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 nonself 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 Tcells Interferon gamma (IFN-), 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 isnt 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
% Cases (F:M) # Joints Age at onset

Pauciarticular
60 (5:1) <4 Early childhood, peak 1-2 yr None; uveitis (++)

Polyarticular
30 (3:1) >5 Thru childhood, peak 1-3 yr Mild; unremitting articular involvement 5% 10%/40-50% Guarded to moderately good

Systemic
10 (1:1) Variable Thru childhood, no peak Systemic selflimited; chronic destructive arthritis ~50% Rare Rare/10% Moderate to poor

Systemic involvement

Chronic Uveitis RF/ANA Prognosis

5-15% Rare/75-85% Excellent except for eyesight

Extra-Articular Manifestations of JRA

Pauciarticular Polyarticular Systemic

Fever Rheumatoid rash Rheumatoid nodules Hepatosplenomegaly Lymphadenopathy Chronic uveitis Pericarditis Pleuritis Abdominal pain

0% 0 0 0 0 20 0 0 0

30% 2 10 10 5 5 5 1 1

100% 95 5 85 70 1 35 20 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 o o o o o o

Erythrocyte sedimentation rate (ESR) CBC with differential and platelet count Alanine aminotransferase (ALT) test Urinalysis with microscopic examination Antinuclear antibody Rheumatoid factor Total protein, albumin, fibrinogen, D-dimer (for
systemic JRA)

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; higherdose 0.25 to 1.0 mg/kg/day (maximum single dose 40 mg) Adverse events: hypertension, iatrogenic Cushings 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.