Pathogenesis, Disease Course, and Prognosis of Adult-Onset Still’s Disease

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Pathogenesis, Disease Course, and Prognosis of Adult-Onset Still’s Disease: An Update and Review

Adult-onset Still’s disease (AOSD) is a rare systemic autoinflammatory disorder characterized by high spiking fever, evanescent skin rash, polyarthralgia, sore throat, leukocytosis, and hyperferritinemia. First described by Bywaters in 1971, AOSD shares clinical similarities with systemic juvenile idiopathic arthritis but predominantly affects adults, with a median age of diagnosis at 36 years. Epidemiological studies report variable incidence rates, ranging from 0.16 to 0.4 per 100,000 individuals, with higher mortality observed in Asian populations. Recent advances in understanding its pathogenesis, clinical management, and prognostic factors have reshaped approaches to diagnosis and treatment.

Pathogenesis

The etiology of AOSD remains unclear, but a combination of genetic susceptibility, infectious triggers, and dysregulated immune responses drives its pathogenesis.

Genetic Susceptibility

AOSD is a polygenic disorder with no clear familial inheritance but significant associations with human leukocyte antigen (HLA) alleles. HLA-Bw35, HLA-DRB1, and HLA-DQB1 are linked to disease susceptibility across ethnic groups. Polymorphisms in genes encoding interleukin-18 (IL-18), serum amyloid A1 (SAA1), and macrophage inhibitory factor (MIF) further contribute to disease risk. Notably, Mediterranean fever (MEFV) gene mutations, implicated in other autoinflammatory disorders, show no significant association with AOSD.

Infectious Triggers

Viral and bacterial infections are hypothesized to initiate or exacerbate AOSD. Cytomegalovirus (CMV) is strongly implicated, with studies showing elevated CMV DNA loads and antibodies in active AOSD patients. Other pathogens, including Epstein-Barr virus, parvovirus B19, and Yersinia enterocolitica, have also been reported in case studies. Infections may trigger inflammatory cascades through pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs).

Immune Dysregulation

Macrophage Activation: Central to AOSD pathogenesis, macrophages release pro-inflammatory cytokines (IL-1β, IL-18, TNF-α) via NLRP3 inflammasome activation. Danger signals like high mobility group box-1 (HMGB1), S100 proteins, and neutrophil extracellular traps (NETs) stimulate Toll-like receptors (TLRs), amplifying inflammation. Hyperferritinemia, a hallmark of AOSD, reflects macrophage activation and correlates with disease severity. Ferritin, particularly the H-subunit, acts as a pro-inflammatory mediator, exacerbating tissue damage.

Neutrophil Activation: Neutrophils contribute through NETosis, releasing chromatin structures coated with proteases that activate NLRP3 and macrophages. Elevated CD64 (FcγRI) on neutrophils and chemokines like CXCL8 (IL-8) further drive neutrophil recruitment.

NK and T Cell Dysfunction: Reduced NK cell numbers and cytotoxic function impair immune regulation. Th1 and Th17 cells dominate, secreting IFN-γ and IL-17, which sustain macrophage and neutrophil activation. CD4+CD25high regulatory T cells (Tregs) are diminished, reducing anti-inflammatory cytokines like TGF-β.

Clinical Features and Diagnosis

AOSD manifests with four cardinal symptoms: fever (>39°C), arthralgia/arthritis, salmon-pink rash, and leukocytosis (>10,000/mm³). Additional features include sore throat, lymphadenopathy, hepatosplenomegaly, and serositis. Life-threatening complications, such as macrophage activation syndrome (MAS), occur in 10–20% of cases.

Diagnostic Criteria

The Yamaguchi criteria (sensitivity: 96.2%; specificity: 92.1%) and Fautrel criteria (sensitivity: 87%; specificity: 98%) are widely used. Incorporating glycosylated ferritin (GF ≤20%) improves specificity to 98.6%. Exclusion of infections, malignancies, and autoimmune diseases is critical.

Biomarkers

Serum Ferritin: Hyperferritinemia (>5x upper limit) with GF ≤20% is highly specific for AOSD. Elevated ferritin correlates with systemic involvement, MAS, and poor prognosis.

Cytokines: IL-18 is a key biomarker, with levels >50,000 pg/mL distinguishing AOSD from sepsis. IL-1β, IL-6, and TNF-α correlate with disease activity, while IL-10 and IL-37 reflect compensatory anti-inflammatory responses.

Other Biomarkers:

  • Calprotectin (S100A8/A9): Sensitivity 69.4%, specificity 98%.
  • HMGB1: Associated with rash and serositis.
  • MicroRNAs: miR-134 and miR-142-5p correlate with systemic inflammation.
  • Neutrophil CD64: Marker of disease activity.

Disease Course and Prognosis

AOSD follows three patterns:

  1. Monocyclic: Single episode with remission (20–35% of cases).
  2. Polycyclic: Recurrent flares (30–40%).
  3. Chronic: Persistent symptoms, often with destructive arthritis (30–50%).

Poor prognostic factors include pleuritis, interstitial pneumonia, ferritin >3,000 ng/mL, and steroid resistance. Mortality ranges from 3–12%, driven by MAS, hepatic failure, or disseminated intravascular coagulation.

Treatment

Conventional Therapies

  • NSAIDs: Limited efficacy, used for mild cases.
  • Corticosteroids: First-line (0.5–1 mg/kg/day prednisone). Rapid response in 70–80% of patients.
  • DMARDs: Methotrexate (10–25 mg/week) is steroid-sparing. Cyclosporine (3–5 mg/kg/day) and tacrolimus (2–4 mg/day) are alternatives.

Biologic Agents

  • IL-1 Inhibitors: Anakinra (100–200 mg/day) achieves remission in 80–90% of systemic AOSD.
  • IL-6 Inhibitors: Tocilizumab (8 mg/kg/month) is effective in chronic articular disease.
  • TNF-α Inhibitors: Etanercept (50 mg/week) and infliximab (5 mg/kg) show variable responses.

Emerging Therapies

JAK inhibitors (e.g., tofacitinib) and IL-18 blockers (tadekinig alfa) are under investigation.

Conclusion

AOSD remains a diagnostic and therapeutic challenge due to its heterogeneous presentation. Advances in understanding cytokine-driven inflammation, NETosis, and genetic factors have identified novel biomarkers and targeted therapies. Early intervention with IL-1 or IL-6 inhibitors improves outcomes, particularly in systemic and chronic subtypes. Future research should focus on validating biomarkers, optimizing treatment algorithms, and exploring immunopathogenic mechanisms.

doi.org/10.1097/CM9.0000000000000538

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