Is Adult-Onset Still's Disease (AOSD) a disorder of the innate immune system rather than the acquired immune system, particularly in a 42-year-old male patient with a history of pulmonary tuberculosis presenting with persistent high-grade fever, myalgia, fatigue, sore throat, and recurrent rash?

AOSD is Primarily a Disorder of the Innate Immune System

Yes, Adult-Onset Still's Disease (AOSD) is fundamentally a disorder of the innate immune system, classified as a complex polygenic autoinflammatory syndrome, though adaptive immunity becomes involved particularly in patients who develop chronic articular disease. 1

Pathophysiological Basis

Innate Immune System Dominance

The innate immune system plays the predominant role in AOSD pathogenesis through several key mechanisms: 1

• Macrophage and neutrophil hyperactivation is the hallmark of AOSD, distinguishing it from classical autoimmune diseases 2
• The disease is driven by overexpression of inflammatory cytokines including IL-1, IL-6, IL-18, and calcium-binding proteins, all products of innate immune activation 1
• The striking therapeutic response to IL-1 and IL-6 inhibition provides compelling evidence that innate immunity drives the disease, as these cytokines are processed through the inflammasome machinery characteristic of autoinflammatory conditions 1, 2

Autoinflammatory Classification

• AOSD is now considered a complex, polygenic autoinflammatory syndrome rather than an autoimmune disease 1
• A genetic background confers susceptibility to autoinflammatory reactions triggered by environmental factors, similar to other autoinflammatory syndromes 2
• The absence of classical autoimmune features (negative ANA and RF in diagnostic criteria) further supports its autoinflammatory nature 1

Specific Innate Immune Mechanisms in Your Patient

Monocyte/Macrophage Activation Pathways

For your 42-year-old male with persistent fever, myalgia, and rash, the following innate immune mechanisms are likely operative:

• Activation occurs through PAMPs (pathogen-associated molecular patterns) and DAMPs (damage-associated molecular patterns) binding to pattern recognition receptors (PRRs) 3, 4
• NLRP3 inflammasome activation triggers caspase-1, converting pro-IL-1β and pro-IL-18 into mature forms, which then drive the clinical manifestations including fever, rash, and systemic symptoms 3
• Neutrophil extracellular traps (NETs) and their DNA content further stimulate monocytes/macrophages, perpetuating the inflammatory cycle 3, 4

Cytokine Profile

• A predominance of Th1 cytokines (IL-2, IFN-γ, TNF-α) characterizes active AOSD, though this represents innate immune system output rather than primary adaptive immunity 1
• IL-18 is particularly elevated in AOSD (diagnostic accuracy 97.67% when combined with ferritin) and correlates with disease activity 5
• Type II interferon stimulation drives monocyte/macrophage activation in the innate immune cascade 3

Role of Adaptive Immunity (Secondary)

Limited Adaptive Immune Involvement

• While patients do not exhibit classical features of autoimmunity, adaptive immunity becomes involved particularly in those developing chronic articular disease patterns 1
• This secondary adaptive immune activation occurs in approximately one-third of patients who develop the chronic articular phenotype 5, 6
• The adaptive immune involvement appears to be a consequence rather than a primary driver of disease pathogenesis 1

Clinical Implications for Your Patient

Diagnostic Considerations

• The history of pulmonary tuberculosis is relevant as infectious agents may act as environmental triggers in genetically predisposed hosts, activating the innate immune system through PAMPs 1, 4
• His presentation with high-grade fever, myalgia, sore throat, and recurrent rash is consistent with systemic AOSD driven by innate immune hyperactivation 5, 6
• Expect markedly elevated ferritin (potentially 4,000-250,000 ng/mL), leukocytosis with neutrophilia (>15×10⁹ cells/L), and elevated IL-18 5, 6

Treatment Implications

• Target the innate immune system with IL-1 inhibitors (anakinra) or IL-6 receptor inhibitors (tocilizumab) as first-line biologic therapy 7
• These agents directly address the autoinflammatory pathophysiology rather than suppressing adaptive immunity 1, 2
• Early initiation of biologic therapy targeting innate immunity improves outcomes through a "window of opportunity" effect 7

Critical Pitfall to Avoid

• Do not confuse AOSD with autoimmune diseases requiring different therapeutic approaches—the innate immune predominance means that traditional immunosuppressants targeting adaptive immunity (like those used in lupus or rheumatoid arthritis) are less effective than biologics targeting IL-1 or IL-6 1, 2