Department of Dermatology, Normandie University, Université de Rouen, Inserm U1234, CHU Rouen, Rouen, France.
Department of Immunology, Normandie University, Université de Rouen, Inserm U1234, CHU Rouen, Rouen, France.
JAMA Dermatol. 2022 Aug 1;158(8):893-899. doi: 10.1001/jamadermatol.2022.2149.
The clinical relevance of antirituximab antibodies (ARAs) in patients with pemphigus who are treated with rituximab (RTX) is currently unknown.
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.
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.
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.
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).
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.
目前尚不清楚接受利妥昔单抗（RTX）治疗的天疱疮患者体内抗利妥昔单抗抗体（ARAs）的临床相关性。
确定接受 RTX 治疗的天疱疮患者中 ARAs 的患病率及其与完全缓解（CR）和复发的关系。
设计、地点和参与者：这项对 Ritux3 试验的事后分析于 2010 年 1 月至 2015 年 12 月在法国的 25 个皮肤科部门进行，纳入了 42 名中重度天疱疮患者，他们被随机分配接受 RTX 治疗。另外招募了 5 名患者进行辅助研究。根据患者是否存在 ARAs，比较了初始 RTX 治疗周期后达到 CR 或复发的患者比例。
患者在第 1 天和第 15 天接受 1000 mg 的 RTX 治疗，在第 12 个月和第 18 个月接受 2 次 500 mg 的维持输注。
第 36 个月时的复发率和持续 CR。测量 ARAs、抗桥粒芯糖蛋白 1/3 抗体、RTX 血清浓度和外周血 CD19+B 细胞频率。
在有 vs 无 ARAs 的 42 名参与者中，平均（SD）年龄分别为 55（17）岁和 56（17）岁，分别有 25（59.5%）名女性。在第 1 年内，42 名患者中有 13 名（31%）血清样本中检测到抗利妥昔单抗抗体。由于接受了额外的输注，无法进一步分析，因此排除了 9 名在第 12 个月前复发的患者。在其余 33 名患者中，2 名（6.1%）在第 12 个月后复发，31 名（95.9%）在第 36 个月时持续 CR。是否存在 ARAs（13 名中有 11 名 [85%]）并不影响持续 CR 的发生率（20 名中有 20 名 [100%]）（P = .15）。两组（ARA+与 ARA-）的 CD19+B 细胞耗竭和 RTX 水平也相似，但与无 ARAs 的患者相比，有 ARAs 的患者的抗桥粒芯糖蛋白 3 抗体（DSG3 Abs）水平更高（平均[SD]，30.1[50.9] AU/mL 比 4.0[4.3] AU/mL；P = .03）。在第 12 个月后复发的 2 名有 ARAs 的患者中，RTX 水平无法检测到，B 细胞不完全耗竭，抗 DSG3 Abs 水平高于 11 名持续有 ARAs 且 CR 的患者（RTX 平均[SD]浓度，0ug/mL 比 12.5[2.2]ug/mL；P = .03；不完全 B 细胞耗竭，2 名中有 2 名，11 名中有 4 名；P = .19；平均[SD]抗 DSG3 Abs 水平，103.5[61.5] AU/mL 比 19.5[11.0] AU/mL；P = .001），或无 ARAs 的患者（平均[SD]RTX 浓度，0ug/mL 比 13.5[1.8]ug/mL；P = .02；不完全 B 细胞耗竭，2 名中有 2 名，20 名中有 5 名；P = .09；平均[SD]抗 DSG3 Abs 水平，103.5[61.5] AU/mL 比 4.0[1.0] AU/mL；P < .001）。
这项队列研究的结果表明，接受 RTX 治疗的天疱疮患者中经常检测到 ARAs，一般与患者结局无关。只有少数同时存在 ARAs、低 RTX 浓度、不完全 B 细胞耗竭和持续血清抗 DSG3 Abs 的患者似乎有很高的复发风险。
