Systemic Juvenile Idiopathic Arthritis
Systemic juvenile idiopathic arthritis (sJIA) is a distinct autoinflammatory disease characterized by arthritis in ≥1 joint for at least 6 weeks in children <16 years old, with or preceded by daily quotidian fever for at least 2 weeks (documented for ≥3 days), accompanied by one or more extra-articular features including evanescent erythematous rash, generalized lymphadenopathy, hepatomegaly/splenomegaly, or serositis. 1
Clinical Presentation
Defining Features
- Quotidian fever pattern: Daily spiking fevers that are pathognomonic for sJIA, typically occurring once or twice daily with return to baseline or below between spikes 2
- Evanescent salmon-pink rash: Maculopapular rash that appears and disappears, often accompanying fever spikes 2, 3
- Arthritis: Can involve ≥1 joint, though arthritis may be a later feature and is not always present at disease onset 4, 3
Additional Systemic Manifestations
- Generalized lymphadenopathy 1
- Hepatomegaly or splenomegaly 1
- Serositis (pericarditis, pleuritis, peritonitis) 1
Epidemiology and Demographics
- Accounts for approximately 4-15% of all JIA cases 1
- Male-to-female ratio is nearly equal (unlike other JIA subtypes and juvenile SLE which show female predominance) 1
- Peak age of onset: 1-5 years with a second peak in early adolescence 2
Pathophysiology
The inflammatory process in sJIA is fundamentally distinct from other JIA categories, representing an autoinflammatory syndrome rather than a classic autoimmune disease. 5
- Central role of innate immunity with dysregulation of interleukin-1 (IL-1) and interleukin-6 (IL-6) 1, 5
- Abnormalities involve neutrophils and monocytes/macrophages rather than lymphocytes 5
- Elevated IL-18 levels are characteristic 1
- This pathophysiologic distinction explains why sJIA responds differently to treatment compared to other JIA subtypes 1
Life-Threatening Complications
Macrophage Activation Syndrome (MAS)
Approximately 10% of children with sJIA develop overt clinical MAS, a life-threatening complication with mortality rates as high as 6% (potentially higher in some case series). 1
MAS features include:
- Persistent (non-quotidian) fever 1
- Cytopenias or falling cell counts, particularly platelets 1
- Falling erythrocyte sedimentation rate 1
- Hyperferritinemia 1
- Hypertriglyceridemia 1
- Hypofibrinogenemia 1
- Hemophagocytosis 1
- Transaminitis 1
- Coagulopathy 1
- Organomegaly 1
- Low or absent natural killer cell activity 1
- Central nervous system dysfunction 1
Other Serious Complications
- sJIA-associated lung disease (sJIA-LD) 6
- Joint damage and severe growth impairment in patients with refractory disease 1
- Growth disturbances including leg length discrepancy and micrognathia 7
Diagnostic Considerations
Laboratory Findings
- Markedly elevated ferritin levels (>1000 ng/mL) are characteristic 2
- Leukocytosis with neutrophilia 2
- Elevated inflammatory markers (ESR, CRP) 8
- Typically negative antinuclear antibody (ANA) 2
- Normal complement levels (C3, C4) 2
- Anemia of chronic inflammation 9
Key Differential Diagnosis
A critical pitfall is assuming all childhood arthritis with rash and fever is lupus—the specific combination of quotidian fever, evanescent rash, and polyarthritis is pathognomonic for sJIA. 2
sJIA differs from juvenile systemic lupus erythematosus (SLE) in:
- Fever pattern: quotidian vs. low-grade persistent 2
- Rash: evanescent vs. fixed malar rash 2
- Gender: equal ratio vs. 4-5:1 female predominance 1
- Age: younger (1-5 years) vs. older (mean 14.6 years) 2
- Autoantibodies: negative ANA vs. positive ANA, anti-dsDNA, anti-Smith 2
- Complement: normal vs. low C3/C4 2
- Renal involvement: absent vs. common lupus nephritis 2
Other conditions to exclude:
- Infectious arthritis (bacterial, viral, fungal, mycobacterial) 8
- Malignancy (leukemia, lymphoma) 8
- Other autoinflammatory diseases 3
Treatment Goals and Approach
The primary goal is prompt control of active inflammation and prevention of disease- and treatment-related morbidities including growth disturbances, joint damage, and functional limitations. 1
Contemporary Treatment Paradigm
- IL-1 and IL-6 inhibitors are highly effective and have transformed treatment by reducing systemic glucocorticoid dependence 6, 3
- NSAIDs are conditionally recommended as initial monotherapy 7
- Biologic therapy (IL-1 and IL-6 inhibitors) is strongly recommended over conventional synthetic DMARDs for inadequate response 7
- Tocilizumab (IL-6 inhibitor) is FDA-approved for sJIA in patients ≥2 years of age, administered intravenously at 8 or 12 mg/kg based on body weight 10
- JAK inhibitors and agents targeting IL-18 or IFNγ are emerging therapies for refractory cases 6
Relationship to Adult-Onset Still's Disease
Recent evidence strongly supports that sJIA and adult-onset Still's disease (AOSD) represent the same disease across different age groups, forming a continuum. 1
- Pooled prevalence of clinical manifestations does not differ between sJIA and AOSD (except myalgia, sore throat, and weight loss, which are likely underascertained in young children with sJIA) 1
- Biological findings and diagnostic biomarker performance are similar 1
- Both conditions share the same phenotypic dichotomy: systemic inflammatory phenotype vs. chronic articular phenotype 1
- Both are associated with predisposition to MAS, hepatitis, and interstitial lung disease 1
Monitoring Requirements
- Regular assessment for disease activity using validated measures 7
- Surveillance for MAS development, particularly during disease flares 1
- Tuberculosis screening for patients receiving biologic agents 1
- Monitoring for medication-related adverse events including infections, elevated liver enzymes, and cytopenias 10, 3
- Screening for chronic anterior uveitis, particularly in ANA-positive patients 7