Systemic sclerosis and Raynaud phenomenon

• Systemic sclerosis is an autoimmune connective tissue disease in which a triad of small-vessel injury, immune activation, and fibroblast overactivity produces skin thickening and fibrosis of internal organs.
• It is classified by how far the skin thickening extends: limited cutaneous disease (historically called CREST syndrome) and diffuse cutaneous disease.
• The most useful clinical clues are Raynaud phenomenon, puffy then tight fingers, nailfold capillary changes, and specific autoantibodies (anti-centromere, anti-topoisomerase I, anti-RNA polymerase III).
• The ACR/EULAR 2013 score classifies disease with 9 or more points; the treatment approach follows the EULAR 2023 recommendations, organ by organ.
• Pulmonary fibrosis, pulmonary hypertension, and scleroderma renal crisis are the complications that most threaten life; early screening is the difference between good and poor outcomes.

By the end of this page you should be able to:

1. Define systemic sclerosis and distinguish the limited, diffuse, and sine scleroderma forms.
2. Explain the three core processes (vascular, immune, fibrotic) and link them to symptoms.
3. Read the ACR/EULAR 2013 classification score and say what a total of 9 or more means.
4. Recognise the main clinical features, organ by organ, and the characteristic antibody associations.
5. Plan first-line management of Raynaud phenomenon, digital ulcers, interstitial lung disease, and scleroderma renal crisis following the EULAR 2023 recommendations, with doses.
6. Outline screening for interstitial lung disease and pulmonary hypertension and state the most important prognostic determinants.

Systemic sclerosis is a chronic autoimmune connective tissue disease. It combines three abnormalities that occur together in most patients: injury and fibroproliferative change in small blood vessels, activation of the immune system with distinctive autoantibodies, and excessive collagen and matrix production by fibroblasts. These three processes thicken and harden the skin and may fibrose the lungs, heart, gastrointestinal tract, kidneys and other organs. The skin finding (scleroderma) is the hallmark, and "systemic sclerosis" is the preferred term because internal organs are involved.

Limited versus diffuse cutaneous disease. The everyday classification uses the extent of skin thickening.

• Limited cutaneous systemic sclerosis: skin thickening is confined to areas distal to the elbows and knees, often with the face and neck involved. Raynaud phenomenon usually precedes the skin changes by years. The older term CREST syndrome groups five features seen in this form: calcinosis, Raynaud phenomenon, oesophageal dysmotility, sclerodactyly, and telangiectasia. Patients with this form are more likely to develop pulmonary hypertension and severe gastrointestinal disease.
• Diffuse cutaneous systemic sclerosis: skin thickening extends proximal to the elbows and knees and may include the trunk. The interval between Raynaud phenomenon and skin change is usually short, under a year. These patients carry a higher risk of interstitial lung disease, cardiac disease, and scleroderma renal crisis.

A third, uncommon form is systemic sclerosis sine scleroderma: Raynaud phenomenon, systemic sclerosis serology and internal organ fibrosis occur without skin thickening. Up to one fifth of patients have overlap features with other connective tissue diseases such as lupus or myositis.

Limited disease is not limited in importance; internal organ involvement occurs in both forms.

Systemic sclerosis is rare, which is why reported rates differ between studies. A 2024 scoping review of data from 2018 to 2024 estimated global incidence at 1.4 to 8.6 new cases per 100,000 person-years and prevalence at 17.6 to 18.9 per 100,000 people. ^[4] Other recent summaries give a prevalence of about 17.6 per 100,000 and an incidence of about 1.4 per 100,000, with marked geographical variation (roughly 14.8 per 100,000 in Europeans, 25.9 in North Americans, 24.8 in South Americans, 23.8 in Oceania, and 6.8 in Asians). One older perinatal and anaesthetic review quotes an overall global incidence of 1 in 10,000 and a European prevalence of 7 to 33 per 100,000. The difference is explained by varying case definitions and methods; taken together, the disease is uncommon worldwide.

• Sex. Women are affected far more often than men, with female-to-male ratios of 3:1 to 8:1 reported. Overall global incidence is quoted at roughly 1 per 10,000, and the European prevalence is almost four times higher in women. Men develop disease less often but tend to have more severe disease and higher premature mortality.
• Age. Onset usually occurs in the third to fifth decade; children are rarely affected.
• Ethnicity. African ancestry is associated with earlier onset and more severe disease. Indigenous Canadian populations have particularly high reported prevalence.
• Mortality. Standardised mortality is about 2.7 times that of the general population. Five-year survival is reported at about 75 percent, and 10-year survival at about 60 to 66 percent, although figures vary with era and cohort.
• Causes of death. Pulmonary fibrosis and interstitial lung disease account for a large share of deaths (about 19 to 35 percent depending on the cohort), followed by cardiac disease and pulmonary hypertension (about 14 to 26 percent). Scleroderma renal crisis was historically the leading cause of death; it is now much less often fatal because of angiotensin-converting enzyme (ACE) inhibitors.
• Organ involvement timelines. Cardiac involvement and interstitial lung fibrosis develop in roughly half of patients within the first 5 years, and symptomatic cardiac involvement carries a 75 percent 5-year mortality.

The cause is unknown. It arises when environmental triggers act on a susceptible host.

• Genetic susceptibility. Familial aggregation is weak, but strong human leukocyte antigen associations exist, notably HLA-DRB1, DQA1 and DQB1. HLA-B35 in particular is linked to a high risk of pulmonary arterial hypertension in systemic sclerosis. Non-HLA genes (PTPN22, NLRP1, STAT4, IRF5) and microRNAs also influence susceptibility.
• Environmental triggers. Silica dust, organic solvents (toluene, xylene, trichloroethylene), polyvinyl chloride, and certain drugs (bleomycin, taxanes, gemcitabine, gadolinium-containing contrast in renal impairment) are associated with systemic sclerosis-like disease. Silica accounts for only a small fraction of male cases.
• Infections. Cytomegalovirus, Epstein-Barr virus and parvovirus B19 have been implicated, but no single infection is proven to cause disease.
• Other associations. Female sex, silicone breast implants, Native American or African American race, and radiotherapy have been associated with risk. Smoking is not associated with an increased susceptibility to systemic sclerosis, although it worsens lung disease.

There is no proven modifying risk factor that a patient can reliably remove, and no form of primary prevention is established.

Systemic sclerosis is often taught as three interlocking processes, all present in most patients but in varying proportions. ^[5]

1. Vascular. An initial endothelial cell injury reduces nitric oxide and prostacyclin and raises endothelin-1. The result is small-vessel vasospasm, intimal proliferation, and fibroproliferative vasculopathy. This explains Raynaud phenomenon, digital ulcers, gangrene, gastric antral vascular ectasia, renal crisis, and the microvascular changes of nailfold capillaroscopy.
2. Immune. Innate and adaptive immune activation produces characteristic autoantibodies (anti-centromere, anti-topoisomerase I, anti-RNA polymerase III, and others) and cell-mediated autoimmunity. Monocytes polarise towards M2 macrophages; T helper 2 cells and activated B cells release IL-4, IL-6, IL-10, IL-13, TGF-beta, PDGF and CTGF, which recruit more fibroblasts and drive inflammation.
3. Fibrotic. Fibroblasts transform into activated myofibroblasts and secrete collagen, hyaluronic acid, glycosaminoglycans and fibronectin. The dense connective tissue destroys the normal tissue architecture. Tissue hypoxia and mechanical stress amplify the process.

Raynaud phenomenon is probably triggered by endothelial injury and sustained by small-vessel vasculopathy and arterial vasospasm. "Myocardial Raynaud's phenomenon," with coronary vasospasm in arteries without atherosclerosis, has been described and explains ischaemia in some patients.

Three levels of fibrosis result: early (puffy) soft-tissue swelling, established (sclerotic) skin, and late atrophic thinning with loss of adnexae. The skin softens last, but the subcutaneous fibrosis remains.

These three pathways are targets for modern treatment: immunomodulators and anti-IL-6 for the immune arm, ACE inhibitors and vasodilators for the vascular arm, and antifibrotics such as nintedanib and pirfenidone for the fibrotic arm.

Symptoms depend on which organs are involved. Patients rarely present with all features at once.

• Raynaud phenomenon is an almost constant early feature: triphasic colour change of the fingers (white, then blue, then red) with cold or emotion, often asymmetric, with pain, paraesthesia and, later, digital pits, scars or gangrene. Nailfold infarcts and puffy early hands are characteristic.
• Constitutional symptoms: fatigue, weight loss, fever and general malaise, most often with active (diffuse) disease.
• Skin: "puffy" fingers progressing to sclerodactyly (tight, shiny skin), inability to make a full fist, facial tightening with microstomia and radial furrowing around the mouth, loss of wrinkles, and a "salt and pepper" dyspigmentation. Calcinosis (hard subcutaneous nodules) and telangiectases, often on the hands and face, develop later.
• Gastrointestinal: reflux, dysphagia, bloating, constipation, diarrhoea (sometimes from small-intestinal bacterial overgrowth), abdominal distension from chronic pseudo-obstruction, and bleeding from gastric antral vascular ectasia. Oral changes include microstomia, xerostomia and periodontal disease.
• Respiratory: exertional breathlessness, a dry cough, and exercise intolerance from interstitial lung disease or pulmonary hypertension.
• Cardiac: palpitations, atypical chest pain, and symptoms of heart failure.
• Renal: the abrupt onset of severe hypertension with headache, oliguria and progressive renal failure defines a scleroderma renal crisis; creatinine rises rapidly over weeks.
• Musculoskeletal: arthralgia, stiffness, tendon friction rubs, flexion contractures, and myopathy with proximal weakness.
• Psychosocial and functional: hand dysfunction, chronic pain, and anxiety or depression are very common.

Start with the skin:

• Pinch the skin of the fingers: it is indurated, often fixed to the deeper tissues, with loss of normal skin folds and tethering at the proximal interphalangeal joints.
• Press the palms and fingers together: patients with early puffy change cannot approximate the palms ("prayer sign").
• Inspect the fingertips for pitting scars, healed ulcers, active ulcers, or gangrene; record the tufts.
• Look for calcinosis, telangiectasia on the hands and face, and capillary loops visible at the nailfold with a hand lens or dermatoscope.
• Inspect the face for a beaked nose, small mouth, radial furrowing and microstomia, and the hairline for frontoparietal recession.

Measure hand and mouth opening, and assess forearm range and flexion contractures.

Inspect the nails and perform nailfold capillaroscopy. The "scleroderma pattern" is giant capillaries with an apical diameter of at least 50 micrometres, or abnormal vessel morphology with a reduced capillary number.

Listen to the chest for inspiratory crackles (interstitial lung disease) and a loud pulmonary component of the second heart sound (pulmonary hypertension). Listen to the heart for a pericardial rub or arrhythmia, and measure blood pressure in both arms.

Examine the abdomen and do a rectal examination when indicated. Check urine for protein and blood, and palpate for peripheral oedema.

Nailfold capillaroscopy is the standard, non-invasive way to see the microvasculature. It distinguishes primary Raynaud phenomenon (normal pattern) from secondary forms. Early, active and late scleroderma patterns exist. Giant capillaries and haemorrhages dominate early disease; progressive capillary loss and architectural disorganisation follow. Capillaroscopy is also one of the VEDOSS (very early diagnosis of systemic sclerosis) criteria.

Systemic sclerosis is a multisystem fibrosing vasculopathy. Its mimics include conditions that cause Raynaud phenomenon, skin thickening, or internal-organ fibrosis without the full systemic sclerosis triad.

Patients can have systemic sclerosis alongside another connective tissue disease ("overlap syndrome"). In early disease, before the diagnosis is clear, watch capillaroscopy and antibody status change over time.

No test makes the diagnosis alone; the 2013 score (below) is used. But the investigation set both supports the diagnosis and stages the organs.

• Nailfold capillaroscopy: scleroderma pattern (giant capillaries of 50 micrometres or more, or abnormal morphology with reduced capillary count).
• Antinuclear antibody (ANA) with extractable nuclear antigens: anti-centromere, anti-topoisomerase I (anti-Scl-70), and anti-RNA polymerase III are the specific antibodies in the classification score.
• Full blood count and ESR/CRP: inflammatory markers may be raised, anaemia may occur, eosinophilia suggests overlap or eosinophilic disease.
• Renal function panel: serum creatinine, estimated glomerular filtration rate, urinalysis for protein and red cells, and blood pressure monitoring.
• Chest high-resolution CT: the standard imaging for interstitial lung disease; it detects fibrosis and allows pattern recognition.
• Pulmonary function tests: forced vital capacity and gas transfer coefficient, with decline tracking progression.
• Transthoracic echocardiography: screening for pulmonary hypertension (right ventricular size and function, estimated right ventricular systolic pressure) and for cardiac involvement.
• Right heart catheterisation: the gold standard for pulmonary arterial hypertension (mean pulmonary artery pressure greater than 20 mmHg, pulmonary capillary wedge pressure 15 or less, and pulmonary vascular resistance 3 or more Wood units).
• Other: oesophagogastroduodenoscopy for refractory reflux or suspected gastric antral vascular ectasia; small-bowel imaging for malabsorption; electrocardiogram and troponins when cardiac involvement is suspected; renal biopsy in selected renal crisis cases (often thrombotic microangiopathy).

What each test means:

• High-resolution CT and pulmonary function together define interstitial lung disease and allow monitoring.
• A negative ANA does not exclude early systemic sclerosis, but the specific antibodies strongly favour it.
• A rising creatinine with new severe hypertension in a patient with systemic sclerosis is a renal crisis until proven otherwise.

The current standard is the ACR/EULAR 2013 classification criteria (published as van den Hoogen and colleagues, Annals of the Rheumatic Diseases 2013;72:1747-1755, and Arthritis and Rheumatism 2013;65:2737-2747). ^[1] The system assigns weighted points to clinical and laboratory items; a total of 9 or more points classifies systemic sclerosis. Sensitivity and specificity in the validation sample were 0.91 and 0.92 for the new criteria, against 0.75 and 0.72 for the older 1980 ACR criteria, and previously classified patients were all reclassified by the new system.

Clinical-pathological interpretation of antibodies:

• Anti-centromere: generally limited skin disease, vascular (finger vessel) involvement, and a risk of pulmonary hypertension; more benign skin fibrosis.
• Anti-topoisomerase I (anti-Scl-70): diffuse skin involvement and high risk of interstitial lung disease; severe internal-organ involvement.
• Anti-RNA polymerase III: rapidly progressive diffuse skin, renal crisis, gastric antral vascular ectasia, and malignancy risk.

Very early diagnosis. The VEDOSS concept identifies patients with Raynaud phenomenon plus antinuclear antibody positivity, finger oedema, systemic sclerosis-specific autoantibodies, or abnormal nailfold capillaroscopy. Those with Raynaud phenomenon and one or two of these features are at high risk of progression. This supports early screening and specialist referral before organ damage occurs.

Staging and skin scoring: the modified Rodnan skin score tracks skin thickness at standard sites and is used to monitor involvement and response to treatment. Organ staging uses CT, pulmonary function, echocardiography and right heart catheterisation, and renal monitoring rather than a single score.

The treatment of systemic sclerosis follows organ involvement. The 2023 update of the EULAR recommendations for the treatment of systemic sclerosis (final publication Del Galdo and colleagues, Annals of the Rheumatic Diseases 2025;84:29-40; preliminary paper OP0234) is the current European guideline and forms the basis of the management below. It contains 20 recommendations across eight domains (Raynaud phenomenon, digital ulcers, pulmonary arterial hypertension, skin fibrosis, interstitial lung disease, musculoskeletal and gastrointestinal involvement, and renal crisis), up from 16 in 2017. Interventions are graded A to D on the evidence. Two principles recur throughout:

• Treat the organ, not only the skin, because fibrosis in lung, heart and kidney drives mortality.
• Immunomodulators for skin and lung have strong trial evidence; vascular, gastrointestinal and musculoskeletal manifestations still have limited evidence.

• Advise smoking cessation (it does not cause systemic sclerosis but it worsens lung and vascular disease), warmth and stress reduction, and protection of digits from cold and minor trauma.
• Use calcium channel blockers and PDE5 inhibitors early for vascular symptoms.
• Avoid systemic glucocorticoids where possible; if needed, use only moderate, short-course regimens for rapidly progressive diffuse skin disease, because of the risk of renal crisis.
• Involve a rheumatologist and organ specialists early (pulmonary, cardiac, renal, gastroenterology).

Cold avoidance, smoking cessation, digital protection and warming are the foundation. If these fail, drugs come next.

• First-line drug therapy for Raynaud phenomenon is a vasodilator. Vasodilator medicines are the first-line treatment when general measures fail, and dihydropyridine calcium channel blockers such as nifedipine are the most commonly used. Typical dosing is nifedipine 30 to 120 mg daily; long-acting preparations 10 to 40 mg twice daily, or amlodipine 5 to 10 mg once daily, are often preferred to immediate release because they are better tolerated. ^[9] The EULAR 2023 recommendations include Raynaud phenomenon as one of their eight treatment domains. ^[6]
• Phosphodiesterase-5 inhibitors (sildenafil, tadalafil) improve digital blood flow and ulcer healing.
• Intravenous iloprost (a prostacyclin analogue) has grade A evidence for Raynaud phenomenon and digital ulcers, and grade B evidence for pulmonary hypertension. ^[6]
• Fluoxetine, an angiotensin receptor blocker, and topical nitrates are alternatives.
• Intravenous prostacyclins, bosentan and selexipag are used according to specialist advice.
• Botulinum toxin and sympathectomy are reserved for severe, tissue-threatening ischaemia.

Digital ulcers are common in systemic sclerosis and heal slowly. Treatment is as follows:

• Vasodilators, including PDE5 inhibitors and intravenous iloprost, should be considered for digital ulcers. ^[6]
• Bosentan, an endothelin receptor antagonist, should be considered to reduce the number of new digital ulcers. ^[6]
• Local wound care, analgesia, treatment of infection, and review for osteomyelitis or gangrene are essential.
• Phosphodiesterase-5 inhibitors and endothelin receptor antagonists are recommended (by the EULAR 2023 update) for up-front combination use in digital ulcers and pulmonary hypertension. ^[6]

Systemic sclerosis-associated interstitial lung disease is the leading cause of death in modern cohorts. Assess every patient at baseline with high-resolution CT and pulmonary function.

• EULAR 2023 now recommends immunomodulator and antifibrotic therapy for this manifestation for the first time. Recommended options: mycophenolate mofetil, nintedanib, rituximab and tocilizumab. ^[6]
• Mycophenolate mofetil 1500 mg twice daily for 24 months was at least as effective as and better tolerated than oral cyclophosphamide in the SLS II trial. ^[8]
• Cyclophosphamide 2.0 mg/kg per day orally for 12 months (or intravenous pulses given by specialists) improved pulmonary function compared with placebo and has grade A evidence for lung disease. ^[6][8]
• Nintedanib 150 mg orally twice daily reduced the annual decline in forced vital capacity compared with placebo in the SENSCIS trial (about 41 ml per year), although such detailed specialist dosing is often adjusted for tolerability. ^[7]
• Tocilizumab 162 mg subcutaneously weekly (the dose used in SSc-ILD trials and practice) has shown stabilisation of lung disease, especially early in the disease course. ^[10]
• Rituximab has grade A evidence for interstitial lung disease. ^[6]
• Immunosuppressants for progressive diffuse cutaneous disease are commonly used early (mycophenolate mofetil or rituximab), with evidence for improved pulmonary function and reduced extent of interstitial lung disease. ^[3]
• Where disease progresses despite treatment, consider lung transplantation in appropriately selected patients and palliative care planning.

Pulmonary arterial hypertension occurs in 7 to 12 percent of patients. Screen with annual transthoracic echocardiography and confirm with right heart catheterisation.

• EULAR 2023 recommends up-front (initial) combination therapy: a phosphodiesterase-5 inhibitor plus an endothelin receptor antagonist for systemic sclerosis-associated pulmonary arterial hypertension. ^[6]
• Additional agents include prostacyclin analogues (epoprostenol, treprostinil, iloprost) and prostacyclin receptor agonists (selexipag). Iloprost carries grade B evidence for pulmonary hypertension. ^[6]
• Diuretics manage fluid, oxygen is given as needed, and anticoagulation is considered by the specialist team.
• The modified Rodnan skin score does not measure lung disease, so echocardiography and targeted screening tools are required.
• Because pulmonary hypertension often appears about 10 years after the first vascular signs, aggressive treatment of Raynaud phenomenon and digital ulcers may have longer-term vascular benefits, although this needs trial confirmation. ^[6]

• Mycophenolate mofetil is recommended by EULAR 2023 for skin fibrosis and was not present in the 2017 recommendations. ^[6]
• Methotrexate is used for inflammatory musculoskeletal and skin involvement, with immunomodulatory effect. ^[3]
• Rituximab (anti-CD20 depletion) has grade A evidence for skin fibrosis. ^[6]
• Tocilizumab is also used for progressive skin disease in diffuse systemic sclerosis. ^[3]
• Physiotherapy, hand therapy, facial stretching and orthotic support preserve function and mouth opening. Paraffin wax and manual therapy help ischaemic digits.
• Skin calcinosis is managed symptomatically (avoiding trauma, treating infection); no drug has robust evidence.

This is a medical emergency: new severe hypertension, rising creatinine, microangiopathic haemolytic anaemia and thrombocytopenia in a patient with systemic sclerosis. Approximately 50 percent of patients show earlier blood pressure or urinary abnormalities. Proteinuria, thrombotic microangiopathy and complement activation are common.

• Start an ACE inhibitor immediately and titrate to blood pressure; this transformed outcomes and is the established treatment. ^[3]
• Monitor blood pressure and renal function closely (often daily initially), with dialysis if required.
• Avoid high-dose glucocorticoids, which can precipitate or worsen crisis.
• Calcium channel blockers and prostacyclins may help vascular flow, and endothelin or angiotensin blockers are not substitutes for ACE inhibition.
• Renal recovery is possible over months; some patients regain independent renal function.

• Reflux and oesophagitis are treated with proton pump inhibitors, head-of-bed elevation and dietary advice. H2 receptor blockers and antacids are alternatives. ^[3]
• Dysphagia from oesophageal dysmotility is managed with dietary modification and prokinetics; balloon dilatation is used for strictures.
• Small intestinal bacterial overgrowth is treated with rotating antibiotics. ^[6]
• Constipation may require osmotic laxatives; diarrhoea may require nutritional support and antibiotics.
• Gastric antral vascular ectasia (watermelon stomach) with bleeding is treated endoscopically (argon plasma coagulation) and by transfusion.
• Nutritional support by a dietitian is fundamental; severe malnutrition may require enteral or parenteral feeding.

• Inflammatory arthritis is treated with methotrexate and low-dose glucocorticoids as needed; hydroxychloroquine is also used. ^[3]
• Raynaud and digital ulcers increase hand morbidity; hand therapy prevents contractures.
• Calcinosis and tendon friction rubs are markers of more severe disease.
• Methotrexate is graded D for musculoskeletal involvement in EULAR 2023 and should be considered by specialists. ^[6]

A structured programme matters because screening finds silent lung and heart disease.

• Blood pressure and urinalysis at every visit; monthly at first in diffuse disease.
• Skin score every 3 to 6 months in diffuse disease.
• Annual pulmonary function tests (forced vital capacity, diffusing capacity) for all patients.
• High-resolution CT at baseline; repeat if symptoms change or pulmonary function falls.
• Echocardiography (and right heart catheterisation when suggested) for pulmonary hypertension screening, particularly late in the disease.
• Blood counts, liver and renal function during immunosuppressive therapy.
• Nutritional assessment and bone density where steroid use or malabsorption occurs.

Any new systemic sclerosis diagnosis, diffuse progressive disease, rising creatinine or hypertension, new breathlessness, or a mobile digital ulcer should prompt early rheumatology input. Suspected renal crisis goes to acute medical and renal units the same day because of its speed. Rehabilitation, occupational therapy and mental health support improve outcomes and should be part of routine care.

• Interstitial lung disease: the leading cause of death; progressive fibrosis reducing lung volumes and gas transfer.
• Pulmonary arterial hypertension: late, serious, associated with anti-centromere profile; often asymptomatic early.
• Scleroderma renal crisis: malignant hypertension, thrombotic microangiopathy, acute renal failure, risk of dialysis and death.
• Cardiac disease: myocardial fibrosis, diastolic dysfunction, arrhythmia, pericardial disease; systemic sclerosis carries a three-fold increased risk of myocardial ischaemia.
• Digital ulcers, gangrene and amputation from severe vascular disease.
• Gastrointestinal fibrosis: reflux oesophagitis, strictures, gastric antral vascular ectasia, chronic pseudo-obstruction, small-intestinal bacterial overgrowth and malnutrition.
• Musculoskeletal: contractures, tendon friction rubs, proximal weakness, functional loss.
• Calcinosis cutis: painful nodules, infection, sinus tracts.
• Malignancy: an increased risk of breast and lung cancer and other tumours is reported; patients with anti-RNA polymerase III have higher renal and neoplastic risk, and specific screening algorithms exist. ^[2]
• Psychological: depression, anxiety and loss of quality of life are common and should be screened for.

Prognosis has improved over recent decades because of ACE inhibitors for renal crisis, screening, and targeted organ therapies. Nevertheless, systemic sclerosis has the highest mortality among rheumatic diseases in many series.

• Survival: reported 5-year survival around 75 percent and 10-year survival around 60 to 66 percent; deaths in early cohorts were higher before ACE inhibitors.
• Causes of death: interstitial lung disease, pulmonary hypertension and heart disease dominate modern cohorts. Interstitial lung disease accounts for roughly 19 to 35 percent of systemic sclerosis-related deaths and pulmonary hypertension for 14 to 26 percent, with cardiac disease close behind. Figures vary because of cohort and era.
• Adverse features: diffuse skin, older age at onset, male sex, anti-topoisomerase I or anti-RNA polymerase III antibodies, interstitial lung disease, low forced vital capacity or diffusing capacity, pulmonary hypertension, cardiac involvement, scleroderma renal crisis, and severe gastrointestinal disease all predict worse outcome.
• Better profile: limited skin disease, anti-centromere antibody, absence of major organ fibrosis, responding to vasodilators.
• Trajectory: interstitial lung disease is often most active in the first 3 to 5 years; pulmonary hypertension tends to arise around 10 years after vascular symptoms; renal crisis occurs early in diffuse disease. Because of this, classification of cutaneous form and antibody status at baseline help plan screening.

There is no primary prevention. Sensible measures include avoiding silica, solvents and the implicated drugs where exposure is occupational, and treating Raynaud phenomenon and calcium channel blockers early to limit tissue injury.

Secondary prevention means systematic screening for silent disease:

• Very early diagnosis: in patients with Raynaud phenomenon, test antinuclear antibodies, perform nailfold capillaroscopy, and measure systemic sclerosis-specific autoantibodies. Early application of VEDOSS-style criteria identifies patients at high risk of progression. ^[2]
• Annual pulmonary function testing for all patients, with high-resolution CT when disease is suspected.
• Regular transthoracic echocardiography and confirmatory right heart catheterisation for pulmonary hypertension screening.
• Blood pressure and renal monitoring, especially in early diffuse disease, to catch renal crisis.
• Calcium channel blockers and (where available) vasodilators for Raynaud phenomenon are used to prevent tissue damage.
• Cancer screening tailored to patients with risk factors (for example, anti-RNA polymerase III positivity, older age and smoking history), and screening for gastric antral vascular ectasia in those with anaemia.

Pregnancy. Systemic sclerosis does not in itself prevent pregnancy, but outcomes depend on cardiopulmonary and renal involvement. Renal crisis and rapidly progressive disease are the main risks, and pregnancy should be managed by a multidisciplinary obstetric, rheumatology and (where required) cardiac/renal team. Blood pressure and renal function need frequent monitoring, and high-dose corticosteroids are avoided.

Older adults. Comorbidity and polypharmacy often shape drug choice (for example, avoiding nephrotoxic drugs in renal impairment and reviewing antihypertensives in autonomic dysfunction). Treatment targets may shift from disease modification to function and quality of life.

Children and adolescents. Systemic sclerosis is uncommon in this age group, more often overlapping with other connective tissue diseases; management should be delivered by specialist paediatric rheumatology teams.

Immunocompromised and multi-agent therapy. Combination immunosuppression increases infection risk. Live vaccines are usually avoided during heavy immunosuppression and, where appropriate, influenza and pneumococcal vaccination are arranged before starting treatment.

• Transthoracic echocardiography and a handheld lens for nailfold capillaroscopy make the diagnosis in most patients; these tools are available in many district hospitals. ^[3]
• High-resolution CT and pulmonary function are valuable but not mandatory for recognising diffuse fibrosis; clinical findings (crackles, falling exercise tolerance, exertional breathlessness) should trigger referral.
• Affordable, widely used drugs for systemic sclerosis manifestations include: nifedipine for Raynaud phenomenon, ACE inhibitors for renal crisis, proton pump inhibitors for reflux, and methotrexate for musculoskeletal and skin disease.
• Expensive antifibrotics and biologics (nintedanib, tocilizumab, rituximab) may be unavailable; mycophenolate mofetil is a more affordable, effective option for interstitial lung disease.
• Where cardiopulmonary bypass or right heart catheterisation are unavailable, early referral to a tertiary centre for renal crisis, severe pulmonary hypertension, or advancing lung disease is life-saving.
• Send all excised tissue and biopsies for histology, including paraffin blocks when possible.

• Systemic sclerosis is a triad of small-vessel injury, immune activation, and fibroblast fibrosis.
• Skin extent (limited versus diffuse) and antibody type predict the organs at risk.
• Limited disease was formerly called CREST; diffuse disease carries higher risk of lung, heart and kidney involvement.
• ACR/EULAR 2013: 9 or more points classifies systemic sclerosis; the criteria are more sensitive than the 1980 set.
• Anti-centromere suggests limited skin and pulmonary hypertension; anti-Scl-70 diffuse disease with lung fibrosis; anti-RNA polymerase III rapid skin and renal crisis.
• Nailfold capillaroscopy and ANA with extractable nuclear antigens are the diagnostic anchors; HRCT and echocardiography stage the organs.
• Raynaud phenomenon is treated first with vasodilators such as dihydropyridine calcium channel blockers (nifedipine); phosphodiesterase-5 inhibitors improve digital blood flow and help heal ulcers.
• Interstitial lung disease therapy in EULAR 2023 comprises mycophenolate mofetil, nintedanib, rituximab or tocilizumab, with specific doses from major trials.
• Pulmonary hypertension is treated with an up-front combination of a phosphodiesterase-5 inhibitor and an endothelin receptor antagonist.
• Scleroderma renal crisis is a same-day emergency treated with an ACE inhibitor, with daily renal monitoring.
• Mortality centres on lung, heart and pulmonary hypertension; early screening and ACE inhibitors transformed renal outcomes.
• Women outnumber men 3:1 to 8:1; onset is usually in the third to fifth decade.
• No primary prevention exists; secondary prevention is systematic screening (VEDOSS, pulmonary function tests, echocardiography, renal monitoring).

Systemic sclerosis; Raynaud phenomenon; limited cutaneous systemic sclerosis; diffuse cutaneous systemic sclerosis; CREST syndrome; systemic sclerosis-associated interstitial lung disease; pulmonary arterial hypertension; scleroderma renal crisis; nailfold capillaroscopy; mixed connective tissue disease.