Risk of persistent hypogammaglobulinaemia in children with autoimmune bullous dermatoses treated with rituximab

The use of rituximab for treating autoimmune bullous diseases (AIBDs) in children has increased over the past decade.1-3 Rituximab, a chimeric monoclonal antibody targeting CD20+ cells, is known to cause hypogammaglobulinaemia (HGG).4-6 This study aims to assess the incidence and duration of HGG in children with AIBDs receiving rituximab and its clinical consequences. This descriptive, retrospective, multicenter study, conducted in France, included patients under 18 years of age with AIBDs treated with rituximab (375 mg/m2 weekly × 4 or 1 g 2 weeks apart). Patients without immunoglobulin level data and those with known primary immunodeficiency diseases were excluded. HGG was defined as IgG levels ≤2 SD below the age-adjusted reference range (or IgM if immunoglobulin replacement therapy had previously been administered) and was considered persistent if this criterion was found at an interval of 6 months or more. The severity of HGG was not assessed due to the lack of consensus regarding paediatric thresholds. The study included 21 children diagnosed with AIBDs (Table 1). The median age at treatment initiation was 7 years (1–15 years), with a female-to-male ratio of 1.33. All patients had previously failed at least one systemic treatment. Maintenance rituximab infusions following the initial cycle were administered to 15 patients (71%). Hypogammaglobulinaemia occurred in 17 children (81%), including all children under 6 years (7/7), with a median onset of 3 months (1–145 months). In 10 patients (59%), HGG appeared after the first rituximab cycle. Persistent HGG after the last infusion was observed in 12 patients (57%), including eight cases for over 12 months (38%). No significant difference was found between single and multiple cycles regarding the occurrence (p = 0.164) or persistence (p = 0.190) of HGG. No significant differences were found between cumulative doses and the number of infusions either. Significant infections occurred during the follow-up in eight patients (38%); 5 of them (62.5%) had concomitant HGG, all had received maintenance rituximab and concomitant immunosuppressive therapy. No significant association was found between infection risk and the use of immunosuppressants, including mycophenolate mofetil. No increased infection risk was found in children under 6 years (p = 0.346) but the cumulative dose (p = 0.028) and number of infusions (p = 0.019) were significantly higher in the group that had an infection. Preventive measures against infections included immunoglobulin replacement therapy in 12 patients (57%, 7 immunomodulatory doses and 5 substitution doses) and antibiotic prophylaxis in 6 (26%) (Table 2). Rituximab was well-tolerated with only one infusion-related reaction leading to discontinuation. The mean follow-up period was 54 months (8–218 months). This study assesses the risk of HGG in children with AIBDs treated with rituximab, highlighting a significant challenge in integrating rituximab into treatment protocols. The findings are consistent with data from adults with AIBDs, and demonstrate the impact of age on HGG incidence. Nevertheless, no correlation was identified between the various types of concomitant immunosuppressive treatments.7, 8 Compared with other paediatric autoimmune diseases treated with rituximab, HGG appears to be more prevalent in AIBDs: miscellaneous connective tissue diseases (12%), 46% in systemic lupus erythematosus, and 8%–58% in nephrotic syndrome, the most frequent paediatric indication for rituximab.9, 10 The rate of threatening infections was low, and their direct attribution to HGG remains uncertain. Our study highlights significant variability across centers in post-rituximab immunoglobulin level monitoring and a lack of standardized guidelines for infection prophylaxis. Prospective studies are needed to elucidate the mechanisms of persistent HGG, though their feasibility remains limited by the rarity of the disease. A full immunological workup is recommended, with close monitoring of immunoglobulin levels for the first 6 months to allow early prophylaxis against infection. The authors have nothing to report. None declared. Reviewed and approved by Marseille IRB; approval #CSE24-4. The patients in this manuscript have given written informed consent for the publication of their case details. The data that support the findings of this study are available from the corresponding author upon reasonable request.