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)
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
HISTORY
- Arthralgias, fever, fatigue, malaise, myalgias, weight loss, morning stiffness, rash
- Limp, if lower extremity involvement
- Arthritis for ≥6 weeks
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-Sch ¶nlein 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
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
- 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
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
COMPLICATIONS
- Blindness, band keratopathy, glaucoma, short stature, micrognathia if temporomandibular joint involvement, debilitating joint disease, disseminated intravascular coagulation, hemolytic anemia
- NSAIDs: peptic ulcer, GI hemorrhage, CNS reactions, renal disease, leukopenia
- DMARDs: bone marrow suppression, hepatitis, renal disease, dermatitis, mouth ulcers, retinal toxicity (antimalarials; rare)
- TNF antagonists: higher risk of infection
- Osteoporosis, avascular necrosis
- Methotrexate: Folate supplementation decreases hepatic/GI symptoms; may reduce stomatitis (11)[A].
- Macrophage activation syndrome: decreased blood cell precursors secondary to histiocyte degradation of marrow
REFERENCES
11 Restrepo R, Lee EY. Epidemiology, pathogenesis, and imaging of arthritis in children. Orthop Clin North Am. 2012;43(2):213-225.22 Prince FH, Otten MH, van Suijlekom-Smit LW. Diagnosis and management of juvenile idiopathic arthritis. BMJ. 2010;341:c6434.33 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):343-348.44 Beukelman T, Haynes K, Curtis JR, et al. Rates of malignancy associated with juvenile idiopathic arthritis and its treatment. Arthritis Rheum. 2012;64(4):1263-1271.55 Weiss JE, Ilowite NT. Juvenile idiopathic arthritis. Rheum Dis Clin North Am. 2007;33(3):441-470.66 McKay GM, Cox LA, Long BW. Imaging juvenile idiopathic arthritis: assessing the modalities. Radiol Technol. 2010;81(4):318-327.77 Kahn P. Juvenile idiopathic arthritis-current and future therapies. Bull NYU Hosp Jt Dis. 2009;67(3):291-302.88 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):887-890.99 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):465-482.1010 Takken T, Van Der Net J, Helders PJ. Methotrexate for treating juvenile idiopathic arthritis. Cochrane Database Syst Rev. 2001;(4):CD003129.1111 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):CD000951.1212 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
- M08.40 Pauciarticular juvenile rheumatoid arthritis, unsp site
- M08.99 Juvenile arthritis, unspecified, multiple sites
- M08.09 Unspecified juvenile rheumatoid arthritis, multiple sites
- M08.3 Juvenile rheumatoid polyarthritis (seronegative)
- M08.20 Juvenile rheumatoid arthritis with systemic onset, unsp site
ICD9
- 714.30 Polyarticular juvenile rheumatoid arthritis, chronic or unspecified
- 714.31 Polyarticular juvenile rheumatoid arthritis, acute
- 714.33 Monoarticular juvenile rheumatoid arthritis
- 714.32 Pauciarticular juvenile rheumatoid arthritis
SNOMED
- 410502007 juvenile idiopathic arthritis (disorder)
- 445479007 polyarticular juvenile rheumatoid arthritis (disorder)
- 201799006 Monarticular juvenile rheumatoid arthritis (disorder)
- 74391003 Pauciarticular juvenile rheumatoid arthritis (disorder)
- 201796004 |systemic onset juvenile chronic arthritis (disorder)
- 239796000 Juvenile chronic arthritis
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].