INTRODUCTION — Systemic sclerosis (SSc; scleroderma) encompasses a spectrum of related disorders, most of which share a characteristic clinical feature of skin thickening due to an excess of collagen fibers. The simplest division of the scleroderma-related disorders is into localized (table 1) and systemic forms (table 2) (see "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults"). Patients with the systemic forms are more likely to have internal organ involvement, which is usually the target of therapy.
Differentiating between localized and systemic disease and understanding of the SSc subsets, disease staging, and organ involvement are needed to guide effective use of available therapies.
The etiology and pathogenesis of SSc are poorly understood. As a result, treatment of these conditions is difficult, incomplete, and not curative. (See "Risk factors for and possible causes of systemic sclerosis (scleroderma)" and "Pathogenesis of systemic sclerosis (scleroderma)".)
An overview of the management of adults with SSc will be discussed here. Pretreatment evaluation, systemic immunologic modulation, potentially antifibrotic approaches, and localized scleroderma and SSc in children are discussed separately. (See "Pretreatment evaluation of adults with systemic sclerosis (scleroderma)" and "Immunomodulatory and antifibrotic approaches to the treatment of systemic sclerosis (scleroderma)" and "Juvenile localized scleroderma" and "Juvenile systemic sclerosis (scleroderma): Classification, clinical manifestations, and diagnosis".)
OVERVIEW OF PRETREATMENT EVALUATION — An organ-based pretreatment evaluation is presented separately; however, a few basic principles are discussed below. (See "Pretreatment evaluation of adults with systemic sclerosis (scleroderma)".)
Determining disease subset — Prior to initiating therapy for systemic sclerosis (SSc), it is helpful to know whether the patient has limited or diffuse skin involvement and/or has overlap features.
●Patients with diffuse skin disease (or diffuse cutaneous SSc [dcSSc] subset) are more likely to also have involvement of internal organs, particularly the lung, heart and kidneys.
●Patients with limited skin involvement (or limited cutaneous SSc [lcSSc] subset) generally have prominent vascular manifestations including severe Raynaud phenomenon, cutaneous telangiectasia, and less commonly, pulmonary hypertension.
●Patients with features of other autoimmune rheumatic diseases (eg, systemic lupus erythematosus, polymyositis) may require a different therapeutic approach which is guided by the predominant features of the overlap syndrome (eg, arthritis, myositis). (See "Undifferentiated systemic rheumatic (connective tissue) diseases and overlap syndromes".)
Certain autoantibodies are associated with disease subsets and may help predict the risk of future organ involvement (table 3), including lung fibrosis [1]. Detailed discussions of the classification of disease subsets and clinical manifestations of SSc are presented separately. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Background'.)
Up to 10 percent of patients have internal organ involvement without skin involvement, referred to as SSc sine scleroderma. These patients are generally managed in a way similar to those classified as having the limited cutaneous SSc subset, with a focus on vascular symptoms and internal organ complications. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Systemic sclerosis sine scleroderma'.)
Assessing disease severity — The goal of the initial pretreatment assessment is to determine the distribution of organ involvement and, if possible, to decide whether organ dysfunction is related to potentially reversible inflammation or vasoconstriction (active disease) or whether the damage is irreversible with available therapies (eg, fibrosis or ischemic necrosis).
The medical history, physical examination, laboratory tests, and imaging studies that lead to an initial diagnosis of SSc provide much of the information necessary to determine the distribution of organ involvement. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)
Functional tests, additional imaging studies, and/or organ biopsy may be necessary to determine the distribution, severity, and nature of SSc-related processes prior to developing a treatment plan. For each potentially affected organ, particular tests are often recommended.
GENERAL PRINCIPLES OF MANAGEMENT — Due to the wide spectrum of disease manifestations and organ involvement, the management of the disease is tailored to the individual patient, taking into account the disease subset and type of internal organ involvement.
In general, patients with systemic sclerosis (SSc) are treated with therapy to reduce symptoms and to impact organ-based disease. As examples, patients with gastrointestinal reflux are treated with proton-pump inhibitors, patients with Raynaud phenomenon are frequently treated with calcium channel blockers, and patients with hypertensive scleroderma renal crisis are treated with angiotensin-converting enzyme (ACE) inhibitors. (See 'Organ-based treatment' below.)
However, patients with diffuse skin involvement and/or severe inflammatory organ involvement are usually treated more aggressively with systemic immunosuppressive therapy because of the increased risk of complications and organ failure. This includes:
●Patients with diffuse skin involvement that is severe or progressive
●Patients with interstitial lung disease
●Patients with myocarditis
●Patients with severe inflammatory myopathy and/or arthritis
The aim of immunosuppressive therapy is to reduce progression or severity of SSc complications. Treatment should be started as early as possible in the disease course to slow disease progression before further damage occurs. Patients identified as having severe or rapidly progressive diffuse skin or clinically significant lung disease that is extensive on computed tomography (CT) or clearly progressive on serial assessment should be evaluated and managed in specialized centers with expertise for SSc [2,3]. Such patients may be candidates for investigational therapies such as hematopoietic stem cell transplantation, possibly in the context of clinical trials (clinicaltrials.gov). Various immunosuppressive and antifibrotic drugs, as well as investigational therapies, for the treatment of SSc are presented separately. There is trial evidence supporting the potential benefit of intensive immunosuppression and autologous hematopoietic stem cell rescue in some poor-prognosis cases of SSc [4,5]. (See "Immunomodulatory and antifibrotic approaches to the treatment of systemic sclerosis (scleroderma)".)
All patients require screening at routine intervals for the development of major organ complications, particularly cardiac disease, interstitial lung disease, pulmonary hypertension, and renal involvement.
●To screen for cardiac disease, we recommend an annual echocardiogram and electrocardiogram. Additional laboratory tests should be obtained depending upon the suspected presence of a cardiac complication and may include serum troponin I or less specific markers such as troponin T, creatine kinase, and N-terminal pro-brain natriuretic peptide (NT-proBNP).
●Screening recommendations for interstitial lung disease, pulmonary hypertension, and renal involvement are discussed separately. (See "Overview of pulmonary complications of systemic sclerosis (scleroderma)", section on 'Evaluation for lung disease at time of SSc presentation' and "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, risk factors, and screening", section on 'Screening' and "Kidney disease in systemic sclerosis (scleroderma), including scleroderma renal crisis", section on 'Surveillance' and "Overview of pulmonary complications of systemic sclerosis (scleroderma)", section on 'Subsequent monitoring'.)
Our management approach is generally consistent with guidelines developed by professional organizations [2,3].
ORGAN-BASED TREATMENT — The following sections provide an overview of the approach to assessment and treatment of specific organ involvement in systemic sclerosis (SSc).
Skin involvement
Localized scleroderma (morphea) — The treatment of localized scleroderma (or morphea) is discussed separately. (See "Morphea (localized scleroderma) in adults: Management".)
Diffuse skin sclerosis — In patients who have both diffuse cutaneous SSc (dcSSc) and visceral involvement, the treatment intensity is usually dictated by the immunosuppressive therapies used to address visceral disease. Unfortunately, most of these treatments demonstrate only a modest benefit, at best, for skin thickening [6-8].
For patients with progressive and diffuse skin involvement who do not have visceral involvement, we suggest treatment with either methotrexate (MTX) or mycophenolate mofetil (MMF), and ideally initiate therapy within three years of disease onset. The choice to use either MTX or MMF is often guided by the presence of other disease manifestations, since there is no evidence that one medication is more efficacious than the other. Some clinicians prefer MTX for patients who also have arthritis or myositis, while others use MMF for patients with significant interstitial lung disease. We generally reserve the use of cyclophosphamide for progressive skin involvement in patients who are refractory to treatment with either MTX or MMF, or have severe rapidly progressive skin thickening. Target doses for MTX are 15 mg to 25 mg weekly and for MMF 1.5 g to 3 g daily. The minimum target dose should be achieved within first three months and patients evaluated for at least a further three to six months to assess benefit. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dosing and administration' and "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases", section on 'Mycophenolate dose and administration'.)
The efficacy of MTX for the treatment of skin disease in patients with diffuse and progressive skin disease has been evaluated in two randomized, placebo-controlled, double blind trials [9,10]. Both trials demonstrated an improvement in clinician-assessed skin thickening (the modified Rodnan skin score [mRSS]), although neither result was statistically significant. Consistent with an earlier study [6], another large observational cohort study including 326 patients with early dcSSc (within three years of onset) compared the efficacy of four treatment protocols (MTX, MMF, cyclophosphamide, and no immunosuppression) and found a modest improvement in the mRSS across all groups [8]. While there was no significant difference between protocols, there was a trend in favor of the protocols with immunosuppression. Based upon these trials as well as observational data, the European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) endorses the use of MTX for progressive skin involvement in the early stages of disease [3]. However, there is no evidence that MTX is effective for visceral organ involvement.
The benefits of mycophenolate for the improvement of skin sclerosis are based upon small observational studies [11-13]. A prospective study including 15 patients with dcSSc found that those who were administered mycophenolate for at least three months demonstrated significant improvement in the mRSS [11]. Another small prospective study with 25 previously untreated patients with dcSSc of recent onset (less than 24 months) also demonstrated improvement of skin involvement after an average of 18 months of therapy with MMF [12]. Skin biopsies from three of the patients demonstrated histopathological improvement. A larger retrospective analysis of 98 patients with dcSSc treated with mycophenolate found improved mRSS compared with baseline within three months of starting treatment [13]. The improved skin score in dcSSc patients treated with mycophenolate persisted during the 12 months of follow-up when compared with historical controls. A subsequent analysis of two major SSc lung fibrosis trials, Scleroderma Lung Study (SLS)-1 and SLS-II, further support benefit of MMF and cyclophosphamide for skin in dcSSc [14]. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Mycophenolate mofetil'.)
Although cyclophosphamide is generally reserved for dcSSc patients with interstitial lung disease, several studies have also reported improvements in skin involvement [15-17]. A large multicenter, randomized trial evaluated the efficacy of cyclophosphamide in early active alveolitis in 158 patients with SSc-associated interstitial lung disease. At one-year follow-up, cyclophosphamide therapy improved both lung function and skin scores compared with placebo [15]. In a small observational study, 13 patients with early dcSSc were treated with oral cyclophosphamide and low-dose glucocorticoids for one year and demonstrated a significant improvement in mRSS [16]. However, the effect of glucocorticoid use was not evaluated separately from cyclophosphamide. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Intravenous cyclophosphamide'.)
For patients with skin sclerosis refractory to the aforementioned treatments, based upon clinical worsening with increased mRSS or failure of improvement in severe disease over three to six months, other immunomodulatory agents such as intravenous immune globulin (IVIG) or rituximab may be considered as additional or alternative therapy. Our practice is to reserve such approaches for refractory cases, particularly those in which other relevant features such as inflammatory arthritis or myositis are present. In the context of limited evidence, the choice of therapy depends upon factors such as the presence of other complications (eg, lung fibrosis, arthritis, or polymyositis), the potential risk of side effects (eg, infection), as well as clinician and patient preference.
Small uncontrolled trials have demonstrated improvement in dermal fibrosis using IVIG as adjunctive therapy [18]. Additional benefit for other manifestations, such as gastrointestinal complications, has also been reported [19]. (See "Immunomodulatory and antifibrotic approaches to the treatment of systemic sclerosis (scleroderma)", section on 'Intravenous immunoglobulin'.)
There are also limited data that suggest that rituximab has beneficial effects on skin fibrosis [20,21]. In a small trial of 49 patients with SSc who were randomly assigned to receive rituximab or placebo, the absolute change in the mRSS was lower in the rituximab group (-6.3 versus 2.14; difference -8.44, 95% CI -11.0 to -5.88). Among patients with interstitial lung disease, rituximab appeared to improve the predicted forced vital capacity at 24 weeks. The number of adverse events was similar between the two groups. The findings of this study have resulted in regulatory approval in Japan for treatment with rituximab. However, additional studies are needed to establish the long-term efficacy and safety of rituximab before routine use can be recommended. (See "Immunomodulatory and antifibrotic approaches to the treatment of systemic sclerosis (scleroderma)", section on 'Rituximab'.)
Observational and trial data suggest that tocilizumab may be beneficial for refractory skin and joint disease [22-24]. Additional information regarding the possible benefit of the anti-interleukin (IL) 6 receptor antibody, tocilizumab, for the treatment of skin disease in patients with diffuse SSc is presented separately (see "Immunomodulatory and antifibrotic approaches to the treatment of systemic sclerosis (scleroderma)", section on 'Tocilizumab'). The use of tocilizumab for the treatment of interstitial lung disease in patients with SSc is also discussed separately. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)".)
Other cutaneous manifestations
Pruritus — Intense pruritus can occur in the earliest stages of dcSSc, and excessive scratching and excoriation may be a major problem. There is little immediate effective therapy; however, pruritus usually decreases as the disease plateaus from 12 to 24 months after onset of skin thickening in diffuse SSc. Up to that point, responses are variable and treatments may need to be used in combination.
Antihistamines are generally used as first-line treatment but can cause drowsiness. Maintaining adequate lubrication of the skin is essential, and patients should use lubricating creams, especially those that are lanolin-based. Counter-irritants such as capsaicin or menthol may also be used for symptomatic relief. Simple measures such as avoiding repeated exposure to environmental factors associated with itch such as heat or excessive drying after water exposure can also be helpful. Low-dose oral glucocorticoids (less than 10 mg daily dose of prednisone or equivalent) can be effective for severe pruritus, but topical corticosteroids are rarely helpful.
There are anecdotal reports that montelukast or ondansetron may be effective, as they have been in refractory itching in other diseases such as cholestasis or opiate-induced pruritus, although formal trials have not been performed with these agents [25]. In addition, one case series found that low-dose naltrexone may also be helpful [26].
Telangiectasia — Telangiectasia can be a cosmetic problem, particularly on the face. These lesions can be camouflaged with makeup. Laser or other light therapy may be useful for particularly large lesions.
Calcinosis cutis — Calcinosis can lead to significant hand disability, can lead to ulceration of the overlying skin, and can become infected. In patients with ulceration and/or infection due to calcinosis, we treat with oral minocycline, 50 to 100 mg daily for 6 to 12 weeks, in an attempt to resolve the complications and improve pain [27]. If minocycline is ineffective, therapy with MTX, infliximab, or rituximab may be given. However, the evidence to support the use of these agents is limited to case reports [28-30].
We consider surgical removal in patients who fail these therapies and have refractory pain and ulceration. Suitably located lesions can sometimes be removed by using a dental drill; this technique causes less tissue damage than conventional methods [31]. A surgical approach to managing calcinosis cutis in patients with SSc is discussed separately. (See "Hand surgery in patients with systemic sclerosis (scleroderma)", section on 'Treatment of refractory calcinosis cutis'.)
We do not recommend treatment with calcium channel blockers, bisphosphonates, or warfarin [31,32].
Raynaud phenomenon — Vascular involvement is a prominent feature of SSc. Vasoconstriction and obliterative vasculopathy likely contribute to Raynaud phenomenon, scleroderma renal crisis, pulmonary hypertension, and other visceral disease. (See "Pathogenesis and pathophysiology of Raynaud phenomenon".)
Treatment of Raynaud phenomenon is generally the same in patients with and without SSc. (See "Treatment of Raynaud phenomenon: Initial management" and "Treatment of Raynaud phenomenon: Refractory or progressive ischemia".)
Kidney involvement — All patients with SSc should be monitored for kidney involvement. Kidney function, assessed by estimated glomerular filtration rate (eGFR), has also been demonstrated to predict long-term survival in SSc [33]. The presence of acute kidney injury or chronic kidney disease are important considerations for management. (See "Kidney disease in systemic sclerosis (scleroderma), including scleroderma renal crisis", section on 'Surveillance'.)
Patients with early-stage diffuse cutaneous disease, rapidly progressive cutaneous involvement, or autoantibodies to ribonucleic acid (RNA) polymerase III are at greatest risk for scleroderma renal crisis. The findings of elevated or rising blood pressure, of decreased or declining renal function, and/or of heavy proteinuria may be warning signs for scleroderma renal crisis. (See "Kidney disease in systemic sclerosis (scleroderma), including scleroderma renal crisis", section on 'Clinical presentation'.)
The treatment of patients with scleroderma renal crisis is discussed elsewhere. (See "Kidney disease in systemic sclerosis (scleroderma), including scleroderma renal crisis", section on 'Treatment'.)
Gastrointestinal involvement — Gastrointestinal involvement is common in SSc and may involve any or all portions from the mouth to the anus. Assessment of gastrointestinal manifestations is based primarily upon symptomatology. (See "Gastrointestinal manifestations of systemic sclerosis (scleroderma)".)
The treatment of the various gastrointestinal manifestations of systemic sclerosis is presented separately. (See "Treatment of gastrointestinal disease in systemic sclerosis (scleroderma)".)
Pulmonary involvement — The two major types of lung disease in SSc are interstitial lung disease and pulmonary arterial hypertension, which may occur together or separately.
The clinical manifestations, evaluation, and treatment of interstitial lung disease and pulmonary hypertension in patients with SSc are discussed in separate topics. (See "Clinical manifestations, evaluation, and diagnosis of interstitial lung disease in systemic sclerosis (scleroderma)" and "Overview of pulmonary complications of systemic sclerosis (scleroderma)" and "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, risk factors, and screening" and "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Treatment and prognosis" and "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)".)
Musculoskeletal involvement — Arthralgias and myalgias may be initial features of SSc. Joint symptoms may result from severe skin sclerosis. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Musculoskeletal manifestations'.)
Arthralgia and/or arthritis — In patients with arthralgia who do not have arthritis, we typically use non-opioid analgesics such as nonsteroidal antiinflammatory drugs (NSAIDs). Our approach to using NSAIDs for symptomatic relief of arthritis symptoms is presented separately (see "Initial treatment of rheumatoid arthritis in adults", section on 'NSAIDs'). Alternatively, acetaminophen (up to 3g/day in the absence of liver disease or alcohol abuse) may be used if NSAIDs are contraindicated or ineffective.
In patients with inflammatory arthritis associated with SSc, the management is generally consistent with that of rheumatoid arthritis (see "Initial treatment of rheumatoid arthritis in adults"). The following is our initial approach to drug therapy:
●Low-dose glucocorticoids (less than 10mg daily dose of prednisone or equivalent) may be used for a short period, usually lasting less than two to four weeks, to initially control the arthritis.
●We usually initiate treatment with hydroxychloroquine (HCQ) 200 to 400mg daily to control the arthritis. (See "Antimalarial drugs in the treatment of rheumatic disease".)
●For patients with persistent arthritis unresponsive to HCQ, we suggest adding MTX [34]. However, MTX should be avoided in patients with severe lung fibrosis due to concerns about pulmonary toxicity. The dose, side effects, monitoring, and other considerations are presented separately. (See "Initial treatment of rheumatoid arthritis in adults", section on 'Initial therapy with methotrexate'.)
For patients with persistent arthritis unresponsive to HCQ and/or MTX, the alternative disease-modifying antirheumatic drug (DMARD) should take into account the severity of the arthritis as well as patient preference. Patients with rheumatoid factor and/or anti-citrullinated peptide positivity may have an overlap syndrome and require more aggressive therapy (see "Undifferentiated systemic rheumatic (connective tissue) diseases and overlap syndromes"). Biologic agents used to treat rheumatoid arthritis, including tumor necrosis factor (TNF) inhibitors, rituximab, abatacept, tocilizumab, and Janus kinase (JAK) inhibitors can be used [35-40]. A more detailed discussion of the approach to treatment of rheumatoid arthritis resistant to initial therapy is presented separately. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy".)
Physical therapy is important in limiting contractures, which can occur quite rapidly. Therapy should include both active and passive exercises. Adequate analgesia may be required to permit a regular daily regimen. Encouragement from the therapist and clinician is also critical if a regular program is to be performed. The patient should appreciate that skin involvement ultimately plateaus and that the purpose of physical therapy is to limit the loss of function before such plateauing of skin involvement occurs.
Surgery has an uncertain role in this setting [41]. Realignment of contracted fingers by straightening, shortening, and fusing of interphalangeal joints may improve the appearance and may decrease the development of digital ulcers. However, such procedures may not greatly improve function. (See "Hand surgery in patients with systemic sclerosis (scleroderma)".)
Inflammatory myopathy — A mild myopathy with little biochemical or histologic change is a common feature of SSc. A smaller group of patients have an inflammatory myopathy that is clinically and histologically similar to polymyositis. Certain SSc-associated autoantibodies are associated more frequently with myositis such as anti-PM-Scl, anti-Ku, and anti-U3-RNP (fibrillarin) [42]. (See "Neuromuscular manifestations of systemic sclerosis (scleroderma)", section on 'Myopathy'.)
Treatment of patients with SSc and an inflammatory myopathy is similar to that for patients with idiopathic polymyositis. Low-dose glucocorticoids alone or in combination with MTX, azathioprine, or other immunosuppressive agents are generally employed. (See "Initial treatment of dermatomyositis and polymyositis in adults" and "Neuromuscular manifestations of systemic sclerosis (scleroderma)", section on 'Myopathy'.)
High-dose glucocorticoids, above prednisone 20 mg/day (or equivalent), should generally be avoided in this setting because of an increased risk of precipitating scleroderma renal crisis [43]. (See "Kidney disease in systemic sclerosis (scleroderma), including scleroderma renal crisis".)
Cardiac involvement — The direct cardiac manifestations of SSc (ie, those not induced by systemic or pulmonary hypertension) include pericarditis, pericardial effusion, myocardial fibrosis, myocarditis, coronary artery disease, and arrhythmias. Efforts by an expert consensus panel to help define primary cardiac involvement in SSc are ongoing [44]. Treatment of the cardiac manifestations is generally based upon the management of similar clinical events in patients without SSc.
Pericarditis — Pericarditis typically causes chest pain, but effusive disease causing cardiac tamponade physiology may be painless and may present with dyspnea and edema. (See "Diagnosis and treatment of pericardial effusion".)
Pericarditis in patients with SSc is treated in a similar manner as in patients with pericarditis due to other causes. (See "Acute pericarditis: Treatment and prognosis".)
As with other causes of pericarditis, use of glucocorticoids is not advised due to the increased risk of recurrent pericarditis. Also, the use of glucocorticoids may increase the risk of developing scleroderma renal crisis. (See "Acute pericarditis: Treatment and prognosis", section on 'Glucocorticoids'.)
Cardiac tamponade necessitates drainage of the effusion; treatment of tamponade is discussed separately. (See "Cardiac tamponade", section on 'Treatment'.)
The efficacy of pericardiectomy for recurrent pericardial effusions is uncertain; these issues are presented elsewhere. (See "Recurrent pericarditis", section on 'Role of pericardiectomy'.)
Myocardial fibrosis and myocarditis — Symptoms due to myocardial fibrosis and myocarditis may arise from heart failure due to systolic or more commonly diastolic dysfunction, or may be due to cardiac rhythm disturbances resulting from interference with normal cardiac electrical conduction (eg, palpitations, syncope).
Heart failure associated with reduced systolic ejection fraction is treated with standard heart failure treatments, such as angiotensin-converting enzyme (ACE) inhibitors, implantable-cardioverter defibrillators (ICDs), and cardiac resynchronization therapy (CRT). Vasodilating beta blockers may be considered, but often aggravate Raynaud symptoms and may not be tolerated. However, restrictive cardiomyopathy is not likely to respond to these agents. (See "Overview of the management of heart failure with reduced ejection fraction in adults".)
The treatment of diastolic heart failure, with preserved ejection fraction, is presented in detail separately. (See "Treatment and prognosis of heart failure with preserved ejection fraction".)
If heart failure is noted in conjunction with an elevation of a marker of cardiac injury, such as the MB fraction of creatine kinase (CK-MB) or troponin-I that is not due to epicardial coronary artery disease, then combination treatment with glucocorticoids and cyclophosphamide may be necessary [45]. While there are no established treatment practices for myocarditis associated with SSc, immunosuppressive agents are typically used in a manner comparable to that for the treatment of interstitial lung disease associated with SSc. If cyclophosphamide is not tolerated, MMF or MTX might be considered if the degree of heart failure is less severe. Azathioprine is also sometimes used as an alternative. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Initiating therapy'.)
Improvement in measures of cardiac muscle perfusion and function may result from use of a vasodilating calcium channel blocking drug. This was illustrated in a two-week unblinded study in 18 patients who were examined with cardiac magnetic resonance imaging (MRI) and Doppler echocardiography before and after a two-week trial of nifedipine (20 mg three times daily) [46]. In a large observational study with over 7000 SSc patients, previous use of calcium channel blockers was associated with a decreased prevalence of left ventricular dysfunction [47]. Whether or not such improvements in perfusion and in systolic and diastolic function are associated with better longer-term outcome is unknown.
Genitourinary involvement
Erectile dysfunction — Erectile dysfunction (ED) is common in men with SSc, resulting from impaired penile blood flow due both to myointimal proliferation of small arteries and to corporal fibrosis [48]. Treatment with on-demand phosphodiesterase type-5 (PDE-5) inhibitors is usually not effective. Greater clinical benefit may be achieved with fixed daily or alternate day regimens of long-acting PDE-5 inhibitors [48], after addressing modifiable or reversible risk factors for ED, including lifestyle, psychological, or drug-related factors [49]. Consultation with an urologist may be of benefit if other approaches are required. (See "Treatment of male sexual dysfunction".)
PROGNOSIS
Mortality — There is a substantial increase in the risk of death in patients with systemic sclerosis (SSc). This was illustrated in a meta-analysis that included 2691 SSc patients followed within a 40-year period; the standardized mortality ratio (SMR) was almost fourfold higher than that of age- and sex-matched controls in the general population (SMR 3.5, 95% CI 3.03-4.11) [50]. Among 732 deaths, 389 (53 percent) were consider to be related to SSc, whereas 223 (30 percent) deaths were defined as not related to SSc, and 120 deaths (16 percent) were due to unknown causes. Of the 612 deaths from known causes, heart involvement was the most frequent cause of death (29 percent), followed by lung involvement (23 percent), cancer (16 percent), and kidney involvement (11 percent). Thus, while there has been improvement in survival reported for well-characterized cohorts of SSc, especially in the diffuse subset [51], and outcomes for complications such as pulmonary hypertension [52] are better, consistent with a beneficial impact of current management, it is also possible that some of the overall fall in observed SMR in SSc reflects better overall population survival rather than disease-specific gain [53].
Most deaths among patients with SSc are related to pulmonary fibrosis, pulmonary arterial hypertension, or cardiac causes [54-56]. Other significant causes of death include renal disease, malignancy, gastrointestinal, and infectious causes [56].
Risk factors for increased mortality — Various risk factors have been associated with increased mortality, including the presence of extensive skin involvement, cardiac and/or pulmonary involvement, renal disease, and the presence of anti-topoisomerase I antibodies and/or anti-Th/To antibodies [54,56-60]. Male sex has been associated with increased mortality in some but not all studies [61,62]. Younger age at disease onset is also associated with a higher risk of mortality [63].
●Extensive skin involvement – Several studies have demonstrated that patients with diffuse cutaneous SSc (dcSSc) have a higher mortality than patients with limited cutaneous SSc (lcSSc) [57,64-66]. Two cohort studies of 1012 and 309 patients found lower 10-year survival among those with diffuse skin disease compared with those with lcSSc (53 to 62 percent versus 75 to 79 percent, respectively) [64,65]. A large meta-analysis including 3311 European, Japanese, and North American patients also noted an increased risk of premature death in those with diffuse skin involvement (adjusted hazard ratio 1.2, 95% CI 1.0-1.4) [57].
Among those with dcSSc, more severe skin sclerosis, as assessed by skin score, is associated with increased mortality. This was illustrated in a study of 225 patients with diffuse skin disease [58]. Those with severe involvement (modified Rodnan skin score [mRSS] ≥35), compared with those with less skin sclerosis (mRSS <35), had significantly greater cumulative mortality (37 and 21 percent, respectively).
●Pulmonary involvement – The prognosis of patients with specific pulmonary manifestations including pulmonary arterial hypertension and interstitial lung disease is presented separately. (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, risk factors, and screening" and "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Prognosis'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Systemic sclerosis (scleroderma)".)
SUMMARY AND RECOMMENDATIONS
●Pretreatment evaluation – Prior to initiating therapy for systemic sclerosis (SSc), a pretreatment evaluation is necessary to determine the disease subset and assess disease severity. Specific disease subsets and autoantibodies may help predict the risk of future organ involvement (table 3). (See 'Overview of pretreatment evaluation' above.)
●Assessing disease severity – The goal of the initial pretreatment assessment is to determine the distribution of organ involvement and, if possible, to decide whether organ dysfunction is related to potentially reversible inflammation or vasoconstriction (active disease) or whether the damage is irreversible with available therapies (eg, fibrosis or ischemic necrosis). (See 'Assessing disease severity' above.)
●General principles – Due to the wide spectrum of disease manifestations and organ involvement, the management of the disease is tailored to the individual patient, taking into account the disease subset and type of internal organ involvement. In general, patients with SSc are treated with organ-based symptomatic therapy. However, patients with diffuse skin involvement and/or severe inflammatory organ involvement are usually treated with systemic immunosuppressive therapy. (See 'General principles of management' above and 'Organ-based treatment' above.)
●Routine monitoring – All patients require screening at routine intervals for the development of major organ complications, particularly cardiac disease, interstitial lung disease, pulmonary hypertension, and renal involvement. (See 'General principles of management' above.)
●Organ-based treatment – Specific organ-based treatments are discussed above and in separate topics. (See 'Organ-based treatment' above.)
•Diffuse skin sclerosis – For patients with progressive and diffuse skin involvement who do not have visceral involvement, we suggest treatment with either methotrexate (MTX) or mycophenolate mofetil (MMF) rather than cyclophosphamide (Grade 2C). The choice to use either MTX or MMF is often guided by the presence of other disease manifestations, since there is no evidence that one medication is more efficacious than the other. Some clinicians prefer MTX for patients who also have arthritis or myositis, while others use MMF for patients with interstitial lung disease. We generally reserve the use of cyclophosphamide for progressive skin involvement in patients who are refractory to treatment with either MTX or MMF, or have severe rapidly progressive skin thickening. (See 'Diffuse skin sclerosis' above.)
•Other cutaneous manifestations – (See 'Other cutaneous manifestations' above.)
•Raynaud phenomenon – (See 'Raynaud phenomenon' above and "Treatment of Raynaud phenomenon: Initial management".)
•Kidney involvement – (See 'Kidney involvement' above.)
•Gastrointestinal involvement – (See 'Gastrointestinal involvement' above.)
•Pulmonary involvement – (See 'Pulmonary involvement' above.)
•Musculoskeletal involvement – (See 'Musculoskeletal involvement' above.)
•Genitourinary involvement – (See 'Genitourinary involvement' above.)
●Prognosis – There is a substantial increase in the risk of death in patients with SSc. Most deaths among patients with SSc are related to pulmonary fibrosis, pulmonary arterial hypertension, or cardiac causes. Other significant causes of death include renal disease, malignancy, gastrointestinal, and infectious causes. (See 'Mortality' above.)
Various risk factors have been associated with increased mortality, including the presence of extensive skin involvement, cardiac and/or pulmonary involvement, renal disease, and the presence of anti-topoisomerase I antibodies and/or anti-Th/To antibodies. Male sex and younger age at disease onset may also be associated with increased mortality. (See 'Risk factors for increased mortality' above.)
