Elsevier

Clinics in Dermatology

Volume 36, Issue 4, July–August 2018, Pages 459-474
Clinics in Dermatology

Systemic sclerosis: Current concepts of skin and systemic manifestations

https://doi.org/10.1016/j.clindermatol.2018.04.004Get rights and content

Abstract

Systemic sclerosis is an uncommon autoimmune connective tissue disease with multiorgan system involvement and significant associated morbidity and mortality. Cutaneous signs and clinical manifestations are of particular importance, as they may be recognized before systemic manifestations, allowing earlier risk stratification into the limited and diffuse cutaneous subtypes, as well as earlier initiation of treatment. Important cutaneous manifestations include Raynaud’s phenomenon, digital ulcers, cutaneous sclerosis, calcinosis cutis, telangiectasias, pruritus, and dyspigmentation. Despite investigation of a wide variety of treatments, no FDA-approved pharmacologic therapies exist for systemic sclerosis, and data from high-quality studies are limited. In the following review, we will discuss skin-directed therapies. Although there is evidence to support specific treatments for Raynaud’s phenomenon, digital ulcers, and cutaneous sclerosis, there are limited rigorous studies evaluating the treatment of other cutaneous signs and clinical manifestations. Additional randomized-controlled trials and large observational studies are necessary to develop future evidence-based treatment options.

Introduction

Systemic sclerosis (SSc) is a chronic autoimmune connective tissue disease (CTD) characterized most commonly by Raynaud’s phenomenon (RP), skin sclerosis, and proximal nailfold changes, and may affect internal organs such as the lungs, gastrointestinal tract, and kidneys. Clinically, patients can be subdivided into limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc). Classification is important, because dcSSc has a worse overall prognosis. The etiology of SSc is unclear, but cardinal features include microvascular disease, extracellular matrix deposition, and immune activation.

SSc has a prevalence of 240 per million and an incidence rate of approximately 20 per million per year.[1], [2] It affects women at a rate of 4.5-fold higher than men, although men have an increased risk of pulmonary arterial hypertension (PAH), the diffuse cutaneous subtype, digital ulcers (DUs), and heart failure.[1], [3], [4] Black patients are affected at nearly twice the rate of white patients and have an earlier onset, more severe cutaneous and systemic disease, and increased mortality even after controlling for sex, disease subtype, antibody status, and socioeconomic measures.[3], [4], [5], [6], [7], [8] Pediatric patients account for less than 5% of all cases and have better survival, but they have higher rates of overlap syndromes as well as skeletal muscle and cardiac involvement.9

Given the significant morbidity and mortality associated with SSc, early recognition and treatment is critical. Cutaneous signs and clinical manifestations are of particular importance in diagnosis, because they are the earliest, most frequent, and most characteristic manifestations.10 This affords dermatologists a unique opportunity to diagnose patients and assist in coordinating multidisciplinary care. In the following review, we focus on the cutaneous manifestations and treatments of SSc.

Section snippets

Classification

Most studies used the 1980 American College of Rheumatology (ACR) classification criteria until it was replaced by the 2013 ACR-European League Against Rheumatism (EULAR) classification criteria. Both criteria use skin thickening of the fingers of both hands extending proximal to metacarpals as sufficient for SSc classification; however, the 1980 criteria were based on sequelae of disease, whereas the newer 2013 criteria are more sensitive and specific, allowing for additional patients to

Nomenclature

Historically, SSc was referred to as “scleroderma” and morphea was referred to as “localized scleroderma;” however, the current preferred terminology is “systemic sclerosis,” to highlight the affected internal organ systems and “morphea.” This distinct terminology further emphasizes that these two conditions are not on a continuum. SSc is subdivided into lcSSc and dcSSc based upon the clinical phenotype. Subclassification carries prognostic significance, but clinical phenotype is not determined

Autoantibody status

Autoantibody testing is an appropriate prognostic consideration in SSc. Autoantibodies are typically mutually exclusive and are associated with specific phenotypes. The most common autoantibodies in SSc include anticentromere, anti-Scl-70 (antitopoisomerase I), and the nucleolar autoantibodies: anti-Th/To, anti-U1-RNP (antifibrillarin), and anti-PM-Scl in lcSSc, and anti-RNA-polymerase III and anti-U3-RNP in dcSSc.[13], [14]

Raynaud’s phenomenon

RP is characterized by triphasic discoloration due to vasospasm, with initial blanching due to vasoconstriction, progression to painful purple-blue cyanosis, and resolution with red hyperemia (Figure 1a). It is usually induced by cold stimuli and localized symmetrically over the digits of the hands but may involve other acral sites, such as the toes, ears, and nose. RP is present in more than 95% of SSc patients and is often the earliest cutaneous sign.[16], [17] Only a small percentage of

Prognosis

SSc overall has a poor prognosis, with a mortality rate more than 2.7 times higher than sex- and age-matched controls.69 It is greater in dcSSc than in lcSSc.70 Mortality is most often due to cardiopulmonary involvement (including ILD and PAH), with cumulative survival after diagnosis of 74.9% at 5 years and 62.5% at 10 years.[69], [70], [71] Quality of life has repeatedly been shown to be lower among SSc patients than the general population.[72], [73], [74] There are also high direct and

Treatment of cutaneous manifestations

Treatment of SSc has been disappointing, with relatively few randomized-controlled trials (RCTs), and so much of the current evidence is based on observational studies and expert opinion. The recent 2017 EULAR recommendations,76 as well as the 2016 British Society for Rheumatology and British Health Professionals in Rheumatology (BSR/BHPR) guidelines,77 provide valuable insight into treatment considerations for both cutaneous and systemic disease. In the following sections, data from RCTs will

Conclusions

SSc is a chronic autoimmune CTD that requires a coordinated, multidisciplinary approach to care. Due to a preponderance of cutaneous manifestations, particularly early in the course of disease, dermatologists have the distinct opportunity to diagnose and initiate treatment for these patients, and to address and treat the cutaneous manifestations of SSc. Although there are strong data to support treatment modalities for RP, DUs, and both early or advanced cutaneous sclerosis, there is a paucity

Acknowledgment

This work was supported by the United States Department of Veterans Affairs (Veterans Health Administration, Office of Research and Development and Biomedical Laboratory Research and Development).

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