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Arthritis, Juvenile Idiopathic
Donna-Marie McMahon, DO, FAAP
Kathleen M. Vazzana, DO
image BASICS
DESCRIPTION
  • Juvenile idiopathic arthritis (JIA) is the most common chronic pediatric rheumatologic disease.
  • JIA is associated with significant disability
    • Age of onset: <16 years
    • Joint swelling, restricted range of motion, warmth, redness, or pain are the most common symptoms.
    • ≥6 weeks of symptoms before diagnosis is common.
  • Seven (International League of Associations for Rheumatology-ILAR) subtypes, determined by clinical characteristics in the first 6 months of illness (1):
    • Systemic (Still disease): 10%; preceded by febrile onset of ≥2 weeks with rash, serositis, hepatosplenomegaly, or lymphadenopathy (1)
    • Polyarticular rheumatoid factor (RF) (+): 5-10%; ≥5 joints involvement (1); large and small joints; RF positive on two tests ≥3 months apart (2)
    • Polyarticular RF (−): 10-30%; ≥5 (large and small) joints involved (1); RF negative (2)
    • Oligoarticular: 30-60%; involvement of 1 to 4 joints; risk for chronic uveitis in ANA (+) females (1) and axial skeletal involvement in older boys (2). Types: (i) monoarthritis (50%): knee, ankle, elbow; (ii) extended type: >4 joints after first 6 months
    • Psoriatic arthritis: 5%; arthritis with psoriasis or arthritis with >2 of the following: dactylitis, nail changes, psoriasis in a first-degree relative (1)
    • Enthesitis arthritis: 1-7%; oligo-polyarthritis in small or large joints and enthesis plus two of the following: sacroiliac or lumbosacral pain, Reiter syndrome family history or presence of acute anterior uveitis, HLA-B27 (+), ankylosing spondylitis, inflammatory bowel disease (1)[C]
    • Undifferentiated arthritis: arthritis that does not fulfill above categories or patients overlapping ≥2 categories (2)
  • System(s) affected: musculoskeletal, hematologic, lymphatic, immunologic
  • Synonyms: juvenile chronic arthritis; juvenile arthritis; juvenile rheumatoid arthritis (JRA); Still disease (2)
EPIDEMIOLOGY
  • Male = female (1); onset: throughout childhood; 54% of cases occur in children 0 to 5 years (3).
  • Polyarticular RF (+): female > male, 3:1 (2); onset: late childhood or adolescence (1)
  • Polyarticular RF (−): female > male, 3:1; onset: early peak, 2 to 4 years; late peak, 6 to 12 years (2)
  • Oligoarticular: female > male, 5:1; onset: 2 to 4 years (2)
  • Psoriatic: female > male, 1:0.95 (2); onset: early peak, 2 to 3 years; late peak, 10 to 12 years (1)
  • Enthesitis: female > male, 1:7; onset: early peak, 2 to 4 years; late peak, 6 to 12 years (2)
  • Affected patients have an increased risk of developing cancer, although short-term risk is low (4).
Incidence
2 to 20/100,000 children <16 years in developed nations
Prevalence
16 to 150/100,000 children <16 years in developed nations (1)
ETIOLOGY AND PATHOPHYSIOLOGY
  • Immunodysregulation of both humoral and cellular immunity. T lymphocytes play a key role.
  • Genetic predisposition. IL2RA/CD25 and VTCN1 have been implicated as genetic loci.
  • Environmental triggers, possibly infectious
    • Rubella or parvovirus B19 (5)
    • Heat shock proteins (5)
  • Immunoglobulin or complement deficiency
Genetics
  • Human leukocyte antigen (HLA) class I and II alleles
  • HLA-A2 = early onset oligoarthritis in females
  • HLA-DRB1*11 increases risk of systemic and oligo-JIA.
  • HLA-B27 increases risk of enthesitis-related arthritis.
  • HLA-DR4 is associated with polyarthritis RF (+) (5).
RISK FACTORS
Female gender 3:1
GENERAL PREVENTION
None identified.
COMMONLY ASSOCIATED CONDITIONS
Other autoimmune disorders, chronic anterior uveitis (iridocyclitis), nutritional impairment, growth issues (5)
image DIAGNOSIS
Clinical criteria: age of onset <16 years and >6 weeks duration of objective arthritis (swelling or restricted range of motion of a joint accompanied by heat, pain, or tenderness with no other form of childhood arthritis) in ≥1 joints
PHYSICAL EXAM
  • Arthritis: swelling, effusion, limited range of motion, tenderness, pain with motion, warmth
  • Rash, rheumatoid nodules, lymphadenopathy, hepato- or splenomegaly, enthesitis, dactylitis
DIFFERENTIAL DIAGNOSIS
  • Legg-Calve-Perthes, toxic synovitis, growing pains, Perthes disease
  • Septic arthritis, osteomyelitis, viral infection, mycoplasmal infection, Lyme disease
  • Reactive arthritis: postinfectious, rheumatic fever, Reiter syndrome
  • Inflammatory bowel disease: Crohn disease or ulcerative colitis
  • Hemoglobinopathies, rickets
  • Leukemia (particularly acute lymphocytic leukemia), bone tumors (osteoid osteoma), neuroblastoma
  • Vasculitis, Henoch-Schönlein purpura, Kawasaki disease
  • Systemic lupus erythematosus, dermatomyositis, mixed connective tissue disease, sarcoidosis, systemic sclerosis, collagen disorders
  • Farber disease
  • Accidental or nonaccidental trauma
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • CBC: leukocyte count is normal or markedly elevated (systemic), lymphopenia, reactive thrombocytosis, anemia. LFT (rule out hepatitis) and renal function studies (prior to therapy with potentially nephrotoxic drugs)
  • Joint-fluid aspiration/analysis: Exclude infection.
  • ESR and C-reactive protein are typically elevated. CRP often disproportionately elevated.
  • Myeloid-related proteins (MRP 8/14) associated with flares
  • Antinuclear antibodies (ANA)-positive patients have increased risk of uveitis. ANA positive in up to 70% with oligoarticular JIA
  • RF (+): 2-10% (usually polyarticular); poor prognosis
  • HLA-B27 positive: enthesitis-related arthritis
  • Diagnostic radiography, MRI, US, and CT; no one modality has superior diagnostic value (6)[A].
  • Radiograph of affected joint(s): early radiographic changes: soft tissue swelling, periosteal reaction, juxta-articular demineralization; later changes: joint space loss, articular surface erosions, subchondral cyst formation, sclerosis, joint fusion
  • If orthopnea, obtain ECG to rule out pericarditis.
  • Radionuclide scans: for infection/malignancy
  • CT is best for bony abnormalities. MRI can assess synovial hypertrophy and cartilage degeneration. Also more sensitive to monitor clinical responsiveness to treatment in peripheral joints and disease activity
Follow-Up Tests & Special Considerations
  • RF and ANA are present in mixed connective tissue disease (7)[B].
  • When interpreting results of dual energy x-ray photon absorptiometry scans, it is important to use pediatric, not adult, controls as normative data.
Diagnostic Procedures/Other
Synovial biopsy: if synovial fluid cannot be aspirated or if infection is suspected in spite of negative synovial fluid culture
Test Interpretation
Synovial biopsy→ synovial cells hyperplasia, hyperemia, infiltration of small lymphocytes, and mononuclear cells
image TREATMENT
GENERAL MEASURES
  • Goal is to control active disease, extraarticular manifestations, and achieve clinical remission.
  • All patients require regular (every 3 to 4 months for oligo-JIA and in ANA-positive patients) ophthalmic exams to uncover asymptomatic eye disease, particularly for 3 years following diagnosis.
  • Moist heat or electric blanket for morning stiffness
  • Splints for contractures
  • Aerobic exercise: weight-bearing or aquatic therapy to improve functional capacity (8)
MEDICATION
First Line
  • ≤4 joints
  • NSAIDs: adequate in ˜50%, symptoms often improve within days, full efficacy 2 to 3 months
  • Drugs for children include the following:
    • Ibuprofen: 30 to 50 mg/kg/day, divided QID; max dose 2,400 mg/day
    • Naproxen: 10 mg/kg/day, divided BID; max dose 1,250 mg/day
    • Tolmetin sodium: 20 mg/kg/day, TID or QID; max dose 30 mg/kg/day
    • Diclofenac: 2 to 3 mg/kg, divided TID; max dose 50 mg TID
    • P.77

    • Indomethacin: 1 to 2 mg/kg/day, divided BID to QID; max dose of 4 mg/kg/day
    • NSAIDs are contraindicated if known allergy.
    • Precautions: may worsen bleeding diatheses; use caution in renal insufficiency and hypovolemic states; take with food.
    • Significant possible interactions: may lower serum levels of anticonvulsants and blunt the effect of loop diuretics. NSAIDs may increase serum methotrexate levels.
  • Intra-articular long-acting corticosteroids: immediately effective. Improve synovitis, joint damage, and contractures and prevent leg length discrepancy (7)[B].
    • Indication: patients with oligoarthritis who have failed a 2-month NSAID trial or with poor prognosis factors (9)[C]
    • Example: triamcinolone hexacetonide
  • ≥5 Joints
    • If high disease activity or a failed 1 to 2 months NSAID trial→methotrexate (9)[C]
Second Line
  • 30-40% of patients require addition of disease-modifying antirheumatic drugs (DMARDs): methotrexate, sulfasalazine, leflunomide, and tumor necrosis factor (TNF) antagonists (etanercept, infliximab, adalimumab); newer biologic therapies, including IL-1 and IL-6 receptor antagonists, are currently under investigation
  • Methotrexate: 10 mg/m2/wk PO or SC (7)[B]
    • Plateau of efficacy reached with 15 mg/m2/wk; further increase in dosage is not associated with therapeutic benefit (10)[A].
  • Sulfasalazine: oligoarticular and HLA-B27 spondyloarthritis (7)[B]
  • Etanercept: 0.8 mg/kg (max of 50 mg/dose) given SC q1wk or 0.4 mg/kg SC twice a week (max of 25 mg/dose)
  • Infliximab: 5 mg/kg q6-8wk
  • Adalimumab: if weight 15 kg to <30 kg, 20 mg SC q2wk; if weight ≥30 kg, 40 mg SC q2wk
  • Tocilizumab: IL-6 antibody demonstrating efficacy in phase III open label trials; ongoing studies to evaluate efficacy and appropriate dosing (7)[B]
  • Anakinra: IL-1 receptor antibody under investigation with phase II and III clinical trials for systemic JIA(7)[B]
  • Begin treatment with TNF-α inhibitors in children with a history of arthritis in ≤4 joints and significant active arthritis despite treatment with methotrexate or arthritis in ≥5 joints and any active arthritis following an adequate trial of methotrexate (9)[C].
  • Begin treatment with anakinra in children with systemic arthritis and active fever whose treatment requires a second medication, in addition to systemic glucocorticoids (9)[C].
  • Analgesics, including narcotics for pain control
ISSUES FOR REFERRAL
  • Pediatric rheumatologist for management of JIA
  • Orthopedics as needed for articular complicatoins
  • Ophthalmology: for suspected uveitis
  • Physical therapy to maintain range of motion, improve muscle strength and prevent deformities
  • Occupational therapy to maintain and improve appropriate age-related functional activities
  • Behavioral health if difficulty coping with disease
SURGERY/OTHER PROCEDURES
  • Total hip and/or knee replacement for severe disease
  • Soft tissue release if splinting/traction unsuccessful
  • Correct limb length or angular deformities
  • Synovectomy is rarely performed.
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
  • Patient nonambulatory
  • Signs/symptoms of pericarditis
  • Persistent fever or diagnostic confusion to facilitate evaluation and workup
  • Need for surgery
Discharge Criteria
Resolution of fever and swelling or serositis
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
Determined by medication and disease activity
  • NSAIDs: periodic CBC, urinalysis, liver function tests (LFTs), renal function tests
  • Aspirin and/or other salicylates: transaminase and salicylate levels, weekly for 1st month, then every 3 to 4 months
  • Methotrexate: monthly LFTs, CBC, BUN, creatinine
DIET
Regular diet with special attention to adequate calcium, iron, protein, and caloric intake
PATIENT EDUCATION
  • Ongoing education of patients and families with attention to psychosocial needs; school issues; educational needs; behavioral strategies for dealing with pain and noncompliance; use of health care resources; support groups
  • Printed and audiovisual information available from local arthritis foundation
PROGNOSIS
  • 50-60% ultimately remit, but functional ability depends on adequacy of long-term therapy (disease control, maintaining muscle and joint function).
  • Poor prognosis is noted in patients with active disease at 6 months, polyarticular disease, extended pauciarticular disease course, female gender, RF (+), ANA (+), persistent morning stiffness, rapid appearance of erosions, hip involvement
REFERENCES
1. Restrepo R, Lee EY. Epidemiology, pathogenesis, and imaging of arthritis in children. Orthop Clin North Am. 2012;43(2):213-225.
2. Prince FH, Otten MH, van Suijlekom-Smit LW. Diagnosis and management of juvenile idiopathic arthritis. BMJ. 2010;341:c6434.
3. Behrens EM, Beukelman T, Gallo L, et al. Evaluation of the presentation of systemic onset juvenile rheumatoid arthritis: data from the Pennsylvania Systemic Onset Juvenile Arthritis Registry (PASOJAR). J Rheumatol. 2008;35(2):343-348.
4. Beukelman T, Haynes K, Curtis JR, et al. Rates of malignancy associated with juvenile idiopathic arthritis and its treatment. Arthritis Rheum. 2012;64(4):1263-1271.
5. Weiss JE, Ilowite NT. Juvenile idiopathic arthritis. Rheum Dis Clin North Am. 2007;33(3):441-470.
6. McKay GM, Cox LA, Long BW. Imaging juvenile idiopathic arthritis: assessing the modalities. Radiol Technol. 2010;81(4):318-327.
7. Kahn P. Juvenile idiopathic arthritis—current and future therapies. Bull NYU Hosp Jt Dis. 2009;67(3):291-302.
8. Klepper S. Making the case for exercise in children with juvenile idiopathic arthritis: what we know and where we go from here. Arthritis Rheum. 2007;57(6):887-890.
9. Beukelman T, Patkar NM, Saag KG, et al. 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res (Hoboken). 2011;63(4):465-482.
10. Takken T, Van Der Net J, Helders PJ. Methotrexate for treating juvenile idiopathic arthritis. Cochrane Database Syst Rev. 2001;(4):CD003129.
11. Shea B, Swinden MV, Tanjong Ghogomu E, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev. 2013;(5):CD000951.
12. Kemper AR, Van Mater HA, Coeytaux RR, et al. Systematic review of disease-modifying antirheumatic drugs for juvenile idiopathic arthritis. BMC Pediatr. 2012;12:29.
Additional Reading
Chang HJ, Burke AE, Glass RM. JAMA patient page. Juvenile idiopathic arthritis. JAMA. 2010;303(13):1328.
Codes
ICD10
  • M08.90 Juvenile arthritis, unspecified, unspecified site
  • M08.80 Other juvenile arthritis, unspecified site
  • M08.00 Unsp juvenile rheumatoid arthritis of unspecified site
Clinical Pearls
  • JIA is the most common form of arthritis in children.
  • JIA should be included in the differential diagnosis for a limping child.
  • High-titer RF correlates with disease severity; positive RF titers confer poorer prognosis.
  • DMARDs improve JIA-associated symptoms (12)[A].