Department of Dermatology, University of Rome Tor Vergata, Rome, Italy.
Br J Dermatol. 2013 Aug;169(2):458-63. doi: 10.1111/bjd.12331.
Our understanding of the genetic basis of predisposition to psoriasis is increasing exponentially due to the progress of genetic studies. However, so far little is known about genetic predisposition in relation to the response to psoriasis treatments. Recent data identified genetic predictors for the clinical outcome of conventional treatments such as methotrexate, acitretin and vitamin D derivatives, but few studies are available on genetic predictors of response to biologics. We hypothesized that genetic variations associated with increased risk of developing psoriasis may also act as predictors for the outcome of biologic therapy.
The aim of our study was to analyse the presence of three different psoriasis susceptibility genetic variations (HLA-Cw6; TNFAIP3 rs610604 polymorphism; LCE3B/3C gene deletions) in a cohort of patients affected by moderate to severe psoriasis under ustekinumab treatment. Our primary endpoint was to evaluate the association between Psoriasis Area and Severity Index (PASI) 75 response at week 12 and HLA-Cw6 status.
Fifty-one patients were genotyped by standard methods and psoriasis severity (PASI score) was evaluated at day 0 and after 4, 12, 24 and 40 weeks of treatment.
We observed increased response to ustekinumab in Cw6-positive (Cw6POS) patients [PASI 75 at week 12: 96·4% in Cw6POS vs. 65·2% in Cw6-negative (Cw6NEG) patients; P = 0·008]. In addition, we show that HLA-Cw6POS patients responded faster to ustekinumab, 89·3% of them reaching PASI 50 at week 4, after a single injection (vs. 60·9% of HLA-Cw6NEG patients). The superior response of HLA-Cw6POS patients was maintained throughout the study period, reaching the highest statistical significance for PASI 75 at week 28 (96·35% Cw6POS vs. 72·7% Cw6NEG; odds ratio 9·8). Analysis of TNFAIP3 rs610604 polymorphism and LCE3B/3C gene deletions did not show any significant association with response to ustekinumab.
Our observations underline the role of HLA-Cw6 not only as a psoriasis susceptibility gene, but also as a pharmacogenetic marker of response to ustekinumab in psoriasis.
由于遗传研究的进展，我们对银屑病易感性的遗传基础的理解呈指数级增长。然而，目前我们对银屑病治疗反应的遗传易感性知之甚少。最近的数据确定了传统治疗方法（如甲氨蝶呤、阿维 A 和维生素 D 衍生物）临床疗效的遗传预测因子，但关于生物制剂反应的遗传预测因子的研究很少。我们假设与银屑病发病风险增加相关的遗传变异也可能成为生物治疗疗效的预测因子。
本研究旨在分析中重度银屑病患者接受乌司奴单抗治疗时，三种不同的银屑病易感性遗传变异（HLA-Cw6；TNFAIP3 rs610604 多态性；LCE3B/3C 基因缺失）的存在情况。我们的主要终点是评估第 12 周时银屑病面积和严重程度指数（PASI）75 缓解与 HLA-Cw6 状态之间的关系。
采用标准方法对 51 例患者进行基因分型，并在治疗第 0 天及 4、12、24 和 40 周时评估银屑病严重程度（PASI 评分）。
我们观察到 Cw6 阳性（Cw6POS）患者对乌司奴单抗的反应增加[第 12 周时 PASI 75：Cw6POS 患者为 96.4%，Cw6 阴性（Cw6NEG）患者为 65.2%；P=0.008]。此外，我们还发现 HLA-Cw6POS 患者对乌司奴单抗的反应更快，89.3%的患者在单次注射后第 4 周达到 PASI 50（而 HLA-Cw6NEG 患者为 60.9%）。HLA-Cw6POS 患者的这种优势反应在整个研究期间得以维持，在第 28 周时达到 PASI 75 的最高统计学显著性（96.35% Cw6POS 对 72.7% Cw6NEG；比值比 9.8）。TNFAIP3 rs610604 多态性和 LCE3B/3C 基因缺失分析未显示与乌司奴单抗反应有任何显著相关性。
我们的观察结果强调了 HLA-Cw6 不仅作为银屑病易感基因的作用，而且作为银屑病对乌司奴单抗反应的药物遗传学标记的作用。
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