Novel Autoinflammatory Syndromes: LAVLI, LIRSA, ROSAH and COPA

Recent advances in immunogenetics have broadened the spectrum of monogenic autoinflammatory diseases and refined our understanding of innate immune dysregulation and inflammation-driven tissue injury. LAVLI, LIRSA, ROSAH and COPA syndromes represent recently described entities with important implications for diagnosis, classification and precision therapy in contemporary rheumatology.

LAVLI (Lyn kinase–Associated Vasculopathy and Liver Fibrosis)

LAVLI is caused by gain-of-function mutations in the LYN gene encoding a Src-family tyrosine kinase. The disease presents early in life with neutrophilic small-vessel vasculitis, severe systemic inflammation and progressive hepatic fibrosis. Constitutive Lyn activation enhances endothelial ICAM-1 expression and β2-integrin–mediated neutrophil adhesion, leading to exaggerated neutrophil recruitment, microvascular injury and fibrosis.

LIRSA (Loss of IL-1R1 Sensitivity to IL-1Ra)

LIRSA represents a novel IL-1–mediated autoinflammatory mechanism in which pathogenic IL-1 receptor variants preserve IL-1β signalling but abolish inhibition by IL-1 receptor antagonist. Clinically, patients develop severe chronic recurrent multifocal osteomyelitis with systemic inflammation and show poor response to anakinra, highlighting the importance of genotype-guided therapeutic strategies.

ROSAH Syndrome

ROSAH syndrome is an autosomal dominant autoinflammatory disease caused by gain-of-function mutations in ALPK1, resulting in constitutive NF-κB activation. Initially described with retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and headache, the phenotype now includes inflammatory arthritis and chronic uveitis, often leading to diagnostic delay.

COPA Syndrome

COPA syndrome is an autosomal dominant interferonopathy caused by mutations affecting COPI-mediated endoplasmic reticulum–Golgi trafficking. Defective retrograde transport leads to aberrant STING retention and exaggerated type I interferon signalling. Clinically, COPA frequently phenocopies ANCA-associated vasculitis with alveolar haemorrhage, interstitial lung disease, pauci-immune glomerulonephritis and ENT involvement. Most inborn errors associated with ANCA positivity converge on the type I interferon pathway, positioning COPA at the intersection of monogenic autoimmunity and vasculitis biology. Disease penetrance is incomplete, partly explained by the HAQ-STING polymorphism.

Table 1. Schematic overview of pathogenic pathways

Suggested Reading

• Watkin LB et al. COPA syndrome: a novel autoimmune disease caused by mutations in COPA. Journal of Experimental Medicine.
• Deng Z et al. Loss of IL-1R1 sensitivity to IL-1Ra defines a new autoinflammatory disease. Nature Immunology.
• Zhou Q et al. ALPK1 gain-of-function mutations cause ROSAH syndrome. Journal of Clinical Investigation.
• Autoimmunity Reviews. Monogenic interferonopathies and systemic autoinflammation.