Genetic Predisposition in Recurrent Pericarditis: Clinical Implications for Diagnosis and Treatment

Background Recurrent pericarditis (RP) has traditionally been classified as idiopathic in most patients. Over the last decade, however, accumulating evidence suggests that a subset of RP is driven by underlying genetic and autoinflammatory mechanisms. Variants affecting innate immunity pathways have been increasingly reported, particularly in patients with early disease onset, systemic inflammatory features, and a refractory clinical course. Clarifying the genetic background of RP may improve patient stratification and support a more individualized therapeutic approach. Methods A systematic review of the literature was performed using MEDLINE, Embase, and Scopus databases, covering the period from 2012 to September 2025. Eligible studies included patients with recurrent pericarditis or pericarditis with autoinflammatory features who underwent germline genetic testing. Data extraction focused on variant type, associated clinical phenotypes, and potential therapeutic implications, particularly response to interleukin–1 (IL–1) inhibition. Results Across referral–center cohorts and smaller observational series, variants in genes involved in innate immunity—most commonly MEFV, NLRP3, and TNFRSF1A—were identified in a relevant proportion of patients with difficult–to–treat RP. Genetic positivity was consistently associated with younger age at onset, systemic inflammatory manifestations such as fever or polyserositis, and steroid dependence or colchicine resistance. These patients frequently exhibited an autoinflammatory disease profile and tended to show a more predictable and sustained clinical response to IL–1 inhibitor. Emerging studies also report novel or rare variants, highlighting the need for standardized genetic panels and harmonized data collection. Conclusions Current evidence supports a contributory genetic role in a subset of recurrent pericarditis. Selective genetic testing in early–onset or refractory cases may refine diagnostic evaluation, facilitate risk stratification, and guide earlier initiation of targeted anti–inflammatory therapies. Prospective multicenter studies and genotype–guided registries are warranted to further define the role of genetics in personalized management of recurrent pericarditis.