Systemic JIA

Introduction

Interleukin-1 (IL-1) family cytokines serve as key pathogenic drivers.
Marked elevation in interleukin-6 (IL-6) drives systemic inflammatory manifestations.
Interleukin-18 (IL-18) acts as central driver, showing significant serum elevation.

Fever: Intermittent, high-spiking quotidian fever exceeding 39°C. Peaks once or twice daily, typically evening. Rapid return to normal or subnormal baseline.
Rash: Evanescent, salmon-pink, maculopapular eruptions. Distributed mainly over trunk and proximal extremities. Migratory, nonpruritic, transient lasting less than one hour. Demonstrates Koebner phenomenon, evoked by superficial trauma or heat.
Visceral Involvement: Generalized lymphadenopathy, hepatosplenomegaly.
Serositis: Pleuritis and pericarditis common; myocarditis rare.

Arthritis often absent at initial presentation, developing later in disease course.
Symmetrical polyarticular pattern common, affecting knees, wrists, ankles, cervical spine, hips.

Criterion Type	Specific Requirements
Mandatory	Arthritis in $\geq$ 1 joint with or preceded by documented quotidian fever $\geq$ 2 weeks (daily for $\geq$ 3 days)
Additive (Requires $\geq$ 1)	Evanescent erythematous rash
	Generalized lymph node enlargement
	Hepatomegaly or splenomegaly
	Serositis
Exclusions	Psoriasis in patient or first-degree relative
	HLA-B27 positive male onset > 6 years
	Ankylosing spondylitis, enthesitis-related arthritis, inflammatory bowel disease in relative
	Positive IgM rheumatoid factor twice, 3 months apart

Life-threatening complication occurring in 5-8% of cases overtly, subclinical in up to 30%.
Driven by excessive activation of macrophages and T lymphocytes.
Clinical shift: Fever becomes unremitting.
New onset central nervous system encephalopathy.
Dramatic laboratory shift: Sudden drop in erythrocyte sedimentation rate (ESR) due to hypofibrinogenemia.
Rapid development of pancytopenia (leukopenia, thrombocytopenia) replacing previous elevations.
Extreme hyperferritinemia (>10,000 ng/mL), hypertriglyceridemia, elevated hepatic transaminases.

Rare, potentially fatal complication.
Predominant pathology features pulmonary alveolar proteinosis and endogenous lipoid pneumonia.
Associated with younger age onset, prior macrophage activation syndrome, and high IL-18.

Treatment Tier	Pharmacologic Agents	Indications & Efficacy
First Line	Nonsteroidal anti-inflammatory drugs (NSAIDs)	Initial symptomatic relief; rarely controls severe systemic disease alone.
Bridge / Severe	Systemic Corticosteroids	Controls severe systemic illness, macrophage activation syndrome. Avoid long-term use.
Targeted Biologics	IL-1 Inhibitors (Anakinra, Canakinumab)	Highly effective for profound systemic features; often initiates rapid remission.
Targeted Biologics	IL-6 Inhibitors (Tocilizumab)	Controls refractory systemic disease, normalizes acute phase reactants.
Conventional	Methotrexate	Adjunctive therapy primarily targeting persistent articular involvement.

Tumor necrosis factor (TNF) inhibitors remain less effective for systemic symptoms compared to IL-1 and IL-6 blockade.
Emergent intravenous methylprednisolone pulse therapy alongside cyclosporine required for macrophage activation syndrome.