that agents are
producing.

 The most important shift for the treatment of RA has been the realization that patients should
be treated early and to a target of low disease activity or remission.
Measures of disease activity
Remission on treatment
Drugs in rheumatoid arthritis
 Conventional DMARD
 The conventional DMARDs in current use are methotrexate, sulfasalazine,
hydroxychloroquine, leflunomide, and minocycline.

 These medications take 2–6 months to reach maximal effect. Therefore, other measures, such
as low-dose glucocorticoid therapy, may be needed to control the disease while these
medications show their effect.

 The choice of synthetic DMARD depends on the activity of the disease, comorbid conditions,
concerns about toxicity, and monitoring issues.
 DMARDS
• DMARDs) comprise small molecule inhibitors of the immune
response, glucocorticoids and biologic DMARDs.
• Small-molecule inhibitors are either classical DMARDs (cDMARDs),
which have relatively non-specific inhibitory effects on the immune
response or targeted synthetic DMARDs (tsDMARDs), which are
designed to inhibit the effects of a specific target molecule.
• Biologic DMARDs (‘biologics’) are monoclonal antibodies, fusion
proteins or decoy receptors targeted towards speci c cytokines,
receptors and other cell-surface molecules regulating the
 Methotrexate
 Anchor drug in RA

 Methotrexate is administered as a single dose once a week , never on a daily basis.

 The typical starting dose is 7.5 mg orally once a week; the dose then is increased by 2.5 mg to 7.5
mg increments as needed to a maximum of 20–25 mg.

Contraindications :
 Preexisting liver disease.
 Infection with hepatitis B or C.
 Ongoing alcohol use.
 Renal impairment (Creatinine clearance <30ml/min)
 Methotrexate
Toxicity :

 Oral ulcers, nausea, hepatotoxicity, bone marrow suppression and pneumonitis are the most commonly
encountered toxicities.

 With the exception of pneumonitis(which is a hypersensitivity reaction) these toxicities respond to

dose adjustments and are reduced by the concomitant use of folic acid.

 Pneumonitis, while rare, is unpredictable and may be fatal, particularly if the methotrexate is not
stopped or is restarted.

 Oral folate (1–4 mg daily) reduces side effects and should be administered concomitantly.
 Methotrexate
 Oral absorption of methotrexate is variable; therefore, subcutaneous methotrexate may be effective if
the response to oral methotrexate is suboptimal.

 Patient on Methotrexate should be monitored for:

1. Blood cell counts.

2. Liver transaminase levels.

3. Serum creatinine.

 Frequency of monitoring :

1. Every 2–4 weeks during initiation or after dose adjustments.

2. Every 12 weeks for the duration of methotrexate therapy.

 LEFLUNOMIDE
 Activation of T cells results in progression from the
resting phase to the G1 phase, where ribonucleotides are
synthesized, and then to the S phase, where cellular DNA
is replicated in preparation for mitosis.

 T cell activation requires significant increases in de novo

pyrimidine and purine biosynthesis.

 Leflunomide, a pyrimidine antagonist, is

immunomodulatory, with the net effect being a reduction
in activated T lymphocytes.

 Because of enterohepatic recirculation, leflunomide has a

very long half-life.
 LEFLUNOMIDE
 Contraindications :
1. Active infection
2. WBC <3000/mm3, Platelet <50,000/mL3
3. history of myelodysplasia or recent lymphoproliferative disorder
4. LFT >2 × ULN
5. acute or chronic HBV or HCV
6. pregnancy, lactation
 Sulfasalazine
Mechanism :

 Inhibition of arachidonic acid cascade

 SSZ downregulates neutrophil chemotaxis, migration, and proteolytic enzyme production and
degranulation

 Inhibition of ATIC→ ↑ Adenosine

 SSZ inhibits fibroblast proliferation and metalloproteinase synthesis.

 Finally, SSZ has been shown to inhibit the formation of osteoclasts and may be antiresorptive in RA

 One potential site of action for SSZ that may explain its systemic action despite low serum levels is the
mucosa associated lymphoid tissue (MALT) in the small bowel.
 Sulfasalazine
Evidence that some of the efficacy of SSZ may be mediated via MALT is described as follows
 Treatment with SSZ has been shown to decrease circulating immunoglobulin (Ig) A-producing cells and
serum levels of IgA, correlating with disease improvement.

 SSZ has been shown to reduce gut mucosa lymphocytes in treated patients

Contra indications:
1. Sulfa allergy
2. Platelets <50,000/mL3
3. LFT >2 ×ULN
4. HBV/HCV
 Anti Malarial
 Antimalarial agents have both immunomodulatory and anti-inflammatory properties.

 HCQ and CQ are weak bases, they can pass through cytoplasmic membranes into cytoplasmic
vesicles and accumulate, thereby increasing the vesicle pH from around 4.0 to 6.0.

 This increased pH has immunoregulatory effects inform of stabilization of lysosomal membranes,

attenuation of antigen processing and presentation, and inhibition of cell-mediated cytotoxicity.

 Macrophages and monocytes require precise pH concentrations for protein digestion and antigen
processing, which is altered with an increased pH.
 Anti Malarial
 An uncommon but serious complication is retinal toxicity, which correlates with cumulative dose and
can be prevented by regular screening.

 toxicity increases substantially after 5–7 years of use or a cumulative dose of 1000 g.

 Annual ophthalmologic screening is warranted after initiation of treatment for more than 5 years.
 GLUCOCORTICOIDS

 Can be administered in low to moderate doses to achieve rapid disease control before the onset of
fully effective DMARD therapy.

 Can be used as a 1- to 2-week burst for the management of acute disease flares, with dose and
duration guided by the severity of the exacerbation.

 Chronic administration of low doses (5–10 mg/d) of prednisone may also be warranted to control
disease activity in patients with an inadequate response to DMARD therapy.

 High-dose glucocorticoids may be necessary for treatment of severe extraarticular manifestations of

RA, such as ILD.

 Intraarticular injection of triamcinolone acetonide for rapid control of inflammation in the setting of
a limited number of affected joints.
 GLUCOCORTICOIDS

 Osteoporosis ranks as an important long-term complication of chronic prednisone use.

 Strong recommendations for primary prevention with a bisphosphonate in patient receiving 5 mg/d or
more of prednisone for greater than 3 months.
 AZATHIOPRINE
• Azathioprine (AZA) is most commonly used in vasculitis and SLE, often in combination
with other drugs.
• It is metabolised to 6-mercaptopurine (6-MP), which blocks lymphocyte proliferation by
inhibiting DNA synthesis.
• The typical starting dose is 1 mg/kg body weight per day, increasing to 2.5 mg/kg until a
response is observed or toxicity occurs.
• Side effect : Bone marrow suppression, nausea.
 CYCLOPHOSPHAMIDE
• Cyclophosphamide is a cytotoxic alkylating agent that cross-links DNA and halts cell division,
causing immunosuppression.
• It is mainly used to induce remission in life-threatening systemic vasculitis and SLE.
• It can be given orally in a dose of 2 mg/kg/day for 3–6 months or intravenously in a dose of 15
mg/kg every 3–4 weeks on 6–8 occasions.
• Adverse effects include nausea, anorexia, vomiting, bone marrow suppression, cardiac toxicity,
alopecia and haemorrhagic cystitis.
 MMF
• Mycophenolate mofetil (MMF) works by inhibiting inosine monophosphate dehydrogenase, a rate-
limiting enzyme in the synthesis of guanosine nucleotides in lymphocytes. MMF is used in SLE and
vasculitis in doses of 2–4 g daily orally. Haematological toxicity is the main adverse effect.
 CICLOSPORIN A
• Ciclosporin A is a calcineurin inhibitor that inhibits
lymphocyte activation. It is occasionally used in the treatment
of RA and PsA at a dose of 2.5–4 mg/kg/day orally.
 TARGETED SYNTHETIC DMARDS
• Janus-activated kinase (JAK) inhibitors work by inhibiting JAK enzymes, which are a
family of intracellular signalling molecules that play a key role in transducing the effects
of several pro-inflammatory cytokines.
• The main adverse effects of JAK inhibitors are an increased risk of infections, screen
patients for evidence of occult infection with HIV, hepatitis C, hepatitis B and previous
TB before commencing therapy.
• Tofacitinib (5 mg twice daily or 10 mg daily) is indicated for adults with RA and PsA. It is
usually prescribed in combination with MTX, but can be used as monotherapy in patients
where MTX is poorly tolerated or contraindicated.
• Baricitinib (2–4 mg once daily) and filgotinib (200 mg daily) are both indicated for RA.
• Upadacitinib (15 mg daily) is also indicated as monotherapy or in combination with MTX,
for RA, PsA and AxSpA.
• Tofactinib requires long-term blood monitoring for marrow and liver toxicity, lipid profile.
• Apremilast is used in the treatment of PsA. It is a small molecule inhibitor of
phosphodiesterase 4, an enzyme that breaks down cyclic adenosine monophosphate
(cAMP).
• Apremilast is given orally in a dose of 30 mg twice daily. The main adverse effects are
gastrointestinal upset, weight loss and an increased risk of depression.
 Biological DMARD
 They are protein therapeutics designed mostly to target cytokines and cell-surface molecules.

 The TNF inhibitors were the first biologicals approved for the treatment of RA.

 Patients are screened for latent tuberculosis prior to starting anti-TNF therapy.

 Patients are skin tested using an intradermal injection of purified protein derivative (PPD)

 Individuals with skin reactions of more than 5 mm are presumed to have had previous exposure to
tuberculosis and are evaluated for active disease and treated accordingly.

 The QuantiFERON IFN-γ release assay may also be used in selected circumstances to screen for previous
exposure to tuberculosis.
TNF alpha inhibitors
 TNF alpha inhibitors
Postulated mechanism of action Adverse effects
 Tocilizumab
 Previously referred to as myeloma receptor antibody (MRA), tocilizumab is a humanized IgG1 monoclonal
antibody that binds with high affinity to soluble and membrane-bound forms of the 80-kD component of
the IL-6R.

 This agent has been shown to increase LDL cholesterol

however, it is not known as yet if this effect on lipid
levels increases the risk for development of atherosclerotic
 Abatacept
 Abatacept is a novel, fully human fusion protein comprising the extracellular portion of CTLA-4 and the
Fc fragment of a human IgG-1.

 Abatacept is generally considered as a biologic option in RA patients with inadequate responses to TNF
inhibitors.
 Rituximab
 Rituximab is a chimeric mouse-human monoclonal antibody directed against the extracellular domain of the
CD20 antigen.

 It initiates complement-mediated B cell lysis and may permit antibody-dependent, cell-mediated cytotoxicity
when the Fc portion of the antibody is recognized by corresponding receptors on cytotoxic cells.

 Rituximab is currently indicated for the treatment of patients with moderate to severe RA who show no
response, experience a loss of response with time, or have adverse effects to anti-TNF alpha agents.

 The findings of recently reported studies indicate that rituximab is also efficacious in a proportion of both
treatment-naïve and methotrexate patients with RA, particularly if seropositive.
 Rare and lethal adverse effect progressivemultifocal leukoencephalopathy (PML),
 Anakinra
 Anakinra blocks the activity of IL-1 by competitively inhibiting IL-1 binding to the IL-1RI receptor.

 Anakinra should not be combined with an anti-TNF drug due to the high rate of serious infections as
observed with this regimen.
• Ustekinumab is an antibody to p40, which is a subunit shared by the cytokines IL-23
and IL-12. It acts as an inhibitor of both IL-12 and IL-23 signalling and is indicated in
adults with PsA who have not responded adequately to cDMARDs. Adverse effects
include an increased risk of infections, hypersensitivity reactions and an exfoliative
dermatitis.
• Guselkumab is an antibody directed against the p19 protein of IL-23, which acts as a
specific inhibitor of IL-23 signalling. It is effective in the treatment of PsA and can be
used alone or in combination with MTX.
 IL-17 INHIBITORS
• IL-17 inhibitors. There are two drugs in this class; secukinumab is a monoclonal
antibody to IL-17A and ixekizumab, which binds both IL-17A and IL-17A/F.
• These drugs are indicated in adults with PsA and axSpA who have not responded
adequately to cDMARDs and/or anti-TNF-α.
• Adverse effects include an increased risk of triggering bouts of IBD, infections,
nasopharyngitis and headache. Adverse effects include infections and exacerbation of
IBD
 Treatment recommendations
Factors associated with poor prognosis
Treatment recommendations- Early disease
Treatment recommendations- Established disease
Thank you