Dear Editor,

We read with great interest the article by Chevalier et al. recently published in the Journal of Internal Medicine, which explores the clinical trajectory of 330 patients with mixed connective tissue disease (MCTD) [1]. This multicenter retrospective study demonstrated that only 85 (25.6%) patients evolved toward a diagnostic of another CTD, the most represented CTD being systemic sclerosis (SSc) in 52 patients (15.8%) according to the ACR/EULAR 2013 classification criteria. Based on this result, the authors concluded that “MCTD is a distinct entity.” The strength of this study is the exclusion of patients fulfilling criteria for other CTDs at baseline. Nonetheless, the way the ACR/EULAR 2013 classification criteria were used in this study could be questioned. In the absence of proximal skin thickening, the ACR/EULAR 2013 classification criteria for SSc includes seven additive items with varying weights for each: skin thickening of the fingers (sclerodactyly four points or puffy fingers two points), fingertip lesions (digital ulcers two points, pitting scars three points), telangiectasia (two points), abnormal nailfold capillaries (two points), interstitial lung disease or pulmonary arterial hypertension (two points), Raynaud's phenomenon (three points), and SSc-related autoantibodies (three points) [2]. The total score is determined by adding the maximum weight in each category. Patients with a total score of ≥9 are classified as having definite SSc. Based on this classification, almost no U1-RNP patients can obtain the three points for autoantibodies, as only anti-centromere, anti-topoisomerase, and anti-RNA polymerase III antibodies are included in this classification. Because autoantibodies are mutually exclusive in SSc, the positivity for SSc-related antibody is largely unlikely—although not impossible, as suggested by the two patients with anti-centromere antibodies—in the case of U1-RNP positivity. To reach the nine point-threshold, U1-RNP patients needed to have many SSc-related clinical manifestations, even more SSc-related clinical manifestations than a patient with definite SSc and SSc-specific antibodies as defined in the ACR-EULAR classification criteria for SSc. Therefore, one could argue that at least six points based on non-immunological parameters from the classification criteria for SSc should be sufficient to be classified as SSc in a population of U1-RNP patients (e.g., Raynaud's phenomenon, SSc-capillaroscopic landscape, and ILD; or Raynaud's phenomenon and pitting scars), because such patients may only lack the three points from SSc-specific autoantibodies to reach nine points and to be classified as SSc. Before concluding that “MCTD is a distinct entity,” we would suggest, (1) assessing the prevalence of patients with six points from the classification criteria for SSc in this large population of 330 MTCD patients and (2) comparing the clinical trajectories of these “SSc-like” U1-RNP patients to patients with definite SSc with other antibody subtypes (from historical cohorts). If the natural history of “SSc-like” U1-RNP patients and definite SSc patients is comparable, we may conclude that the nosology of MCTD and SSc should be reframed and U1-RNP considered in an updated classification of SSc [3, 4]. In other words, if their clinical presentation is similar and the only difference is the antibody subtype, should we not lump these disorders within the same nosological entity, with a common name—that is, SSc? [5] The cohort from Chevalier et al. offers a unique opportunity to explore this question and to enrich the debate on the existence of MCTD as a distinct entity [6, 7].

亲爱的编辑，

我们饶有兴趣地阅读了 Chevalier 等人的文章。最近发表在《内科杂志》上，探讨了 330 名混合性结缔组织病（MCTD）患者的临床轨迹[ 1 ]。这项多中心回顾性研究表明，根据 ACR/EULAR 2013 年分类标准，只有 85 名 (25.6%) 患者发展为另一种 CTD 诊断，其中 52 名患者 (15.8%) 中最具代表性的 CTD 是系统性硬化症 (SSc)。基于这一结果，作者得出结论：“MCTD 是一个独特的实体。” 这项研究的优势在于排除了基线时满足其他 CTD 标准的患者。尽管如此，本研究中使用 ACR/EULAR 2013 分类标准的方式可能会受到质疑。在没有近端皮肤增厚的情况下，ACR/EULAR 2013 SSc 分类标准包括七个附加项目，每个项目的权重不同：手指皮肤增厚（指端硬化 4 分或手指浮肿 2 分）、指尖病变（手指溃疡 2 分） 、凹陷性疤痕三分）、毛细血管扩张（两分）、甲襞毛细血管异常（两分）、间质性肺疾病或肺动脉高压（两分）、雷诺现象（三分）和SSc相关自身抗体（三分）[ 2]。总分是通过将每个类别中的最大权重相加来确定的。总分≥9的患者被归类为具有明确的SSc。根据该分类，几乎没有U1-RNP患者可以获得自身抗体三分，因为该分类仅包括抗着丝粒、抗拓扑异构酶和抗RNA聚合酶III抗体。由于 SSc 中的自身抗体是相互排斥的，因此在 U1-RNP 阳性的情况下，SSc 相关抗体呈阳性的可能性很大，尽管并非不可能，正如两名具有抗着丝粒抗体的患者所暗示的那样。为了达到九点阈值，U1-RNP 患者需要有许多 SSc 相关临床表现，甚至比 ACR-EULAR 分类标准中定义的具有明确 SSc 和 SSc 特异性抗体的患者有更多的 SSc 相关临床表现。科学硕士。因此，有人可能认为，基于 SSc 分类标准中的非免疫学参数，至少有 6 个点足以在 U1-RNP 患者群体中被分类为 SSc（例如，雷诺现象、SSc 毛细血管镜景观和ILD；或雷诺现象和凹陷性疤痕），因为此类患者可能只缺少 SSc 特异性自身抗体的 3 分，达到 9 分并被归类为 SSc。在得出“MCTD 是一个独特实体”的结论之前，我们建议，(1) 在 330 名 MTCD 患者的庞大人群中评估 SSc 分类标准中得分为 6 分的患者的患病率，以及 (2) 比较这些患者的临床轨迹“SSc 样”U1-RNP 患者到具有其他抗体亚型（来自历史队列）的明确 SSc 患者。如果“SSc 样”U1-RNP 患者和明确的 SSc 患者的自然史具有可比性，我们可以得出结论，应该重新构建 MCTD 和 SSc 的疾病分类，并在更新的 SSc 分类中考虑 U1-RNP [3, 4 ] 。换句话说，如果它们的临床表现相似，唯一的区别是抗体亚型，我们是否应该将这些疾病归入同一疾病分类实体中，并使用一个共同的名称，即 SSc？[ 5 ]Chevalier 等人的队列。提供了一个独特的机会来探索这个问题并丰富关于 MCTD 作为一个独特实体是否存在的辩论 [ 6, 7 ]。