Genetically determined cardio-inflammatory phenotypes in recurrent pericarditis: a systematic review and meta-analysis

Background

Recurrent pericarditis is a chronic inflammatory heart disease associated with repeated relapses, frequent corticosteroid dependence and prolonged disease course. Although often labelled as idiopathic, increasing evidence suggests that a subset of patients may have an underlying genetic predisposition, particularly involving autoinflammatory pathways. However, the prevalence and clinical significance of pathogenic genetic variants in recurrent pericarditis remain unclear.

Methods

We performed a systematic review and meta-analysis according to PRISMA recommendations. PubMed, Embase and Scopus were searched from inception to September 2025 for studies reporting genetic testing in adult patients with recurrent pericarditis, with or without myocardial involvement. Genetic variants were classified according to ACMG criteria. The primary outcome was the pooled prevalence of pathogenic or likely pathogenic (P/LP) variants. A random-effects model was used. Associations with clinical phenotype and long-term outcomes were explored through qualitative synthesis.

Results

Twenty-seven studies including approximately 1,200 patients with recurrent pericarditis were analysed. Genetic testing, mainly based on whole-exome sequencing or targeted autoinflammatory panels, identified P/LP variants in a pooled proportion of 14% (95% CI 10–18%), with substantial heterogeneity across studies. In the largest whole-exome sequencing cohorts, the prevalence of disease-associated variants ranged from 10.2% to 22.9%. Variants were most frequently detected in genes involved in inflammasome and interleukin-1 signalling pathways, including MEFV, NLRP3, TNFRSF1A and MVK.

Across cohorts, genotype-positive patients consistently showed a more severe cardio-inflammatory phenotype, characterized by earlier disease onset, higher recurrence burden and increased corticosteroid dependence. In prospective observational data with a median follow-up of up to 47 months, long-term remission was achieved less frequently in genetically predisposed patients compared with genotype-negative individuals (33.3% vs 67.3%, log-rank p=0.03), with genetic predisposition independently associated with a reduced likelihood of sustained remission (adjusted HR 0.47, 95% CI 0.24–0.98). Several studies reported increased use and favourable response to interleukin-1 inhibition in this subgroup. Variants of uncertain significance were commonly reported.

Conclusions

A genetically determined cardio-inflammatory phenotype is identifiable in approximately one in seven patients with recurrent pericarditis and is associated with a more aggressive disease course and poorer long-term remission. Genetic testing may support risk stratification and guide individualized therapeutic strategies in selected patients with recurrent or corticosteroid-dependent disease. Further prospective studies are needed to define the role of genetic testing in routine clinical practice.