Beyond NLRP3: expanding the spectrum of NLR-associated autoinflammatory diseases

OBJECTIVES: Gain-of-function mutations in NLRP3 represent the prototypical cause of inflammasome-driven systemic autoinflammatory diseases(SAIDs). Other members of the nucleotide-binding domain and leucine-rich repeat-containing(NLR) family, including NLRP1, NLRP7, NLRP12, and NLRC4, may also contribute to systemic inflammatory phenotypes. We aimed to characterize patients carrying NLR-variants. METHODS: Patients referred for SAIDs and harboring NLR-variants were retrospectively analyzed. All patients underwent targeted next-generation sequencing and variants were interpreted according to ACMG criteria. Demographics, clinical manifestations, laboratory, and treatment data were recorded. RESULTS: Thirty-three patients(70% female; age 19-62 years) were included. Recurrent fever was the predominant manifestation and frequently accompanied by musculoskeletal symptoms and prominent mucocutaneous findings, including erythematous and urticarial rashes, erythema nodosum-like lesions, oral aphthae, and conjunctivitis. Distinct phenotypic patterns were observed across variant groups. NLRP1 variants were often associated with FMF-like features, including recurrent fever and serositis, occasionally with autoimmune features. NLRP7 variants presented with recurrent febrile episodes with mucocutaneous involvement. NLRP12 variants typically presented with periodic fever syndromes and maculopapular or erythema nodosum-like lesions. NLRC4 variants were observed with episodic systemic inflammation with gastrointestinal involvement and atypical cutaneous manifestations including erysipelas-like erythema and angioedema. Coexisting MEFV variants were identified in a subset. Approximately one-third responded to colchicine, whereas another third required IL-1 blockade. CONCLUSION: Patients carrying rare non-NLRP3 NLR variants demonstrated a broad and overlapping spectrum of systemic autoinflammatory phenotypes, frequently marked by mucocutaneous involvement. These descriptive observations highlight the need for further functional studies to clarify the pathogenic significance of these variants and importance of expanded genetic evaluation beyond MEFV in patients with atypical inflammatory presentations and describe clinical responses to colchicine and IL-1 inhibition in a subset of patients.