Insights from a novel monogenic autoinflammatory disease: overview of a multicentric European cohort of 38 patients with COPA syndrome

Objectives: COPA (coatomer subunit alpha) syndrome is a rare monogenic autoinflammatory disease due to heterozygous mutations in COPA. It has phenotypic overlap with STING (Stimulator of interferon genes)-associated vasculopathy with onset in infancy (SAVI), although the spectrum of clinical manifestations is not yet fully defined. Our aim was to better delineate the clinical phenotype of this rare disorder in a European cohort. Methods: Methods include assessment of clinical, imaging, and immunological data from 46 individuals (29 families) carrying a COPA mutation. Results: Among the 46 individuals carrying a COPA mutation, 38 had at least 1 clinical manifestation likely related to their mutant state (clinical penetrance of 83%). Twenty-two (58%) symptomatic patients were female, with a median age at disease onset of 3 years (range 0-50 years). Pulmonary involvement was observed in 34 patients, with interstitial lung disease in most cases (n = 31) and diffuse alveolar haemorrhage in 11 individuals. Twenty-six patients demonstrated joint involvement, and 7 had documented kidney disease. Previously undescribed features included skin (n = 12), cardiac (n = 8), gastrointestinal (n = 7), and hepatic involvement (n = 5). All but 1 patient tested positive for autoantibodies, and increased interferon signalling was noted in all those tested. Twenty-two patients were treated with Janus kinase inhibitors with promising efficacy. Conclusions: We report a large European cohort of patients with COPA syndrome. While confirming the core organ features (lung, joint, and kidney) of the disease, our data expand the phenotype to include cardiac, skin, and gastrointestinal features, further demonstrating the clinical overlap with SAVI and other type I interferonopathies.