Objectives To maximize the cost-effectiveness of tofacitinib, one of Janus kinase inhibitors, there is an unmet need to identify predictors of therapeutic response. Utilizing phage immunoprecipitation sequencing (PhIP-Seq), we aim to identify peptide biomarkers for predicting good response to tofacitinib in rheumatoid arthritis (RA) patients. Methods We enrolled 106 patients who had received 24-week tofacitinib therapy, including twelve patients undergoing PhIP-Seq analysis in the discovery stage and ninety-four patients validated with enzyme-linked immunosorbent assay (ELISA) in the replication stage. Disease activity was assessed using the 28-joint disease activity score-erythrocyte sedimentation rate, and therapeutic response was evaluated using EULAR response criteria. Plasma levels of caspase-1 and IL-18 were determined using ELISA. Results PhIP-Seq analysis identified antibodies to sucrose non-fermenting-related kinase (SNRK) and HUWE1 (ubiquitin E3 ligase) as peptide biomarkers for discriminating good responders from the non-good responders. Using ELISA for validation on another cohort, an optimal cut-off value of anti-SNRK antibody for predicting good response was 0.381, with AUC 0.823, specificity 80.6%, and sensitivity 78.1% (p = 3.01E-07), and anti-HUWE1 antibody at 0.362, with AUC 0.740, specificity 74.2%, and sensitivity 62.5% (p < 0.001). Plasma levels of anti-SNRK and anti-HUWE1 antibodies were positively correlated with levels of caspase-1 and IL-18 (both p < 0.05). Multivariate logistic regression analysis revealed anti-SNRK antibody as a significant predictor of good therapeutic response. After tofacitinib therapy, anti-SNRK antibody levels significantly declined in good responders, but not in non-good responders. Conclusion We identify two peptide antibodies, anti-SNRK and anti-HUWE1 antibodies, as pretreatment predictors of good therapeutic response to tofacitinib in RA patients.

中文翻译：

---

抗肽抗体、抗 SNRK 和抗 HUWE1 抗体作为类风湿关节炎患者对托法替布治疗良好反应的潜在预测因子


目的 为了最大限度地提高托法替布（Janus 激酶抑制剂之一）的成本效益，确定治疗反应的预测因子的需求尚未得到满足。利用噬菌体免疫沉淀测序 （PhIP-Seq），我们的目标是确定用于预测类风湿性关节炎 （RA） 患者对托法替布的良好反应的肽生物标志物。方法 纳入 106 例接受 24 周托法替布治疗的患者，其中 12 例在发现期接受 PhIP-Seq 分析，94 例在复制期接受酶联免疫吸附测定 （ELISA） 验证的患者。使用 28 关节疾病活动评分-红细胞沉降率评估疾病活动度，并使用 EULAR 反应标准评估治疗反应。使用 ELISA 测定血浆 caspase-1 和 IL-18 水平。结果 PhIP-Seq 分析确定了针对蔗糖非发酵相关激酶 （SNRK） 和 HUWE1 （泛素 E3 连接酶） 的抗体作为区分良好反应者和非良好反应者的肽生物标志物。使用 ELISA 对另一个队列进行验证，抗 SNRK 抗体预测良好反应的最佳临界值为 0.381，AUC 为 0.823，特异性为 80.6%，敏感性为 78.1% （p = 3.01E-07），抗 HUWE1 抗体为 0.362，AUC 为 0.740，特异性为 74.2%，敏感性为 62.5% （p < 0.001）。血浆抗 SNRK 和抗 HUWE1 抗体水平与 caspase-1 和 IL-18 水平呈正相关 （均 p < 0.05）。多变量 logistic 回归分析显示，抗 SNRK 抗体是良好治疗反应的重要预测因子。托法替布治疗后，良好反应者的抗 SNRK 抗体水平显着下降，但非良好反应者的抗 SNRK 抗体水平没有下降。 结论 我们确定了两种肽抗体，抗 SNRK 和抗 HUWE1 抗体，作为 RA 患者对托法替布治疗反应良好的治疗前预测因子。