Hinchcliff Monique, Khanna Dinesh, De Lorenzis Enrico, Di Donato Stefano, Carriero Antonio, Ross Rebecca L, Huang Suiyuan, Aren Kathleen A, Bernstein Elana J, Carns Mary, Castelino Flavia V, Domsic Robyn T, Frech Tracy M, Gordon Jessica K, Hant Faye N, Shah Ami A, Shanmugam Victoria K, Steen Virginia D, Assassi Shervin, Del Galdo Francesco
Department of Internal Medicine, Section of Rheumatology, Allergy, and Immunology, Yale School of Medicine, New Haven, CT, USA.
Division of Rheumatology, Scleroderma Program, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Lancet Rheumatol. 2025 Jun;7(6):e403-e414. doi: 10.1016/S2665-9913(24)00403-X. Epub 2025 Mar 31.
Type I interferon (IFN) pathway activation has been associated with severe systemic sclerosis. We aimed to examine the association of serum IFN scores with disease activity and outcomes in two cohorts of patients with diffuse cutaneous systemic sclerosis.
In this retrospective cohort study, we included adult (aged >18 years) patients with diffuse cutaneous systemic sclerosis enrolled in the US Prospective Registry of Early Systemic Sclerosis (PRESS; incident cohort) or in the UK observational cohort (Stratification for Risk of Progression in Scleroderma [STRIKE]; prevalent cohort) registries and healthy controls (volunteers). Sera were analysed by Myriad-Rules Based Medicine's Luminex xMAP Technology Multiplex Assay (Austin, TX, USA), and IFN scores were generated using concentrations of CCL2, CCL8, CCL19, CXCL9, CXCL10, and CXCL11. Patients were classified as IFN-high (vs IFN-low) when mean sum of the natural logarithm of the six chemokines was greater than (or within) two standard deviations of healthy controls. The main outcome measures were the baseline and the minimal clinically important differences for modified Rodnan Skin Score, forced vital capacity (FVC), diffusing capacity for carbon monoxide (DLCO), and Health Assessment Questionnaire-Disability Index at 12 months. A person with lived experience of systemic sclerosis was involved in writing the report.
Patients with diffuse cutaneous systemic sclerosis in the PRESS incident cohort were recruited between April 1, 2012, and Jan 1, 2019, and healthy controls and patients in the STRIKE prevalent cohort were recruited between Dec 1, 2014, and Dec 1, 2018. IFN scores were generated for 110 patients in the incident cohort (mean age 50·2 years [SD 15·0], 76 [69%] women and 34 [31%] men, 87 [79%] White) and 72 patients in the prevalent cohort (mean age 51·7 years [SD 10·9], 50 [69%] women and 22 [31%] men, 64 [89%] White), and 32 healthy controls (mean age 47·0 years [SD 12·4]; 19 [59%] women and 13 [41%] men; 24 [75%] White). 50 (45%) of 110 patients in the incident cohort and 27 (38%) of 72 patients in the prevalent cohort were classified as IFN-high. In the incident cohort, patients classified as IFN-high had worse baseline disease compared with patients classified as IFN-low, as assessed by mean predicted FVC (72·0% [SD 18·9] vs 85·3% [18·5]; p=0·0028), DLCO (56·8% [SD 21·6] vs 76·6% [25·3]; p=0·0008), and median Health Assessment Questionnaire-Disability Index (1·4 [IQR 0·8-2·0] vs 0·8 [0·4-1·5]; p=0·0033). Differences in FVC and DLCO persisted at last follow-up (median 34 months [IQR 19·8- 54·0] for FVC and median 34 months [IQR 22·5- 54·0] for DLCO). In the prevalent cohort, patients classified as IFN-high had a shorter median disease duration (2·2 years [IQR 0·7-8·2] vs 5·0 years [1·9-10·0]; p=0·035) compared to those classified as IFN-low, and worse 12-month lung outcomes independent of baseline FVC or immunosuppression (5% relative worsening of FVC in nine [39%] of 23 patients with IFN-high vs seven [17%] of 41 patients with IFN-low; p=0·051). Moreover, cumulative 5-year mortality was 24·9% (95% CI 14·9-39·7) for IFN-high versus 8·6% (3·6-19·9) for IFN-low (p=0·052).
Serum IFN score assessment for patients with diffuse cutaneous systemic sclerosis could identify patients with high disease activity who are more likely to have worse 12-month prognosis and overall survival.
National Scleroderma Foundation, National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases Rheumatic Disease Research Core Centers, National Institute of Health Research Leeds Biomedical Research Centre, and Kennedy Trust for Rheumatology Research.
I型干扰素（IFN）通路激活与严重的系统性硬化症有关。我们旨在研究血清IFN评分与两个弥漫性皮肤系统性硬化症患者队列的疾病活动及预后之间的关联。
在这项回顾性队列研究中，我们纳入了美国早期系统性硬化症前瞻性注册研究（PRESS；新发队列）或英国观察性队列（硬皮病进展风险分层[STRIKE]；现患队列）注册研究中的成年（年龄>18岁）弥漫性皮肤系统性硬化症患者以及健康对照（志愿者）。血清通过Myriad基于规则医学的Luminex xMAP技术多重检测法（美国德克萨斯州奥斯汀）进行分析，并使用CCL2、CCL8、CCL19、CXCL9、CXCL10和CXCL11的浓度生成IFN评分。当六种趋化因子自然对数的平均总和大于（或在）健康对照的两个标准差之内时，患者被分类为IFN高（vs IFN低）。主要结局指标为改良Rodnan皮肤评分、用力肺活量（FVC）、一氧化碳弥散量（DLCO）的基线值以及12个月时的健康评估问卷残疾指数的最小临床重要差异。一名有系统性硬化症生活经历的人参与了报告撰写。
PRESS新发队列中弥漫性皮肤系统性硬化症患者于2012年4月1日至2019年1月1日入组，STRIKE现患队列中的健康对照和患者于2014年12月1日至2018年12月1日入组。为新发队列中的110名患者（平均年龄50.2岁[标准差15.0]，76名[69%]女性和34名[31%]男性，87名[79%]白人）、现患队列中的72名患者（平均年龄51.7岁[标准差10.9]，50名[69%]女性和22名[31%]男性，64名[89%]白人）以及32名健康对照（平均年龄47.0岁[标准差12.4]；19名[59%]女性和13名[41%]男性；24名[75%]白人）生成了IFN评分。新发队列中110名患者中的50名（45%）和现患队列中72名患者中的27名（38%）被分类为IFN高。在新发队列中，与IFN低分类的患者相比，IFN高分类的患者基线疾病更严重，通过平均预测FVC评估（72.0%[标准差18.9] vs 85.3%[18.5]；p=0.0028）、DLCO（56.8%[标准差21.6] vs 76.6%[25.3]；p=0.0008）以及健康评估问卷残疾指数中位数（1.4[四分位间距0.8 - 2.0] vs 0.8[0.4 - 1.5]；p=0.0033）。FVC和DLCO的差异在末次随访时仍然存在（FVC中位数34个月[四分位间距19.8 - 54.0]，DLCO中位数34个月[四分位间距22.5 - 54.0]）。在现患队列中，与IFN低分类的患者相比，IFN高分类的患者疾病持续时间中位数更短（2.2年[四分位间距0.7 - 8.2] vs 5.0年[1.9 - 10.0]；p=0.035），并且12个月时肺部结局更差，与基线FVC或免疫抑制无关（23名IFN高患者中有9名[39%]FVC相对恶化5%，而41名IFN低患者中有7名[17%]；p=0.051）。此外，IFN高患者的5年累积死亡率为24.9%（95%CI 14.9 - 39.7），而IFN低患者为8.6%（3.6 - 19.9）（p=0.052）。
对弥漫性皮肤系统性硬化症患者进行血清IFN评分评估可以识别出疾病活动度高且更有可能有更差的12个月预后和总体生存率的患者。
国家硬皮病基金会、美国国立卫生研究院国立关节炎和肌肉骨骼及皮肤病研究所风湿性疾病研究核心中心、英国国立卫生研究院利兹生物医学研究中心以及肯尼迪风湿病研究信托基金。
