Juvenile rheumatoid

arthritis (JRA)
 BACKGROUND

Chronic Arthritis in Childhood is

characterized as
Juvenile Rheumatoid Arthritis
(JRA)
Age of onset < 16 years of age.
 BACKGROUND
 Pathogenesis and Etiology of JRA: Multi-factorial
 Genetic, Hormonal, Immunologic

 Pathogenesis

• Characterized by chronic inflammation of the

synovium;
• Presence of articular cartilage damage;
• Accompanied by extra-articular systemic
manifestations.
 Heterogeneity of JRA

• At least 3 primary types of onset of JRA:

 Pauciarticular (Oligoarticular)

 Polyarticular and

 Systemic
 BACKGROUND
 Pathogenesis (Continued)
 Genetic

• Basis of immune distinction between self and non-

self is the major histocompatibility complex (MHC)
that in humans is called the human leukocyte
antigen (HLA).
• HLA system comprises a family of polymorphic
genes located on the short arm of chromosome 6.
• Polymorphisms of JRA suggest a non-mendelian
inheritance.

 Hormonal Factors
• Differences in the sex ratio of JRA subtype onset
• Pre-adolescent or post-adolescent peaks
 BACKGROUND
 Immune Mechanisms
 Disease process involves loss of tolerance towards

auto-antigens  chronic synovitis;

 Production of auto-antibodies:

• Anti-nuclear antibodies (ANA): associated with

increased risk of iridocyclitis (eye inflammation);
• Rheumatoid factors (RF): auto-antibodies directed
against the Fc fragment of IgG (associated with
~10% of polyarticular JRA);
• Complement activation by circulating immune
complexes may also contribute to the disease
process.
 BACKGROUND
 Immune Mechanisms (Continued)
 Cytokines: act on the immune system and other cells

to initiate and sustain inflammation:

 Intercellular mediators: Interleukin-1 (IL-1), IL-6,

and tumor necrosis factor-alpha (TNF-);

 Immunomodulatory cytokines produced by T-

cells  Interferon gamma (IFN-γ), IL-4, IL-2.

 CLASSIFICATION OF JRA
 ACR (American College of Rheumatology) Criteria
 Age at onset: < 16 years of age;

 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 and
• Increased heat in one or more joints;
 Duration of disease > 6 weeks;

 Onset type is defined by the type of disease in the first 6

months:
• Oligoarticular (Pauciarticular) < 5 inflamed joints;
• Polyarticular: > 5 inflamed joints;
• Systemic onset: arthritis with characteristic fever.

 Exclusion of other forms of childhood arthritis.

General history of JRA includes the following:
 Disease onset is either insidious or abrupt, with morning
stiffness and arthralgia during the day.
 Their abilities to participate in physical education classes
may reflect severity of the disease.
 Limping may be observed in individuals with more severe
JRA; however, the presence of limping also raises the
possibility of trauma or another orthopedic problem.
 A preceding illness raises the possibility of infectious trigger
of JRA or postinfectious arthritis.
 Very severe joint pain raises isn’t typical for JRA and shows
the possibility of acute rheumatic fever (also suggested by
migratory but not additive arthritis, with fevers).
 Weight loss without diarrhea may be observed in individuals
with active JRA and sometimes associated with anorexia.
CLINICAL MANIFESTATIONS of JRA
 JRA by the Type-of-Onset
Characteristic Pauciarticular Polyarticular Systemic

% Cases (F:M) 60 (5:1) 30 (3:1) 10 (1:1)

# Joints <4 >5 Variable

Age at onset Early Thru Thru

childhood, childhood, childhood,
peak 1-2 yr peak 1-3 yr no peak

None; Mild; Systemic self-

Systemic uveitis (++) unremitting limited; chronic
involvement articular destructive
involvement arthritis ~50%

5% Rare
Chronic Uveitis 5-15%
10%/40-50% Rare/10%
RF/ANA Rare/75-85%
Guarded to Moderate to
Prognosis Excellent moderately poor
except for good
eyesight
 Extra-Articular Manifestations of JRA

Pauciarticular Polyarticular Systemic

Fever 0% 30% 100%

Rheumatoid rash 0 2 95
Rheumatoid nodules 0 10 5
Hepatosplenomegaly 0 10 85
Lymphadenopathy 0 5 70
Chronic uveitis 20 5 1
Pericarditis 0 5 35
Pleuritis 0 1 20
Abdominal pain 0 1 10
Systemic-onset JRA is characterized
by spiking fevers, typically occurring several
times each day
 Evanescent salmon-pink rash, often linear, is found

on the trunk and the extremities; this rash is worse

with fever.
 Hepatosplenomegaly.

 Lymphadenopathy.

 Muscle tenderness to palpation.

 Ocular: Photophobia, in uveitis (usually

asymptomatic on onset), and synechiae (irregular

iris perimeter resulting from postinflammatory
adhesions of iris to lens) may be found
 Cardiovascular: myocarditis occurs in individuals

with systemic JRA.

Pauciarticular form is characterized by arthritis
affecting 4 or fewer joints.
 Typically, large weight-bearing joints, knees, and
ankles are affected.
 Involvement of a few small joints in the hands is
atypical and suggests eventual development of
polyarticular JRA.
 Muscle atrophy, often of extensor muscles
(vastus lateralis, quadriceps when knee affected)
is found.
 Flexion contractures in the knees and, less
commonly, the wrists are found.
Picture 1. Patient with active pauciarticular disease. (significant
suprapatellar swelling (effusion), loss of natural contour medial to
the patella).

                               
Polyarticular form affects at least 5 joints
 Both large and small joints can be involved,
often in symmetric bilateral distribution.
 Severe limitations in motion are usually
accompanied by weakness and decreased
physical function.
Picture 2. Patient with active polyarticular arthritis. (swelling of all
proximal interphalangeal joints, boney overgrowth, lack of distal
interphalangeal joint involvement. The patient has interosseus
muscle wasting and subluxation and ulnar deviation of the wrists
are present).

                               
Laboratory studies should include the following:
o
Erythrocyte sedimentation rate (ESR)
o
CBC with differential and platelet count
o Alanine aminotransferase (ALT) test
o
Urinalysis with microscopic examination
o
Antinuclear antibody
o
Rheumatoid factor
o Total protein, albumin, fibrinogen, D-dimer (for
systemic JRA)
o Imaging Studies: radiography of affected
joints, bone scanning, MRI, CT scanning of
long bones, echocardiography
Picture 3. Wrist radiographs of the patient with active polyarticular arthritis shown
in Image 2. (severe loss of cartilage in the intercarpal spaces and the radiocarpal
space of the right wrist, large erosion is present in the articular surface of the
ulnar epiphysis. The view of the left wrist shows boney ankylosis involving the
lateral 4 carpal bones with sparing of the pisiform. Erosions are present in the
distal radius and ulna.

                               
 PROGNOSIS OF JRA
 Pauciarticular JRA
 Boys may be affected in older childhood or
adolescence; this may represent an early
manifestation of a spondyloarthropathy.
 Leg length discrepancy from asymmetric knee
synovitis and bone growth may cause flexion
contractures, gait abnormalities and long-term growth
abnormalities.
 Eye involvement as anterior uveitis, may lead to
scarring or blindness in ~ 15-20% of children.
 Active arthritis into adulthood in 40% to 50% of
patients.
 Radiographic joint damage within 5 years.
 PROGNOSIS OF JRA
 Polyarticular JRA and Systemic JRA
 Active arthritis into adulthood: 50% to 70% of polyarticular
or systemic onset JRA;

 Long-term disabilities: 30% to 40% of children

• Unemployment: 25% to 50% of adult JRA patients;
• May need major surgery (joint replacement).

 Radiographic joint damage within 2 years;

 Mortality rate: 0.4% to 2% (greater risk with systemic JRA

than with polyarticular JRA).
 Traditional Approach to the
Treatment of JRA
Before the 1990s …
Pyramid Approach

Cytotoxic Drugs

Disease Modifying
Anti-Rheumatic Drugs
(DMARDs)

Intra-Articular/Oral Corticosteroids

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

 Treatments with Indications for JRA
 Non-Selective NSAIDs
 Aspirin, tolmetin sodium, ibuprofen, naproxen

 Naproxen [Tablets and Suspension]

• Indicated for patients 2 years and older with juvenile

arthritis.
• Daily dose: approximately 10 mg/kg/day as a BID
dose (5 mg/kg given twice-a-day). Total daily dose is
not to exceed 15 mg/kg/day.
• Adverse events: gastrointestinal, central nervous
system (headache, dizziness, drowsiness, vertigo),
rash (ecchymoses, purpura), pruritus, sweating,
special senses (tinnitus, visual disturbances, hearing
disturbances), cardiovascular (edema, palpitations)
prolonged bleeding times.
 Treatments with Indications for JRA
 Non-Selective NSAIDs/COX-2 Selective Inhibitors
 MOBIC (meloxicam) [Tablets and Suspension]

• Indicated for the relief of the signs and symptoms of

pauciarticular and polyarticular course JRA in patients 2 yrs
and older.
• 0.125 mg/kg once daily up to a maximum of 7.5 mg.
• Adverse events: abdominal pain/upper, vomiting, diarrhea,
headache, infection (rhinitis), cough, pyrexia, rash. urticaria,
slight increases in systolic blood pressure.
 VIOXX (rofecoxib) [Tablets and Suspension]
• Withdrawn from the global market September 2004.
• Indicated for the relief of the signs and symptoms of juvenile
rheumatoid arthritis in patients 2 years and older.
 Treatment of JRA
 Corticosteroids
 Used for uncontrolled or life-threatening systemic

disease;
 Treatment of chronic uveitis as local ophthalmic

drops; or
 Intra-articular agents (Pauci- and polyarticular JRA)

 Intermediate-acting corticosteroids: Prednisone;

methyl-prednisolone (Intravenous pulse therapy for

severely active JRA).
• Prednisone low-dose as 0.1 to 0.2 mg/kg; higher-
dose 0.25 to 1.0 mg/kg/day (maximum single dose
40 mg)
• Adverse events: hypertension, iatrogenic
Cushing’s syndrome, growth suppression,
fractures, cataracts, increased susceptibility to
infection.
 Treatment of JRA
 DMARDs and Biologic DMARDs
 Methotrexate (MTX): used when NSAIDs fail to bring

relief.
• Indicated for polyarticular JRA. MTX is the most
widely used DMARD for JRA treatment.
• Starting dose 7.5 mg/m2 per week; maximum dose of
15 mg/m2 per week.
• Methotrexate compared to leflunomide (Lef): 240 JRA
pts, 16-week DB + 6 mo Ext + optional 30 mo Ext in
JRA; JRA Definition of Improvement > 30% (JRA DOI
> 30): 89% MTX compared to 68% Lef.
• Adverse events: stomatitis, leukopenia, nausea/
abdominal pain, gastrointestinal bleeding, anorexia,
malaise, fatigue, chills and fever, headache, alopecia,
rash, decreased resistance to infection, elevated
hepatic enzymes.
 Treatment of JRA
 DMARDs and Biologic DMARDs (Continued)
 Sulfasalazine

• Indicated for polyarticular JRA who have responded

inadequately to salicylates or other non-steroidal
anti-inflammatory drugs.
• Children 6 yrs and older: 40 - 60 mg/kg/day divided
into 3 to 6 doses.
• Maintenance dose: 30 mg/kg/day divided into 4
doses.
• Adverse events: anorexia, headache, vomiting,
gastric distress, rash, urticaria, hemolytic anemia.
 Treatment in JRA
 DMARDs and Biologic DMARDs (Continued)
 ENBREL (etanercept): a cytokine antagonist

• Indicated for moderate to severe polyarticular course JRA

patients 4 to 17 years of age who had an inadequate response
to one or more DMARDs.
• Dosage: 0.4 mg/kg/week (maximum 25 mg/ dose given twice
weekly) as subcutaneous injection pre-filled syringe, 72-96 hrs.
apart.
• Adverse events: headache, nausea, abdominal pain, and
vomiting. Infection was reported in 43 of 69 (62%) of JRA
patients during the 3-month (open-label phase). Serious AEs
reported in the study: varicella, gastroenteritis, depression/
personality disorder, cutaneous ulcer, esophagitis/ gastritis,
group A streptococcal septic shock, Type 1 diabetes, soft tissue
and post-operative wound infection.
 Treatment in JRA
 DMARDs indicated for RA without an indication for JRA
 Hydroxychloroquine, injectable gold, leflunomide and

d-penicillamine.

 Other Immunomodulatory or Cytotoxic Drugs

 Indicated in RA without a JRA indication:

• Azathioprine
• Cyclosporine A
 Without a RA or a JRA indication:

• Chlorambucil
• Thalidomide
 Treatment of JRA in 2008

 Pauciarticular
 25% to 33% will respond to NSAIDs;

 Patients not responsive to NSAIDS after 4 - 6 weeks

with flexion contractures or leg length discrepancy 

intra-articular corticosteroids.
 Patients with extended pauciarticular JRA or small

joint involvement  treat as polyarticular JRA.

 Treatment of JRA in 2008
 Polyarticular
 RF (-) or (+), NSAID (symptom control) alone is usually

not as effective as a NSAID + DMARD.

 NSAID trial for several weeks  add oral MTX.

 If oral MTX is not effective  parenteral route MTX.

 If NSAID + MTX (oral or parenteral) is not effective 

anti-TNF medication.
• No current evidence whether a combination of MTX +
anti-TNF medication are more effective than only anti-
TNF medication.
 Treatment of JRA in 2008
 Systemic
 NSAIDs 2 to 3 weeks with caution  risk of

Disseminated Intravascular Coagulation (DIC),

(macrophage activation syndrome);
 Intravenous pulse methylprednisolone;

 Oral corticosteroids 

• Lowest effective dose;

• Steroid sparing  immunomodulatory approach is
under evaluation for steroid sparing effects.
 Complications:
 Systemic-onset JRA
 Pericarditis

 Hemolytic anemia

 Disseminated intravascular coagulopathy.

 Macrophage activation syndrome

 Endarteritis resulting in circulatory compromise of the digits

with threatened autoamputation

 Pauciarticular JRA
 Knee flexion contractures:

 Uveitis (Picture 7).

 Leg length discrepancy (can result from neovascularization

of growth plates of an affected knee)

 Polyarticular JRA
 Skeletal abnormalities - (Picture 5-6).

 Cervical spine involvement

Picture 5. Patient with inactive polyarticular arthritis. Long-term sequelae of
polyarticular disease includes joint subluxation (note both wrists and thumbs),
joint contractures (at proximal interphalangeal joints and distal interphalangeal
joints), boney overgrowth), and finger deformities (swan-neck or boutonniere
deformities).

                               
Picture 6. Hand and wrist radiographs of the patient with inactive polyarticular
arthritis shown in Image 5. Long-term sequelae of polyarticular disease includes
periarticular osteopenia, generalized increase in the size of epiphyses,
accelerated bone age, narrowed joint space, boutonniere deformities (at left third
and fourth interphalangeal joints), and medial subluxation of the first
metacarpophalangeal joints bilaterally.

                               
Picture 7. Sequelae of chronic anterior uveitis. Note the posterior synechiae
(weblike attachments of the pupillary margin to the anterior lens capsule) of the
right eye secondary to chronic anterior uveitis. This patient has a positive
antinuclear antibodies and initially had a pauciarticular course of her arthritis.