Division of Dermatology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Division of Allergy, Immunology, and Rheumatology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Bangkok, Thailand.
Front Immunol. 2023 Mar 15;14:1138765. doi: 10.3389/fimmu.2023.1138765. eCollection 2023.
By depleting circulating B lymphocytes, rituximab time-dependently suppresses coronavirus disease 2019 (COVID-19) vaccines' humoral immunogenicity for a prolonged period. The optimal time to vaccinate rituximab-exposed immune-mediated dermatologic disease (IMDD) patients is currently unclear.
To estimate the vaccination timeframe that equalized the occurrence of humoral immunogenicity outcomes between rituximab-exposed and rituximab-naïve IMDD patients.
This retrospective cohort study recruited rituximab-exposed and age-matched rituximab-naïve subjects tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immunity post-vaccination. Baseline clinical and immunological data (i.e., immunoglobulin levels, lymphocyte immunophenotyping) and SARS-CoV-2-specific immunity levels were extracted. The outcomes compared were the percentages of subjects who produced neutralizing antibodies (seroconversion rates, SR) and SARS-CoV-2-specific IgG levels among seroconverters. The outcomes were first analyzed using multiple regressions adjusted for the effects of corticosteroid use, steroid-spearing agents, and pre-vaccination immunological status (i.e., IgM levels, the percentages of the total, naïve, and memory B lymphocytes) to identify rituximab-related immunogenicity outcomes. The rituximab-related outcome differences with a 95% confidence interval (CI) between groups were calculated, starting by including every subject and then narrowing down to those with longer rituximab-to-vaccination intervals (≥3, ≥6, ≥9, ≥12 months). The desirable cut-off performances were <25% outcome inferiority observed among rituximab-exposed subgroups compared to rituximab-naïve subjects, and the positive likelihood ratio (LR+) for the corresponding outcomes ≥2.
Forty-five rituximab-exposed and 90 rituximab-naive subjects were included. The regression analysis demonstrated a negative association between rituximab exposure status and SR but not with SARS-CoV-2-specific IgG levels. Nine-month rituximab-to-vaccination cut-off fulfilled our prespecified diagnostic performance (SR difference between rituximab-exposed and rituximab-naïve group [95%CI]: -2.6 [-23.3, 18.1], LR+: 2.6) and coincided with the repopulation of naïve B lymphocytes in these patients.
Nine months of rituximab-to-vaccination interval maximize the immunological benefits of COVID-19 vaccines while avoiding unnecessary delay in vaccination and rituximab treatment for IMDD patients.
通过耗尽循环中的 B 淋巴细胞，利妥昔单抗会在很长一段时间内时间依赖性地抑制新型冠状病毒病 2019（COVID-19）疫苗的体液免疫原性。目前尚不清楚利妥昔单抗暴露的免疫介导性皮肤病（IMDD）患者接种疫苗的最佳时间。
估计接种疫苗的时间框架，使利妥昔单抗暴露和利妥昔单抗未暴露的 IMDD 患者的体液免疫原性结果相等。
这项回顾性队列研究招募了利妥昔单抗暴露和年龄匹配的利妥昔单抗未暴露的患者，这些患者在接种疫苗后检测针对严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）的特异性免疫。提取基线临床和免疫学数据（即免疫球蛋白水平、淋巴细胞免疫表型）和 SARS-CoV-2 特异性免疫水平。比较的结果是产生中和抗体的患者比例（血清转化率，SR）和血清转化率中的 SARS-CoV-2 特异性 IgG 水平。首先使用多元回归分析来分析结果，该回归分析调整了皮质类固醇使用、类固醇增效剂以及接种前免疫状态（即 IgM 水平、总、幼稚和记忆 B 淋巴细胞的百分比）的影响，以确定与利妥昔单抗相关的免疫原性结果。计算了组间具有 95%置信区间（CI）的利妥昔单抗相关结局差异，并从纳入所有患者开始，然后缩小到具有更长利妥昔单抗至接种间隔（≥3、≥6、≥9、≥12 个月）的患者。将观察到的利妥昔单抗暴露亚组与利妥昔单抗未暴露组相比，结果劣于 25%的理想截断值作为利妥昔单抗暴露亚组的优势比（LR+）的标准，对于相应的结果为≥2。
共纳入 45 名利妥昔单抗暴露和 90 名利妥昔单抗未暴露的患者。回归分析表明，利妥昔单抗暴露状态与 SR 呈负相关，但与 SARS-CoV-2 特异性 IgG 水平无关。9 个月的利妥昔单抗至接种间隔符合我们预先指定的诊断性能（利妥昔单抗暴露组和利妥昔单抗未暴露组之间的 SR 差异[95%CI]：-2.6[-23.3，18.1]，LR+：2.6），并且与这些患者中幼稚 B 淋巴细胞的重新填充一致。
9 个月的利妥昔单抗至接种间隔可以最大限度地提高 COVID-19 疫苗的免疫效果，同时避免 IMDD 患者不必要地延迟接种和利妥昔单抗治疗。
