OBJECTIVES: Treatment of rheumatoid arthritis (RA) relies on immunomodulatory drugs that can compromise immunity, inducing secondary immunodeficiency (SID). However, features of SID, such as hypogammaglobulinaemia and severe/recurrent infections, occur in only a minority of patients, suggesting a potential underlying genetic predisposition. Given the expanding spectrum of genes implicated in inborn errors of immunity (IEIs) and the fact that IEIs can present with rheumatic manifestations, we hypothesised that a subset of patients with RA with SID harbour IEI-related variants. METHODS: We screened 701 patients with RA for SID, defined as persistent hypogammaglobulinaemia or susceptibility to infections requiring prophylactic anti-infective therapy. Patients with SID underwent targeted whole-exome sequencing to identify rare variants in IEI-associated genes. RESULTS: Among 701 evaluated patients, 70 (10%) had SID. SID was more frequently observed in patients with earlier onset of RA, seronegative disease and in those receiving rituximab therapy. Genetic analysis identified 17 putatively pathogenic variants in 15 of 70 patients with SID (21.4%). All variants were monoallelic, with 7 of 17 (41.2%) affecting genes involved in canonical NF-kappaB signalling. Two patients (3.1%) harboured variants previously reported as pathogenic. CONCLUSIONS: Although rare, underlying IEIs can account for immunodeficiency in patients with RA. Identifying patients with IEIs among those with RA may have important implications for disease management, as it can guide the selection of immunomodulatory therapy and help prevent infectious complications. Furthermore, it may refine our interpretation of drug safety, particularly in cases of unusual infections that may instead be attributable, rather, to an underlying germline defect.
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