Digital ulcers and cutaneous subsets of systemic sclerosis: Clinical, immunological, nailfold capillaroscopy, and survival differences in the Spanish RESCLE Registry

https://doi.org/10.1016/j.semarthrit.2016.04.007Get rights and content

Abstract

Objective

Digital ulcers (DU) are the most common vascular complication of systemic sclerosis (SSc). We compared the characteristics between patients with prior or current DU with those never affected and evaluated whether a history of DU may be a predictor of vascular, organ involvement, and/or death in patients with SSc.

Methods

Data from SSc patients with or without prior or current DU were collected by 19 referral centers in an ongoing registry of Spanish SSc patients, named Registro de ESCLErodermia (RESCLE). Demographics, organ involvement, autoimmunity features, nailfold capillary pattern, survival time, and causes of death were analyzed to identify DU related characteristics and survival of the entire series and according to the following cutaneous subsets—diffuse cutaneous SSc (dcSSc), limited cutaneous SSc (lcSSc), and SSc sine scleroderma (ssSSc).

Results

Out of 1326, 552 patients enrolled in the RESCLE registry had prior or current DU, 88% were women, the mean age was 50 ± 16 years, and the mean disease duration from first SSc symptom was 7.6 ± 9.6 years. Many significant differences were observed in the univariate analysis between patients with and without prior/current DU. Multivariate analysis identified that history of prior/current DU in patients with SSc was independently associated to younger age at SSc diagnosis, diffuse cutaneous SSc, peripheral vascular manifestations such Raynaud’s phenomenon, telangiectasia, and acro-osteolysis but no other vascular features such as pulmonary arterial hypertension or scleroderma renal crisis. DU was also associated to calcinosis cutis, interstitial lung disease, as well as worse survival. Multivariate analysis performed in the cutaneous subsets showed that prior/current DU were independently associated: (1) in dcSSc, to younger age at SSc diagnosis, presence of telangiectasia and calcinosis and rarely a non-SSc pattern on nailfold capillaroscopy; (2) in lcSSc, to younger age at SSc diagnosis, presence of Raynaud’s phenomenon as well as calcinosis cutis, interstitial lung disease, and higher incidence of death from all causes; and (3) in ssSSc, to younger age at first SSc symptom and greater incidence of death from all causes.

Conclusions

Digital ulcers develop in patients with SSc younger at diagnosis, mainly in patients with dcSSc and lcSSc, and they are associated to other peripheral vascular manifestations such as Raynaud’s phenomenon, telangiectasia, and acro-osteolysis but also to calcinosis, and interstitial lung disease. History of DU in SSc leads to worse survival, also noticeable for lcSSc and ssSSc subsets but not for dcSSc patients.

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.

Section snippets

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.

References (39)

  • M. Baron et al.

    Consensus opinion of a North American Working Group regarding the classification of digital ulcers in systemic sclerosis

    Clin Rheumatol

    (2014)
  • I. Mouthon et al.

    Impact of digital ulcers on disability and health-related quality of life in systemic sclerosis

    Ann Rheum Dis

    (2010)
  • C. Mihai et al.

    Digital ulcers predict a worse disease course in patients with systemic sclerosis

    Ann Rheum Dis

    (2015)
  • B.C. LeRoy et al.

    Criteria for the classification of early systemic sclerosis

    J Rheumatol

    (2001)
  • C.P. Simeón-Aznar et al.

    Systemic sclerosis sine scleroderma and limited cutaneous systemic sclerosis: similarities and differences

    Clin Exp Rheumatol

    (2014)
  • H. Poormoghim et al.

    Systemic sclerosis sine scleroderma: demographic, clinical and serologic features and survival in forty-eight patients

    Arthritis Rheum

    (2000)
  • No authors listed

    Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee

    Arthritis Rheum

    (1980)
  • F. van den Hoogen et al.

    classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative

    Arthritis Rheum

    (2013)
  • C.P. Simeon et al.

    Mortality and prognostic factors in Spanish patients with systemic sclerosis

    Rheumatology (Oxford)

    (2003)
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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.

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