Digital ulcers and cutaneous subsets of systemic sclerosis: Clinical, immunological, nailfold capillaroscopy, and survival differences in the Spanish RESCLE Registry
Introduction
Systemic sclerosis (SSc) is a chronic autoimmune systemic disease characterized by skin and visceral fibrosis with a proliferative and obstructive vasculopathy of small blood vessels. A growing body of evidence supports the role of the microvasculopathy as the primary pathogenetic event mediated by autoimmunity [1], [2], [3]. Raynaud’s phenomenon (RP) is a reversible vascular hyperreactivity that affects early and almost universally SSc patients. Unlike primary RP, vascular dysfunction that characterizes SSc includes capillary loss, vascular remodeling, and progressive narrowing of the lumen of small arteries evolving to skin ischemia [3], [4]. Persistent digital ischemia may lead to digital ulcers (DU) that occur rather early in the course of the illness [5], [6] and thus they may be a good candidate as predictor of clinical evolution. Up to 63% of SSc patients develop DU, depending on the clinical subtype, and its occurrence has been identified as predictor of organ involvements and disease worsening [5], [7], [8], [9], [10]. However, despite its great incidence, information about clinical, immunological, and capillaroscopic features, as well as survival of SSc patients who experienced at least one digital ulcer during the course of the disease is heterogeneous.
The present report is a cross-sectional analysis of SSc patients enrolled in the first ongoing nationwide registry by the RESCLE investigators. The objectives of our study were to compare the clinical characteristics and prognosis of SSc patients with prior or current digital ulcers with those never affected by digital ulcers and to compare both groups of patients according to their cutaneous subsets. By understanding the SSc features associated with digital ulcers, clinicians may be better able to stratify risk patients and understand the burden of digital ulcers in this disease. We used a modification of the classification proposed by LeRoy and Medsger [11] on three subsets but patients with SSc sine scleroderma (ssSSc) were considered separately because ssSSc patients have lesser incidence of DU than lcSSc patients, as shown in previous studies [8], [12], [13]. No data are currently available on the characteristics of patients with or without history of DU of these four differentiated SSc subsets in a large population of patients.
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Patients and methods
The Spanish Scleroderma Study Group (SSSG) was created by the Spanish Internal Medicine Society in 2006 with the aim of compiling a large series of patients with SSc in a registry named RESCLE (Registro de ESCLErodermia as Spanish nomenclature). A total of 19 Spanish centers with substantial experience in the management of these patients participated in the recruitment of 1326 SSc patients up to September 2013. All participating centers obtained the Ethics Committee approval. To avoid excluding
Variable definitions
We used the following definitions.
Prior or current digital ulcers
Presence of active DU or a history of DU related to digital ischemia. Ulcers overlying bony prominence secondary to trauma at the site of joint contractions, areas of calcium extrusion and skin fissures were not included.
SSc onset (first symptom)
The date of the first self-reported symptom (Raynaud’s phenomenon in the majority of patients).
SSc diagnosis
The date when the patient fulfilled the 1980 ACR preliminary classification criteria [14] or the modified classification proposed by LeRoy and Medsger [11].
Peripheral vascular manifestations
Defined by the presence of
Nailfold capillaroscopy
Nailfold capillaroscopy was carried out in each participating center following the recommendations of the Working Group for the Study of Capillaroscopy (GREC), sponsored by the Autoimmune Diseases Study Group (GEAS), available from http://www.capilaroscopia.es/#/. Capillaroscopy images of the nailfold bed of the second to fifth fingers of both hands were obtained by ×80–200 magnification lenses. Nailfold beds presenting trauma, microtrauma, or severe digital ischemia phenomena were disregarded.
Characteristics of SSc patients with and without prior/current digital ulcers
Baseline demographic and clinical characteristics for the entire SSc group (n = 1326), according to the presence (n = 552, 41.6%) and absence (n = 774, 58.4%) of prior/current of DU are shown in Table 1. Digital ulcers history was more frequent in dcSSc than in lcSSc patients, and in both subsets more frequent than in ssSSc patients, as shown in Figure 1. In addition, the elapsed time from first SSc symptom to the DU appearance and SSc diagnosis was lesser in dcSSc patients compared to lcSSc
Discusion
In this cross-sectional analysis of 1326 SSc patients recruited in a large ongoing Spanish multicenter registry named RESCLE, prior or current DU were recorded in 41.6% of the series. By univariate analysis of the database, many differences have been identified between patients with or without history of DU including peripheral and visceral vascular manifestations, organ involvements, immunologic profile, capillaroscopy patterns, and prognosis. However, multivariate analysis only confirmed that
Acknowledgments
The authors acknowledge the RESCLE investigators; the RESCLE Registry Coordinating Center, S&H Medical Science Service, for their quality control, logistic, and administrative support; and Prof. Salvador Ortiz, Universidad Autónoma de Madrid and Statistical Advisor S&H Medical Science Service, for the statistical analysis of the data presented in this article.
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This project was funded by an unrestricted educational scholarship granted by Laboratorios Actelion. Actelion had no access to the data of the RESCLE Registry database. The authors have no conflicts of interest to disclose.