Department of Rheumatology, IDIPHISA, Puerta de Hierro - Segovia de Arana Health Research Institute, Majadahonda, Madrid, Spain.
Department of Rheumatology, University Hospital Rey Juan Carlos, Móstoles, Madrid, Spain.
Int J Rheum Dis. 2019 Aug;22(8):1529-1537. doi: 10.1111/1756-185X.13607. Epub 2019 May 22.
Tumor necrosis factor inhibitors (TNFi) are effective in controlling disease activity in spondyloarthritis (SpA). However, in a proportion of patients these treatments are ineffective or lead to adverse events. Recently, alternative therapies, such as interleukin (IL)-17 or IL-23 inhibitors, have emerged in the treatment of these pathologies. This study aimed to determine clinical and genetic predictors of non-response to TNFi treatment in 118 spondyloarthritis patients diagnosed according to Assessment in SpondyloArthritis International Society (ASAS) criteria.
From the literature, 41 single nucleotide polymorphisms (SNPs) were selected that had previously been associated with TNFi treatment response in spondyloarthropathies, rheumatoid arthritis and psoriasis. A clinical non-response was defined as a decrease of <50% of initial Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in axial involvement, or a reduction of less than 1.2 of initial Disease Activity Score of 28 joints-C-reactive protein (DAS28-CRP) in patients with only peripheral involvement. Univariate and multivariate hazard ratios (HR) were determined using Cox proportional hazard models to analyze the potential prognostic factors affecting non-response to TNFi treatment.
The clinical factors that significantly increased the non-response rate were: global visual analog scale (VAS), CRP, BASDAI, Bath Ankylosing Spondylitis Functional Index (BASFI), and the number of TNFi used. Only rs11591741 SNP showed an association with non-response. In the multivariate analysis, females had a non-response rate 4.46 times higher than males; each one-point increase in the BASFI index increased the non-response rate by 75%, and being a genotype GG vs GC or CC carrier was associated with an almost 4 times greater non-response rate.
We developed a clinical-genetic model to identify SpA patients with a long-term non-response to TNFi therapy.
肿瘤坏死因子抑制剂（TNFi）在控制脊柱关节炎（SpA）的疾病活动方面是有效的。然而，在一部分患者中，这些治疗方法无效或导致不良反应。最近，在这些疾病的治疗中出现了替代疗法，如白细胞介素（IL）-17 或 IL-23 抑制剂。本研究旨在确定根据评估强直性脊柱炎国际协会（ASAS）标准诊断的 118 例 SpA 患者对 TNFi 治疗无反应的临床和遗传预测因子。
从文献中选择了 41 个单核苷酸多态性（SNP），这些 SNP 先前与脊柱关节病、类风湿关节炎和银屑病的 TNFi 治疗反应有关。临床无反应定义为初始 Bath 强直性脊柱炎疾病活动指数（BASDAI）在轴性受累方面的下降<50%，或在仅有外周受累的患者中初始 28 关节 C 反应蛋白（DAS28-CRP）降低小于 1.2。使用 Cox 比例风险模型确定单变量和多变量风险比（HR），以分析影响 TNFi 治疗无反应的潜在预后因素。
显著增加无反应率的临床因素是：总体视觉模拟评分（VAS）、CRP、BASDAI、Bath 强直性脊柱炎功能指数（BASFI）和使用的 TNFi 数量。只有 rs11591741 SNP 与无反应相关。在多变量分析中，女性的无反应率是男性的 4.46 倍；BASFI 指数每增加 1 分，无反应率增加 75%，而 GG 基因型与 GC 或 CC 基因型携带者相比，无反应率增加近 4 倍。
我们开发了一种临床-遗传模型，以识别对 TNFi 治疗长期无反应的 SpA 患者。
