Version May 2024
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 — 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.
●Diffuse skin involvement – 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.
●Limited skin involvement – 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.
●No skin involvement – 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'.)
●Overlap syndromes – 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'.)
An organ-based pretreatment evaluation is presented separately (See "Pretreatment evaluation of adults with systemic sclerosis (scleroderma)".)
GENERAL PRINCIPLES OF MANAGEMENT — The aim of immunosuppressive therapy is to reduce progression or severity of systemic sclerosis (SSc) complications. Treatment should be started as early as possible in the disease course to slow disease progression before further damage occurs. Our management approach is generally consistent with guidelines developed by professional organizations [2,3].
Organ-based approach to therapy — 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 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. Selection of immunosuppression, if indicated, is based on the organ requiring the most aggressive therapy.
Severe or rapidly progressive disease — 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 (see 'Initial therapy' below)
●Interstitial lung disease (see "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Choice of initial agent')
●Myocarditis (see 'Myocarditis' below)
●Severe inflammatory myopathy and/or arthritis (see 'Inflammatory myopathy' below and 'Joint involvement' below)
In particular, 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]. Intensive immunosuppression and autologous hematopoietic stem cell rescue may benefit some poor-prognosis cases of SSc [4,5]. Other patients may be candidates for investigational therapies, possibly in the context of clinical trials [6]. Various immunosuppressive and antifibrotic drugs, including investigational therapies, for the treatment of SSc are presented separately. (See "Immunomodulatory and antifibrotic approaches to the treatment of systemic sclerosis (scleroderma)".)
Avoidance of glucocorticoids — Glucocorticoids have been identified as a risk factor for scleroderma renal crisis. In a study of 110 patients with SSc, scleroderma renal crisis was associated with the use of prednisone doses of 15 mg daily (or greater) [7]. Because of this association, we suggest limiting the use of glucocorticoids to short courses using low doses. (See "Kidney disease in systemic sclerosis (scleroderma), including scleroderma renal crisis", section on 'Risk factors'.)
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 — Many patients will present simultaneously with diffuse cutaneous systemic sclerosis (dcSSc) and other disease manifestations requiring immunosuppressive therapies (eg, interstitial lung disease, myocarditis, myositis, arthritis). For these patients, treatment selection is driven by the noncutaneous disease manifestations. In particular, the treatment of interstitial lung disease, myocarditis, and myositis are prioritized because they may lead to potentially life-threatening morbidity.
In the absence of such disease manifestations, immunosuppression is still used for patients with progressive and diffuse skin involvement. However, most of these treatments demonstrate only a modest benefit, at best, for skin thickening [8-10].
Initial therapy — For patients with progressive and diffuse skin involvement, we suggest treatment with either methotrexate (MTX) or mycophenolate mofetil (MMF), and we initiate therapy as soon as possible, ideally while the skin disease is still active.
For patients who have other disease manifestations that also require immunosuppression (eg, arthritis, myositis, interstitial lung disease), the choice to use either MTX or MMF is often guided by these 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.
In the absence of other indications for immunosuppression, the choice between MTX and MMF is generally guided by clinician familiarity, local practice, and drug contraindications.
MMF or MTX is not generally added for dcSSc if the patient is already being treated with cyclophosphamide.
●Methotrexate – The dosing and administration of MTX is the same as those used for rheumatoid arthritis, which are discussed elsewhere. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dosing and administration'.)
The efficacy of MTX for the treatment diffuse and progressive skin disease has been evaluated in two randomized, placebo-controlled, double-blind trials [11,12]. Both trials demonstrated an improvement in clinician-assessed skin thickening (the modified Rodnan skin score [mRSS]), although neither result was statistically significant.
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 greater improvement in mRSS among patients receiving immunosuppression, although the differences between groups were not statistically significant [10].
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.
●Mycophenolate mofetil – The dosing and administration of MMF for dcSSc are the same as those used for interstitial lung disease in SSc, which are discussed elsewhere. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Mycophenolate mofetil'.)
A retrospective analysis of Scleroderma Lung Study (SLS) I and SLS-II indicates that MMF is associated with greater improvement in mRSS than placebo for patients with dcSSc [13].
The use of MMF for the treatment of skin sclerosis is also supported by small observational studies [14-16].
•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 [14].
•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 [15]. 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 [16]. The improved skin score in dcSSc patients treated with mycophenolate persisted during the 12 months of follow-up when compared with historical controls. Unlike methotrexate, MMF is not associated with lung injury. Data supporting the use of MMF for interstitial lung disease are discussed elsewhere. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Mycophenolate mofetil'.)
Management of resistant disease — For patients with skin sclerosis refractory to the aforementioned treatments (defined as lack of improvement in mRSS over three to six months), we suggest other immunosuppressive or immunomodulatory agents such as intravenous immune globulin (IVIG), rituximab, or tocilizumab. Our practice is to reserve such approaches for refractory cases, particularly those who have other features of scleroderma that benefit from immunosuppression. We generally reserve cyclophosphamide for severe rapidly progressive skin thickening when other options cannot be used. Cyclophosphamide may not be as efficacious as rituximab for the treatment of skin disease [17].
In the context of limited evidence, the choice of therapy depends upon factors such as the presence of other disease manifestations (eg, lung fibrosis, arthritis, or polymyositis), the potential risk of side effects (eg, infection), as well as clinician and patient preference. Interstitial lung disease occurs in over 60 percent of patients with SSc and is therefore a particularly important consideration for many patients [18]. In patients with concomitant skin and lung disease, rituximab and tocilizumab may be preferable, since they have efficacy against both manifestations.
●IVIG – The dosing and administration of IVIG are discussed elsewhere. (See "Immunomodulatory and antifibrotic approaches to the treatment of systemic sclerosis (scleroderma)", section on 'Intravenous immunoglobulin'.)
Small uncontrolled trials have demonstrated improvement in dermal fibrosis using IVIG as adjunctive therapy [19]. Additional benefit for other manifestations, such as gastrointestinal complications, has also been reported [20].
●Rituximab – The dosing and administration of rituximab are discussed elsewhere. (See "Immunomodulatory and antifibrotic approaches to the treatment of systemic sclerosis (scleroderma)", section on 'Rituximab'.)
There are also limited data that suggest that rituximab has beneficial effects on skin fibrosis [21,22]. However, additional studies are needed to establish the long-term efficacy and safety of rituximab before routine use can be recommended.
In a small trial of 56 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). Among the 48 patients with SSc who also had interstitial lung disease, rituximab was associated with preservation of the forced vital capacity (FVC; change in percent predicted FVC at 24 weeks 0.09 versus -2 percent). The number of adverse events was similar between the two groups [22].
A second retrospective study of 29 patients who received rituximab 375 mg/m2 weekly for four weeks indicated a similar improvement in mRSS at the end of one year (median change in mRSS -7) [23].
The RECITAL clinical trial compared rituximab with intravenous cyclophosphamide for connective tissue disease associated interstitial lung disease. Although lung function improved with both, only rituximab was associated with improvement in mRSS at 16 weeks. The difference between the mRSS in the two arms, in an adjusted mixed effects model, was -4.47 units (95% CI -7.99 to -0.95 units, p = 0.013) at 24 weeks in favor of rituximab [17,24].
●Tocilizumab – The dosing and administration of tocilizumab is discussed elsewhere. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Tocilizumab'.)
Data from clinical trials have suggested a potential antifibrotic effect of blocking interleukin 6 (IL-6) signaling using tocilizumab [25-27].
One study of 210 patients with dcSSc demonstrated a statistically significant reduction in the progression of skin fibrosis only for patients with early-stage active skin disease and elevated acute phase reactants [28]. In an open-label extension trial, patients with interstitial lung disease at baseline demonstrated sustained treatment benefit at 96 weeks when compared with patients treated with placebo (change in percent predicted FVC: -3.3 versus -0.5 percent) [29].
In another study of 51 patients with dcSSc, there was greater improvement in mRSS in patients receiving 48 weeks of weekly subcutaneous tocilizumab compared with placebo, although this difference was not statistically significant (mean change in mRSS -.5.6 versus -3.1) [27].
One small case series indicates that discontinuation of tocilizumab may be associated with disease recrudescence [30].
●Cyclophosphamide – The dosing and administration of cyclophosphamide are discussed elsewhere. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Intravenous cyclophosphamide'.)
We generally reserve the use of cyclophosphamide for patients who have severe rapidly progressive skin thickening where other options are not feasible.
Although cyclophosphamide is generally reserved for dcSSc patients with interstitial lung disease, several studies have also reported improvements in skin involvement [31-33].
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 [31].
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 [32]. However, the effect of glucocorticoid use was not evaluated separately from cyclophosphamide.
Other cutaneous manifestations
Pruritus — Intense pruritus can occur in the earliest stages of dcSSc, and excessive scratching and excoriation may be a major problem. 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. We suggest the following interventions for as long as the patient is symptomatic:
●Avoidance of environmental triggers, such as heat
●Topical emollients, especially those that are lanolin based
●Counterirritants, such as topical capsaicin or menthol
●Antihistamines, such as hydroxyzine or diphenhydramine 25 to 50 mg orally before bedtime
For patients who are refractory to these measures, we suggest a short courses of low-dose oral glucocorticoids (eg, less than 10 mg daily dose of prednisone for less than four weeks). Higher doses of glucocorticoids may increase the risk of developing scleroderma renal crisis. Topical corticosteroids are rarely helpful. (See "Kidney disease in systemic sclerosis (scleroderma), including scleroderma renal crisis", section on 'Risk factors'.)
Alternate therapies include montelukast, ondansetron, and naltrexone, although there are minimal data supporting their use for patients with SSc [34,35].
A detailed discussion of topical and systemic agents for pruritus may be found elsewhere. (See "Pruritus: Therapies for generalized pruritus", section on 'Antipruritic therapies' and "Pruritus: Therapies for localized pruritus", section on 'Topical therapies'.)
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 but may recur.
Calcinosis cutis — Calcinosis can lead to significant hand disability, can lead to ulceration of the overlying skin, and can become infected.
●Pharmacotherapy – In patients with ulceration and/or infection due to calcinosis, we suggest treatment with oral minocycline, 50 to 100 mg daily for 6 to 12 weeks, in an attempt to resolve the complications and improve pain [36]. If minocycline is ineffective, options include MTX, infliximab, or rituximab. We would use MTX or infliximab preferentially in a patient with concurrent arthritis, and we would use rituximab in a patient with concurrent myositis. However, the evidence to support the use of these agents is limited to case reports [37-39]. We do not recommend treatment with calcium channel blockers, bisphosphonates, or warfarin [40,41].
●Surgery – 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 [40]. 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'.)
VISCERAL INVOLVEMENT
Kidney involvement — Scleroderma renal crisis may be accompanied by elevated/rising blood pressure, decreased/declining renal function, and/or proteinuria. 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. (See "Kidney disease in systemic sclerosis (scleroderma), including scleroderma renal crisis", section on 'Clinical presentation'.)
Scleroderma renal crisis is not managed with immunosuppressive therapies. 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 systemic sclerosis (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 SSc 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.
In general, interstitial lung disease, but not pulmonary arterial hypertension, is managed with immunosuppression. 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)".)
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 [42]. 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 "Pericardial effusion: Approach to diagnosis".)
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".)
Cardiac tamponade necessitates drainage of the effusion; treatment of tamponade is discussed separately. (See "Pericardial effusion: Approach to management".)
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'.)
The efficacy of pericardiectomy for recurrent pericardial effusions is uncertain; these issues are presented elsewhere. (See "Recurrent pericarditis", section on 'Role of pericardiectomy'.)
Myocarditis — Symptoms due to myocardial fibrosis and myocarditis may arise from heart failure due to systolic or more commonly diastolic dysfunction, or they may be due to cardiac rhythm disturbances resulting from interference with normal cardiac electrical conduction (eg, palpitations, syncope). 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 [43]. 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, we use mycophenolate mofetil (MMF) or methotrexate (MTX) if the degree of heart failure is less severe. We sometimes use azathioprine as an alternative. We prefer to use no more than 30 mg of prednisolone daily (or equivalent) due to the risk of scleroderma renal crisis, although this decision must be individualized. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Initiating therapy'.)
Heart failure — Heart failure with reduced 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.
Adding a vasodilating calcium channel blocker to standard therapies may lead to additional improvements in cardiac muscle perfusion and function. 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) [44]. 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 [45]. Whether or not such improvements in perfusion and in systolic and diastolic function are associated with better longer-term outcome is unknown.
The management of heart failure is discussed separately. (See "Overview of the management of heart failure with reduced ejection fraction in adults", section on 'Pharmacologic therapy' and "Treatment and prognosis of heart failure with preserved ejection fraction", section on 'Pharmacotherapy'.)
MUSCULOSKELETAL INVOLVEMENT — Arthralgias and myalgias may be initial features of systemic sclerosis (SSc). Joint symptoms may result from severe skin sclerosis. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Musculoskeletal manifestations'.)
Joint involvement
●Arthralgias – In patients with arthralgia who do not have arthritis, we typically use nonopioid 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 3 g daily in the absence of liver disease or alcohol abuse) may be used if NSAIDs are contraindicated or ineffective.
●Inflammatory arthritis
•Pharmacotherapy – In patients with inflammatory arthritis associated with SSc, we suggest the following approach:
-We suggest treatment with hydroxychloroquine (HCQ) 200 to 400 mg 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 methotrexate (MTX) [46]. 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'.)
-We generally avoid glucocorticoids because of the risk of precipitating scleroderma renal crisis. However, for patients with debilitating inflammatory arthritis , we use low-dose glucocorticoids (ie, less than 10 mg daily dose of prednisone or equivalent) for a short period (ie, less than two to four weeks) to achieve rapid disease control.
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 [47-53].
The management of SSc-associated inflammatory arthritis is similar to the management of rheumatoid arthritis, which is presented separately. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy".)
•Physical 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 – Surgery has an uncertain role in this setting [54]. 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. These issues are discussed in detail elsewhere. (See "Hand surgery in patients with systemic sclerosis (scleroderma)".)
Inflammatory myopathy
●Clinical presentations – 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) [55]. (See "Neuromuscular manifestations of systemic sclerosis (scleroderma)", section on 'Myopathy'.)
●Treatment – 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 "Neuromuscular manifestations of systemic sclerosis (scleroderma)", section on 'Myopathy'.)
High-dose glucocorticoids, above prednisone 20 mg daily (or equivalent), should generally be avoided in this setting because of an increased risk of precipitating scleroderma renal crisis [7]. (See "Kidney disease in systemic sclerosis (scleroderma), including scleroderma renal crisis", section on 'Risk factors'.)
VASCULAR INVOLVEMENT
Raynaud phenomenon — Vascular involvement is a prominent feature of systemic sclerosis (SSc). Vasoconstriction and obliterative vasculopathy likely contribute to Raynaud phenomenon, scleroderma renal crisis, pulmonary hypertension, and other visceral disease.
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".)
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 [56].
We suggest fixed daily or alternate day regimens of long-acting phosphodiesterase type-5 (PDE-5) inhibitors (eg, tadalafil) [56], after addressing modifiable or reversible risk factors for ED, including lifestyle, psychological, or drug-related factors [57]. Treatment with on-demand PDE-5 inhibitors (eg, sildenafil) is usually not effective. Consultation with a urologist may be of benefit if other approaches are required.
These issues are discussed in detail elsewhere. (See "Treatment of male sexual dysfunction".)
MONITORING — All patients require screening at routine intervals for the development of major organ complications, particularly cardiac disease, interstitial lung disease, pulmonary hypertension, and kidney involvement. The frequency of these evaluations may depend on the patient’s prior history, time since initial diagnosis, and autoantibody status.
●Cardiac disease – To monitor for cardiac disease, we suggest an annual echocardiogram and electrocardiogram for all patients. Additional laboratory tests may be necessary for patients suspected of having specific disease manifestations (eg, myocarditis, heart failure)
●Interstitial lung disease
•Pulmonary function testing – For patients without a known history of lung involvement, we obtain annual pulmonary function tests (ie, spirometry, diffusing capacity, exertional pulse oxygenation saturation) for five years after the initial diagnosis. We decrease the frequency of pulmonary function tests to once every two years under the following circumstances:
-Systemic sclerosis (SSc) for longer than five years, normal exercise capacity, and normal diffusing capacity for carbon monoxide (DLCO) on pulmonary function tests
-Stable pulmonary function tests for at least three years
Patients with preexisting lung involvement may require more frequent pulmonary function testing, depending on their clinical stability. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Monitoring response to therapy'.).
•Computed tomography – High-resolution CT (HRCT) should be performed to evaluate changes in pulmonary symptoms or pulmonary function tests.
●Pulmonary hypertension – In addition to an annual echocardiogram, we obtain a plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) annually for the following types of patients:
•SSc for longer than three years
•Low diffusing capacity on pulmonary function testing
Patients who may have worsening pulmonary hypertension (eg, declining diffusing capacity on pulmonary function testing, or new or worsening pulmonary symptoms) may require more frequent NT-proBNP testing
●Kidney disease – We suggest checking blood pressure twice weekly for all patients. We suggest daily home blood pressure measurements for the following types of patients:
•Early-stage diffuse cutaneous disease
•Rapidly progressive cutaneous involvement with tendon friction rubs
•Autoantibodies to RNA polymerase III
An increase in systolic blood pressure of 15 mmHg or diastolic blood pressure of 10 mmHg should trigger an immediate evaluation for scleroderma renal crisis. (See "Kidney disease in systemic sclerosis (scleroderma), including scleroderma renal crisis", section on 'Establishing the diagnosis'.)
Screening recommendations are discussed in greater detail elsewhere. (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'.)
PROGNOSIS
Mortality — There is a substantial increase in the risk of death in patients with systemic sclerosis (SSc). Most deaths among patients with SSc are related to pulmonary fibrosis, pulmonary arterial hypertension, or cardiac causes [58-60]. Other significant causes of death include kidney disease, malignancy, and gastrointestinal and infectious causes [60]. The overall survival of patients with SSc has improved over time, but the proportion of deaths related to SSc has increased.
In a meta-analysis of 2691 SSc patients followed over 40 years, the standardized mortality ratio (SMR) was almost four times higher among SSc patients versus age- and sex-matched controls in the general population (SMR 3.5, 95% CI 3.03-4.11) [61]. Among 732 deaths, 389 (53 percent) were considered 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).
Well-characterized cohorts of SSc have reported improvements in survival compared with older cohorts [62] especially in the diffuse subset [63]. Additionally, outcomes for complications such as pulmonary hypertension have improved, likely due to better management strategies [64]. However, a meta-analysis of 2719 deaths in patients with SSc indicates that there has been an increase in SSc-specific mortality over time [65].
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 [58,60,66-69]. Male sex has been associated with increased mortality in some but not all studies [70,71]. Younger age at disease onset is also associated with a higher risk of mortality [72].
●Extensive skin involvement – Several studies have demonstrated that patients with diffuse cutaneous SSc (dcSSc) have higher mortality than patients with limited cutaneous SSc (lcSSc) [66,73-75]. 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) [73,74]. 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 [HR] 1.2, 95% CI 1.0-1.4) [66].
Among those with dcSSc, 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 [67]. Those with severe involvement (modified Rodnan skin score [mRSS] ≥35) had significantly greater cumulative mortality when compared with those with less skin sclerosis (37 and 21 percent, respectively).
●Antibody status – A cohort study of 10,711 patients demonstrated that scleroderma-specific autoantibodies were better than skin involvement at predicting overall survival, disease progression, scleroderma renal crisis, and pulmonary fibrosis after four years of follow-up [76]. Anti-topoisomerase I, anti-Th/To, and anti-RNA polymerase III antibodies are all associated with increased mortality [66,69,76].
●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
●General principles – In general, patients with systemic sclerosis (SSc; scleroderma) 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. We avoid glucocorticoids whenever possible due to their association with scleroderma renal crisis; if necessary, we treat with short courses of low-dose glucocorticoids. (See 'General principles of management' above.)
●Diffuse skin sclerosis – For patients with progressive and diffuse skin involvement, we suggest treatment with either methotrexate (MTX) or mycophenolate mofetil (MMF) rather than cyclophosphamide (Grade 2C). For patients with other disease manifestations that also require immunosuppression (eg, arthritis, myositis, interstitial lung disease), the choice of immunosuppression is often guided by the presence of other disease manifestations, since there is no evidence that one medication is more efficacious than the other. We use MTX for patients who also have arthritis or myositis, we use and MMF for patients with interstitial lung disease.
For patients with resistant disease, we suggest intravenous immunoglobulin (IVIG), rituximab, or tocilizumab (Grade 2C). We generally reserve cyclophosphamide for progressive skin involvement in patients who are refractory to treatment with either MTX or MMF or who have severe rapidly progressive skin thickening. (See 'Skin involvement' above.)
●Other cutaneous manifestations – For patients with pruritus, we use topical emollients (eg, lanolin), counterirritants (eg, topical capsaicin, menthol), and antihistamines (eg, hydroxyzine, diphenhydramine). (See "Pruritus: Therapies for localized pruritus", section on 'Topical therapies'.)
For refractory pruritus, we suggest a short course of low-dose oral glucocorticoids (eg, less than 10 mg of prednisone daily for less than four weeks) (Grade 2C).
Patients may conceal telangiectasis with cosmetics. We treat larger telangiectasias with laser therapy.
For patients with calcinosis cutis, we suggest treatment with minocycline (Grade 2C). When calcinosis cutis is refractory to minocycline, options include MTX, infliximab, or rituximab. We consider surgical removal of lesions for patients with significant pain and disability. (See 'Other cutaneous manifestations' above.)
●Visceral involvement – Many forms of visceral involvement, including scleroderma renal crisis, gastrointestinal dysmotility, heart failure, and pulmonary hypertension, are not managed with immunosuppression.
Interstitial lung disease, myocarditis, and pericarditis require immunosuppressive therapies, but we attempt to avoid glucocorticoids, which may precipitate scleroderma renal crisis.
Management of specific organ involvement is discussed elsewhere:
•(See "Gastrointestinal manifestations of systemic sclerosis (scleroderma)".)
•(See "Cardiac manifestations of systemic sclerosis (scleroderma)", section on 'Cardiac manifestations'.)
●Musculoskeletal involvement – We treat arthralgias with nonsteroidal antiinflammatory drugs (NSAIDs). We suggest hydroxychloroquine (HCQ) for treatment of inflammatory arthritis (Grade 2C). We add MTX for patients with refractory symptoms. For patients with inflammatory arthritis, physical and occupational therapy helps prevent contractures, but the role of surgery is uncertain. (See 'Musculoskeletal involvement' above.)
We treat inflammatory myopathy using the same strategies used for idiopathic polymyositis. However, prednisone above 20 mg daily (or equivalent) should be avoided, to prevent precipitating scleroderma renal crisis. (See "Neuromuscular manifestations of systemic sclerosis (scleroderma)", section on 'Management'.)
●Vascular involvement – Raynaud phenomenon is the hallmark of SSc and is treated similarly to patients without SSc. (See "Treatment of Raynaud phenomenon: Initial management".)
For erectile dysfunction (ED) that persists after addressing modifiable or reversible risk factors, we suggest fixed daily or alternate-day regimens of long-acting phosphodiesterase type-5 (PDE-5) inhibitors (eg, tadalafil 2.5 to 5 mg once daily) (Grade 2C). (See 'Vascular involvement' above.)
●Monitoring – All patients require screening at routine intervals for the development of major organ complications, particularly cardiac disease, interstitial lung disease, pulmonary hypertension, and kidney involvement. The frequency of monitoring depends on the patient’s prior history, time since initial diagnosis, and autoantibody status. (See 'Monitoring' above.)
•In general, we obtain an annual echocardiogram and electrocardiogram for all patients. We also monitor blood pressure twice weekly. (See "Cardiac manifestations of systemic sclerosis (scleroderma)", section on 'Screening for cardiac involvement' and "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, risk factors, and screening", section on 'Echocardiography' and "Kidney disease in systemic sclerosis (scleroderma), including scleroderma renal crisis", section on 'Surveillance'.)
•We obtain annual pulmonary function tests for at least five years following diagnosis to monitor for interstitial lung disease; after that, less frequent monitoring is reasonable for patients with stable findings. Patients with known interstitial lung disease may require more frequent testing. Changes in symptoms or pulmonary function tests should be followed by high-resolution CT. (See "Overview of pulmonary complications of systemic sclerosis (scleroderma)", section on 'Diagnosis of lung disease in systemic sclerosis'.)
In patients with SSc for longer than three years or who have a low diffusing capacity for carbon monoxide (DLCO), we test plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) annually to monitor for pulmonary hypertension. (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, risk factors, and screening", section on 'Abnormal pulmonary function (low diffusion)'.)
•We check blood pressure daily in patients with early-stage diffuse cutaneous disease, rapidly progressive cutaneous involvement with tendon friction rubs, or autoantibodies to RNA polymerase III to monitor for scleroderma renal crisis. An increase in systolic blood pressure of 15 mmHg or diastolic blood pressure of 10 mmHg should trigger an immediate evaluation for scleroderma renal crisis. (See "Kidney disease in systemic sclerosis (scleroderma), including scleroderma renal crisis", section on 'Establishing the diagnosis'.)
●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 kidney disease, malignancy, gastrointestinal, and infectious causes. (See 'Mortality' above.)
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