Adult-onset Still’s disease (AOSD) is a rare, systemic inflammatory disorder characterized by a constellation of systemic and musculoskeletal manifestations. First described by George Still in 1897 as a childhood illness (Still’s disease), it was later recognized as a distinct entity in adults, now termed Adult-Onset Still’s Disease. AOSD affects approximately 1.4 to 12.3 cases per million individuals annually, with a peak incidence in the second and third decades of life, although it can occur at any age. The disease is considered idiopathic, meaning its exact cause remains unknown, but current evidence supports a complex interplay between genetic predisposition, environmental triggers, and dysregulation of the innate immune system.

Clinical Presentation and Diagnostic Criteria

The hallmark features of AOSD include high spiking fevers (often >39°C), migratory polyarthritis, and a characteristic salmon-pink maculopapular rash. These symptoms are typically episodic, with fever spikes occurring once or twice daily, often in the late afternoon or evening, and lasting for several hours before resolving. The rash, which appears during febrile episodes, is transient and non-pruritic, usually affecting the trunk and proximal extremities.

Recent clinical studies emphasize that systemic inflammation is the core of AOSD pathophysiology, leading to multi-organ involvement beyond the joints. Key clinical features include:

• Arthralgia/Arthritis: Symmetrical polyarthritis affecting large joints (knees, wrists, ankles) in 70–90% of patients. Chronic joint damage may occur in up to 30% of cases, particularly in those with delayed diagnosis or inadequate treatment.
• Systemic Symptoms: High fevers (≥39°C), fatigue, malaise, and weight loss are nearly universal.
• Hepatosplenomegaly and Lymphadenopathy: Seen in 50–70% of patients, often detectable via imaging.
• Serositis: Pericarditis and pleuritis may occur in 10–30% of cases, contributing to chest pain and dyspnea.
• Hematologic Abnormalities: Leukocytosis with neutrophilia is a consistent finding, often with an elevated neutrophil count (>10 × 10⁹/L). Serum ferritin levels are markedly elevated in most patients, often exceeding 1000 µg/L and sometimes reaching >10,000 µg/L, serving as a key biomarker. In recent years, ferritin has been included in the 2023 ACR/EULAR classification criteria for AOSD, with levels >2000 µg/L considered highly suggestive.
• Negative Serologies: Anti-nuclear antibodies (ANA) and rheumatoid factor (RF) are typically negative, helping differentiate AOSD from autoimmune diseases such as systemic lupus erythematosus or rheumatoid arthritis.

Pathogenesis and Immunological Insights

While the precise etiology of AOSD remains elusive, current research strongly supports autoinflammatory mechanisms driven by innate immune system dysregulation. Unlike autoimmune diseases (e.g., rheumatoid arthritis), where adaptive immunity (T and B cells) is central, AOSD is classified as an autoinflammatory syndrome, characterized by uncontrolled activation of the innate immune system, particularly the NLRP3 inflammasome and IL-1β pathway.

Key immunological findings include:

• Elevated Pro-inflammatory Cytokines: Patients exhibit high levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-18 (IL-18), and tumor necrosis factor-alpha (TNF-α). These cytokines drive systemic inflammation and contribute to fever, rash, and organ damage.
• IL-1β and IL-6 as Therapeutic Targets: The pivotal role of IL-1β is supported by the efficacy of IL-1 inhibitors (e.g., anakinra, canakinumab) in refractory cases. Similarly, IL-6 signaling (via the IL-6 receptor) is central to disease activity, with tocilizumab (an IL-6 receptor antagonist) showing significant clinical response in multiple trials.
• Genetic Susceptibility: Genome-wide association studies (GWAS) have identified polymorphisms in genes related to innate immunity, including HLA-DRB1, HLA-DQA1, and NLRP3, suggesting a heritable component. However, AOSD is not considered hereditary, as transmission risk among first-degree relatives remains low.

Emerging evidence also implicates dysregulated macrophage activation and hemophagocytic lymphohistiocytosis (HLH) in severe or fulminant cases. This can lead to macrophage activation syndrome (MAS), a life-threatening complication characterized by cytopenias, hyperferritinemia, and multiorgan failure.

Diagnostic Approach and Classification Criteria

Diagnosis of AOSD is clinical and relies on a combination of symptoms, laboratory findings, and exclusion of other conditions (e.g., infections, malignancies, other autoimmune diseases). The 2023 ACR/EULAR classification criteria provide a validated framework for diagnosis, incorporating the following:

1. Fever ≥39°C for at least 1 week.
2. Arthralgia or arthritis lasting ≥2 weeks.
3. Rash (salmon-pink, macular or maculopapular).
4. Leukocytosis ≥10 × 10⁹/L.
5. Ferritin ≥2000 µg/L (with exclusion of HLH or malignancy).
6. Negative ANA and RF.

A diagnosis is confirmed if ≥4 of these criteria are met, with ferritin ≥2000 µg/L and neutrophilic leukocytosis being the most sensitive and specific markers.

Additional diagnostic tools include:

• Imaging: Ultrasound and MRI may reveal synovitis, tenosynovitis, or early joint damage. Chest X-ray or CT may detect pleural effusions or pericardial thickening.
• Laboratory Tests: Elevated C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and serum ferritin are routine markers of disease activity. Liver enzymes (ALT/AST) may be elevated due to hepatic involvement.

Treatment Strategies and Therapeutic Advances

Treatment of AOSD is staged based on disease severity and response to therapy. The primary goal is to control systemic inflammation, prevent joint damage, and reduce the risk of life-threatening complications.

1. First-Line Therapy

• Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Used for mild disease or in early stages to manage fever and joint pain. However, NSAIDs are insufficient for controlling systemic inflammation in most cases.

2. Corticosteroids

• Glucocorticoids (e.g., prednisone): First-line for moderate-to-severe disease. Doses of 0.5–1 mg/kg/day are typically used initially, followed by tapering over months. Long-term use is associated with significant side effects (osteoporosis, diabetes, hypertension), necessitating early transition to steroid-sparing agents.

3. Disease-Modifying Antirheumatic Drugs (DMARDs)

• Methotrexate: Used as a steroid-sparing agent in chronic or recurrent cases. It reduces disease activity and may delay joint damage.
• Hydroxychloroquine: May have a modest role in some patients, particularly those with persistent rash or arthritis.

4. Biologic Agents (Targeted Therapies)

Biologics have revolutionized AOSD management, particularly in refractory or severe cases:

• IL-1 Inhibitors:
  • Anakinra (IL-1 receptor antagonist): Rapid onset of action; effective in controlling fever and systemic symptoms. Used in acute or severe cases.
  • Canakinumab (anti-IL-1β monoclonal antibody): Approved in some regions for AOSD; long-acting and well-tolerated.
• IL-6 Inhibitors:
  • Tocilizumab (anti-IL-6 receptor): Highly effective in reducing ferritin, CRP, and clinical symptoms. Multiple case series and open-label trials show remission in 70–90% of patients.
• TNF-α Inhibitors:
  • Etanercept and adalimumab have shown variable efficacy. They are less effective than IL-1 or IL-6 inhibitors but may be used in select cases.

5. Emerging Therapies

• IL-18 Inhibition: Tadekinig alfa (an IL-18 binding protein) is under investigation in clinical trials for AOSD and MAS.
• JAK Inhibitors: Tofacitinib and baricitinib are being explored due to their broad anti-inflammatory effects, particularly in patients unresponsive to biologics.
• Hematopoietic Stem Cell Transplantation: Reserved for severe, refractory cases with recurrent HLH or MAS, though data remain limited.

Complications and Prognosis

AOSD can lead to significant morbidity and, rarely, mortality. Common complications include:

• Chronic Arthritis and Joint Destruction: Persistent inflammation can cause irreversible joint damage, particularly in the wrists and knees.
• Cardiac Involvement: Pericarditis, myocarditis, and valvular dysfunction may develop. Echocardiography is recommended for early detection.
• Pulmonary Complications: Pleural effusions, interstitial lung disease, and respiratory failure may occur, especially in severe or untreated cases.
• Hepatic Involvement: Elevated transaminases and, rarely, fulminant hepatitis.
• Neurological and Auditory Complications: Aseptic meningitis, sensorineural hearing loss, and encephalopathy have been reported.
• Hemophagocytic Lymphohistiocytosis (HLH): A life-threatening condition with high mortality (up to 50%) if not promptly recognized and treated. Features include prolonged fever, cytopenias, hyperferritinemia, and organ dysfunction.

Long-term outcomes have improved significantly with early diagnosis and biologic therapy. However, up to 30% of patients experience chronic or relapsing disease, requiring prolonged treatment. Mortality remains low (1–5%) in modern cohorts but increases with complications like HLH, cardiac failure, or sepsis.

Conclusion

Adult-onset Still’s disease is a complex, multisystem autoinflammatory disorder requiring a high index of suspicion for diagnosis. Recent advances in understanding its pathogenesis—particularly the central role of IL-1β, IL-6, and IL-18—have led to more effective targeted therapies. The integration of serum ferritin, cytokine profiling, and classification criteria has improved diagnostic accuracy. With timely intervention using biologics and multidisciplinary care, many patients achieve remission and maintain long-term disease control. Ongoing research into genetic, environmental, and immunological factors promises further refinement of treatment strategies and better prognostic outcomes.