Systemic Sclerosis

1. Overview

Systemic sclerosis (SSc), also known as scleroderma, is a rare autoimmune connective-tissue disease characterised by three features: autoimmunity, fibrosis (scarring) of the skin and internal organs, and vasculopathy (damage to small blood vessels). The organ systems most commonly affected are the skin, the gastrointestinal tract and the lungs, and the heart, kidneys, joints and muscles can also be involved. The 2023 Lancet Seminar on the disease notes that systemic sclerosis has the highest mortality among the rheumatic diseases (Volkmann et al., 2023, PubMed PMID: 36442487).

Systemic sclerosis is usually divided into two subtypes by how far skin thickening extends. A 2,205-patient cohort study grouped patients by the pattern of skin fibrosis (none, limited to the metacarpophalangeal joints, distal to the elbows and knees, or proximal to the elbows and knees); its authors concluded that the usual two-subtype split misclassifies an intermediate group with its own autoantibody profile, lung-disease risk and survival (Cottrell et al., 2014).

• Limited cutaneous SSc (lcSSc) — skin thickening stays distal to the elbows and knees. A limited form of systemic sclerosis is also called CREST syndrome, after its features: Calcinosis, Raynaud's phenomenon, Esophageal dysmotility, Sclerodactyly and Telangiectasia (Nahar et al., 2025). In lcSSc, the first symptom other than Raynaud's typically appears 5 to 10 years after Raynaud's begins. Anti-centromere antibodies are the antibody most associated with this subtype and are linked to pulmonary arterial hypertension (Volkmann 2023).
• Diffuse cutaneous SSc (dcSSc) — skin thickening extends proximal to the elbows and knees. People with dcSSc typically develop their first non-Raynaud's symptom within 1 to 2 years of Raynaud's onset, and some develop it at the same time or within weeks. Anti-topoisomerase I (anti-Scl-70) antibodies are associated with progressive interstitial lung disease, and anti-RNA polymerase III antibodies with scleroderma renal crisis and cancer (Volkmann 2023). In a London cohort followed for up to 15 years, clinically significant pulmonary fibrosis developed in 42% of patients with dcSSc and 22% with lcSSc (Nihtyanova et al., 2014).

A small subset (under 5%) of people with established systemic sclerosis have no clinically detectable skin fibrosis; they are classified as having SSc sine scleroderma (Volkmann 2023). The 2023 Seminar describes treatment as organ-directed and tailored to the patient's goals of care, balancing side effects against efficacy, and reports that early treatment of scleroderma renal crisis with ACE inhibitors raised 1-year survival from 10% to 85%.

2. Epidemiology

A 2021 meta-analysis of 61 prevalence studies and 39 incidence studies estimated an overall pooled prevalence of 17.6 per 100,000 and a pooled incidence of 1.4 per 100,000 person-years. Estimates varied widely by region, with North American studies reporting considerably higher figures than other regions, and the pooled incidence and prevalence in women were five times those in men (Bairkdar et al., 2021). In a census of the Detroit area (1989–1991), prevalence was estimated at 276 cases per million adults and annual incidence at 19.3 new cases per million adults (Mayes et al., 2003).

In the Detroit census, prevalence was significantly higher in Black than in white adults; Black patients were diagnosed at a younger average age and were almost twice as likely to have diffuse disease. Male sex and older age at diagnosis were associated with shorter survival (Mayes et al., 2003). In observational studies, male patients, African American patients and patients with anti-Scl-70 antibodies were more likely to have progressive interstitial lung disease, although one analysis of two treatment trials found similar outcomes in African American and other participants, suggesting that confounding factors such as access to care need to be considered when interpreting the observational studies (Volkmann 2023).

Among full-blooded Choctaw people in southeastern Oklahoma, prevalence was at least 469 per 100,000 over 1990–1994; most cases had diffuse disease, pulmonary fibrosis and anti-topoisomerase I antibodies, and the strongest risk factor found was an Amerindian HLA haplotype (Arnett et al., 1996). Family history: in three US cohorts, systemic sclerosis occurred in one or more first-degree relatives in 1.6% of families with the disease, compared with an estimated general-population prevalence of 0.026%; the authors noted that the absolute risk for each family member remained low, under 1% (Arnett et al., 2001).

Survival over time: at one US centre, 10-year survival rose steadily from 54% to 66% across five 5-year periods (patients first seen 1972–1996), while renal crisis fell from 42% to 6% of scleroderma-related deaths and pulmonary fibrosis rose from 6% to 33% (Steen and Medsger, 2007). A meta-analysis of nine cohort studies (2,691 patients) found a pooled standardised mortality ratio of 3.53 and no significant change in it over the 40 years studied (Elhai et al., 2012).

3. Pathophysiology

The 2023 Lancet Seminar organises the disease around three pathological hallmarks — inflammation, fibrosis and vasculopathy — and notes that labels such as "immunosuppressant" and "anti-fibrotic" oversimplify how the drugs work: mycophenolate and tocilizumab can have anti-fibrotic effects, and nintedanib can have anti-inflammatory ones (Volkmann 2023).

Vasculopathy

Microvascular damage and endothelial cell dysfunction are described as crucial in systemic sclerosis. Early in the disease, disturbance of the blood-vessel lining leads to overproduction of vasoactive factors such as the vasoconstrictor endothelin 1, together with platelet activation and increased expression of adhesion molecules. The result is recurrent ischaemia–reperfusion injury, abnormal regulation of reactive oxygen species and microvascular damage. There is growing recognition that vascular proliferation, rather than vasoconstriction, is a major driver of the serious vascular complications such as pulmonary arterial hypertension; dysfunction of bone morphogenetic protein receptor 2 signalling is associated with its development (Volkmann 2023). Raynaud's phenomenon and fatigue are among the earliest signs of the disease, though neither is specific to it.

Immune Activation

B cells infiltrate several organs in systemic sclerosis, including the skin, lungs and gastrointestinal tract, and can promote profibrotic T-helper-2 responses by inducing dendritic-cell maturation. Functional autoantibodies, for example against the angiotensin II type-1 receptor and the endothelin-1 type A receptor, have been found. Interleukin-6 (IL-6) levels are raised in some patients and correlate with the extent of skin involvement; C-reactive protein, whose rise is mediated by IL-6, is raised in a subset of patients and is associated with a higher risk of progressive fibrosis, pulmonary arterial hypertension and death (Volkmann 2023). Disease-specific autoantibodies, which mark distinct clinical subsets, are described under Diagnosis below.

Fibrosis

The distinguishing pathological hallmark is aberrant and excessive deposition of extracellular matrix, producing fibrosis in several organ systems. Contributors include increased myofibroblast activation, abnormal fibrotic signalling, and increased production and cross-linking of matrix molecules. Specific cytokines, chemokines and growth factors can induce myofibroblast differentiation; transforming growth factor-β (TGF-β) is a potent profibrotic mediator. The drug nintedanib inhibits several tyrosine-kinase receptors, including those for platelet-derived, fibroblast and vascular endothelial growth factors (Volkmann 2023).

4. Clinical Presentation

Raynaud's Phenomenon

Most people with systemic sclerosis have Raynaud's phenomenon, and it is often more severe than Raynaud's without an underlying disease (Thompson et al., 2001); in the validation sample of the 2013 classification criteria, 96% of the systemic sclerosis cases had it. The criteria define it as at least a two-phase colour change in the fingers, and often the toes, consisting of pallor, cyanosis and/or reactive hyperaemia in response to cold or emotion, usually with pallor as one phase (van den Hoogen et al., 2013). In a prospective study summarised in the 2023 Seminar, 65.9% of people with Raynaud's who had both a systemic sclerosis-specific antibody and a scleroderma pattern on nailfold capillaroscopy developed definite systemic sclerosis within 5 years and 72.7% within 10 years, compared with 1.3% at 5 years of those with neither. In the criteria's validation sample, 40% of the systemic sclerosis cases had digital tip ulcers and 39% had fingertip pitting scars.

Skin Involvement

Skin fibrosis starts in the distal fingers and toes and progresses proximally, and its extent varies widely between patients and within one patient over time. In the early phases the fingers become puffy from microvascular changes and inflammation; over time, excess collagen thickens the skin and limits movement over the joints, causing contractures of large and small joints in some patients; after years of disease the skin can become tight, "hide-bound" and sometimes atrophic (Volkmann 2023). The extent of skin thickening is measured with the modified Rodnan skin score (mRSS), in which a physician rates skin thickness on a 0–3 scale in 17 body areas (Khanna et al., 2017). The 2023 Seminar describes it as having acceptable reliability in diffuse disease but as unable to distinguish early fibrotic skin from the hide-bound skin of later disease. In the EUSTAR cohort, a higher skin score was an independent risk factor for death (hazard ratio 1.20 per 10 score points; Tyndall et al., 2010). Other skin features:

• Sclerodactyly — skin thickening of the fingers distal to the knuckles (metacarpophalangeal joints) but proximal to the proximal interphalangeal (PIP) joints (2013 criteria definitions)
• Calcinosis — calcium deposits in the skin, which develop in about 25% of patients; they are often painful and can push inwards into deeper tissue or outwards to cause ulceration (Volkmann 2023)
• Telangiectasias — in the scleroderma pattern, round, well-demarcated dilated vessels on the hands, lips and inside of the mouth, or large mat-like telangiectasias (2013 criteria definitions)
• Microstomia (a reduced mouth opening) and an itchy rash are among the symptoms for which the 2023 Seminar lists symptom treatments

Gastrointestinal Involvement

At least 90% of people with systemic sclerosis have gastrointestinal involvement, which can appear at any point in the disease (Volkmann 2023):

• Oesophagus — dysfunction is common and causes reflux with or without oesophagitis; oesophagitis can be symptom-free and is diagnosed by endoscopy; difficulty swallowing commonly follows oesophageal dysmotility
• Stomach — delayed gastric emptying causes abdominal distension and bloating, particularly after meals; gastric antral vascular ectasia ("watermelon stomach") is a potentially life-threatening cause of rapid or slow blood loss
• Lower gastrointestinal tract — involved in up to 50% of patients and associated with increased illness and death: small intestinal bacterial overgrowth (SIBO), malabsorption, constipation, diarrhoea and recurrent intestinal pseudo-obstruction, which affects 4–10% of patients and is painful, often recurrent and at times life-threatening
• Anorectal — dysfunction affects 22–77% of patients, most often as faecal incontinence; rectal prolapse can also occur
• Nutrition — severe lower-gut involvement can require total parenteral nutrition, and micronutrient deficiencies can occur

Pulmonary Involvement

• Interstitial lung disease (ILD) — now the leading cause of death in systemic sclerosis. About 50–65% of patients show interstitial lung abnormalities on high-resolution CT (HRCT); some have a stable course without treatment and others progress, rapidly or slowly. Non-specific interstitial pneumonia is the most common pattern on lung tissue, and usual interstitial pneumonia is present in 10–25% of cases (Volkmann 2023).
• Pulmonary arterial hypertension (PAH) — high blood pressure in the lung arteries, with a reported 3-year mortality between 21% and 48%. It is more prevalent in people with anti-centromere antibodies, extensive telangiectasias and longer disease duration, and possibly with anti-Th/To antibodies; compared with idiopathic PAH, systemic sclerosis-associated PAH has a poorer prognosis even with similar haemodynamics. Pulmonary pressure can also rise from left-heart disease, from ILD and, less commonly, from pulmonary veno-occlusive disease. Right-heart catheterisation is the gold standard for diagnosis (Volkmann 2023). In the London cohort, the cumulative incidence of pulmonary hypertension did not differ significantly between subtypes (24% in lcSSc, 18% in dcSSc), at 1–2% per year (Nihtyanova et al., 2014).

Scleroderma Renal Crisis

Scleroderma renal crisis (SRC) is a rapid deterioration of kidney function with malignant hypertension; untreated, it can progress to the need for kidney replacement within a few weeks. Its reported prevalence ranges from 1% to 14% by region, with the USA, the UK and Australia reporting the highest rates. Microangiopathic haemolytic anaemia with thrombocytopenia is common. Reported risk factors are diffuse disease, early disease, African American race, pericardial effusion, tendon friction rubs, recent use of more than 15 mg/day of prednisolone and anti-RNA polymerase III antibodies. Some patients are normotensive, and these patients have a poor prognosis (Volkmann 2023). In a case-control study of 110 patients with renal crisis, high-dose corticosteroids (15 mg/day or more of prednisone or equivalent) in the preceding 6 months had been given to 36% of cases versus 12% of matched controls (odds ratio 4.37), while new low-dose use was not associated with higher risk (Steen and Medsger, 1998).

Cardiac Involvement

No standardised definition of cardiac involvement in systemic sclerosis exists. Reported abnormalities include myocarditis, congestive heart failure, arrhythmia, symptom-free patchy fibrosis and impaired relaxation of the ventricles, and heart involvement accounts for a substantial share of disease-related deaths (Volkmann 2023). In the EUSTAR cohort, 26% of deaths attributed to systemic sclerosis were from cardiac causes, mainly heart failure and arrhythmias (Tyndall et al., 2010).

Musculoskeletal Involvement

Joint pain is common, and some patients develop erosive arthritis. Tendon friction rubs (a crackling felt over moving tendons) occur mainly early in diffuse disease and are a poor prognostic sign. Early diffuse disease can bring mild creatine kinase elevations from a scleroderma-specific myopathy, which typically resolve once immunomodulatory treatment starts, while a subgroup has a true overlap myositis with marked muscle-enzyme elevations (Volkmann 2023).

5. Diagnosis

2013 ACR/EULAR Classification Criteria

The 2013 ACR/EULAR classification criteria (van den Hoogen et al., PubMed PMID: 24092682) were built for research, to decide who can enter a study. The 2023 Seminar notes that they are not diagnostic criteria and that a diagnosis does not require meeting them. A total score of 9 or more classifies a patient as having definite systemic sclerosis; within each item, only the highest sub-item counts:

• Skin thickening of the fingers of both hands extending proximal to the metacarpophalangeal (MCP) joints — 9 points (sufficient on its own)
• Skin thickening of the fingers — puffy fingers 2 points, or sclerodactyly (distal to the MCP but proximal to the PIP joints) 4 points
• Fingertip lesions — digital tip ulcers 2 points, or fingertip pitting scars 3 points
• Telangiectasia — 2 points
• Abnormal nailfold capillaries — 2 points
• Pulmonary arterial hypertension and/or ILD — 2 points (maximum 2)
• Raynaud's phenomenon — 3 points
• Scleroderma-related antibodies (anti-centromere, anti-topoisomerase I, or anti-RNA polymerase III) — 3 points (maximum 3)

In the validation sample, sensitivity was 0.91 and specificity 0.92, against 0.75 and 0.72 for the 1980 criteria. The criteria are not applied to patients whose skin thickening spares the fingers, or to patients with a scleroderma-like disorder that better explains their findings (van den Hoogen et al., 2013).

Autoantibody Testing

A positive antinuclear antibody (ANA) by indirect immunofluorescence is found in up to 95% of patients. More specific antibodies mark distinct groups, and patients seldom produce more than one of them (Volkmann 2023, Table 1):

• Anti-centromere — limited disease; pulmonary arterial hypertension
• Anti-topoisomerase I (anti-Scl-70) — diffuse disease; progressive ILD. The Seminar notes that immunodiffusion is the preferred test method, because multibead assays have high false-positive rates
• Anti-RNA polymerase III — diffuse disease; renal crisis and cancer. Cancer screening regardless of age has been suggested for people who test positive at diagnosis
• Anti-U3-RNP (anti-fibrillarin) — diffuse disease; pulmonary arterial hypertension and myositis
• Anti-U1-RNP — limited disease; mixed connective tissue disease
• Anti-Pm-Scl — limited disease; myositis
• Anti-Th/To — limited disease; ILD and pulmonary arterial hypertension

In the Pittsburgh databank, anti-U3-RNP, anti-U1-RNP and anti-topoisomerase I antibodies were seen more often in African American patients and anti-centromere antibodies in older white women; renal crisis was strongly associated with anti-RNA polymerase III, and severe interstitial fibrosis was rarely seen with that antibody (Steen, 2005). A subgroup of patients has a positive ANA without any scleroderma-specific antibody; these patients can develop rapidly progressive disease with high mortality (Volkmann 2023).

Nailfold Capillaroscopy

Nailfold videocapillaroscopy examines the tiny blood vessels at the base of the fingernail. In a study of 97 consecutive patients, Cutolo and colleagues described three patterns: early (giant capillaries and haemorrhages, relevant to early diagnosis), active (the same changes, more evident) and late (loss of capillaries, disorganised vascular architecture and ramified or "bushy" capillaries, the clearest sign of advanced microvascular damage). The patterns correlated with the duration of both Raynaud's and systemic sclerosis and did not differ between limited and diffuse disease (Cutolo et al., 2000). The 2013 criteria describe the abnormal pattern as enlarged capillaries and/or capillary loss, with or without small haemorrhages.

Organ-Specific Assessment

The 2023 Lancet Seminar summarises the assessments used at diagnosis and repeated during the disease course, with screening adjusted to disease duration and progression:

• HRCT of the chest — the most sensitive way to detect early ILD; it can also show a widened (patulous) oesophagus or a dilated pulmonary artery
• Pulmonary function tests with forced vital capacity (FVC) and diffusing capacity (DLCO) — of limited sensitivity for diagnosing ILD but central to monitoring its progression; a fall in DLCO out of proportion to FVC, or an isolated fall in DLCO, can suggest pulmonary hypertension. A clinical practice guideline defines progressive pulmonary fibrosis as meeting at least two of three criteria within the past year (worsening symptoms, radiological progression and physiological progression) with no other explanation
• Echocardiogram and electrocardiogram — the Seminar describes heart evaluation with both regardless of symptoms, with cardiac MRI when they suggest involvement and Holter recording or an implantable loop recorder for those at risk of serious arrhythmia
• NT-proBNP — a blood marker of early pulmonary arterial hypertension, used with algorithms such as DETECT to select patients for right-heart catheterisation
• Blood markers of lung disease — C-reactive protein, IL-6, Krebs von den Lungen-6 and chemokine ligand 18 have been linked to ILD severity or progression
• Systolic blood pressure — described as paramount for timely detection of renal crisis, with a blood smear for haemolysis
• Upper endoscopy in patients with anaemia, because of gastric antral vascular ectasia
• mRSS to follow skin disease

6. Treatment

The 2023 Seminar notes that no single treatment algorithm fits all patients, that evidence-based clinical practice guidelines do not exist for some complications such as gastrointestinal and cardiac involvement, and that referral to a scleroderma centre may improve care. The 2016 EULAR recommendations cover Raynaud's phenomenon, digital ulcers, pulmonary arterial hypertension, skin and lung disease, renal crisis and gastrointestinal involvement (Kowal-Bielecka et al., 2017). Doses below are those used in the trials named, not instructions; decisions about medicines belong with a clinician.

Raynaud's Phenomenon and Digital Ulcers

• Calcium channel blockers — the dihydropyridines nifedipine and amlodipine are commonly used as first-line drugs (Volkmann 2023). A meta-analysis of 8 small randomised trials (109 patients with systemic sclerosis) found fewer and less severe attacks — a mean of 8.3 fewer attacks in 2 weeks and 35% less severity — and its authors judged the effect "moderate at best" (Thompson et al., 2001)
• Phosphodiesterase-5 (PDE-5) inhibitors (sildenafil, tadalafil) — the 2016 EULAR recommendations added them for Raynaud's and digital ulcers; the 2023 Seminar describes varying amounts of evidence and lists them, with bosentan, as often used second-line for Raynaud's and first-line for digital ulcers
• Fluoxetine — added to the EULAR recommendations for Raynaud's in 2016; the Seminar lists it, with iloprost, as often considered for treatment-refractory Raynaud's and digital ulcers
• Intravenous iloprost — a prostacyclin analogue considered for severe refractory Raynaud's with digital ischaemia; the Seminar reports it prevents new digital ulcers and helps existing ones heal
• Bosentan (an endothelin receptor antagonist) — in two placebo-controlled trials it reduced the number of new digital ulcers (by 48% over 16 weeks in 122 patients, Korn et al., 2004; by 30% over 24 weeks in 188 patients in RAPIDS-2, Matucci-Cerinic et al., 2011) but did not speed healing of existing ulcers; raised liver enzymes occurred with bosentan in both trials

Interstitial Lung Disease

• Mycophenolate mofetil (MMF) — in Scleroderma Lung Study II (142 patients), 24 months of MMF (target dose 1,500 mg twice daily) was compared with 12 months of oral cyclophosphamide followed by 12 months of placebo. FVC (% predicted) improved by 2.19 points with MMF and 2.88 with cyclophosphamide, with no significant difference between the groups, so the trial was negative for its primary endpoint: the hypothesis that MMF would be more effective at 24 months was not confirmed. In a post-hoc analysis, FVC improved significantly within both groups. MMF was better tolerated: leucopenia occurred in 4 patients on MMF versus 30 on cyclophosphamide and thrombocytopenia in 0 versus 4, and fewer patients on MMF stopped the study drug early (20 vs 32). The authors concluded that the findings support the present preference for MMF because of its better tolerability and toxicity profile (Tashkin et al., 2016), and the 2023 Seminar describes MMF as the common first-line therapy for SSc-ILD.
• Nintedanib — in the SENSCIS trial (576 patients; 150 mg twice daily; 48.4% already on mycophenolate), the adjusted annual rate of FVC decline was 52.4 mL per year with nintedanib versus 93.3 mL per year with placebo (difference 41.0 mL per year, P = 0.04; sensitivity analyses gave P values of 0.06 to 0.10). Skin score and respiratory quality of life did not differ, and diarrhoea was reported in 75.7% on nintedanib versus 31.6% on placebo (Distler et al., PubMed PMID: 31112379). The Seminar reports that patients already on mycophenolate who were assigned nintedanib had the slowest decline, and lists nintedanib among second-line options. The FDA approved nintedanib on 6 September 2019 "to slow the rate of decline in pulmonary function" in SSc-ILD (FDA approval letter, NDA 205832/S-012).
• Cyclophosphamide — in Scleroderma Lung Study I (158 patients), one year of oral cyclophosphamide had a significant but modest benefit on lung function (a 2.53-point difference in FVC % predicted at 12 months), breathlessness, skin thickening and quality of life, with more adverse events than placebo (Tashkin et al., 2006). The Seminar notes that it is typically not a first-line drug because of its safety profile, including a raised risk of cancer; leucopenia, neutropenia and blood in the urine were more common than with placebo.
• Tocilizumab (an IL-6 receptor antibody) — neither the phase 2 faSScinate trial (87 patients; Khanna et al., 2016) nor the phase 3 focuSSced trial (210 patients with early diffuse disease, 162 mg subcutaneously each week; Khanna et al., 2020) met its primary skin-score endpoint. In focuSSced, FVC % predicted at 48 weeks, a secondary endpoint, favoured tocilizumab (difference 4.2 points, nominal P = 0.0002). The FDA approved it on 4 March 2021 for slowing the rate of decline in pulmonary function in adults with SSc-ILD (FDA approval letter, BLA 125276/S-131).
• Rituximab (an anti-CD20 antibody) — the Seminar describes a 56-patient randomised trial in which it improved skin score compared with placebo at 6 months, and a trial against cyclophosphamide in connective-tissue-disease ILD with similar lung-function gains and better tolerability; it is associated with impaired antibody responses to COVID-19 vaccination
• Autologous haematopoietic stem cell transplantation (HSCT) — compared with monthly intravenous cyclophosphamide in two randomised trials. In ASTIS (156 patients with early diffuse disease), the transplant group had more events in the first year (13 events, including 8 treatment-related deaths, versus 8 events and no treatment-related deaths) but better long-term event-free survival (hazard ratio 0.34 at 4 years; van Laar et al., 2014). In SCOT (36 transplant and 39 cyclophosphamide participants with severe disease), the composite primary endpoint at 54 months favoured transplantation; at 72 months, event-free survival was 74% versus 47% and overall survival 86% versus 51%, with treatment-related mortality of 3% at 54 months and 6% at 72 months versus 0% (Sullivan et al., PubMed PMID: 29298160). The Seminar describes HSCT as costly and associated with life-threatening adverse events, generally considered for early diffuse disease as a second-line approach or, in carefully selected patients, first-line; the 2016 EULAR recommendations added it for selected patients with rapidly progressive disease.

Pulmonary Arterial Hypertension

The 2023 Seminar lists sildenafil or tadalafil and bosentan or ambrisentan, alone or in combination, as commonly used first-line for systemic sclerosis-associated PAH, with selexipag, riociguat and prostacyclin therapy most often second-line. Studies have associated combination therapy with a PDE-5 inhibitor and an endothelin receptor antagonist with better survival than monotherapy, and early combination therapy is often favoured over sequential add-on therapy:

• Endothelin receptor antagonists (ambrisentan, bosentan, macitentan) — approved for PAH; for bosentan and ambrisentan the Seminar lists improved exercise capacity, haemodynamics and functional class, with lower-leg swelling and liver-function test abnormalities as safety issues (Volkmann 2023)
• PDE-5 inhibitors (sildenafil, tadalafil) — improved exercise capacity, haemodynamics and functional class; hypotension is a concern, particularly with other vasodilators. In the AMBITION trial of 500 previously untreated people with PAH of any cause (WHO functional class II or III), initial ambrisentan 10 mg plus tadalafil 40 mg once daily lowered the risk of clinical failure compared with either drug alone (18% vs 31% of the pooled monotherapy groups; hazard ratio 0.50) (Galiè et al., 2015)
• Prostacyclin-pathway drugs — intravenous epoprostenol, subcutaneous treprostinil and the oral prostacyclin-receptor agonist selexipag are associated with improved outcomes in systemic sclerosis-associated PAH (Volkmann 2023)
• Riociguat (a soluble guanylate cyclase stimulator) — improved haemodynamics, functional class and 6-minute walk distance in a trial of connective-tissue-disease PAH in which 66 of 111 patients had systemic sclerosis (Volkmann 2023). The US label lists use with PDE-5 inhibitors and pregnancy among its contraindications (FDA drug label, openFDA)
• Other causes of pulmonary hypertension — PAH drugs may bring little benefit when pulmonary hypertension comes from left-heart disease, and in patients with both pulmonary hypertension and ILD, starting vasodilators can precipitate pulmonary oedema (Volkmann 2023)

Scleroderma Renal Crisis

• ACE inhibitors — the 2023 Seminar reports that early treatment with angiotensin-converting enzyme inhibitors improved 1-year survival after renal crisis from 10% to 85%
• Long-term outcomes — in a cohort of 145 patients with renal crisis treated with ACE inhibitors, 61% had good outcomes (no dialysis or temporary dialysis); more than half of those who first needed dialysis could stop it 3 to 18 months later, and 39% had bad outcomes (permanent dialysis or early death). The authors' conclusion favoured continuing ACE inhibitors even after dialysis begins, in the hope that dialysis can later be stopped (Steen and Medsger, 2000)
• ACE inhibitors before renal crisis — observational studies linked previous ACE inhibitor exposure with worse outcomes once renal crisis began, and possibly with a higher risk of it; the Seminar calls this controversial because the data are subject to confounding
• Corticosteroids — the authors of the 1998 case-control study concluded that their results argue against high-dose corticosteroids in early diffuse scleroderma in people at increased risk of renal crisis (Steen and Medsger, 1998)

Gastrointestinal Management

Treatments listed for gastrointestinal symptoms in the 2023 Seminar are proton pump inhibitors, histamine-2 receptor blockers and dietary adjustments for heartburn and reflux; promotility drugs (such as prucalopride), antibiotics when SIBO is present, and small, frequent meals for distension and bloating; dietary adjustments, antibiotics for SIBO and anti-diarrhoeal drugs for diarrhoea; laxatives and promotility drugs for constipation; and physiotherapy, biofeedback and sacral nerve stimulation for faecal incontinence. Some patients with severe lower-gut involvement need total parenteral nutrition. The Seminar notes that these recommendations rest on observational studies and expert opinion, and rigorous trials are scarce.

Skin and Musculoskeletal Disease

• Mycophenolate — the 2023 Seminar describes it as commonly used first-line for diffuse cutaneous disease, citing clinically meaningful decreases in skin score; rituximab, cyclophosphamide and HSCT are most often used for treatment-refractory diffuse disease
• Methotrexate — in a 71-patient placebo-controlled trial in early diffuse disease, results trended in favour of methotrexate, but the differences were small and the authors concluded that the trial did not show it to be significantly effective (Pope et al., 2001)
• Joint contractures — the Seminar lists physiotherapy, occupational therapy and infrared heat
• Calcinosis — the Seminar lists surgical excision, bisphosphonates and diltiazem, while noting that rigorous trials for these symptom treatments are scarce

7. Complications

• Interstitial lung disease — the leading cause of death; in the EUSTAR cohort, 35% of deaths attributed to systemic sclerosis were from pulmonary fibrosis (Tyndall et al., 2010)
• Pulmonary arterial hypertension — 26% of the EUSTAR disease-related deaths; a reported 3-year mortality of 21–48% (Volkmann 2023)
• Heart involvement — 26% of the EUSTAR disease-related deaths, mainly heart failure and arrhythmias
• Scleroderma renal crisis — in the 145-patient ACE-inhibitor cohort, 39% had permanent dialysis or early death (Steen and Medsger, 2000)
• Digital ulcers — present in 40% of the systemic sclerosis cases in the 2013 criteria validation sample; recurrent ulcers lead to pain, impaired function and tissue loss (Korn et al., 2004)
• Gastrointestinal complications — intestinal pseudo-obstruction (4–10% of patients) and bleeding from gastric antral vascular ectasia can be life-threatening; malnutrition can impair immune function and raise the risk of opportunistic infection, especially with immunomodulatory drugs (Volkmann 2023)
• Joint contractures — of large and small joints in some patients, from skin fibrosis
• Calcinosis — in about 25% of patients; often painful and can ulcerate
• Cancer — people with systemic sclerosis are at heightened risk of certain cancers, particularly those with anti-RNA polymerase III antibodies (Volkmann 2023); in EUSTAR, cancers caused 31% of the deaths not attributed to the disease
• Infections — infections caused 33% of the EUSTAR deaths not attributed to the disease, and a quarter of all deaths not attributed to the disease were from causes such as pneumonia, sepsis and gastrointestinal bleeding in which disease complications may have played a part (Tyndall et al., 2010)
• Erectile dysfunction — many men with systemic sclerosis have severe erectile dysfunction, for which current therapies have limited success
• Fatigue and depression — fatigue is common and often refractory; depression is common and can reduce adherence to treatment and quality of life
• Pregnancy — associated with an increased risk of complications for both mother and baby (Volkmann 2023)

8. Prognosis

Survival figures vary by cohort and era. In the Detroit census, median survival was approximately 11 years (Mayes et al., 2003). In the London cohort of 398 patients followed for up to 15 years, survival at the end of follow-up was 57% in limited and 50% in diffuse disease (Nihtyanova et al., 2014). At one US centre, 10-year survival rose from 54% to 66% across five 5-year periods of patients first seen between 1972 and 1996 (Steen and Medsger, 2007). The 2023 Seminar notes that advances in the treatment and timely diagnosis of PAH have improved its prognosis.

Causes of death: in the EUSTAR cohort (5,860 patients), 55% of deaths were attributed directly to systemic sclerosis and 41% to other causes. Of the disease-related deaths, 35% were from pulmonary fibrosis, 26% from PAH and 26% from heart causes; among the other deaths, infections (33%), cancers (31%) and cardiovascular causes (29%) led (Tyndall et al., 2010). A meta-analysis of nine cohort studies found heart involvement the most frequent cause among 732 deaths (29%), followed by lung involvement (Elhai et al., 2012). At one US centre, renal crisis fell from 42% to 6% of scleroderma-related deaths between 1972 and 2002 (Steen and Medsger, 2007).

Autoantibodies and organ risk: in the London cohort, anti-topoisomerase I antibodies predicted clinically significant pulmonary fibrosis and anti-centromere antibodies were protective against it, while anti-RNA polymerase III or anti-U3-RNP antibodies were associated with a higher risk of pulmonary hypertension and anti-topoisomerase I with a lower one (Nihtyanova et al., 2014). In the Pittsburgh databank, survival within limited disease was lower with anti-Th/To than with anti-centromere antibodies, and within diffuse disease patients with anti-RNA polymerase III had the best survival (Steen, 2005).

Other predictors of worse survival: in EUSTAR, independent risk factors for death were proteinuria (hazard ratio 3.34), PAH on echocardiography (2.02), FVC below 80% of predicted (1.64), breathlessness above New York Heart Association class II (1.61), lower DLCO (1.20 per 10% decrease), older age at onset of Raynaud's (1.30 per 10 years) and higher skin score (1.20 per 10 points) (Tyndall et al., 2010). In the London cohort, greater age at onset, diffuse disease, lower DLCO, lower haemoglobin, higher serum creatinine, and pulmonary hypertension or heart involvement independently predicted worse survival (Nihtyanova et al., 2014); in Detroit, male sex was associated with shorter survival (hazard ratio 1.81). The 2023 Seminar notes that systemic sclerosis can drastically alter quality of life and life expectancy, that patients often face considerable personal health-care costs, and that it is not uncommon for patients to have to stop working.

Table of Contents

1. Overview
2. Epidemiology
3. Pathophysiology
4. Clinical Presentation
5. Diagnosis
6. Treatment
7. Complications
8. Prognosis
9. Key Research Papers
10. Connections
11. Featured Videos

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Key Research Papers

1. Volkmann ER, Andréasson K, Smith V, 2023: Systemic sclerosis. Lancet. 401(10373):304–318. — PubMed PMID: 36442487
2. van den Hoogen F et al., 2013: 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Ann Rheum Dis. 72(11):1747–1755 (also published in Arthritis Rheum. 65(11):2737–2747, PubMed PMID: 24122180). — PubMed PMID: 24092682
3. Tashkin DP et al., 2016: Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med. 4(9):708–719. — PubMed PMID: 27469583
4. Distler O et al., 2019: Nintedanib for systemic sclerosis-associated interstitial lung disease (SENSCIS trial). N Engl J Med. 380(26):2518–2528. — PubMed PMID: 31112379
5. Steen VD, Medsger TA Jr, 2000: Long-term outcomes of scleroderma renal crisis. Ann Intern Med. 133(8):600–603. — PubMed PMID: 11033587
6. Steen VD, 2005: Autoantibodies in systemic sclerosis. Semin Arthritis Rheum. 35(1):35–42. — PubMed PMID: 16084222
7. Matucci-Cerinic M et al., 2011: Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 70(1):32–38. — PubMed PMID: 20805294
8. Korn JH et al., 2004: Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum. 50(12):3985–3993. — PubMed PMID: 15593188
9. van Laar JM et al., 2014: Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial (ASTIS). JAMA. 311(24):2490–2498. — PubMed PMID: 25058083
10. Sullivan KM et al., 2018: Myeloablative autologous stem-cell transplantation for severe scleroderma (SCOT trial). N Engl J Med. 378(1):35–47. — PubMed PMID: 29298160
11. Cutolo M et al., 2000: Nailfold videocapillaroscopy assessment of microvascular damage in systemic sclerosis. J Rheumatol. 27(1):155–160. — PubMed PMID: 10648032
12. Tashkin DP et al., 2006: Cyclophosphamide versus placebo in scleroderma lung disease (SLS I trial). N Engl J Med. 354(25):2655–2666. — PubMed PMID: 16790698
13. Khanna D et al., 2016: Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet. 387(10038):2630–2640. — PubMed PMID: 27156934
14. Khanna D et al., 2020: Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial (focuSSced). Lancet Respir Med. 8(10):963–974. — PubMed PMID: 32866440
15. Kowal-Bielecka O et al., 2017: Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 76(8):1327–1339. — PubMed PMID: 27941129
16. Bairkdar M et al., 2021: Incidence and prevalence of systemic sclerosis globally: a comprehensive systematic review and meta-analysis. Rheumatology (Oxford). 60(7):3121–3133. — PubMed PMID: 33630060
17. Mayes MD et al., 2003: Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 48(8):2246–2255. — PubMed PMID: 12905479
18. Arnett FC et al., 1996: Increased prevalence of systemic sclerosis in a Native American tribe in Oklahoma. Association with an Amerindian HLA haplotype. Arthritis Rheum. 39(8):1362–1370. — PubMed PMID: 8702445
19. Arnett FC et al., 2001: Familial occurrence frequencies and relative risks for systemic sclerosis (scleroderma) in three United States cohorts. Arthritis Rheum. 44(6):1359–1362. — PubMed PMID: 11407695
20. Elhai M et al., 2012: Trends in mortality in patients with systemic sclerosis over 40 years: a systematic review and meta-analysis of cohort studies. Rheumatology (Oxford). 51(6):1017–1026. — PubMed PMID: 21900368
21. Steen VD, Medsger TA, 2007: Changes in causes of death in systemic sclerosis, 1972–2002. Ann Rheum Dis. 66(7):940–944. — PubMed PMID: 17329309
22. Tyndall AJ et al., 2010: Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis. 69(10):1809–1815. — PubMed PMID: 20551155
23. Nihtyanova SI et al., 2014: Prediction of pulmonary complications and long-term survival in systemic sclerosis. Arthritis Rheumatol. 66(6):1625–1635. — PubMed PMID: 24591477
24. Cottrell TR et al., 2014: The degree of skin involvement identifies distinct lung disease outcomes and survival in systemic sclerosis. Ann Rheum Dis. 73(6):1060–1066. — PubMed PMID: 23606705
25. Khanna D et al., 2017: Standardization of the modified Rodnan skin score for use in clinical trials of systemic sclerosis. J Scleroderma Relat Disord. 2(1):11–18. — PubMed PMID: 28516167
26. Steen VD, Medsger TA Jr, 1998: Case-control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis. Arthritis Rheum. 41(9):1613–1619. — PubMed PMID: 9751093
27. Thompson AE et al., 2001: Calcium-channel blockers for Raynaud's phenomenon in systemic sclerosis. Arthritis Rheum. 44(8):1841–1847. — PubMed PMID: 11508437
28. Pope JE et al., 2001: A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma. Arthritis Rheum. 44(6):1351–1358. — PubMed PMID: 11407694
29. Galiè N et al., 2015: Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension (AMBITION). N Engl J Med. 373(9):834–844. — PubMed PMID: 26308684
30. Nahar NU et al., 2025: Echoes of scleroderma: a case report unmasking CREST (calcinosis, Raynaud's phenomenon, oesophageal dysmotility, sclerodactyly, and telangiectasia) syndrome with point-of-care ultrasound in acute medicine. Cureus. 17(10):e95671. — PubMed PMID: 41322914

PubMed Topic Searches

1. PubMed: Topic search: SSc pulmonary arterial hypertension treatment
2. PubMed: Topic search: SSc gastrointestinal dysmotility SIBO malabsorption
3. PubMed: Topic search: TGF-beta fibrosis scleroderma myofibroblast

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Connections

• Rheumatology
• Raynaud's Disease
• Sjogren's Syndrome
• Lupus
• Rheumatoid Arthritis
• Antiphospholipid Syndrome
• Interstitial Lung Disease
• Pulmonary Hypertension
• Chronic Kidney Disease
• SIBO
• GERD
• Vasculitis
• Fibromyalgia
• Hypothyroidism
• Vitamin D3
• Magnesium
• Turmeric
• NAC (N-Acetylcysteine)
• Fatigue
• Osteoporosis
• Ehlers-Danlos Syndrome
• Scleroderma (Systemic Sclerosis) — the dermatology view of the same spectrum, including the skin-limited forms.
• Morphea (Localized Scleroderma) — skin-only fibrosis with no Raynaud's and no internal organ involvement.

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Featured Videos