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A. Epidemiologynavigator

  1. Most common rheumatic condition of childhood
  2. Annual incidence of ~1.4 cases / 100,000
  3. Prevalence varies greatly, ~10-150 per 100,000
  4. May be accompanied by rheumatoid factor (RF) and/or antinuclear antibodies (ANA)
  5. HLA Associations in JCA
    1. Similar to adult rheumatoid arthritis (RA) (HLA-DR2 and 4)
    2. Boys with oligoarthopathy similar to adult spondyloarthropathy: HLA-B27
  6. Children with JCA are often growth impaired
  7. Often associated with iridocyclitis (uveitis)
  8. Previously called Juvenile Rheumatoid Arthritis (JRA)

B. Classificationnavigator

  1. Systemic Onset (Still's Disease) ~15%
  2. Polyarticular Arthritis - rheumatoid factor (RF) positive ~5% (F>>M)
  3. Polyarticular Arthritis - RF negative ~20% (F>>M)
  4. Oligoarticular (Pauciarticular) Onset ~40% (persistent or extended variants); F>>>M
  5. Juvenile Spondyloarthropathy Syndromes
    1. Psoriatic Arthritis (6%) - F>M
    2. Enthesitis Arthritis (7%) - M>>F
    3. Ankylosing Spondylitis in children
  6. Unclassified / Undifferentiated ~10%

C. Pathogenesis [1] navigator

  1. Appears to be an imbalance between Th1 and Th2 type lymphocytes and cytokines
    1. Many Th1 cytokines stimulate monocytes and macrophages
    2. Activated macrophages appear to be the major cells which cause joint destruction
  2. Anti-inflammatory molecules are also relatively underexpressed in severe JCA
    1. Soluble TNF receptor (s-TNFR) levels are reduced in polyarticular and psoriatic JCA
    2. Interleukin 1 (IL-1) receptor antagonist levels may also be depressed
    3. Polymorphisms in IL-1a and other genes have shown some correlations with activity
  3. Fevers associated with bioactive IL1, IL6 and TNFa levels
  4. MHC (HLA) linkages are distinct in different subtypes of the disease
  5. These data suggest that T cell abnormalities are involved in disease pathogenesis
  6. Elevated levels of tumor necrosis factor alpha (TNFa) likely involved in most patients

D. Systemic Onset JCA (Still's Disease) navigator

  1. Onset throughout childhood, Female (F) = Male (M)
  2. Symptoms
    1. Macular erythematous rash, may be fleeting; often with fever onset
    2. Intermittent fever >39.4°
    3. Fatigue - often due to inflammation and anemia
    4. Pericarditis ± effusion
    5. Hepatosplenomegaly
    6. Arthritis usually involves multiple joints
    7. Risk of uveitis is low; ophthalmological exams every 12 months recommended
  3. Laboratory
    1. Anemia - mainly of chronic disease (IL6 induced iron sequestration)
    2. Leukocytosis - quite marked; may have leukemoid reactions
    3. Elevated erythrocyte sedimentation rate (ESR) and CRP
    4. Usually HLA-DR5
    5. May be accompanied by macrophage activation syndrome (MAS) in ~5% of cases [3]
  4. Inflammatory Changes
    1. Substantial auto-inflammatory component
    2. IL1ß levels substantially elevated during fevers and flares
    3. IL6 levels elevated, drive increased CRP and ESR
    4. Levels of IL-10 are depressed and IL-6 levels are elevated

E. Polyarticular Seronegative Arthritisnavigator

  1. RF IgM negative; ~20% of JCA
  2. Much more common in females (F>>M)
  3. Defined as arthritis in >4 joints for >6 months
  4. Three Distinct Subtypes
    1. Subtype 1: Similar to early onset oligoarticular JCA, often ANA+, associated with HLA-DRB1*0801, and usually presents as asymmetric polyarthritis
    2. Subtype 2: Similar to adult onset RF- rheumatoid arthritis - usually symmetric
    3. Subtype 3: Dry synovitis, negligible joint swelling, but stiffness, flexion contractiures, normal or slightly elevated ESR
  5. High (ANA+) to moderate (ANA-) risk uveitis / iridocyclitis; exam q3 (high risk) to q6 months
  6. Many patients require joint replacement by age 20-30 due to polyarticular JCA damage,

F. Polyarticular Seropositive Arthritis navigator

  1. RF+; ~5% of JCA (F>>M)
  2. Defined as arthritis in >4 joints for >6 months with positive RF
  3. Same disease as adult rheumatoid arthritis
    1. Usually occurs in girls <7 years old who are ANA positive
    2. Absence of rheumatoid rash and intermittent fevers
    3. Usually presents as symmetric polyarthritis in small joints of hands and feet
    4. Large joints, including knees and ankles, can be affected, but usually with small joints
    5. Anemia, pericarditis, hepatosplenomegaly not uncommon
    6. Rheumatoid nodules can be found at usual sites (forearm, elbow) in ~35% of patients
  4. HLA-DRw6 carries more severe prognosis; HLA-DR2 and 4 more common [2]
  5. High (ANA+) to moderate (ANA-) risk uveitis / iridocyclitis; exam q3 (high risk) to q6 months
  6. Early erosive disease is seen and therapy should be generally aggressive

G. Oligoarticular Arthritisnavigator

  1. Majority of (>80%) JCA cases
  2. Pauciarticular: arthritis in <5 joints in first 6 months of disease
  3. Absence of rash and intermittent fevers
  4. Two subtypes: persistent and extended
    1. Persistent has <5 joints throughout course
    2. About 85% of the persistent type are girls with positive ANA, onset usually age <6
    3. Boys <6 years old may have the extended form, which progresses to >4 joints
    4. Boys are usually ANA negative
    5. Extended oligoarthritis has poorer outcomes than localized
    6. Elevated ESR and involvement of upper limb joints predict extended and severe outcomes
  5. Ocular Disease
    1. Particularly concerning with this form of JCA
    2. Iridocyclitis occurs in 30-40% (girls more than boys)
    3. Uveitis, particularly in girls, can be asymptomatic initially but lead to long term deficits
    4. Uveitis must therefore be followed by an ophthalmologist q3-4 months
  6. Knee joint usually affected, followed by ankle joints
  7. Aggressive therapy often required to prevent joint destruction

H. Spondyloarthropathies navigator

  1. Enthesitis associated arthritis
    1. Late childhood or adolescence, most patients are HLA-B27 positive
    2. Often combination of enthesopathy, peripheral oligoarthritis, iridocyclitis
    3. A subset develop spondylitis (of these, ~95% HLA-B27+)
    4. Enthesitis usually at calcaneal insertion of Achilles tendon, plantar fascia, tarsal area
    5. Arthritis usually in lower extremities; hip involvement common at presentation
    6. Four or fewer joints involved
  2. Psoriatic Arthritis
    1. Arthritis (asymmetric) with typical psoriatic rash
    2. Early peak age 2-4; late peak 9-11 years
    3. Distal ICP joints are often involved ("dactylitis" is swelling of fingers beyond joint margins)
    4. If no rash, must have any two of the following: family history of psoriasis in 1st degree relative, dactylitis, and nail pitting
  3. Juvenile Ankylosing Spondylitis
    1. Nearly all (~95%) patients are HLA-B27+
    2. Usually occurs in boys
    3. Increased incidence of psoriasis relative to other groups
  4. Other Types
    1. Reactive arthritis
    2. Arthritis of Inflammatory Bowel Disease (IBD)

I. Evaluationnavigator

  1. Careful history and physical to rule out other causes (see differential diagnosis)
  2. Full laboratory evaluation including autoantibodies (ANA, RF, others)
  3. Careful monitoring for exacerbations
  4. All JCA patients must be seen by an ophthalmologist evaluate uveitis / iridocyclitis [1]
    1. Different subtypes of JCA have distinct serious ophthalmologic risks
    2. Frequency of ophthalmological exams depend on type of disease and concommitant risks
    3. High Risk (exam q3-4 months): oligo- or polyarticular onset at age <7 years and ANA+
    4. Medium Risk (exam q6 months): oligo- or polyarticular onset at age <7 years and ANA-; or oligo- or polyarticular onset at age >7 years with any ANA result
    5. Low Risk (exam q12 months): systemic onset JCA

J. Differential Diagnosis (Across All JCA Subtypes) [1]navigator

  1. Infection
    1. Sepsis
    2. Bacterial endocarditis
    3. Brucellosis
    4. Typhoid Fever
    5. Leishmaniasis
    6. Viral Infections
  2. Malignancy
    1. Leukemia
    2. Lymphoma
    3. Neuroblastoma
  3. Rheumatic Fever
  4. Connective Tissue Disease
    1. Systemic lupus erythematosus
    2. Kawaski Syndrome
    3. Polyarteritis
    4. Vasculitis
  5. Inflammatory Bowel Disease
  6. Castleman's Disease (Giant Lymph Node Hyperplasia)
  7. Autoinflammatory Syndromes

K. Treatment Overview [2] navigator

  1. Combinations of pharmacotherapy, occupational/physical therapy, social support
    1. Swimming and cycling are encouraged
    2. Physiotherapy and social support are required
  2. Overview of Pharmacologic Agents
    1. Anti-inflammatory: NSAIDS, glucocorticoids
    2. Methotrexate (MTX) or Leflunomide or other oral agents
    3. TNFa Blockers, IL1 Receptor Antagonist
  3. NSAIDS
    1. Effective in a minority of patients, primarily those with oligoarticular disease
    2. Naproxen, ibuprofen, indomethacin are most commonly used
    3. Ibuprofen (Pediprofen®) - 20mg/kg/day in divided doses (comes as 100mg/5mL)
    4. Tolmetin (Tolectin®) is also effective and well torelated agent (200-400mg po qd-bid)
    5. Meloxican has been safe and effective in a controlled trial
    6. Aspirin should be avoided due to risk of Rye's Syndrome
  4. Glucocorticoids
    1. Local glucocorticoid injections (such as triamcinolone hexacetonide) - often very helpful in mono- or oligoarticular disease; very effective, particularly in knees
    2. For severe and polyarticular disease, 0.5-2mg/kg/d po may be used
    3. In highly resistant disease, combined IV glucocorticoids and immunosuppressants used
    4. Therefore, reducing inflammation in severe disease could improve outcomes
  5. Resistant JRA [1,2]
    1. Methotrexate (MTX) is effective and relatively safe (10-20mg/m2 q week)
    2. Must follow liver function tests and complete blood counts
    3. MTX 15-20mg/m2 orally each week is effective in extended pauciarticular JCA
    4. MTX is effective in oligoarthritis, polyarthritis, but only minimally in systemic JCA [1,2]
    5. TNFa blockade and IL1RA are also effective (see below)
    6. Sulfasalazine and lefluonomide are alternatives to MTX
    7. MTX slightly superior to leflunomide (Areva®) in polyarticular JCA [4]
    8. Leflunomide has less liver toxicity than MTX in JCA and can be used in MTX intolerance [4]
    9. Etanercept has been effective and very well tolerated in MTX resistant disease
    10. Severe systemic or polyarticular JCA has been treated effectively with autologous stem cell transplantation after anti-thyomocyte globulin, cyclosporin, radiation [5]
  6. Etanercept (Enbrel®) [6]
    1. Recombinant extracellular soluble p75 TNFa receptor molecule linked to human IgG1 Fc
    2. FDA approved for treatment of JCA
    3. Dosed 0.4mg/kg twice weekly for 3 months
    4. Etanercept time to disease flare >116 days versus 28 days for placebo
    5. Etanercept was very well tolerated and should be considered in patients with JCA
    6. Effective in MTX non-responsive polyarticular JCA, less effective in systemic JCA [2]
  7. Anakinra (Kineret®) [7]
    1. Recombinant non-glycosylated form of natural soluble IL1 receptor (IL1RA)
    2. Absorbs and inactivates IL1; modest activity in moderate or severe RA
    3. May be used alone or in combination with MTX
    4. Marked efficacy in NOMID (neonatal onset multisystem inflammatory disease) and other auto-inflammatory diseases including MAS
    5. Good activity in Still's disease, particularly with reduction of fever, rash
    6. Side Effects: ruritus, rash, erythema, pain at injection site, neutropenia (8%)
    7. Standard dose is 100-150mg daily sc for adults
  8. Tocilizumab [8]
    1. Humanized mAb binds both cell-bound and soluble forms of interleukin 6 (IL6) receptor
    2. Evaluated in systemic-onset JCA
    3. Dose 8mg/kg IV q2 weeks x 6 weeks, then randomized to placebo or drug for 12 weeks
    4. After week 18, 80% of tocilizumab and 17% of placebo maintained ACR Pedi 30 responses
    5. Generally well tolerated, with minimal anaphylactoid and other serious adverse events
    6. May be reasonable treatment for systemic onset JCA
  9. Other Agents
    1. Hydroxychloroquine (Plaquenil®) is good for skin and joint disease; dose 5-7mg/kg/day
    2. Hydroxycholoroquine showed reduction in pain on movement versus placebo in JCA
    3. Leflunomide can be used in MTX intolerance in JCA and is nearly as effective [2,4]
    4. Sulfasalazine - especially in spondylitic variants
    5. Cyclosphosphamide - intravenous pulse for severe disease is effective
    6. Penicillamine and gold are ineffective for JCA
  10. Iridocyclitis [1]
    1. Glucocorticoid + mydriatics eye drops
    2. Disease resistant to topical therapy treated with systemic glucocorticoids
    3. MTX, cyclosporin A (CsA), alkylating agents may be beneficial
    4. Etanercept of equivocal efficacy but infliximab has shown activity
  11. Growth Effects
    1. Concern about growth stunting can be monitored with osteocalcin, IGF-1 levels
    2. Recombinant hGH (human growth hormone) can normalize growth
    3. HGH more effective in absence of inflammation

References navigator

  1. Ravelli A and Martini A. 2007. Lancet. 369(9563):767 abstract
  2. Hashkes PJ and Laxer RM. 2005. JAMA. 294(13):1671 abstract
  3. Ravelli A, Magni-Manzoni S, Pistorio A, et al. 2005. J Pediatr. 146(5):598 abstract
  4. Silverman E, Mouy R, Spiegel L, et al. 2005. NEJM. 352(16):1655 abstract
  5. Wulffraat N, van Royen A, Bierings M, et al. 1999. Lancet. 353(9152):550 abstract
  6. Lovell DJ, Giannini EH, Reiff A, et al. 2000. NEJM. 342(11):763 abstract
  7. Olsen NJ and Stein CM. 2004. NEJM. 350(21):2167 abstract
  8. Yokota S, Imagawa T, Mori M, et al. 2008. Lancet. 371(9617):998 abstract