Evaluation of Clinical Relevance and Biological Effects of Antirituximab Antibodies in Patients With Pemphigus.

Importance: The clinical relevance of antirituximab antibodies (ARAs) in patients with pemphigus who are treated with rituximab (RTX) is currently unknown. Objective: To determine the prevalence of ARAs in patients with pemphigus who are treated with RTX and their association with complete remission (CR) and relapse. Design, Setting, and Participants: This post hoc analysis of the Ritux3 trial was conducted from January 2010 to December 2015 in 25 dermatology departments in France and included 42 patients with moderate-to-severe pemphigus who were randomized to receive treatment with RTX. Five additional patients were recruited for an ancillary study. The proportions of patients who achieved CR or relapsed after an initial treatment cycle of RTX were compared depending on whether patients had ARAs. Exposures: Patients were treated with 1000 mg of RTX on days 1 and 15 and 2 maintenance infusions of 500 mg at months 12 and 18. Main Outcomes and Measures: Rates of relapse and sustained CR at month 36. Levels of ARAs, antidesmoglein 1/3 antibodies, RTX serum concentrations, and peripheral blood CD19+ B-cell frequency were measured. Results: Of 42 participants with vs without ARAs, the mean (SD) age was 55 (17) years and 56 (17) years, respectively; 25 (59.5%) were women. Antirituximab antibodies were detected in the serum samples of 13 of 42 patients (31%) during the first year. Nine patients who experienced relapse before month 12 were excluded because they received additional infusions and could not be further analyzed. Among the 33 remaining patients, 2 patients (6.1%) experienced relapse after month 12, and 31 (95.9%) maintained a sustained CR until month 36. The rate of sustained CR was not different whether patients had ARAs (11 of 13 [85%]) or not (20 of 20 [100%]) (P = .15). Both groups (ARA+ vs ARA-) also had similar CD19+ B-cell depletion and RTX levels, but patients with ARAs had higher anti-desmoglein 3 antibody (DSG3 Abs) levels compared with those without ARAs (mean [SD], 30.1 [50.9] AU/mL vs 4.0 [4.3] AU/mL; P = .03). The 2 patients with ARAs who experienced relapse after month 12 had an undetectable RTX level, incomplete B-cell depletion, and higher anti-DSG3 Abs level than the 11 patients who maintained a sustained CR with ARAs (RTX mean [SD] concentration, 0 ug/mL vs 12.5 [2.2] ug/mL; P = .03; incomplete B-cell depletion, 2 of 2 vs 4 of 11; P = .19; mean [SD] anti-DSG3 Abs levels, 103.5 [61.5] AU/mL vs 19.5 [11.0] AU/mL; P = .001) or patients without ARAs (mean [SD] RTX concentration, 0 ug/mL vs 13.5 [1.8] ug/mL; P = .02; incomplete B-cell depletion, 2 of 2 vs 5 of 20; P = .09; mean [SD] anti-DSG3 Abs level, 103.5 [61.5] AU/mL vs 4.0 [1.0] AU/mL; P < .001). Conclusions and Relevance: The results of this cohort study suggest that ARAs are frequently detected in patients with pemphigus who are treated with RTX and generally are not associated with patient outcomes. Only a few patients with the combination of ARAs, low RTX concentration, incomplete B-cell depletion, and persistent serum anti-DSG3 Abs seem at high risk of relapse.