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Juvenile rheumatoid arthritis (JRA

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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 Multi Genetic, Hormonal, Immunologic  Pathogenesis ‡ Characterized by chronic inflammation of the synovium; ‡ Presence of articular cartilage damage; ‡ Accompanied by extra-articular systemic extramanifestations.  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 nonnonself is the major histocompatibility complex (MHC) that in humans is called the human leukocyte antigen (HLA).  Hormonal Factors ‡ Differences in the sex ratio of JRA subtype onset ‡ Pre-adolescent or post-adolescent peaks Prepost- . ‡ HLA system comprises a family of polymorphic genes located on the short arm of chromosome 6. ‡ Polymorphisms of JRA suggest a non-mendelian noninheritance.

. ‡ Complement activation by circulating immune complexes may also contribute to the disease process.BACKGROUND  Immune Mechanisms  Disease process involves loss of tolerance towards autoauto-antigens p chronic synovitis. ‡ Rheumatoid factors (RF): auto-antibodies directed autoagainst the Fc fragment of IgG (associated with ~10% of polyarticular JRA).  Production of auto-antibodies: auto‡ Anti-nuclear antibodies (ANA): associated with Antiincreased risk of iridocyclitis (eye inflammation).

Interleukin. factor(TNF Immunomodulatory cytokines produced by TTcells p Interferon gamma (IFN.). IL-2.IL- . IL-6.(IL. IL-4.ILand tumor necrosis factor-alpha (TNF-w). (IFN.BACKGROUND  Immune Mechanisms (Continued)  Cytokines: act on the immune system and other cells Cytokines: to initiate and sustain inflammation:  Intercellular mediators: Interleukin-1 (IL-1).IL.

.CLASSIFICATION OF JRA  ACR (American College of Rheumatology) Criteria  Age at onset: < 16 years of age.  Arthritis . ‡ Polyarticular: > 5 inflamed joints.swelling or effusion or the presence of 2 or more of the following signs: ‡ Limitation of range of motion.  Exclusion of other forms of childhood arthritis. ‡ Systemic onset: arthritis with characteristic fever.  Duration of disease > 6 weeks.  Onset type is defined by the type of disease in the first 6 months: ‡ Oligoarticular (Pauciarticular) < 5 inflamed joints. ‡ Tenderness or pain on motion and ‡ Increased heat in one or more joints.

A preceding illness raises the possibility of infectious trigger of JRA or postinfectious arthritis. with fevers). Limping may be observed in individuals with more severe JRA.General history of JRA includes the following:       Disease onset is either insidious or abrupt. 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 morning stiffness and arthralgia during the day. Weight loss without diarrhea may be observed in individuals with active JRA and sometimes associated with anorexia. Their abilities to participate in physical education classes may reflect severity of the disease. . however. the presence of limping also raises the possibility of trauma or another orthopedic problem.

CLINICAL MANIFESTATIONS of JRA .

uveitis (++) Polyarticular 30 (3:1) >5 Thru childhood. unremitting articular involvement 5% 10%/40-50% Guarded to moderately good Systemic 10 (1:1) Variable Thru childhood. peak 1-2 yr None.JRA by the Type-of-Onset Type-ofCharacteristic % Cases (F:M) # Joints Age at onset Pauciarticular 60 (5:1) <4 Early childhood. no peak Systemic selflimited. peak 1-3 yr Mild. 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 .

ExtraExtra-Articular Manifestations of JRA Pauciarticular Fever Rheumatoid rash Rheumatoid nodules Hepatosplenomegaly Lymphadenopathy Chronic uveitis Pericarditis Pleuritis Abdominal pain 0% 0 0 0 0 20 0 0 0 Polyarticular 30% 2 10 10 5 5 5 1 1 Systemic 100% 95 5 85 70 1 35 20 10 .

this rash is worse with fever. in uveitis (usually asymptomatic on onset). often linear.SystemicSystemic-onset JRA is characterized by spiking fevers. typically occurring several times each day       Evanescent salmon-pink rash. Hepatosplenomegaly. Lymphadenopathy. and synechiae (irregular iris perimeter resulting from postinflammatory adhesions of iris to lens) may be found Cardiovascular: myocarditis occurs in individuals with systemic JRA. Ocular: Photophobia. is found salmonon the trunk and the extremities. Muscle tenderness to palpation. .

large weight-bearing joints. the wrists are found. Muscle atrophy. Involvement of a few small joints in the hands is atypical and suggests eventual development of polyarticular JRA. often of extensor muscles (vastus lateralis. less commonly. . and weightankles are affected. quadriceps when knee affected) is found.Pauciarticular form is characterized by arthritis affecting 4 or fewer joints. Flexion contractures in the knees and. knees.     Typically.

(significant suprapatellar swelling (effusion). patella) . the patella).Picture 1. Patient with active pauciarticular disease. loss of natural contour medial to (effusion).

often in symmetric bilateral distribution. .Polyarticular form affects at least 5 joints   Both large and small joints can be involved. Severe limitations in motion are usually accompanied by weakness and decreased physical function.

The patient has interosseus muscle wasting and subluxation and ulnar deviation of the wrists are present). boney overgrowth. lack of distal joints. present) . overgrowth. interphalangeal joint involvement. (swelling of all proximal interphalangeal joints. Patient with active polyarticular arthritis.Picture 2.

fibrinogen. CT scanning of long bones. MRI. albumin. bone scanning.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. echocardiography . D-dimer (for Dsystemic JRA) o Imaging Studies: radiography of affected joints.

Erosions are present in the distal radius and ulna. ulnar epiphysis. large erosion is present in the articular surface of the wrist. . (severe loss of cartilage in the intercarpal spaces and the radiocarpal space of the right wrist.Picture 3. Wrist radiographs of the patient with active polyarticular arthritis shown in Image 2. The view of the left wrist shows boney ankylosis involving the lateral 4 carpal bones with sparing of the pisiform.

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

   . ‡ May need major surgery (joint replacement). Radiographic joint damage within 2 years. Mortality rate: 0.4% to 2% (greater risk with systemic JRA rate: than with polyarticular JRA). LongLong-term disabilities: 30% to 40% of children disabilities: ‡ Unemployment: 25% to 50% of adult JRA patients.PROGNOSIS OF JRA  Polyarticular JRA and Systemic JRA  Active arthritis into adulthood: 50% to 70% of polyarticular adulthood: or systemic onset 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) .

hearing disturbances). rash (ecchymoses. central nervous system (headache. dizziness. visual disturbances. ‡ Adverse events: gastrointestinal. pruritus. tolmetin sodium. ibuprofen. sweating. . special senses (tinnitus. naproxen  Naproxen [Tablets and Suspension] ‡ Indicated for patients 2 years and older with juvenile arthritis. drowsiness. vertigo). ‡ Daily dose: approximately 10 mg/kg/day as a BID dose (5 mg/kg given twice-a-day). palpitations) prolonged bleeding times. Total daily dose is twicenot to exceed 15 mg/kg/day.Treatments with Indications for JRA  NonNon-Selective NSAIDs  Aspirin. purpura). cardiovascular (edema.

vomiting. cough. rash. slight increases in systolic blood pressure. infection (rhinitis). ‡ 0. diarrhea. headache.Treatments with Indications for JRA  NonNon-Selective NSAIDs/COX-2 Selective Inhibitors NSAIDs/COX 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. pyrexia. ‡ Adverse events: abdominal pain/upper.5 mg. . urticaria. ‡ Indicated for the relief of the signs and symptoms of juvenile rheumatoid arthritis in patients 2 years and older.125 mg/kg once daily up to a maximum of 7.  VIOXX (rofecoxib) [Tablets and Suspension] ‡ Withdrawn from the global market September 2004.

1 to 0.2 mg/kg. fractures. ‡ Prednisone low-dose as 0. iatrogenic Cushing¶s syndrome.0 mg/kg/day (maximum single dose 40 mg) ‡ Adverse events: hypertension. growth suppression. or  Intra-articular agents (Pauci.Treatment of JRA  Corticosteroids  Used for uncontrolled or life-threatening systemic lifedisease. increased susceptibility to infection. higherlowhigherdose 0. cataracts.25 to 1. .  Treatment of chronic uveitis as local ophthalmic drops. Intermediatemethylmethyl-prednisolone (Intravenous pulse therapy for severely active JRA).and polyarticular JRA) Intra(Pauci Intermediate-acting corticosteroids: Prednisone.

5 mg/m2 per week. ‡ Methotrexate compared to leflunomide (Lef): 240 JRA pts. decreased resistance to infection. headache. ‡ Indicated for polyarticular JRA. ‡ Adverse events: stomatitis. elevated hepatic enzymes. gastrointestinal bleeding. ‡ Starting dose 7. malaise. . alopecia. maximum dose of 15 mg/m2 per week. 16-week DB + 6 mo Ext + optional 30 mo Ext in 16JRA. leukopenia. MTX is the most widely used DMARD for JRA treatment. rash. nausea/ abdominal pain.Treatment of JRA  DMARDs and Biologic DMARDs  Methotrexate (MTX): used when NSAIDs fail to bring relief. anorexia. JRA Definition of Improvement > 30% (JRA DOI > 30): 89% MTX compared to 68% Lef. chills and fever. fatigue.

hemolytic anemia. urticaria. vomiting. .60 mg/kg/day divided into 3 to 6 doses. rash.Treatment of JRA  DMARDs and Biologic DMARDs (Continued)  Sulfasalazine ‡ Indicated for polyarticular JRA who have responded inadequately to salicylates or other non-steroidal nonantianti-inflammatory drugs. ‡ Children 6 yrs and older: 40 . headache. ‡ Maintenance dose: 30 mg/kg/day divided into 4 doses. gastric distress. ‡ Adverse events: anorexia.

Type 1 diabetes. nausea. cutaneous ulcer. pre72apart.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. and vomiting. abdominal pain. soft tissue and post-operative wound infection. ‡ Adverse events: headache. esophagitis/ gastritis. 72-96 hrs. Infection was reported in 43 of 69 (62%) of JRA patients during the 3-month (open-label phase). ‡ Dosage: 0. depression/ personality disorder. group A streptococcal septic shock. Serious AEs 3(openreported in the study: varicella. post- .4 mg/kg/week (maximum 25 mg/ dose given twice weekly) as subcutaneous injection pre-filled syringe. gastroenteritis.

leflunomide and d-penicillamine. injectable gold. 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 in JRA  DMARDs indicated for RA without an indication for JRA  Hydroxychloroquine.

 Patients with extended pauciarticular JRA or small joint involvement p treat as polyarticular JRA.6 weeks with flexion contractures or leg length discrepancy p intraintra-articular corticosteroids.Treatment of JRA in 2008  Pauciarticular  25% to 33% will respond to NSAIDs.  Patients not responsive to NSAIDS after 4 . .

 If NSAID + MTX (oral or parenteral) is not effective p antianti-TNF medication.Treatment of JRA in 2008  Polyarticular  RF (-) or (+).  NSAID trial for several weeks p add oral MTX.  If oral MTX is not effective p parenteral route MTX. NSAID (symptom control) alone is usually (not as effective as a NSAID + DMARD. . ‡ No current evidence whether a combination of MTX + antianti-TNF medication are more effective than only antiantiTNF medication.

Treatment of JRA in 2008  Systemic  NSAIDs 2 to 3 weeks with caution p risk of Disseminated Intravascular Coagulation (DIC). ‡ Steroid sparing p immunomodulatory approach is under evaluation for steroid sparing effects. .  Oral corticosteroids p ‡ Lowest effective dose. (macrophage activation syndrome).  Intravenous pulse methylprednisolone.

5 Cervical spine involvement  .  Leg length discrepancy (can result from neovascularization of growth plates of an affected knee)  Polyarticular JRA  Skeletal abnormalities . (Picture 7).  Macrophage activation syndrome  Endarteritis resulting in circulatory compromise of the digits with threatened autoamputation  Pauciarticular JRA  Knee flexion contractures:  Uveitis (Picture 7).Complications: SystemicSystemic-onset JRA  Pericarditis  Hemolytic anemia  Disseminated intravascular coagulopathy.(Picture 5-6).

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

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

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