Centre for Musculoskeletal Research, The University of Manchester, Manchester, United Kingdom.
Centre for Musculoskeletal Research and NIHR Manchester Biomedical Research Centre, The University of Manchester, Manchester, United Kingdom.
Arthritis Rheumatol. 2024 Nov;76(11):1602-1610. doi: 10.1002/art.42942. Epub 2024 Jul 31.
Inhibitors of the interleukin 13 (IL-13) pathway, such as dupilumab, are licensed for atopic dermatitis and asthma. Adverse events resembling psoriatic disease after dupilumab initiation have been reported, but evidence is limited to case reports with uncertain causality. We aimed to investigate whether genetically mimicked IL-13 inhibition (IL-13i) is associated with risk of psoriatic arthritis (PsA) and psoriasis.
We instrumented IL-13i using a protein-coding variant in the IL13 gene, rs20541, that is associated with circulating eosinophil count (biomarker of IL-13i) at genome-wide significance in a study of 563,946 individuals. Outcome genetic data were taken from studies of PsA, psoriasis, and related spondyloarthritis traits in up to 10,588 cases and 209,287 controls. Colocalization analysis was performed to examine genetic confounding. We additionally used circulating IgE as a biomarker to test whether associations were replicated, both in the test and in an independent genetic dataset. We also replicated analyses using individual-level data from the UK Biobank.
Genetically proxied IL-13i was associated with increased risk of PsA (odds ratio [OR] 37.39; 95% confidence interval [95% CI] 11.52-121.34; P = 1.64 × 10) and psoriasis (OR 20.08; 95% CI 4.38-92.01; P = 1.12 × 10). No consistent associations were found for Crohn disease, ulcerative colitis, ankylosing spondylitis, or iritis. Colocalization showed no strong evidence of genetic confounding for psoriatic disease. Results were replicated using circulating IgE for the exposure, using independent outcome data and using individual-level data.
We provide supportive genetic evidence that IL-13i is linked to increased risk of PsA and psoriasis. Physicians prescribing IL-13 inhibitors should be vigilant for these adverse events.
白细胞介素 13（IL-13）通路抑制剂，如度普利尤单抗，已获批准用于治疗特应性皮炎和哮喘。在开始使用度普利尤单抗后，出现了类似于银屑病疾病的不良反应已有报道，但这些证据仅限于因果关系不确定的病例报告。我们旨在研究是否遗传模拟的白细胞介素 13 抑制（IL-13i）与银屑病关节炎（PsA）和银屑病的风险相关。
我们利用白细胞介素 13 基因中的一个编码蛋白变异体 IL13 基因中的 rs20541 来模拟 IL-13i，该变异体在一项对 563946 个人进行的研究中与循环嗜酸性粒细胞计数（IL-13i 的生物标志物）具有全基因组显著性关联。在多达 10588 例病例和 209287 例对照的 PsA、银屑病和相关脊柱关节炎特征的研究中获取了结果遗传数据。共定位分析用于检查遗传混杂。我们还使用循环 IgE 作为生物标志物来测试关联是否在测试和独立遗传数据集中得到复制。我们还使用英国生物银行的个体水平数据复制了分析。
遗传上接近的 IL-13i 与 PsA（优势比 [OR] 37.39；95%置信区间 [95%CI] 11.52-121.34；P = 1.64×10）和银屑病（OR 20.08；95%CI 4.38-92.01；P = 1.12×10）的风险增加相关。未发现克罗恩病、溃疡性结肠炎、强直性脊柱炎或虹膜炎的一致关联。共定位显示，银屑病疾病没有遗传混杂的强有力证据。使用暴露的循环 IgE、使用独立的结果数据和使用个体水平数据进行了复制。
我们提供了支持性的遗传证据，表明 IL-13i 与 PsA 和银屑病的风险增加相关。开处方使用白细胞介素 13 抑制剂的医生应警惕这些不良反应。
