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IF 15 1区医学 Q1 RHEUMATOLOGY

Lancet Rheumatology Pub Date : 2025-02-27 DOI:10.1016/S2665-9913(24)00348-5

Jerome Hadjadj, Anna Wolfers, Oleg Borisov, Derek Hazard, Ronan Leahy, Marie Jeanpierre, Alexandre Belot, Shahrzad Bakhtiar, Fabian Hauck, Pui Y Lee, Stephano Volpi, Serena Palmeri, Vincent Barlogis, Nathalie Aladjidi, Georg Ebetsberger-Dachs, Jerome Avouac, Fabienne Charbit-Henrion, Morgane Cheminant, Jean Donadieu, Sujal Ghosh, David P Hoytema van Konijnenburg, Julia Körholz, Jacinta Bustamante, Jeremie Rosain, Lisa Forbes Satter, Ingrid Selmeryd, Georgios Sogkas, Benedicte Neven, Frederic Rieux-Laucat, Stephan Ehl

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引用次数: 0

摘要

背景：细胞因子信号抑制因子 1（SOCS1）功能不全是一种先天性免疫错误，会影响细胞因子和生长因子信号的负调控。我们旨在进一步了解 SOCS1 基因缺陷患者的临床表现、疾病轨迹、疾病渗透率以及 Janus 激酶（JAK）抑制剂的效果：本研究使用了两个独立队列的数据：欧洲免疫缺陷协会（ESID）登记处和英国生物库。欧洲免疫缺陷协会登记处的参与者来自九个欧洲国家（奥地利、比利时、法国、德国、爱尔兰、意大利、葡萄牙、瑞典和乌克兰）、中国大陆、中国台湾和美国。如果ESID登记处的参与者具有杂合的、功能验证的SOCS1变异体，则符合条件；如果英国生物库的参与者具有在ESID登记处队列中检测到的任何SOCS1变异体或任何其他被归类为高影响的SOCS1变异体，则符合条件。英国生物样本库收集了参与者的 ICD-10 诊断代码，记录了潜在 SOCS1 功能不全的临床表现，并将其归纳为九个亚组。ESID登记处的参与者在当地实验室接受了相关自身抗体检测。ESID 登记参与者对 JAK 抑制剂治疗的反应由主治医生使用视觉模拟量表进行评估。分析采用描述性统计方法。有生活经验者未参与研究设计：我们纳入了 119 名 SOCS1 功能不全的参与者：67 名来自 ESID 登记处，登记时间为 2021 年 2 月 15 日至 2023 年 12 月 31 日，52 名来自英国生物库。在来自ESID登记处的67名参与者中，39人（58%）为女性，28人（42%）为男性，中位年龄为28岁（IQR 15-44，范围2-85）。在这些参与者中发现了 27 种不同的单并列 SOCS1 变异。在 ESID 登记队列的 67 名参与者中，62 人（93%）有症状，5 人（7%）为无症状的家庭成员；在 62 名有症状的参与者中，过敏（33 [50%]）、炎症性胃肠道（22 [36%]）和皮肤（18 [29%]）表现、自身免疫性全血细胞减少（24 [39%]）和淋巴细胞增生（23 [37%]）最为常见。风湿病表现（23 [37%]）包括系统性红斑狼疮、斯约格伦病和类风湿性关节炎，并伴有典型的自身抗体特征。在 62 名有症状的参与者中，42 人（68%）至少有三种不同的表现。在英国生物库中，我们发现了 52 名携带高影响 SOCS1 变异的参与者；其中 29 人（56%）为女性，23 人（44%）为男性，年龄中位数为 72 岁（65-78 岁，57-86 岁）。这些参与者中只有 30 人（58%）出现了可能与 SOCS1 功能不全有关的表现。与 ESID 登记相比，英国生物库的参与者中过敏和风湿病表现更为常见。英国生物库中有症状的参与者也以女性为主（30 名参与者中有 21 名[70%]为女性，9 名[30%]为男性）。在ESID登记的13名参与者中，12人（92%）接受了JAK抑制剂治疗，并取得了良好效果：解读：SOCS1功能不全与其他遗传性自身免疫淋巴细胞增生性疾病不同，它经常出现特应性和风湿病表现。发病率不完全，女性高于男性。对于SOCS1功能不全的患者，JAK抑制是一种很有前景的靶向疗法：德国研究基金会（DFG）。

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Clinical manifestations, disease penetrance, and treatment in individuals with SOCS1 insufficiency: a registry-based and population-based study.

Background: Suppressor of cytokine signalling 1 (SOCS1) insufficiency is an inborn error of immunity affecting the negative regulation of cytokine and growth factor signalling. We aimed to enhance the understanding of clinical manifestations, disease trajectories, disease penetrance, and the effect of Janus kinase (JAK) inhibition in individuals with SOCS1 insufficiency.

Methods: This study used data from two independent cohorts: the European Society for Immunodeficiencies (ESID) registry and the UK Biobank. Participants from the ESID registry were from nine European countries (Austria, Belgium, France, Germany, Ireland, Italy, Portugal, Sweden, and Ukraine), China, Taiwan, and the USA. Participants from the ESID registry were eligible if they had heterozygous, functionally validated SOCS1 variants; participants from the UK Biobank were included if they had any SOCS1 variant detected in the ESID registry cohort or any other SOCS1 variant that was classed as high-impact. Clinical manifestations of the underlying SOCS1 insufficiency were documented and summarised into nine subgroups, with ICD-10 diagnosis codes collected for participants from the UK Biobank. Participants from the ESID registry were tested for relevant autoantibodies in their local laboratory. Responses to JAK inhibitor treatment in participants from the ESID registry were assessed by the treating physician using a visual analogue scale. Descriptive statistics were used for analysis. People with lived experience were not involved in the study design.

Findings: We included 119 participants with SOCS1 insufficiency: 67 from the ESID registry, enrolled between Feb 15, 2021, and Dec 31, 2023, and 52 from the UK Biobank. Of the 67 participants from the ESID registry, 39 (58%) were female, 28 (42%) were male, and the median age was 28 years (IQR 15-44, range 2-85). 27 different monoallelic SOCS1 variants were identified in these participants. 62 (93%) of the 67 participants in the ESID registry cohort were symptomatic and five (7%) were asymptomatic family members; of the 62 participants with symptoms, allergy (33 [50%]), inflammatory gastrointestinal (22 [36%]) and skin (18 [29%]) manifestations, autoimmune cytopenia (24 [39%]), and lymphoproliferation (23 [37%]) were most frequent. Rheumatological manifestations (23 [37%]) included systemic lupus erythematosus, Sjögren's disease, and rheumatoid arthritis, with typical autoantibody profiles. 42 (68%) of the 62 symptomatic participants had at least three different manifestations. In the UK Biobank we found 52 participants carrying high-impact SOCS1 variants; 29 (56%) were female, 23 (44%) were male, and the median age was 72 years (65-78, 57-86). Only 30 (58%) of these participants had developed manifestations that were potentially related to SOCS1 insufficiency. Allergy and rheumatological manifestations were more common in participants from the UK Biobank than the ESID registry. Female predominance (21 [70%] of 30 participants were female and nine [30%] were male) was also found among symptomatic participants from the UK Biobank. Treatment with JAK inhibitors showed promising results in 12 (92%) of 13 participants in the ESID registry.

Interpretation: SOCS1 insufficiency differs from other genetic autoimmune lymphoproliferative disorders by the presence of frequent atopic and rheumatological manifestations. Penetrance is incomplete and is higher in females than in males. JAK inhibition is a promising targeted therapy for patients with SOCS1 insufficiency.

Funding: German Research Foundation (DFG).

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来源期刊

Lancet Rheumatology RHEUMATOLOGY-

CiteScore

34.70

自引率

3.10%

发文量

279

期刊介绍： The Lancet Rheumatology, an independent journal, is dedicated to publishing content relevant to rheumatology specialists worldwide. It focuses on studies that advance clinical practice, challenge existing norms, and advocate for changes in health policy. The journal covers clinical research, particularly clinical trials, expert reviews, and thought-provoking commentary on the diagnosis, classification, management, and prevention of rheumatic diseases, including arthritis, musculoskeletal disorders, connective tissue diseases, and immune system disorders. Additionally, it publishes high-quality translational studies supported by robust clinical data, prioritizing those that identify potential new therapeutic targets, advance precision medicine efforts, or directly contribute to future clinical trials. With its strong clinical orientation, The Lancet Rheumatology serves as an independent voice for the rheumatology community, advocating strongly for the enhancement of patients' lives affected by rheumatic diseases worldwide.