Bellando-Randone Silvia, Del Galdo Francesco, Lepri Gemma, Minier Tunde, Huscher Dörte, Furst Daniel E, Allanore Yannick, Distler Oliver, Czirják László, Bruni Cosimo, Guiducci Serena, Avouac Jerome, Cutolo Maurizio, Smith Vanessa, Matucci-Cerinic Marco
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Department of Geriatric Medicine, Division of Rheumatology and Scleroderma Unit, Azienda Ospedaliero Universitaria Careggi, Florence, Italy.
Raynaud's and Scleroderma Programme, National Institute for Health Research Biomedical Research Centre, Leeds, UK; Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and NIHR Biomedical Research Centre, Chapel Allerton Hospital, Leeds, UK.
Lancet Rheumatol. 2021 Dec;3(12):e834-e843. doi: 10.1016/S2665-9913(21)00244-7.
Preliminary criteria for the very early diagnosis of systemic sclerosis (VEDOSS) have been previously proposed to identify signs and symptoms in patients with Raynaud's phenomenon. Patients with all signs or symptoms of the VEDOSS criteria already fulfil the 2013 American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) classification criteria for systemic sclerosis. However, prospective data for the evolution to fulfilling these criteria do not exist. We therefore aimed to determine the clinical value of the VEDOSS criteria to identify patients with Raynaud's phenomenon who progress to systemic sclerosis within 5 years.
The VEDOSS project was a multicentre, longitudinal registry study done in 42 European Scleroderma Trial and Research group centres located in 20 countries in Europe, North America, and South America. Patients with Raynaud's phenomenon were eligible for enrolment. Those who had fulfilled the 1980 ACR or the 2013 ACR-EULAR classification criteria for systemic sclerosis, as well as of any other ACR or EULAR classification criteria for other definite connective tissue diseases at enrolment were excluded. Data were recorded each year during follow-up visits and included the four VEDOSS criteria (ie, positivity for antinuclear antibodies [ANAs], puffy fingers, systemic sclerosis-specific autoantibodies, and abnormal nailfold capillaroscopy). The primary endpoint was the fulfilment of the 2013 ACR-EULAR classification criteria for systemic sclerosis (ie, progression from enrolment to follow-up). Proportion of progressors and VEDOSS criteria interaction were reported descriptively. Predictors of progression of the distinct VEDOSS criteria interactions were determined based on the point prevalence at 5 years. To investigate the intermediate course of progression of the distinct VEDOSS criteria and their combinations, Kaplan-Meier analysis was done.
Between March 1, 2010, and Oct 4, 2018, we enrolled 1150 patients with Raynaud's phenomenon in the VEDOSS database. 764 (66·4%) of 1150 patients met the VEDOSS criteria for study inclusion. Of the 764 patients, 553 (72·4%) had at least one available follow-up visit and the median duration of follow-up was 3·6 years (IQR 1·7-5·8). The mean age was 45·9 years (SD 15·0), 507 (91·7%) of 553 participants were female, and the median time since the onset of Raynaud's phenomenon was 4·0 years (IQR 1·7-10·0). At baseline, 401 (73·7%) of 544 patients with Raynaud's phenomenon had detectable ANA, with 208 (39·5%) of 527 patients positive for systemic sclerosis-specific autoantibodies. Nailfold capillaroscopy abnormalities were present in 182 (36·0%) of 505 patients and puffy fingers were detected in 96 (17·8%) of 540 at baseline. 1885 follow-up visits were recorded. 254 (45·9%) of 553 patients completed the study with progression or a 5-year follow-up; of whom, 133 reached the primary endpoint, resulting in an overall progression rate of 52·4%. The absence of ANA at baseline was the factor most strongly associated with a lack of progression within 5 years, with only four (10·8%) of 37 ANA-negative patients progressing. Conversely, positivity at baseline for systemic sclerosis-specific autoantibodies and puffy fingers was the combination having the highest risk of progression (16 [94·1%] of 17).
Our results from the VEDOSS project offers a useful tool for a stratified risk approach to patients with Raynaud's phenomenon. The absence of ANA is a strong protective factor that identifies patients with very low risk of developing systemic sclerosis whereas the presence of one or two VEDOSS criteria in patients with Raynaud's phenomenon confers a progressively higher risk for systemic sclerosis over time. This stratification tool can be used both for clinical management and to inform early interventional trials.
European Scleroderma Trial And Research and World Scleroderma Foundation.
先前已提出系统性硬化症极早期诊断的初步标准（VEDOSS），以识别雷诺现象患者的体征和症状。符合VEDOSS标准所有体征或症状的患者已满足2013年美国风湿病学会-欧洲抗风湿病联盟（ACR-EULAR）系统性硬化症分类标准。然而，目前尚无关于达到这些标准进展情况的前瞻性数据。因此，我们旨在确定VEDOSS标准对识别5年内进展为系统性硬化症的雷诺现象患者的临床价值。
VEDOSS项目是一项多中心纵向登记研究，在位于欧洲、北美和南美20个国家的42个欧洲硬皮病试验与研究组中心开展。有雷诺现象的患者符合入组条件。排除入组时已满足1980年ACR或2013年ACR-EULAR系统性硬化症分类标准，以及其他任何ACR或EULAR其他明确结缔组织病分类标准的患者。随访期间每年记录数据，包括四个VEDOSS标准（即抗核抗体[ANA]阳性、手指肿胀、系统性硬化症特异性自身抗体及甲襞毛细血管镜异常）。主要终点是满足2013年ACR-EULAR系统性硬化症分类标准（即从入组到随访的进展）。描述性报告进展者比例和VEDOSS标准相互作用情况。根据5年时的点患病率确定不同VEDOSS标准相互作用进展的预测因素。为研究不同VEDOSS标准及其组合的进展中间过程，进行了Kaplan-Meier分析。
2010年3月1日至2018年10月4日，我们将1150例雷诺现象患者纳入VEDOSS数据库。1150例患者中有764例（66.4%）符合研究纳入的VEDOSS标准。在这764例患者中，553例（72.4%）至少有一次可用的随访，随访中位持续时间为3.6年（IQR 1.7 - 5.8）。平均年龄为45.9岁（标准差15.0），553例参与者中有507例（91.7%）为女性，自雷诺现象发作以来的中位时间为4.0年（IQR 1.7 - 10.0）。基线时，544例雷诺现象患者中有401例（73.7%）ANA可检测到，527例患者中有208例（39.5%）系统性硬化症特异性自身抗体阳性。505例患者中有182例（36.0%）甲襞毛细血管镜异常，540例中有96例（17.8%）在基线时检测到手指肿胀。记录了1885次随访。553例患者中有254例（45.9%）完成研究，有进展或进行了5年随访；其中，133例达到主要终点，总体进展率为52.4%。基线时ANA阴性是与5年内无进展最密切相关的因素，37例ANA阴性患者中只有4例（10.8%）进展。相反，基线时系统性硬化症特异性自身抗体阳性和手指肿胀是进展风险最高的组合（17例中有16例[94.1%]）。
我们VEDOSS项目的结果为雷诺现象患者的分层风险评估提供了一个有用的工具。ANA阴性是一个强有力的保护因素，可识别出发生系统性硬化症风险极低的患者，而雷诺现象患者中存在一或两个VEDOSS标准会随着时间推移使系统性硬化症风险逐渐升高。这种分层工具可用于临床管理并为早期干预试验提供信息。
欧洲硬皮病试验与研究及世界硬皮病基金会。
