Autoinflammatory diseases (AIDs) are a group of rare disorders caused by overactivation of the body's innate immune system. They are marked by repeated episodes of fever, widespread inflammation, and damage to various organs. Because their symptoms can affect many different systems and often resemble other conditions, AIDs are frequently misdiagnosed or remain undetected for long periods.
The term "AIDs" covers more than 50 known single-gene (monogenic) diseases, as well as multi-gene (polygenic) conditions without an identified genetic cause. Examples include Still's disease, Behçet's disease, and certain types of inflammatory bowel disease. Adult-onset systemic autoinflammatory diseases (SAIDs) include Still's disease, Schnitzler syndrome, and idiopathic recurrent autoimmune pericarditis (IRAP). Common symptoms are periodic fevers of unknown origin, skin rashes, inflammation of membranes around organs (serositis), swollen lymph nodes, and joint pain or swelling. Laboratory findings often reveal elevated inflammatory markers such as ESR and CRP. These conditions can be further classified by their underlying pathways, including inflammasome-related diseases, type I interferonopathies, proteasome-related disorders, and NF-κB pathway-associated diseases.
Still's disease is a particularly rare type of SAID. It presents with high fevers, multiple joint pain, rash, and markedly increased inflammatory markers. The disease affects an estimated 2-6 people per million each year worldwide, but rates vary across populations. A serious complication, macrophage activation syndrome (MAS), develops in about 10-15% of patients. MAS involves uncontrolled immune activation and a massive release of inflammatory proteins known as cytokines-a process often called a "cytokine storm." Without rapid treatment, MAS can lead to multi-organ failure and has a mortality rate above 50%.
The exact cause of Still's disease and MAS remains unclear, but research shows it involves several intertwined processes: excessive immune cell activation, abnormal cytokine release, amplification of inflammation, and injury to multiple organs. Key inflammatory mediators include IL-1β, IL-6, IL-18, IFN-γ, and TNF-α. These molecules activate immune cells such as macrophages, neutrophils, and certain T cells, setting off a self-perpetuating cycle of inflammation. In addition, the formation of neutrophil extracellular traps (NETs) appears to play a role in tissue injury.
Because current diagnostic tools cannot reliably detect MAS early, and treatments-mainly glucocorticoids and immunosuppressants-are only partly effective and carry significant side effects, there is a pressing need for better understanding of the disease mechanisms. This study aims to follow a well-characterized cohort of patients with autoinflammatory diseases, particularly those with Still's disease and MAS, to identify new molecular targets and specific diagnostic biomarkers. The goal is to improve early detection, guide more precise treatments, and ultimately reduce mortality in these high-risk patients.
