Scleroderma (Systemic Sclerosis)

Table of Contents

  1. Overview
  2. Classification: Limited vs Diffuse Systemic Sclerosis
  3. Raynaud's Phenomenon: The First Sign
  4. Skin Manifestations
  5. Internal Organ Involvement
  6. Diagnosis and Monitoring
  7. Treatment: Disease-Modifying Therapies
  8. Living with Scleroderma
  9. Complementary and Supportive Approaches
  10. Key Research Papers
  11. Connections
  12. Featured Videos

Overview

Scleroderma — from the Greek for "hard skin" — is the common name for systemic sclerosis, an immune-mediated rheumatic disease characterised by fibrosis of the skin and internal organs and by damage to small blood vessels (vasculopathy). The organ systems most often affected are the skin, the gastrointestinal tract and the lungs; the heart and kidneys can also be involved (Volkmann et al., 2023 Lancet Seminar, PubMed PMID: 36442487). Most people with systemic sclerosis have Raynaud's phenomenon, and it is often more severe than Raynaud's without an underlying disease (Thompson 2001); in the validation sample of the 2013 classification criteria, 96% of the systemic sclerosis cases had it (van den Hoogen 2013).

Scleroderma is not a single disease but a spectrum. The word refers both to a purely skin-limited form (morphea, covered separately on the Morphea page) and to two systemic forms that are the focus of this article: limited cutaneous systemic sclerosis (lcSSc) and diffuse cutaneous systemic sclerosis (dcSSc).

A census of the Detroit area (1989–1991) estimated a prevalence of 276 cases per million adults. Prevalence was significantly higher in women than in men and in Black than in white adults; Black patients were almost twice as likely as white patients to have diffuse disease, and male sex and older age at diagnosis were associated with shorter survival (Mayes et al., 2003).

There is no cure. Survival has changed 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 the share of deaths from scleroderma renal crisis fell (Steen and Medsger, 2007). In a 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).

Classification: Limited vs Diffuse Systemic Sclerosis

Systemic sclerosis is divided into subsets by how far skin thickening extends. In the scheme used by a 2,205-patient cohort study, skin involvement distal to the elbows and knees corresponds to the limited form and involvement proximal to the elbows and knees to the diffuse form (Cottrell et al., 2014). That study also found an intermediate group whose autoantibody profile, lung-disease risk and survival differed from both, and its authors concluded that the two-subset classification misclassifies these patients. A small subset (under 5%) of people with established disease have no clinically detectable skin fibrosis, classed as systemic sclerosis sine scleroderma (Volkmann 2023).

Limited Cutaneous Systemic Sclerosis (lcSSc)

In lcSSc, skin thickening stays distal to the elbows and knees. A limited form of systemic sclerosis is also called CREST syndrome, an acronym for its main features (Nahar et al., 2025):

The antibody most associated with lcSSc is anti-centromere antibody (ACA), which is linked to pulmonary arterial hypertension (Volkmann 2023, Table 1). In the Pittsburgh databank, ACA was seen more often in older, white women (Steen, 2005). In people with lcSSc, the first symptom other than Raynaud's typically appears 5 to 10 years after Raynaud's begins (Volkmann 2023).

Diffuse Cutaneous Systemic Sclerosis (dcSSc)

In 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 (Volkmann 2023). In the London cohort, clinically significant pulmonary fibrosis developed in 42% of patients with dcSSc and 22% with lcSSc over the follow-up period (Nihtyanova et al., 2014).

Antibodies associated with dcSSc include:

Overlap Syndromes

Some people with systemic sclerosis also have features of other autoimmune diseases, such as rheumatoid arthritis, Sjögren's syndrome, myositis or primary biliary cholangitis. The 2023 Lancet Seminar describes these overlap syndromes as poorly defined clinically (Volkmann 2023). Antibody links reported there include:

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Raynaud's Phenomenon: The First Sign

Raynaud's phenomenon is episodic narrowing of the small arteries of the fingers (and often the toes) in response to cold or emotion. The 2013 classification criteria define it as at least a two-phase colour change consisting of:

  1. Pallor (white) — usually one of the phases
  2. Cyanosis (blue)
  3. Reactive hyperaemia (red) — as blood flow returns

Raynaud's phenomenon and fatigue are among the earliest signs of systemic sclerosis, though neither is specific to it (Volkmann 2023). The gap before other features appear depends on the subset: typically 1–2 years in dcSSc and 5–10 years in lcSSc.

Primary vs Secondary Raynaud's

Primary Raynaud's occurs without an underlying disease. Secondary Raynaud's — associated with systemic sclerosis or other connective tissue diseases — is often more severe (Thompson 2001) and can be accompanied by digital ulcers and pitting scars at the fingertips.

Nailfold capillaroscopy is a non-invasive examination of the tiny blood vessels at the base of the fingernail, used to distinguish primary from secondary Raynaud's and to monitor disease progression (Smith et al., 2020). The 2013 criteria describe the abnormal pattern as enlarged capillaries and/or capillary loss, with or without small haemorrhages. In the studies summarised in the 2023 Lancet Seminar, 65.9% of people with Raynaud's who had both a systemic sclerosis-specific antibody and a scleroderma pattern on capillaroscopy developed definite systemic sclerosis within 5 years, compared with 1.3% of those with neither.

Raynaud's Treatments Studied in Systemic Sclerosis

Digital ulcers — painful sores on the fingertips — are a major source of disability. In two placebo-controlled trials, the endothelin receptor antagonist bosentan 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, RAPIDS-2, Matucci-Cerinic et al., 2011) but did not speed healing of existing ulcers; raised liver enzymes occurred with bosentan in both trials. In the United States, the FDA label for bosentan lists pulmonary arterial hypertension as its indication, not digital ulcers (FDA drug label, openFDA).

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Skin Manifestations

Skin fibrosis in systemic sclerosis starts in the fingers and toes and moves towards the trunk (proximally), and its extent varies widely between people and over time (Volkmann 2023).

Edematous Phase

In the early phases, the fingers become puffy from small-vessel changes and inflammation. The 2013 criteria define puffy fingers as a diffuse, usually non-pitting swelling of the digits that hides the normal tapered contours of the fingers.

Induration Phase

Over time, excess collagen thickens the skin and limits movement over the joints, leading in some patients to contractures of large and small joints. Sclerodactyly is skin thickening of the fingers. The degree of skin thickening is measured by the modified Rodnan skin score (mRSS), in which a physician rates skin thickness from 0 to 3 in 17 body areas (Khanna et al., 2017); it is the usual skin outcome in clinical trials.

Other skin features include:

Atrophic Phase

After years of disease, the skin can become tight, "hide-bound" and sometimes atrophic (thinned) (Volkmann 2023).

Facial Changes

Microstomia (a reduced mouth opening) is a recognised problem; mouth-stretching and oral exercises, and botulinum toxin or hyaluronidase injections, are among the symptom treatments listed in the 2023 Seminar, which notes that rigorous trials for these symptom treatments are scarce.

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Internal Organ Involvement

Internal organ involvement, rather than skin disease, accounts for most deaths. In the EUSTAR cohort (5,860 patients), 55% of deaths were attributed directly to systemic sclerosis; of these, 35% were from pulmonary fibrosis, 26% from pulmonary arterial hypertension and 26% from heart causes (Tyndall et al., 2010). At one US centre, renal crisis fell from 42% to 6% of scleroderma-related deaths over the 30-year study period (1972–2002), while pulmonary fibrosis rose from 6% to 33% (Steen and Medsger, 2007).

Lungs

Interstitial lung disease (ILD) — scarring of lung tissue — is 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 (Volkmann 2023). Male patients, African American patients and those with anti-Scl-70 antibodies are more likely to have progressive ILD in observational studies, although one analysis of two trials found similar outcomes in African American and other participants. Pulmonary function tests measure forced vital capacity (FVC) and diffusing capacity (DLCO); they are central to monitoring progression.

Drugs studied in randomised trials for SSc-ILD:

Pulmonary arterial hypertension (PAH) — high blood pressure in the lung arteries — is reported in the 2023 Seminar as more prevalent in people with anti-centromere antibodies, extensive telangiectasias and longer disease duration, with a reported 3-year mortality between 21% and 48%. In the London cohort, the cumulative incidence of pulmonary hypertension did not differ significantly between subsets (24% in lcSSc, 18% in dcSSc), at 1–2% per year (Nihtyanova et al., 2014). Right-heart catheterisation is the gold standard for diagnosis. Drugs used for systemic sclerosis-associated PAH include:

Gastrointestinal Tract

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

Kidneys: Scleroderma Renal Crisis

Scleroderma renal crisis (SRC) is a rapid decline in kidney function with malignant hypertension. Its reported prevalence ranges from 1% to 14% by region. Reported risk factors include diffuse disease, early disease, African American race, pericardial effusion, tendon friction rubs, anti-RNA polymerase III antibodies and recent use of more than 15 mg/day of prednisolone. Some patients are normotensive, and they have a poor prognosis (Volkmann 2023).

The 2023 Seminar reports that early treatment with angiotensin-converting enzyme (ACE) inhibitors improved 1-year survival after renal crisis from 10% to 85%. In a cohort of 145 patients treated with ACE inhibitors, 61% had good outcomes; more than half of those who needed dialysis at first could stop it 3 to 18 months later, and 39% had bad outcomes (permanent dialysis or early death). The authors concluded that patients should continue ACE inhibitors even after starting dialysis (Steen and Medsger, 2000). Taking an ACE inhibitor to prevent renal crisis is a different question: observational studies linked prior ACE inhibitor use with worse outcomes once renal crisis began, a finding the 2023 Seminar calls controversial because of confounding.

Corticosteroids and renal crisis: 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 were used by 36% of cases versus 12% of matched controls (odds ratio 4.37); new low-dose use was not associated with higher risk. The authors concluded that the results argue against high-dose corticosteroids in early diffuse scleroderma (Steen and Medsger, 1998).

Heart

Heart involvement includes myocarditis, congestive heart failure, arrhythmias, symptom-free patchy fibrosis and impaired relaxation of the heart muscle, and it accounts for a substantial share of disease-related deaths. The 2023 Seminar states that patients should have an electrocardiogram and echocardiogram regardless of symptoms, with cardiac MRI when those suggest involvement and Holter monitoring or an implantable loop recorder for those at risk of serious arrhythmia.

Joints and Muscles

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 signal a poorer prognosis (Volkmann 2023).

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Diagnosis and Monitoring

2013 ACR/EULAR Classification Criteria

The 2013 ACR/EULAR classification criteria (van den Hoogen et al., PubMed PMID: 24092682; also published in Arthritis & Rheumatism) were built for research, to decide who can enter a study. They are not diagnostic criteria, and a diagnosis does not require meeting them (Volkmann 2023). In the validation sample, their sensitivity was 0.91 and specificity 0.92, against 0.75 and 0.72 for the 1980 criteria. A total score of 9 or more classifies a patient as having definite systemic sclerosis; within each item, only the highest sub-item counts:

Key Antibody Tests

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

In the Pittsburgh databank, anti-U3-RNP, anti-U1-RNP and anti-topoisomerase I antibodies were seen more often in African American patients (Steen, 2005). A subgroup of patients has a positive ANA without any scleroderma-specific antibody; these patients can have rapidly progressive disease with high mortality (Volkmann 2023).

Baseline Workup and Monitoring

The 2023 Lancet Seminar summarises the assessments used at diagnosis and during the disease course:

Screening is repeated during the disease course and adjusted to disease duration and progression (Volkmann 2023).

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Treatment: Disease-Modifying Therapies

There is currently no cure for scleroderma. Treatment targets skin and organ fibrosis, symptoms and organ-specific complications. The 2023 Lancet Seminar notes that referral to a scleroderma centre may improve care through early diagnosis and risk stratification.

Skin and Immune Disease

Autologous Hematopoietic Stem Cell Transplantation (HSCT)

Autologous HSCT (high-dose immune suppression followed by return of the patient's own stem cells) has been compared with monthly intravenous cyclophosphamide in two randomised trials:

The 2016 EULAR recommendations added HSCT for selected patients with rapidly progressive disease (Kowal-Bielecka et al., 2017).

ILD-Specific Treatment

As described in the organ involvement section, the SENSCIS trial found that nintedanib slowed the decline in FVC over 52 weeks compared with placebo, with no benefit for skin or other manifestations (Distler et al., PubMed PMID: 31112379). The 2023 Seminar reports that patients already on mycophenolate who were assigned nintedanib had the slowest decline, and it describes MMF as the common first-line drug, with nintedanib, rituximab, cyclophosphamide and HSCT most often used second-line; tocilizumab can be considered first- or second-line in early ILD with signs of active inflammation.

Raynaud's and Digital Ulcers

See the Raynaud's section above for the trial evidence. Bosentan reduced new digital ulcers in two trials but did not speed healing; in the United States it is labelled for pulmonary arterial hypertension.

PAH Treatment

The 2023 Seminar reports that early combination therapy is often favoured over sequential add-on therapy for systemic sclerosis-associated PAH, and that its treatment often involves pulmonologists and cardiologists. For pulmonary hypertension caused by left-heart disease, PAH drugs may bring little benefit, and in patients with both pulmonary hypertension and ILD, vasodilators can precipitate pulmonary oedema.

Gastroprotection and GI Management

Treatments listed for gastrointestinal symptoms in the 2023 Seminar are proton pump inhibitors, H2 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; and laxatives or anti-diarrhoeal drugs as needed. Some patients with severe lower-gut involvement need total parenteral nutrition, and micronutrient deficiencies can occur. The Seminar notes that rigorous trials for these symptom treatments are scarce.

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Living with Scleroderma

Systemic sclerosis can change daily life a great deal. The 2023 Lancet Seminar notes that it can drastically alter quality of life, that patients often bear considerable personal health-care costs, and that it is not uncommon for patients to stop working.

Hand Function

For joint contractures, the 2023 Seminar lists physiotherapy, occupational therapy and infrared heat. The evidence on paraffin wax baths is mixed: in a 17-patient pilot study, the hand treated with paraffin plus exercise improved more in extension, stiffness and skin elasticity than the hand treated with exercise alone (Sandqvist et al., 2004), but a 36-patient randomised trial found no added benefit of daily wax baths over daily hand exercises alone (Gregory et al., 2019).

Mouth and Dental Health

Microstomia makes dental care harder. Mouth-stretching and oral exercises are listed among its treatments; for dry mouth, the Seminar lists cholinergic agonists, sugar-free lozenges and frequent dental hygiene visits (Volkmann 2023).

Nutrition and Eating

Gastrointestinal involvement can lead to malnutrition and micronutrient deficiencies; malnutrition can in turn impair immune function (Volkmann 2023). Small, frequent meals are among the measures listed for bloating. A 2025 meta-analysis found lower vitamin D levels in people with systemic sclerosis than in healthy controls, and lower levels were associated with ILD and higher skin scores (Dhaouadi et al., 2025); these are associations, not evidence that supplements change the disease.

Cold and Raynaud's

Cold is a main trigger of Raynaud's attacks. In a meta-analysis of complementary treatments for Raynaud's, a single trial of therapeutic gloves favoured the gloves, though its authors noted that the result may not generalise (Malenfant et al., 2009).

Pain and Fatigue

Fatigue is common and often refractory (Volkmann 2023). In a European randomised trial of 170 people with systemic sclerosis, mostly with limited disease, a 12-week supervised programme of high-intensity interval and resistance training improved pain, fatigue, depression, quality of life and function compared with usual care (Mitropoulos et al., 2025). Low-dose naltrexone is sometimes discussed for scleroderma, but the only scleroderma report a 2023 review found was a case description of 3 patients in whom it relieved itching (de Carvalho and Skare, 2023).

Emotional Health

Depression is common in systemic sclerosis and can reduce adherence to treatment and quality of life (Volkmann 2023). Patient organisations such as the Scleroderma Foundation (scleroderma.org) run support groups and a peer-mentor programme.

Pregnancy

Pregnancy in systemic sclerosis carries a higher risk of complications for mother and baby (Volkmann 2023). In a Pittsburgh study of 91 pregnancies in 59 women, miscarriage was not more frequent except in long-standing diffuse disease; 29% of births were preterm, and all but one infant survived. Raynaud's tended to improve during pregnancy while reflux worsened, and all three cases of renal crisis occurred in women with early diffuse disease. The authors concluded that women with systemic sclerosis can have healthy pregnancies, and that women with early diffuse disease should wait until it stabilises (Steen, 1999). The FDA labels for mycophenolate mofetil and methotrexate carry boxed warnings for embryo-fetal toxicity: mycophenolate use in pregnancy is linked to first-trimester pregnancy loss and congenital malformations.

Employment and Disability

The 2023 Seminar reports that it is not uncommon for people with systemic sclerosis to have to stop working, and that patients often face considerable personal costs, such as therapies that are not reimbursed.

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Complementary and Supportive Approaches

Complementary approaches have been studied mainly for Raynaud's phenomenon. A 2009 meta-analysis of 20 randomised trials of complementary treatments for Raynaud's found that most trials were negative, of poor quality and done before 1990, and that none of the nutritional supplements studied showed significant differences (Malenfant et al., 2009).

Antioxidants

Abnormal regulation of reactive oxygen species is part of the cycle of small-vessel injury in systemic sclerosis (Volkmann 2023). Clinical results so far:

Omega-3 Fatty Acids

The same meta-analysis included three trials of essential fatty acids for Raynaud's and found no significant differences for the nutritional supplements studied (Malenfant et al., 2009).

Herbal and Natural Compounds

Skincare and Physical Therapies

For itch, the 2023 Seminar lists limiting time in hot baths and showers, minimising harsh soaps, and simple oils such as olive or jojoba oil without fragrance, while noting that rigorous trials are scarce. For the evidence on paraffin wax, see Hand Function above.

Exercise

In the European randomised trial described above, a 12-week supervised programme combining high-intensity interval and resistance training was reported as safe and improved pain, fatigue, depression, quality of life, function, strength and cardiorespiratory fitness compared with usual care (Mitropoulos et al., 2025).

Mind-Body Practices

Biofeedback — learning to warm the hands voluntarily — has been tested in five randomised trials for Raynaud's. In the 2009 meta-analysis it did not reduce the frequency, duration or severity of attacks, and the results favoured sham biofeedback (Malenfant et al., 2009).

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Key Research Papers

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. Wigley FM, 2002: Raynaud's phenomenon. N Engl J Med. 347(13):1001–1008. — PubMed PMID: 12324557
  9. Smith V et al., 2020: Standardisation of nailfold capillaroscopy for the assessment of patients with Raynaud's phenomenon and systemic sclerosis. Autoimmun Rev. 19(3):102458. — PubMed PMID: 31927087 (replaces an entry, "Herrick AL et al., 2012, Nailfold capillaroscopy as a classification tool for systemic sclerosis, Arthritis Rheum 64(11):3461–3469", that could not be found in PubMed or Crossref)
  10. Steen VD, 2005: Autoantibodies in systemic sclerosis. Semin Arthritis Rheum. 35(1):35–42. — PubMed PMID: 16084222 (replaces an entry, "Guillevin L et al., 1999, Systemic sclerosis with overlap syndrome: clinical features and outcome, J Rheumatol 26(3):522–531", that could not be found in PubMed or Crossref; those pages of that issue hold an unrelated paper)
  11. Volkmann ER, Andréasson K, Smith V, 2023: Systemic sclerosis. Lancet. 401(10373):304–318. — PubMed PMID: 36442487
  12. 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
  13. 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
  14. 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
  15. 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
  16. 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
  17. Steen VD, Medsger TA Jr, 2000: Long-term outcomes of scleroderma renal crisis. Ann Intern Med. 133(8):600–603. — PubMed PMID: 11033587
  18. 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
  19. 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
  20. 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
  21. 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
  22. 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
  23. 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
  24. Thompson AE et al., 2001: Calcium-channel blockers for Raynaud's phenomenon in systemic sclerosis. Arthritis Rheum. 44(8):1841–1847. — PubMed PMID: 11508437
  25. Pang C et al., 2025: A systematic review of botulinum toxin as a treatment for Raynaud's disease secondary to scleroderma. Clin Rheumatol. 44(1):81–96. — PubMed PMID: 39615000
  26. 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
  27. Steen VD, 1999: Pregnancy in women with systemic sclerosis. Obstet Gynecol. 94(1):15–20. — PubMed PMID: 10389711
  28. Sandqvist G et al., 2004: Evaluation of paraffin bath treatment in patients with systemic sclerosis. Disabil Rehabil. 26(16):981–987. — PubMed PMID: 15371046
  29. Gregory WJ et al., 2019: A randomised controlled trial of wax baths as an additive therapy to hand exercises in patients with systemic sclerosis. Physiotherapy. 105(3):370–377. — PubMed PMID: 30318128
  30. Dhaouadi T et al., 2025: Vitamin D association with systemic sclerosis and its clinical features: a systematic review, meta-analysis, and meta-regression. J Scleroderma Relat Disord. 10(2):101–120. — PubMed PMID: 39544900
  31. Mitropoulos A et al., 2025: High-intensity interval and resistance training programme improves pain and fatigue outcomes in people with systemic sclerosis: a European multicentre randomised controlled trial. RMD Open. 11(4):e005946. — PubMed PMID: 41219127
  32. de Carvalho JF, Skare T, 2023: Low-dose naltrexone in rheumatological diseases. Mediterr J Rheumatol. 34(1):1–6. — PubMed PMID: 37223594
  33. Malenfant D et al., 2009: The efficacy of complementary and alternative medicine in the treatment of Raynaud's phenomenon: a literature review and meta-analysis. Rheumatology (Oxford). 48(7):791–795. — PubMed PMID: 19433434
  34. Correa MJ et al., 2014: Oral N-acetylcysteine in the treatment of Raynaud's phenomenon secondary to systemic sclerosis: a randomized, double-blind, placebo-controlled clinical trial [in Portuguese]. Rev Bras Reumatol. 54(6):452–458. — PubMed PMID: 25458027
  35. Muir AH et al., 2002: The use of Ginkgo biloba in Raynaud's disease: a double-blind placebo-controlled trial. Vasc Med. 7(4):265–267. — PubMed PMID: 12710841
  36. Bredie SJ, Jong MC, 2012: No significant effect of ginkgo biloba special extract EGb 761 in the treatment of primary Raynaud phenomenon: a randomized controlled trial. J Cardiovasc Pharmacol. 59(3):215–221. — PubMed PMID: 22030896
  37. Mittal S et al., 2024: Pigmentary changes in systemic sclerosis are associated with more severe cutaneous sclerosis and severity of other systems: a cross-sectional study from India. Indian J Dermatol. 69(4):365. — PubMed PMID: 39296704
  38. 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

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Connections

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