Adults with Unclassified Systemic Autoinflammatory Disease: Insights from a Canadian Autoinflammatory Clinic

Objectives 1) Describe the clinical and genetic characteristics of adult patients with Unclassified Systemic Autoinflammatory Disease (USAID). 2) Hypothesize on potential causal factors behind USAID. Methods Inclusion criteria were age ≥18 years, with unexplained recurrent or chronic inflammation (≥1 of: fevers, serositis, peritonitis, pharyngitis, mucocutaneous ulceration, skin lesions, elevated CRP, response to colchicine or IL-1 blockade). Gene panel testing was performed via Next Generation Sequencing at the Hospital for Sick Children. All patients provided written consent to be included in a case series. Results A total of 48 patients were included (85% female). The cohort was ethnically diverse, including Caucasian (77%), South Asian (10%), East Asian, African and Middle Eastern (each 4%). The median age at enrollment was 36 years, and first symptom onset at 25 years. A family history of similar symptoms was present in 23%. Prior to first onset, an antecedent event was recalled in 40% of patients. The most common were concussion (8/48, 17%), and frequent viral infections (6/48, 12.5%). The most common manifestations were joint pain/swelling (83%), dermatologic lesions (77%), and recurrent fevers >38°C (75%). In those with dermatologic lesions, the most subtypes were nonspecific rash (62%), mucocutaneous ulcerations (57%) and urticaria-like lesions (38%). Skin biopsy was performed in 11, with neutrophilic infiltration found in 5. CRP was elevated during flares in 32/39 (82%) of patients, and in 9/48 (19%) at baseline. Autoinflammatory gene variants were found in 40/48 (83%) patients. MEFV variants were present in 30/48 (63%) for which the most common was E148Q (12/30, 40%). NOD2 variants were present in 25/48 (52%), the most common being L1007fs (5/25, 25%). NLRP12 variants were present in 5/48 (10%). Variants were also found (in fewer numbers) in NLRP3, TNFRSF1A, NLRC4, and MVK. Colchicine was beneficial in 32/39 patients. IL-1 inhibitor was trialed in 9 patients, with 8 showing clinical and biochemical improvement. Conclusion USAID remains an important area of study given the large number of autoinflammatory patients that lack a monogenic explanation. It remains unclear whether USAID patients have a monogenic disease in a yet unknown gene, or a multifactorial condition with genetic susceptibility factors. Indeed, a ‘2 hit hypothesis’ appears plausible given the significant proportion of patients carrying a genetic variant and recalling a triggering event. Only 1 patient in the cohort denied any antecedent events and lacked autoinflammatory gene variants, highlighting these as likely important factors in disease pathogenesis.