Systemic sclerosis: Current concepts of skin and systemic manifestations
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).
References (231)
Scleroderma epidemiology
Rheum Dis Clin
(2003)Autoantibodies in systemic sclerosis
Semin Arthritis Rheum
(2005)Natural history of systemic sclerosis and the assessment of disease activity, severity, functional status, and psychologic well-being
Rheum Dis Clin N Am
(2003)- et al.
Orofacial manifestations of scleroderma. A literature review
Rev Stomatol Chir Maxillofac Chir Orale
(2016) - et al.
Calcinosis is associated with digital ulcers and osteoporosis in patients with systemic sclerosis: A Scleroderma Clinical Trials Consortium study
Semin Arthritis Rheum
(2016) - et al.
Hand radiological damage in systemic sclerosis: Comparison with a control group and clinical and functional correlations
Semin Arthritis Rheum
(2011) - et al.
Ultrastructure and three-dimensional reconstruction of several macular and papular telangiectases
J Invest Dermatol
(1983) - et al.
The impact of pain and itch on functioning and health-related quality of life in systemic sclerosis: An exploratory study
J Pain Symptom Manag
(2016) - et al.
A new skin manifestation of progressive systemic sclerosis
J Am Acad Dermatol
(1984) - et al.
Mortality and survival in systemic sclerosis: Systematic review and meta-analysis
Semin Arthritis Rheum
(2014)
Skin ulcers in systemic sclerosis: Determinants of presence and predictive factors of healing
J Am Acad Dermatol
Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population
Arthritis Rheum
Race and association with disease manifestations and mortality in scleroderma
Medicine (Baltimore)
A gender gap in primary and secondary heart dysfunctions in systemic sclerosis: A EUSTAR prospective study
Ann Rheum Dis
Racial differences in scleroderma among women in Michigan
Arthritis Rheum
Gender and ethnicity differences in the prevalence of scleroderma-related autoantibodies
Clin Rheumatol
Gender and ethnicity differences in patients with diffuse systemic sclerosis—analysis from three large randomized clinical trials
Rheumatology (Oxford)
A clinical and serologic comparison of African American and Caucasian patients with systemic sclerosis
Arthritis Rheum
Childhood onset systemic sclerosis: Classification, clinical and serologic features, and survival in comparison with adult onset disease
J Rheumatol
Cutaneous manifestations of scleroderma and scleroderma-like disorders: A comprehensive review
Clin Rev Allergy Immunol
2013 classification criteria for systemic sclerosis: An american college of rheumatology/European league against rheumatism collaborative initiative
Arthritis Rheum
Progress in understanding the diagnostic and pathogenic role of autoantibodies associated with systemic sclerosis
Curr Opin Rheumatol
Autoantibody profiles in systemic sclerosis: Predictive value for clinical evaluation and prognosis
J Dermatol
Incidence and predictors of cutaneous manifestations during the early course of systemic sclerosis: A 10-year longitudinal study from the EUSTAR database
Ann Rheum Dis
Systemic sclerosis: Demographic, clinical, and serologic features and survival in 1,012 Italian patients
Medicine (Baltimore)
One decade distinct features, morbidity and mortality of scleroderma: A cross-sectional study
Clin Exp Rheumatol
Evolution of primary raynaud’s phenomenon (raynaud’s disease) to connective tissue disease
Arthritis Rheum
Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud’s phenomenon to systemic sclerosis: A twenty-year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosi
Arthritis Rheum
Preliminary analysis of the Very Early Diagnosis of Systemic Sclerosis (VEDOSS) EUSTAR multicentre study: Evidence for puffy fingers as a pivotal sign for suspicion of systemic sclerosis
Ann Rheum Dis
Natural history of ischemic digital ulcers in systemic sclerosis: Single-center retrospective longitudinal study
J Rheumatol
Clinical risk assessment of organ manifestations in systemic sclerosis: A report from the EULAR Scleroderma Trials and Research group database
Ann Rheum Dis
Digital ulcers: Overt vascular disease in systemic sclerosis
Rheumatology (Oxford)
Demographic, clinical and antibody characteristics of patients with digital ulcers in systemic sclerosis: data from the DUO Registry
Ann Rheum Dis
Functional impairment of systemic scleroderma patients with digital ulcerations: Results from the DUO registry
Clin Exp Rheumatol
Measuring disease activity and functional status in patients with scleroderma and Raynaud’s phenomenon
Arthritis Rheum
A prospective study of systemic sclerosis-related digital ulcers: prevalence, location, and functional impact
Scand J Rheumatol
Associations with digital ulcers in a large cohort of systemic sclerosis: Results from the canadian scleroderma research group registry
Arthritis Care Res
Capillaroscopic skin ulcer risk index: A new prognostic tool for digital skin ulcer development in systemic sclerosis patients
Arthritis Care Res
Predictive role of capillaroscopic skin ulcer risk index in systemic sclerosis: a multicentre validation study
Ann Rheum Dis
Prediction risk chart for scleroderma digital ulcers: A composite predictive model based on capillaroscopic, demographic and clinico-serological parameters
Clin Hemorheol Microcirc
Nailfold capillaroscopy for day-to-day clinical use: construction of a simple scoring modality as a clinical prognostic index for digital trophic lesions
Ann Rheum Dis
Improvement in skin thickening in systemic sclerosis associated with improved survival
Arthritis Rheum
Natural history of mild-moderate pulmonary hypertension and the risk factors for severe pulmonary hypertension in scleroderma
J Rheumatol
The natural course of progressive systemic sclerosis patients with interstitial lung involvement
Clin Rheumatol
A systematic review of the epidemiology, disease characteristics and management of systemic sclerosis in Australian adults
Int J Rheum Dis
Skin thickness score as a predictor and correlate of outcome in systemic sclerosis: High-dose versus low-dose penicillamine trial
Arthritis Rheum
Inter and intraobserver variability of total skin thickness score (Modified Rodnan TSS) in systemic sclerosis
J Rheumatol
Daily activities and hand function in women with scleroderma
Scand J Rheumatol
The frequency of sicca symptoms and Sjogren’s syndrome in patients with systemic sclerosis
Int J Rheum Dis
Increased incidence of carcinoma of the tongue in patients with systemic sclerosis
J Rheumatol
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2023, Journal of AutoimmunityCitation Excerpt :Similar to catapol, sirolimus also restores the Tfh/Tfr cell ratio and brings the disease activity of pSS under control [107]. SSc is characterized by skin fibrosis, microangiopathy and autoantibody production [117–119]. In SSc patients, Tfh cell infiltration can be found in their skin lesions, and Tfh cells may promote skin fibrosis through IL-21 and matrix metalloproteinase 12 (MMP12)-dependent mechanisms [120].
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2022, Autoimmunity ReviewsCitation Excerpt :The disease is cutaneous and affects a variety of organs [1,2], and almost all patients exhibit Raynaud's phenomenon [3]. Although its etiology remains poorly understood, generally, the pathological course of SSc mainly includes microvascular damage, inflammation, and immune abnormalities [4,5]. The immune system, especially the cell-mediated immune response, plays a leading role in the pathogenesis of SSc, and the excessive activation of T cells, especially CD4+ T cells, is a key factor in the occurrence and development of SSc vascular disease, fibrosis, and humoral immunity (Fig. 1).