Regarding: Clinical presentation, course, and prognosis of patients with mixed connective tissue disease

Abstract

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].

The authors have no conflicts of interest to disclose.