The skin is the most common organ system involved in patients with systemic sclerosis (SSc). Nearly all patients experience cutaneous symptoms, including sclerosis, Raynaud’s phenomenon, digital ulcers, telangiectasias, and calcinosis. In addition to posing functional challenges, cutaneous symptoms are often a major cause of pain, psychological distress, and body image dissatisfaction. The present article reviews the main features of SSc-related cutaneous manifestations and highlights an evidence-based treatment approach for treating each manifestation. This article also describes novel treatment approaches and opportunities for further research in managing this important clinical dimension of SSc.
Key points
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The hallmark of systemic sclerosis (SSc) is cutaneous sclerosis, affecting nearly all patients with this rare and debilitating autoimmune disorder.
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Patients with SSc are classified based on the distribution of cutaneous involvement (ie, limited vs diffuse), and this distinction has important clinical implications.
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Existing treatment options for diffuse cutaneous SSc-cutaneous sclerosis include methotrexate, cyclophosphamide, and hematopoietic stem cell transplantation. Less evidence exists for treatment of limited cutaneous LcSSc-cutaneous sclerosis.
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All SSc patients experience Raynaud’s phenomenon. After general preventative measures are taken, calcium channel blockers, prostacyclin analogs, and phosphodiesterase type 5 inhibitors are often used.
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A paucity of evidence is available for the management of digital ulcers, cutaneous telangiectasias, calcinosis, and pigment changes.
Introduction
Virtually all patients with systemic sclerosis (SSc) experience cutaneous sclerosis and Raynaud’s phenomenon (RP), although substantial variability in the presentation and severity of these cutaneous manifestations exist. Moreover, many patients with SSc exhibit varying degrees of additional and often disabling cutaneous manifestations, such as digital ulcers (DU), cutaneous telangiectasias, calcinosis, and pigment changes. The inherent heterogeneity in these cutaneous manifestations complicates strategies for improving patient care, as well as clinical trial design. This review examines skin changes in SSc and how to manage them.
Introduction
Virtually all patients with systemic sclerosis (SSc) experience cutaneous sclerosis and Raynaud’s phenomenon (RP), although substantial variability in the presentation and severity of these cutaneous manifestations exist. Moreover, many patients with SSc exhibit varying degrees of additional and often disabling cutaneous manifestations, such as digital ulcers (DU), cutaneous telangiectasias, calcinosis, and pigment changes. The inherent heterogeneity in these cutaneous manifestations complicates strategies for improving patient care, as well as clinical trial design. This review examines skin changes in SSc and how to manage them.
Symptoms
Skin Sclerosis
The hallmark of SSc is skin thickening and hardening. Symptoms usually first develop in the fingers and hands. Many patients experience nonpitting edema, erythema, and pruritus before the development of skin induration. Subsequently, the skin becomes firm and taut, adhering to deeper structures and limiting movement ( Fig. 1 ). The presence of skin thickening of the fingers extending proximally to the metacarpophalangeal joints is characteristic of SSc and alone is sufficient to classify a patient as having SSc.
As the disease progresses, the epidermis of the skin atrophies, leading to impaired hair growth and decreased sweating (ie, anhydrosis). Normal skin creases vanish, and the skin can seem to be shiny and undergo pigmentary changes. The combination of atrophy and sclerosis overflexed joints combined with a vasculopathy and dermal inflammation can cause ulceration and a reactive hyperkeratosis. The majority of patients have facial skin sclerosis, producing characteristic changes around the mouth, including increased furrowing of the skin around the lips, recession of the lips, and decreased oral aperture.
The distribution of cutaneous involvement has been classically based on the maximum extent of skin involvement. In patients with diffuse cutaneous SSc (DcSSc), skin thickening occurs proximally to the elbows or knees (as well as finger/hand involvement), and often involves the trunk, whereas in patients with limited cutaneous SSc (LcSSc), skin thickening is confined to the distal extremities, or may only affect the fingers (ie, sclerodactyly; Fig. 2 ). Facial involvement is common and contributes to neither classification nor prognosis. The distinction between limited and diffuse cutaneous involvement has prognostic implications for patients. In fewer than 5% of patients, there is no skin thickening and these patients are classified as SSc sine skin sclerosis/scleroderma.
Nonsclerotic Skin Manifestations
The key nonsclerotic features of SSc are summarized in Table 1 .
| Symptom | Overall Prevalence in SSc | Distribution | Onset of Timing |
|---|---|---|---|
| Raynaud’s phenomenon | >95% overall | Hands, usually asymmetric initially ( Fig. 3 ) | LcSSc: Can precede skin sclerosis by several years DcSSc: Usually precedes onset of skin sclerosis by <1 y |
| Ischemic ulceration | LcSSc: ∼38% DcSSc: ∼50% | Digital tips most common ( Fig. 4 ); Also occurs on extensor surfaces of joints | LcSSc or DcSSc: Finger tip ulcers associated with vasculopathy so may occur early or late |
| Calcinosis | LcSSc: ∼40% DcSSc: ∼24% | Fingers most common ( Fig. 5 ); also commonly occurs around trauma sites, such as elbows, knees, buttocks, feet | LcSSc: Usually the product of damaged tissue in the presence of vasculopathy, so often late, but can occur early DcSSc: Typically late-stage disease |
| Telangiectasia | LcSSc: ∼85% DcSSc: ∼84% | Fingers, lips, and face most common | LcSSc and DcSSc: Late-stage disease more common, but can occur early |
| Pigment changes | Majority of both LcSSc and DcSSc (more easily seen in Hispanics and African Americans) | Hyperpigmentation: Face, lower abdomen and thighs most common Acanthosis nigricans-like changes: Flexure surfaces Vitiligo-like loss of pigment Perifollicular distribution common (salt and pepper) | LcSSc: Typically late-stage disease DcSSc: Typically late-stage disease |
| Cutaneous vasculitis with ulceration | More common in LcSSc | Palpable purpura: Lower extremities Deep ulcerations: Lower extremities | LcSSc and DcSSc: Typically late stage disease |
Diagnosis
Physical Examination
The diagnosis of SSc is usually made on clinical grounds, with supporting laboratory studies. Skin thickening is easily detectable on physical examination and can be reasonably quantified using the validated modified Rodnan skin score (mRSS). Skin thickness at 17 anatomic sites is assessed by palpation and rated on a scale of 0 (normal), 1 (mild), 2 (moderate), or 3 (severe) skin thickening (see Fig. 2 ). The total skin score is the sum of the individual skin assessments and the within-patient variability in scoring is approximately 5 units. The minimal, clinically discernible difference is 4 to 5.1. Ultrasound approaches are being tested, but are not yet validated.
Nonsclerotic skin manifestations (see Table 1 ), such as digital tip ulcers, RP, and telangiectasias, can support a diagnosis of SSc, as documented by the 2013 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) SSc criteria. In addition, enlarged capillaries and/or capillary dropout with or without pericapillary hemorrhages may be appreciated at the nailfold and may predict future organ involvement, although there remains much to be done in this area.
Histopathology of Skin Biopsies
Skin biopsy is performed only in cases of diagnostic uncertainty. Early in the disease, skin histopathology may illustrate perivascular T lymphocytes/monocytes infiltrates and thickened collagen bundles in the deep dermis. With disease progression, the epidermis atrophies and the dermis accumulates compact hyalinized collagen bundles, fibronectin, and other structural matrix proteins. Late skin lesions demonstrate a paucity of dermal inflammatory cells and capillaries. Moreover, collagen may replace fat cells in the subcutaneous tissue.
Differential Diagnosis
Although the new ACR/EULAR classification system for SSc has an improved sensitivity and specificity compared with the previous 1980 ACR preliminary criteria, with sensitivity of 91% and specificity of 92%, skin thickening is a common feature of several other inflammatory and immune-mediated diseases. The pattern of skin involvement, combined with salient features of the patient’s past medical history and exposures, can help to discern the underlying cause of skin thickening ( Table 2 ). Notably, the presence of RP is usually absent in SSc mimics (with rare exception in scleromyxedema). Additional diseases, which are not presented in Table 2 , can have associated skin sclerosis; these conditions are usually diagnosed based on the patient history (eg, amyloidosis, overlap connective tissue diseases, necrobiosis diabeticorum, chronic graft-versus-host disease, sarcoidosis, myxedema, porphyria cutanea tarda, acromegaly), followed by appropriate laboratory testing.
| Disease | Distribution of Skin Thickening | Appearance | Key Dermal Histopathology | Associated Conditions |
|---|---|---|---|---|
| Scleromyxedema | Head, neck, upper trunk, forearm, hands, thighs | Waxy, closely spaced papules | Increased mucin, collagen, fibroblasts | Monoclonal gammopathy (especially immunoglobulin G lambda) |
| Scleroderma | Neck, upper back, shoulders | Erythematous induration | Increased mucin, collagen | Monoclonal gammopathy; diabetes mellitus; postinfectious |
| Morphea | Localized, linear, deep, or generalized | Erythematous plaque→ hyperpigmented or hypopigmented | Increased collagen (no increase in mucin) | None |
| Nephrogenic systemic sclerosis | Starts distally and spreads proximally (spares face) | Peau d’orange; cobblestone | Increased mucin, collagen, fibroblasts | Renal insufficiency with gadolinium exposure |
| Eosinophilic fasciitis | Proximal extremities (spares hands, feet) | Rapid swelling→ Peau d’orange; groove sign | Increased eosinophils in the deep dermis and fascia | Antecedent vigorous exercise Cytopenias, aplastic anemia |
Natural History
Although there is variability in the natural history of SSc skin disease, characteristic patterns are found for DcSSc and LcSSc and are outlined.
Diffuse Cutaneous Involvement
In patients with DcSSc, rapid and intense increases in skin thickening are observed early in the disease course, peaking 1 to 3 years after disease onset. Skin thickening commences distally and progresses proximally to the forearms, arms, and legs, and occasionally the trunk, within several months. The onset of RP typically precedes the development of skin changes by 1 year or less in patients with diffuse skin disease and may even start after the onset of skin thickening.
A single-center, observational study characterized the progression of skin disease in DcSSc patients (n = 826). The authors calculated the skin thickness progression rate (STPR) by dividing the mRSS at the first clinical visit by the duration, in years, from when the patient reported or a physician judged/recorded the onset of skin thickening. The study demonstrated that patients with a rapid STPR (defined as ≥40 units/y) had a higher median total skin score and a shorter interval between the onset of skin thickening and their first clinical visit compared with patients with an intermediate (15–40 units/y) or slow (<15 units/y) STPR. Moreover, rapid STPR was found to be an independent predictor of both mortality (odds ratio, 1.72; P = .01) and renal crisis (odds ratio, 2.05; P = .02) within 2 years from first evaluation.
Cutaneous improvement most often occurs first in the areas that were last affected (ie, trunk, abdomen, upper arms). Despite regression of skin thickening in proximal areas, finger and joint contractures often persist. Improvements in skin thickening have been associated with improved survival in observational cohorts.
Limited Cutaneous Involvement
In general, the rate of STPR is much slower in LcSSc compared with DcSSc. The onset of RP typically precedes the development of skin changes by several years (occasionally decades) in patients with LcSSc. In the early stages of limited disease, puffy hands predominate. As skin thickening progresses, involvement remains confined to the hands, distal forearms, lower legs, and feet, with or without the face. Late-stage LcSSc is typically characterized by no further skin thickening, but is often associated with additional skin changes, including the development of subcutaneous calcinosis, digital tip ischemia, and telangiectasias. Occasionally, palpable purpura can occur when vasculitis develops. Visceral involvement can and does occur, particularly in the gastrointestinal tract and lungs, but it tends to occur later in the disease.
Management of skin sclerosis
Existing Therapies
Methotrexate
A folate analog originally designed to inhibit dihydrofolate reductase, methotrexate (MTX) has been used extensively for the treatment of rheumatoid arthritis since the 1950s. Concerns regarding pulmonary fibrosis may have hindered the introduction of MTX into the SSc clinical research arena. However, encouraging observations from small, uncontrolled studies in the early 1990s led to the development of the first randomized, controlled trial (RCT) of MTX in SSc. In this study of patients with both LcSSc (n = 18) and DcSSc (n = 11), there was a trend for an improvement in skin score in patients treated with weekly MTX at 24 weeks ( P = .06).
A study of 71 patients with early (<3 years disease duration) DcSSc found that between-group differences for changes in skin score at 12 months favored MTX (change in mRSS was -4.3 in the MTX group vs 1.8 in the placebo group [ P <.009]). However, this study observed the greatest difference in skin scores between the treatment and placebo groups early in the trial (3 months), and the difference decreased with time. A follow-up analysis of these data using a Bayesian statistical approach demonstrated that MTX had a 90.4% probability of improving skin scores in DcSSc.
The EULAR and the European Scleroderma Trials and Research Group (EUSTAR) have recommended that MTX be considered for treatment of sclerosis in early DcSSc. Safety concerns regarding the development of pulmonary fibrosis with MTX use have not been substantiated, although this issue has not been formally and systematically addressed.
Practice tip: Consider using MTX for early diffuse skin disease in SSc.
Cyclophosphamide
Although cyclophosphamide (CYC) has been predominantly studied in the context of SSc-associated interstitial lung disease (ILD), this alkylating agent may have beneficial effects on SSc-cutaneous sclerosis. For example, in the Scleroderma Lung Study (SLS) I, 158 SSc patients with both LcSSc and DcSSc (<7 years from first non-Raynaud’s SSc manifestation), were randomized to treatment with daily oral CYC (up to 2 mg/kg per day) for 12 months versus placebo. Patients with DcSSc randomized to CYC had an improvement in mRSS of -5.3 at 12 months, whereas the patients in the placebo group had an improvement in mRSS of only -1.7 at 12 months ( P = .008). For an additional 6 months after stopping the CYC, skin continued to improve. However, beyond that point, skin rapidly worsened so that by 24 months, there was no difference between CYC and placebo ( P = .23). Although not proven, it is tempting to allow patients to use CYC for a year, stop the drug for some period of time and then consider retreating when skin worsens (personal opinion).
The potential benefits of CYC in treating DcSSc are tempered by the plethora of adverse effects associated with CYC use. One of the most potent immunosuppressive drugs used in rheumatology, CYC can cause serious and life-threatening adverse effects. However, examination of the SLS I study comparing CYC with placebo, showed only increases in neutropenia and infections with very few cases of hematuria or other significant adverse effects during the 12-month trial (including no differences in death or cancer). Notably, this study did not follow patients over then long term, so it did not address the incidence of long-term cancers, which have been documented when using CYC. Most experts consider using CYC for diffuse cutaneous disease only when ILD is also present.
Practice tip: Consider using CYC for patients with early DcSSc when concurrent, clinically significant ILD is present. It should not be considered as the first drug of choice secondary to its potential toxicities.
Autologous hematopoietic stem cell transplantation
Hematopoietic stem cell transplantation (HSCT) has recently emerged as a potentially effective treatment option for carefully selected patients with progressive DcSSc with a poor prognosis. To date, nearly all experience is with autologous HSCT. Early trials demonstrated the feasibility of autologous HSCT in DcSSc and found a significant reduction in mRSS. The improvement in mRSS seems to be sustained based on an observational study of 26 transplanted SSc patients followed for 7 years after HSCT. The Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial was the first phase III RCT designed to compare the efficacy and safety of autologous HSCT versus monthly intravenous CYC for 12 months. This 29-center European study included 156 patients with DcSSc (<4 years duration) and without serious comorbidities. In the first year, mortality was higher in the HSCT group (8 treatment-related deaths), compared with the CYC group (no treatment-related deaths); however, the HSCT group experienced statistically better event-free survival; events included need for dialysis and need for oxygen, and so on (median follow-up time was 5.8 years). The mean improvement in mRSS from baseline to 24 months was greater in the HSCT group (a decrease of 19.9 in the mRSS) than in the control group (a decrease of 8.8; P <.001). Results of the North American phase III RCT (Scleroderma: Cyclophosphamide Or Transplantation, or SCOT trial) are awaiting publication. Future studies are needed to evaluate long-term potential HSCT-related complications (ie, infertility, secondary autoimmune disease, and malignancy), to determine the appropriate timing of HSCT, and to optimize the patient selection criteria to minimize early HSCT-related mortality.
Practice tip: Consider referral for HSCT in patients with DcSSc with poor prognosis, for whom the duration of nonsevere internal organ involvement is less than 4 years and for whom conventional therapies have failed. This should be considered a third-line therapy only.
Ineffective Therapies
Several RCTs and open-label trials have investigated the efficacy of additional experimental agents for the treatment of skin sclerosis in early stage DcSSc. These agents failed to demonstrate a beneficial effect on skin disease outcomes and/or were not tolerated:
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N -Acetylcysteine,
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d -Penicillamine,
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Anti-transforming growth factor β-1 antibody,
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Recombinant human relaxin,
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Interferon alpha,
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Imatinib, and
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Bosentan.
Questionable Therapies
These studies demonstrated negative findings:
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Tumor necrosis factor inhibitors, and
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Oral type I collagen ; post hoc analysis demonstrated cutaneous improvement in patients with late dsSSc.
Experimental Therapies
Advances toward understanding the pathogenesis of SSc-cutaneous sclerosis have augmented the arsenal of candidate therapies for this devastating illness. Diverse molecular targets are presently under preclinical and clinical evaluation.
B-cell target therapies
Previous studies have demonstrated an increased number of B cells in the skin of SSc patients, and that B-cell depletion reduces skin fibrosis in mouse models. To this end, clinical studies have investigated the safety and efficacy of the anti-CD20 antibody, rituximab. Three open-label studies of rituximab in SSc patients, one of which showed a significant decrease in hyalinized collagen content and myofibroblast positivity, demonstrated that rituximab may improve the mRSS. These findings indicate that rituximab needs to be further tested in controlled studies.
Interleukin-6
Evidence suggests that the pleiotropic cytokine, interleukin (IL)-6, is overexpressed in the skin of patients with SSc, and may play a unique role in moderating endothelial cell dysfunction and fibrogenesis in this disease. This has led to 2 open-label trials of tocilizumab, the humanized monoclonal antibody to the IL-6 receptor. An uncontrolled EUSTAR observational study of 15 SSc patients with arthritis did not show a significant improvement in the mRSS after treatment with tocilizumab after 5 months. However, the primary endpoint for this study was arthritis. Moreover, this study included patients with both LcSSc and DcSSc. An 83-patient, placebo-controlled, multicenter, phase 2 RCT recently demonstrated favorable trends in skin score and lung function at 24 weeks (although the primary skin score endpoint was not met). A fully powered phase 3 trial is clearly needed.
Intravenous immunoglobulin
A paucity of evidence supports the use of intravenous immunoglobulin for SSc. Studies suggest that intravenous immunoglobulin administration is associated with fibrosis resorption in a variety of immune disorders. A small study of 15 patients with both LcSSc and DcSSc demonstrated that monthly intravenous immunoglobulin infusions (2 g/kg infused over a 5-day period for 6, 4, or 3 cycles) was associated with a significant decrease in mRSS of 35% ( P <.001). Future RCTs are necessary to determine whether this intervention is beneficial.
Mycophenolate mofetil
Mycophenolate mofetil (MMF) is the prodrug to mycophenolic acid, which reversibly inhibits inosine monophosphate dehydrogenase, thereby impairing purine synthesis and lymphocyte proliferation. MMF has both antifibrotic and immunomodulatory effects in animals and may improve skin sclerosis in DcSSc. Thus far, only open-label trials or observational studies have been published. Two small, open-label trials showed significant skin improvements in DcSSc. The Medoza and colleagues study also found a decrease in the abundance and thickness of collagen bundles in the dermis in 3 patients who underwent histopathological skin examination before and after MMF treatment.
Although no RCT of MMF in SSc have been published, a large, double-blind multicenter, RCT comparing CYC with MMF for the treatment of SSc-ILD (SLS II) is underway and the results of this study should be available in the second or third quarter of 2015; it will undoubtedly include an examination of the skin. At present, MMF is considered a second-line medication for the treatment of DcSSc.
Hyperimmune caprine serum
Hyperimmune caprine serum (AIMSPRO, Anti-inflammatory IMmuno -Suppressive PROduct) is a novel, therapeutic product that primarily contains caprine immunoglobulins, but also consists of cytokines IL-4 and IL-10, propiomelanocortin, arginine vasopressin, β-endorphin, and corticotropin-releasing factor. In a very small (n = 20), double-blind, placebo-controlled, parallel group study of late-stage DcSSc patients, subjects were randomized to receive 1 mL of AIMSPRO or placebo subcutaneously twice weekly for 6 months. The mean mRSS decreased by only 1.4 units in the AIMSPRO group, whereas it increased by 2.1 units in the placebo group. A secondary responder analysis revealed a clinically meaningful improvement in mRSS at 26 weeks in 5 actively treated patients (50%) compared with 1 (10%) in the control group ( P = .06). No additional trials of AIMSPRO in SSc have been published to date.
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