# Juvenile Idiopathic Arthritis

## Introduction

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease of childhood and a leading cause of acquired disability in children. JIA is defined as arthritis of unknown etiology that begins before age 16 and persists for at least 6 weeks, after exclusion of other causes. The term JIA replaced previous nomenclature including juvenile rheumatoid arthritis (JRA) and juvenile chronic arthritis (JCA). JIA encompasses a heterogeneous group of subtypes with distinct clinical features, immunologic profiles, and outcomes. Early recognition, aggressive treatment to achieve disease control, and prevention of joint damage and functional disability are the cornerstones of management.

## Classification (ILAR Criteria)

| Subtype | Frequency | Sex/Age | Joints | ANA | Key Feature | Uveitis Risk |
|---------|-----------|---------|--------|-----|-------------|-------------|
| Oligoarticular | 50-60% | Girls, 2-4 yr | ≤4 (knee, ankle, wrist) | 70-80% + | Most common subtype | High (30%, chronic, asymptomatic) |
| Polyarticular RF- | 20-25% | Girls | ≥5, symmetric | 25% + | Moderate prognosis | Moderate |
| Polyarticular RF+ | 5-10% | Adolescent girls | ≥5, small joints, erosive | Negative | Resembles adult RA, worst joint outcome | Low |
| Systemic (sJIA) | 10-15% | Equal sex | Variable (may be delayed) | Negative | Quotidian fevers, salmon rash, MAS risk | Rare |
| Enthesitis-related | 10-15% | Boys >6 yr | Lower extremity, SI joints | Negative (HLA-B27+) | Enthesitis, may become AS | Acute anterior (symptomatic) |
| Psoriatic | 5-10% | Bimodal | Variable | Variable | Dactylitis, nail pitting | Variable |

### Oligoarticular JIA

Oligoarticular JIA is the most common subtype, accounting for 50-60% of JIA cases, and affects 4 or fewer joints in the first 6 months of disease. It predominantly affects girls, with a peak onset at age 2-4 years, and most commonly involves large joints such as the knees, ankles, and wrists. ANA is positive in 70-80% of cases. These patients carry a high risk of chronic anterior uveitis (up to 30% of ANA-positive patients), which is often asymptomatic and requires routine ophthalmologic screening. Extended oligoarthritis, defined as involvement of more than 4 joints after the first 6 months, carries a less favorable prognosis.

### Polyarticular JIA

Polyarticular JIA affects 5 or more joints in the first 6 months. RF-negative polyarthritis accounts for 20-25% of JIA and features symmetric involvement of small and large joints, with ANA positivity in 25% and moderate uveitis risk. RF-positive polyarthritis (5-10% of JIA) closely resembles adult rheumatoid arthritis, predominantly affecting adolescent girls with symmetric small joint involvement of the hands and feet, erosive disease, and rheumatoid nodules. RF-positive polyarthritis carries the worst joint prognosis among all JIA subtypes.

### Systemic JIA (sJIA)

Systemic JIA accounts for 10-15% of cases with equal sex distribution. It is characterized by quotidian (daily) spiking fevers reaching 39 degrees Celsius or higher, typically in the evening with return to normal or below normal, lasting at least 2 weeks. An evanescent, salmon-colored, macular rash appears with fever and resolves between fever spikes. Other systemic features include hepatosplenomegaly, lymphadenopathy, and serositis (pericarditis, pleuritis). Arthritis may be absent at onset, appearing weeks to months after systemic symptoms begin. ANA and RF are typically negative, while ferritin, ESR, CRP, WBC, and platelets are markedly elevated. Macrophage activation syndrome (MAS) is a life-threatening complication occurring in 10% of sJIA patients, characterized by a sudden paradoxical drop in ESR, pancytopenia, hyperferritinemia (often greater than 10,000), elevated triglycerides, elevated LDH, coagulopathy, and hepatitis.

### Enthesitis-Related Arthritis (ERA)

Enthesitis-related arthritis features arthritis with enthesitis, which is inflammation at tendon and ligament insertions. It predominantly affects boys older than 6 years and is often HLA-B27 positive. The lower extremity joints and sacroiliac joints are commonly involved. ERA is associated with acute anterior uveitis, which is symptomatic (painful, red eye), unlike the chronic asymptomatic uveitis of oligoarticular JIA. ERA may evolve into ankylosing spondylitis in adulthood.

### Psoriatic Arthritis

Psoriatic arthritis is defined as arthritis with psoriasis, or arthritis with at least 2 of the following: dactylitis, nail pitting or onycholysis, or psoriasis in a first-degree relative. It has a bimodal age distribution with peaks at 2-4 years (similar to oligoarthritis) and at adolescence, and may have features overlapping with oligoarticular and polyarticular subtypes.

<image>Clinical composite illustration showing the key features of each JIA subtype: oligoarticular (swollen knee in a toddler), polyarticular RF-positive (symmetric hand joint swelling), systemic (child with fever chart showing quotidian pattern and salmon-colored rash photograph), enthesitis-related arthritis (teen with Achilles enthesitis and sacroiliac joint involvement), and psoriatic arthritis (dactylitis and nail pitting), with demographic and laboratory features annotated for each subtype</image>

## Diagnosis

### Clinical Assessment

Arthritis is defined as joint swelling or limitation of range of motion with pain, warmth, or tenderness, persisting for at least 6 weeks. A comprehensive joint examination should document active joint count, limited range of motion, tenderness, swelling, and warmth. Growth assessment is important to identify growth failure and leg length discrepancy from asymmetric growth. An eye examination at baseline and regular screening by an ophthalmologist with slit-lamp examination is essential.

### Laboratory Studies

Inflammatory markers (ESR, CRP) are elevated in active disease and markedly elevated in systemic JIA. ANA is positive in 70-80% of oligoarticular JIA and guides uveitis screening frequency. Rheumatoid factor is positive in RF-positive polyarthritis and serves as a poor prognosis marker. Anti-CCP antibodies are more specific than RF for erosive polyarticular disease. HLA-B27 is associated with enthesitis-related arthritis. CBC may show leukocytosis and thrombocytosis in systemic JIA, along with anemia of chronic disease. Ferritin is markedly elevated in systemic JIA and extremely elevated in MAS.

### Imaging

Radiographs serve as initial baseline imaging and may show soft tissue swelling, periarticular osteopenia, joint space narrowing, and erosions as late findings. Ultrasound is increasingly used for detecting synovitis, effusions, and tenosynovitis and is more sensitive than clinical examination alone. MRI is the gold standard for detecting early synovitis, bone marrow edema, cartilage damage, and erosions, and is essential for sacroiliac joint evaluation in ERA.

### Ophthalmologic Screening

Chronic anterior uveitis is asymptomatic and can lead to blindness if undetected. Screening frequency is based on age of JIA onset, ANA status, and subtype. Patients at highest risk are those with oligoarticular JIA who are ANA-positive with onset at age 6 years or younger, and they should be screened every 3 months for at least 4 years. All JIA subtypes require some frequency of screening. Complications of untreated uveitis include band keratopathy, posterior synechiae, cataracts, glaucoma, and vision loss.

## Management

### Pharmacologic Therapy

NSAIDs (naproxen 10-20 mg/kg/day, ibuprofen, meloxicam) provide symptomatic relief but do not prevent joint damage and are used as monotherapy only for mild oligoarticular disease or as a bridge to other therapy. Intra-articular corticosteroid injections (triamcinolone hexacetonide preferred) are highly effective for oligoarticular disease and can provide remission lasting months to years in a single joint.

Methotrexate (10-15 mg/m2/week, PO or SC) is the first-line disease-modifying antirheumatic drug (DMARD) for polyarticular and extended oligoarticular JIA, with onset of action at 4-8 weeks. Monitoring includes CBC and liver function tests, and supplemental folic acid reduces side effects. Sulfasalazine is an alternative for ERA but is less effective for other subtypes. Leflunomide is an alternative to methotrexate when it is not tolerated.

Among biologic agents, TNF inhibitors (etanercept, adalimumab, infliximab) are the first-line biologics for polyarticular JIA inadequately responsive to methotrexate, with adalimumab preferred when uveitis is present. Tocilizumab (IL-6 inhibitor) is approved for polyarticular and systemic JIA and is particularly effective for systemic JIA. IL-1 inhibitors (anakinra, canakinumab) are first-line for systemic JIA and highly effective for controlling systemic features and fever. Abatacept (T-cell costimulation inhibitor) is used for polyarticular JIA refractory to TNF inhibitors. JAK inhibitors (tofacitinib) are an emerging option for refractory polyarticular JIA. All biologics require screening for tuberculosis and hepatitis B before initiation, and live vaccines are contraindicated during biologic therapy.

<image>Treatment algorithm for juvenile idiopathic arthritis showing a stepwise approach: NSAIDs and intra-articular steroids as initial therapy, escalation to methotrexate for persistent or polyarticular disease, addition of biologic agents (TNF inhibitors, IL-6 inhibitors, IL-1 inhibitors) for refractory disease, with specific pathways for oligoarticular, polyarticular, and systemic JIA subtypes, and parallel management of uveitis</image>

### Non-Pharmacologic Management

Physical therapy and occupational therapy are essential to maintain range of motion, muscle strength, and functional ability. Psychosocial support includes school accommodations, peer support, and addressing pain and fatigue. Nutrition and growth monitoring are important because chronic inflammation and corticosteroid use can impair growth.

## Prognosis

With modern therapy, the majority of children with JIA can achieve inactive disease or clinical remission. Oligoarticular JIA has the best prognosis, with many patients achieving remission, though uveitis remains the major morbidity. RF-positive polyarticular JIA has the worst joint prognosis and often requires long-term biologic therapy. Systemic JIA is variable and can remit completely or follow a chronic destructive course, with MAS as the main life-threatening complication. Long-term complications include joint contractures, growth disturbance, leg length discrepancy, osteoporosis, and medication side effects.

## Clinical Pearls

JIA is a clinical diagnosis of exclusion requiring arthritis persisting for at least 6 weeks with no other identifiable cause. Oligoarticular JIA is the most common subtype, and ANA-positive patients require frequent ophthalmologic screening for asymptomatic chronic anterior uveitis. Systemic JIA presents with quotidian fevers and evanescent rash, and macrophage activation syndrome is a life-threatening complication signaled by a paradoxically falling ESR with rising ferritin. Methotrexate is the first-line DMARD for most JIA subtypes, and biologic agents have dramatically improved outcomes for refractory disease. IL-1 inhibitors are first-line for systemic JIA, while TNF inhibitors are the first-line biologics for polyarticular JIA. Regular ophthalmologic screening with slit-lamp examination is mandatory for all JIA patients to prevent vision-threatening uveitis complications.

## References

1. Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. *Journal of Rheumatology*. 2004;31(2):390-392.
2. Ringold S, Angeles-Han ST, Engel ME, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Treatment of Juvenile Idiopathic Arthritis: Therapeutic Approaches for Non-Systemic Polyarthritis, Sacroiliitis, and Enthesitis. *Arthritis Care & Research*. 2019;71(6):717-734.
3. Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. *Annals of the Rheumatic Diseases*. 2016;75(3):481-489.
4. Angeles-Han ST, Ringold S, Engel ME, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Screening, Monitoring, and Treatment of Juvenile Idiopathic Arthritis-Associated Uveitis. *Arthritis Care & Research*. 2019;71(6):703-716.