JUVENILE RHEUMATOID

ARTHRITIS
Pragna Vanapala
SGU SOM
September 4th, 2015

Background Information
Also known as juvenile idiopathic arthritis
Most common rheumatic disease in children and one of the more common

chronic illnesses of childhood

JRA/JIA a group of disorders that all share clinical manifestations of
arthritis
Etiology and pathogenesis largely unknown, and genetic component is
complex so distinguishing b/w different subtypes is difficult
Multiple classification schemas:
a) Classification Criteria of the American College of Rheumatology (ACR): characterizes
disease into 3 onset types:
1.
Polyarthritis
2.
Oligoarthritis / Pauciarticular
3.
Systemic Disease
b) International League of Association for Rheumatology uses term Juvenile idiopathic
arthritis (JIA)
- Includes above three + Psoriatic arthritis, Enthesitis-related arthritis, undifferentiated

Criteria for classification of Juvenile Rheumatoid Arthritis

Age at onset: <16 yr
Arthritis (swelling or effusion, or the presence of 2 or more

of the following signs: limitation of range of motion,

tenderness or pain on motion, increased heat) in 1 joints
Duration of disease: 6 wk
Onset type defined by type of articular involvement in the
1st 6 mo after onset:
- Polyarthritis: 5 inflamed joints
- Oligoarthritis: 4 inflamed joints
- Systemic disease: arthritis with rash and a
characteristic quotidian (daily) fever
Exclusion of other forms of juvenile arthritis

ACR vs ILAR Classification

Arthritis
300,00 children in US have arthritis;

100,000 with a form of JIA

Etiology of JRA
Not completely understood
2 components necessary: immunogenetic susceptibility and

external trigger
Multiple genes may affect disease susceptibility

Histocompatiblity complex regions: HLA class I and II alleles:

associated with different subtypes
Non HLA loci polymporphisms in genes that encode tumor necrosis
factor (TNF)-a, macrophage inhibitory factor, interleukin-6, and IL-1a
Non genetic triggers: bacterial and viral infections (parvovirus B19,
rubella, Epstein-Barr virus), enhanced immune response to bacterial
or mycobacterial heat shock proteins, abnormal reproductive hormone
levels, joint trauma

Pathogenesis
JRA is an autoimmune disease due to alterations in both humoral and cell-

mediated immunity
Recruitment of T lymphocytes (primarily type 1 helper T cells) release
proinfammatory cytokines (TNF-a, IL-6, IL-1) target synovial non-self antigens
Complement consumption, immune complex formation, and b-cell activation also
promote Inflammation of the synovium inflammatory synovitis
Inflammatory synovitis villous hypertrophy, hyperplasia with hyperemia
and edema of synovial tissue
Hyperplasia of vascular endothelium and is infiltrated by mononuclear, plasma
cells with many T lymphocytes
Persistent inflammation can lead to pannus formation (abnormal layer of
fibrovascular tissue or granulation tissue forms over the joint), cartilage erosions,
and destruction of underling bone and other structures like ligaments and
tendons surrounding the joint.
Note: Inheritance of specific cytokine alleles can also up regulate inflammatory
mediators systemic onset disease or more severe articular disease

Clinical Manifestations for All Types

Arthritis must be present for diagnosis of any subtype of JIA

Definition: intra-articular swelling or presence of 2 or more signs:

limitation in range of motion, tenderness or pain on motion, and increased
heat or erythema

Morning stiffness with limp or gelling (stiffness after rest) after

inactivity; associated with easy fatigability and poor sleep

quality
Involved joints: swollen, warm to touch, painful on movement
or palpation with reduced range of motion but usually not
erythematous
Arthritis in larger joints: first accelerates linear growth
affected limb is longer, as inflammation persists premature
closure of growth plate so shortened bones

Clinical Manifestations cont..

Bone mineral metabolism and skeletal maturation

are affected in every subtype

Have decreased bone mass (osteopenia)
Cytokines TNF-a and IL-6, have deteriorating effects
on bone w/in joint and in axial & appendicular bones

Clinical Manifestations

- 7-year-old boy with juvenile

idiopathic arthritis monarticular involvement of
the left knee
- Inflammatory process
epiphyseal growth stimulation
initial local bony
overgrowth and increased
bone lenghth .
- Eventually, premature
epiphyseal closure
shortening of the involved
bone.

1. Oligoarthritis
Epidemiology: Pauciarticular JIA/ Oligoarthritis most common
subtype (50-60%), more girls than boys are affected (3:1), peak age of
onset: 2-4yrs
4 joints w/in first 6months of disease onset, often only single joint is
involved
Affects large joints of lower extremities knees and ankles
If disease never develops in more than 4 joints persistent
oligoarticular JIA
If disease involves more than 4 joints over time extended
oligoarticular JIA (worse prognosis)
Presence of positive ANA test increased risk of asymptomatic
anterior uveitis
If hip is involved suggest a spondyloarthropathy, never a sign of
oligoarthritis***

Oligoarthritis cont
Oligoarticular Juvenile idiopathic arthritis
with swelling and flexion contracture of
right knee

2. Polyarthritis/ Polyarticular Disease

Epidemiology: Polyarticular: 30-35%, more girls than boys
affected (5:1). Age of onset has a bimodal distribution: 2-4yr,
and 10-14yrs
Inflammation of 5 joints in both upper and lower extremities
If rheumatoid factor is present similar to symmetric
presentation of adult rheumatoid arthritis
RF positive individuals -> rheumatoid nodules on extensor
surfaces of elbows and over Achilles tendons more severe
course
Micrognathia (undersized jaw) reflects chronic TMJ disease
Cervical spine involvement decreased neck extension,
risk of atlantoaxial subluxation, and neurologic symptoms
Hip disease decreased and painful range of motion on exam

Polyarthritis/ Polyarticular Disease cont

Polyarticular juvenile arthritis:
- Progression of joint destruction:
loss of articular cartilage,
destructive changes in PIPs,
DIPs, and metacarophalangeal
joints,
- Destruction and fusion of wrist
bones

Rheumatoid nodules in achilles

tendon (exclusively seen in RF
positive children)

Polyarthritis/ Polyarticular Disease cont

3. Systemic onset disease

Epidemiology: Systemic disease: 10-20%, no sex predominance,
occurs throughout childhood w/out a peak
Arthritis
Fever: spiking temperatures to 30C daily or twice daily for at least
2wks with rapid return to normal or subnormal temperatures
Often present in evening
frequently accompanied by faint, erythematous, macular rash.
The salmon colored lesions are linear or circular and distributed
over the trunk and proximal extremities
Classic rash is nonpruritic and migratory with lesion lasting <1hr
Visceral involvement: hepatosplenomegaly, lymphadenopathy,
serositis (pericarditis)

3. Systemic onset disease cont

Koebner phenomenon cutaneous

hypersensitivity (skin lesions) that appear at site of

superficial trauma; heat from warm bath can also
evoke rash
Some children at the beginning only show systemic
features, but definitive diagnosis requires presence
of arthritis
Arthritis can affect any number of joints, but is
usually polyarticular and also involves hip, cervical
spine, and TMJ

Systemic onset disease cont

Systemic onset JIA: salmon
colored lesions on trunk
and extremities

Koebner phenomenon:
linear maculopapular lesions
that were provoked by making
scratch marks

Systemic onset JIA Macrophage Activation Syndrome

Background:

A rare, but fatal complication of SoJIA that can occur at anytime during course of disease
Also known as secondary hemophagocytic syndrome or hemophagocytic
lymphohistiocytosis (HLH)
Hemophagocytosis: phagocytosis by histiocytes of erythrocytes, leukocytes, platelets, and
their precursor in bone marrow and other tissues
Etiology and Pathophysiology: Trigger like a viral infection or medication
uncontrolled activation and proliferation of macrophages, T lymphocytes, and an increase
in circulating cytokines
Presentation:
Acute onset of severe anemia with thrombocytopenia or leukopenia, high spiking fevers,
lymphadenopathy, and hepatosplenomegaly
Also have purpura, mucosal bleeding, elevated fibrin split products, prolonged PT and
PTT, Decrease in ESR due to low fibrinogen levels and hepatic dysfunction
Diagnosis: clinical criteria, confirmed with bone marrow biopsy showing
hemophagocytosis
Treatment: High dose IV methylprednisolone, cyclosporine, or anakinra

Macrophage Activating System

PRELIMINARY DIAGNOSTIC GUIDELINES FOR MACROPHAGE ACTIVATION SYSTEM
(MAS) COMPLICATING SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS (JIA)
LABORATORY CRITERIA
1. Decreased platelet count (262 109/L).2. Elevations of aspartate aminotransferase (>59 U/L).
3. Decreased white blood cell count (4.0 109/L).
4. Hypofibrinogenemia (2.5 g/L).
CLINICAL CRITERIA
1. Central nervous system dysfunction (irritability, disorientation, lethargy, headache, seizures, coma).
2. Hemorrhages (purpura, easy bruising, mucosal bleeding).
3. Hepatomegaly (edge of liver 3 cm below the costal arch).
HISTOPATHOLOGIC CRITERION
Evidence of macrophage hemophagocytosis in the bone marrow aspirate
DIAGNOSTIC RULE
The diagnosis of MAS requires the presence of any 2 or more laboratory criteria or of any 2 or 3 or
more clinical and/or laboratory criteria. A bone marrow aspirate for the demonstration of
hemophagocytosis may be required only in doubtful cases.

Lab Findings
Elevated ANA in 40-85% of children w/ oligoarticular

or polyarticular JIA but rare in SoJIA

ANA seropositivity associated w/ risk of chronic uveitis

5-10% w/ polyarticular JIA are seropositive for RF

Anti-cyclic citrullinated peptide (CCP) marker for

more aggressive disease

Children w/ SoJIA: elevation in inflammatory
markers, WBC, and platelet counts
Hb levels 7-10g/dl with similarities to anemia of
chronic disease
ESR is usually high except in MAS, ferritin is usually
elevated and can be increased in MAS

Lab Findings cont.

Radiologic changes of arthritis:

Soft tissue swelling, periarticular osteoporosis, periosteal

new bone apposition around affected joints
Subchondral erosion, loss of cartilage, bony destruction,
fusion
Changes in cervical spine at C2-C3 can progress to
atlantoaxial subluxation

MRI can detect changes in early stages of disease

Treatment
Goals of treatment: disease remission, prevent joint damage,

encourage normal growth and development

Pauciarticular disease :

Can respond to NSAIDs alone with improvement in inflammation

and pain
Those w/ no response after 4-6wk of NSAIDs or w/ functional
limitations (joint contracture or leg length discrepancy) intraarticular corticosteroids like Traimcinolone hexacetonide
Disease modifying antirheumatic drugs (DMARDs) for those w/ no
response to above drugs Methotrexate is least toxic
If still no response to methotrexate biologic meds that inhibit
TNF-a and IL-1. TNF-a antagonists (etanercept, adalimumab,
infliximab) are for children w/ poor response to Methotrexate,
poor prognostic factors or w/ severe disease

Treatment (Continued.)
Systemic Steroids Indications
Severe inflammation
Systemic illness
Bridge therapy
Control of uveitis
Steroids side effects: Cushing syndrome, growth retardatoin,
osteopenia
Management of JIA has to include periodic slit-lamp

opthalmologic examinations to monitor for asymptomatic

uveitis
Ophthalmology follow up, physical therapy, occupational
therapy, dietary evaluation and counseling to make sure there is
adequate calcium, vitamin D, protein, and caloric intake

Overview of JRA/JIA

Overview of JRA/JIA cont

Differential Diagnosis
Arthritis:
Manifestation

for many multisystem rheumatic diseases like SLE, juvenile

dermatomyositis, sacroidosis, vasculitic syndromes
Scleroderma limited range of motion due to sclerotic skin over joint can be confused
with chronic inflammatory arthritis
Acute rheumatic fever: joint pain & tenderness, fever, & migratory polyarthritis
Infections associated w/ arthritis: parvovirus B19, rubella, EBV, HepB, HIV, enteric
infections
Lyme disease children with oligoarthritis living in or visiting endemic areas
Kingella kingae monoarticular arthritis unresponsive to inflammatory tx
Septic arthritis: acute onset of fever, painful erythematous, hot joints
Spondyloarthropathy: tenderness over insertion of ligaments, tendons, and lower
extremities in a boy
Inflammatory bowel disease: can manifest as oligoarthritis, affect joints in lower
extremities, GI symptoms, ESR elevation, microcytic anemia
Leukemia or neuroblastoma: can have joint or bone pain due to malignant infiltration
of bone, synovium, or bone marrow. Usually no bone pain on palpation. High ESR w/
leukopenia and low normal platelet count (clue to underlying leukemia)

Prognosis
50% of JIA patients have active disease that persists into early

adulthood w/ severe limitations to physical function

Persistent oligoarticular disease

- Good prognosis w/ majority undergoing remission

Girls w/ ANA positive and onset of arthritis earlier than 6yrs risk for chronic
uveitis which can cause posterior synechiae, cataracts, and band keratopathy leading
to blindness

Polyarticular JIA

Has prolonged course of active joint inflammation and require early and aggressive
therapy
Severe and persistent disease if young age at onset, RF seropositivity, rheumatoid
nodules, anti-CCP antibodies, high number of affected joints

Systemic JIA

Poorer prognosis in children w/ increased inflammatory markers for >6mo, fever

lasting >3mo, polyarticular distribution of arthritis

References

Nelson textbook of Pediatrics

THE END