Systemic sclerosis

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Systemic sclerosis combines small-vessel vasculopathy, autoimmunity and progressive fibrosis. Raynaud phenomenon often precedes other features, followed by puffy fingers, skin tightening and nailfold capillary change. Limited cutaneous disease remains distal to elbows and knees, with or without face involvement; diffuse disease extends proximally or to the trunk. The distinction helps risk-stratify tempo, but organ assessment is mandatory for both. Very early disease may be recognised before definite skin thickening when Raynaud, capillaroscopy and specific antibodies align.

Autoantibodies provide useful risk associations. Anti-centromere often accompanies limited disease and later PAH, anti-topoisomerase-I associates with ILD, and anti-RNA-polymerase-III associates with rapidly progressive skin disease, renal crisis and a close temporal relationship with cancer in some patients. These are not deterministic. Examination should include blood pressure, pulses, fingertip lesions, nailfolds, skin score, tendon friction rubs, joints, strength, chest, heart and nutritional status.

Organ surveillance changes outcome because symptoms lag pathology. Baseline HRCT is more sensitive than chest radiography for ILD; PFT and DLCO track physiology. Annual multimodal PAH screening identifies patients requiring right-heart catheterisation, the haemodynamic reference standard. Renal-crisis education and blood-pressure access are essential, particularly during early diffuse disease or glucocorticoid use. ECG, echocardiography, troponin or cardiac MRI are targeted to myocardial and rhythm risk.

Treatment is organ-specific. Vasodilators protect digits, PPIs and motility or nutritional strategies manage gut disease, immunomodulation treats selected inflammatory skin and lung disease, nintedanib slows fibrotic lung-function decline, and PAH requires specialist combination therapy. Physiotherapy and hand therapy preserve movement while wound care and infection prevention protect ulcers. Pregnancy, anaesthesia and surgery need specialist planning because reflux, airway restriction, PAH and vascular access create additional risk.

Key points

Suspect systemic sclerosis when Raynaud phenomenon accompanies puffy fingers, sclerodactyly, fingertip pits or ulcers, telangiectasia, abnormal nailfold capillaries or characteristic internal-organ disease.
Classify skin involvement as limited or diffuse, but do not use the skin label as a substitute for organ screening; severe PAH, ILD, gut or cardiac disease can occur in either group.
Request ANA with systemic-sclerosis-specific antibodies, perform nailfold capillaroscopy where available and document a modified Rodnan skin score, joints, tendons, ulcers and function.
At diagnosis obtain HRCT chest and pulmonary function tests including DLCO to detect ILD; follow lung trajectory rather than waiting for advanced dyspnoea.
Screen for pulmonary hypertension at least annually using symptoms, examination, PFT or DLCO, NT-proBNP and echocardiography, applying DETECT or local right-heart-catheter criteria in eligible patients.
Check blood pressure and creatinine regularly and during new symptoms or glucocorticoid exposure; anti-RNA-polymerase-III and rapidly progressive diffuse skin disease increase renal-crisis risk.
For Raynaud phenomenon use warmth, smoking cessation and a dihydropyridine calcium-channel blocker; escalate recurrent ulcers or critical ischaemia to sildenafil, intravenous iloprost and specialist vascular care.
Treat reflux early, commonly with a proton-pump inhibitor plus positioning and meal measures; investigate dysphagia, weight loss, anaemia, aspiration or altered bowel habit rather than repeatedly increasing acid suppression.
Mycophenolate is widely used for progressive skin or ILD disease, while nintedanib slows FVC decline in eligible SSc-ILD; neither reverses established scar.
Avoid high-dose glucocorticoid when possible because renal-crisis risk rises; if unavoidable, use the minimum exposure with close home blood-pressure and renal monitoring.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Genetic and immune susceptibility

Multiple HLA and immune-regulatory variants interact with sex-related and environmental factors to permit autoimmunity; ordinary systemic sclerosis is not a single-gene disorder.

Vascular and environmental injury

Endothelial stress from immune activation and selected exposures, including silica and organic solvents, may initiate vasculopathy in susceptible individuals.

Distinct autoantibody phenotypes

Anti-centromere, anti-topoisomerase-I and anti-RNA-polymerase-III antibodies associate with different organ risks but do not determine an individual outcome in isolation.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Obliterative microangiopathy
Endothelial activation, intimal proliferation, vasospasm and defective vascular repair progressively narrow small vessels, causing Raynaud phenomenon, ulcers, PAH and renal crisis.
2
Immune activation
Innate and adaptive immune signals, autoantibodies and cytokines activate fibroblasts and vascular cells before and during clinically visible fibrosis.
3
Excess matrix deposition
Activated fibroblasts deposit collagen and extracellular matrix in skin, lungs, heart and gastrointestinal tissue, distorting architecture and reducing organ compliance.
4
Organ-specific feedback loops
Ischaemia, reflux and aspiration, mechanical restriction and inflammation reinforce injury, so vascular and supportive treatment can be as important as antifibrotic immunomodulation.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Very early vascular phenotype

Raynaud phenomenon plus puffy fingers, systemic-sclerosis-specific autoantibody or a scleroderma nailfold pattern should trigger specialist assessment before fixed skin disease.

Limited cutaneous pattern

Skin thickening distal to elbows and knees, telangiectasia, calcinosis and longstanding Raynaud may precede late pulmonary arterial hypertension.

Diffuse cutaneous pattern

Proximal limb or trunk skin progression, tendon friction rubs and early contractures indicate a phenotype at greater early ILD and renal-crisis risk.

Interstitial lung disease

Dry cough, exertional breathlessness, basal crackles, falling FVC or DLCO and HRCT ground-glass or reticulation indicate SSc-ILD, often before severe symptoms.

Pulmonary hypertensionRed flag

Disproportionate breathlessness, falling DLCO, raised NT-proBNP, syncope or right-heart signs requires rapid specialist evaluation and right-heart catheterisation when indicated.

Critical digital ischaemiaRed flag

Persistent rest pain, pallor, cyanosis, ulcer deepening or gangrene is an emergency distinct from an uncomplicated brief Raynaud attack.

Red flags requiring action

A new headache, visual symptoms, encephalopathy, hypertension, oliguria or creatinine rise may indicate scleroderma renal crisis and requires immediate ACE-inhibitor treatment.
Rest pain, a cold pale or blue digit, ulcer progression or necrosis requires urgent vascular assessment and intravenous vasodilator consideration.
New exertional syncope, rapidly falling exercise tolerance, chest pain or right-heart signs may indicate pulmonary hypertension or myocardial disease.
Acute hypoxia, new diffuse opacity or a sudden lung-function fall requires urgent assessment for infection, ILD acceleration, aspiration, embolism or heart failure.
Dysphagia with aspiration, inability to maintain intake, obstruction symptoms or gastrointestinal bleeding needs urgent gastroenterology and nutritional review.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
ANA and systemic-sclerosis-specific antibodiesFirst step
Why
Support diagnosis and stratify organ surveillance within a compatible clinical phenotype.
Interpretation and limitations
Anti-centromere, anti-topoisomerase-I and anti-RNA-polymerase-III guide vigilance but do not confirm current organ activity or exclude seronegative disease.
02
Nailfold capillaroscopy
Why
Identify giant capillaries, haemorrhage, capillary loss and abnormal repair characteristic of scleroderma-spectrum microangiopathy.
Interpretation and limitations
A scleroderma pattern supports systemic disease in Raynaud; interpret with examination and antibodies because trauma and other CTDs can alter capillaries.
03
Baseline HRCT chest
Why
Detect and map interstitial lung disease at diagnosis even when chest radiography or symptoms are mild.
Interpretation and limitations
NSIP is common, but infection, aspiration and oedema can mimic inflammatory change; quantify extent and compare with physiology.
04
FVC, lung volumes and DLCO
Why
Establish respiratory baseline and serially track restrictive or vascular deterioration.
Interpretation and limitations
Falling FVC supports ILD progression; isolated or disproportionate DLCO decline prompts PAH, anaemia and emphysema assessment.
05
Annual PAH screening
Why
Select patients for definitive haemodynamic testing before advanced right-heart failure.
Interpretation and limitations
Use symptoms, examination, DLCO, NT-proBNP and echocardiography or DETECT in eligible patients; echocardiography estimates probability, not definitive pressure.
06
Right-heart catheterisation
Why
Confirm and classify pulmonary hypertension before PAH-specific treatment.
Interpretation and limitations
This is the haemodynamic reference standard, separating pre-capillary PAH from left-heart or lung-disease mechanisms that require different management.
07
Blood pressure, creatinine and urinalysis
Why
Detect renal crisis and distinguish other kidney processes during follow-up.
Interpretation and limitations
A relative pressure rise may matter even below a conventional severe threshold; AKI with MAHA supports crisis but urine can be modestly abnormal.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Localised scleroderma

Morphoea causes circumscribed or linear skin sclerosis without the characteristic Raynaud, nailfold and internal-organ vasculopathy of systemic sclerosis.

Scleredema or scleromyxoedema

Posterior neck and upper-back induration, diabetes association, papules or paraprotein findings support alternative sclerosing disorders rather than systemic sclerosis.

Eosinophilic fasciitis

Painful symmetrical limb induration, groove sign, eosinophilia and fascial MRI or biopsy changes usually spare fingers and Raynaud phenomenon.

Overlap connective-tissue disease

Prominent inflammatory arthritis, myositis, lupus or Sjogren features with anti-U1-RNP or other antibodies can indicate an overlap syndrome requiring organ-specific interpretation.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01First-line confirmationDefine phenotype and baseline organsFirst stepFirst lineRaynaud, puffy or sclerotic fingers and capillary or antibody features suggest systemic sclerosis.

1Document skin distribution and score, nailfolds, ulcers, pulses, joints, strength, reflux, bowel, respiratory and cardiac symptoms, pressure and weight.
2Request antibodies, FBC, renal and liver profile, urinalysis, ECG, baseline HRCT and PFT with DLCO; obtain echocardiography and NT-proBNP for cardiopulmonary screening.
3Refer to a systemic-sclerosis service, communicating antibody and organ-risk phenotype and arranging early lung, renal, vascular and gastrointestinal prevention.

02Preferred Raynaud sequenceWarm, vasodilate and protect tissuePreferredRecurrent vasospasm causes pain or functional limitation without current critical ischaemia.

1Use whole-body warming, layered gloves, smoking cessation, trigger and medicine review, skin care and prompt treatment of cracks or infection.
2Start and titrate a dihydropyridine calcium-channel blocker such as nifedipine while monitoring pressure, oedema, headache and reflux.
3For persistent severe attacks or ulcers, add sildenafil and involve the specialist team for intravenous iloprost, wound care and vascular imaging when indicated.

03ILD escalationTreat progression, not CT aloneEscalationHRCT and serial physiology show clinically meaningful or progressive SSc-associated ILD.

1Exclude infection, aspiration, pulmonary oedema and PAH and quantify HRCT extent, FVC or DLCO trajectory, exercise oxygenation and patient priorities.
2Use mycophenolate as a common immunomodulatory treatment and consider rituximab or cyclophosphamide for selected inflammatory or severe phenotypes through specialist care.
3Add nintedanib for eligible progressive fibrotic disease, monitoring liver and gastrointestinal toxicity, and refer early for transplant assessment when deterioration continues.

04Annual organ surveillanceLook before symptoms become lateEstablished systemic sclerosis is clinically stable between specialist visits.

1Repeat symptoms, examination, pressure, renal tests, PFT or DLCO and multimodal PAH screening at the interval matched to disease duration and risk.
2Investigate new reflux, dysphagia, weight loss, anaemia, bowel change, palpitations, troponin rise, ulcers or functional loss with the relevant specialty.
3Update vaccinations, cardiovascular and bone risk, rehabilitation, contraception and pregnancy planning, and reinforce emergency renal and digital-ischaemia advice.

Key medicines and prescribing safety5 treatments · regimens, roles and cautions

Usual first oral vasodilator for systemic-sclerosis Raynaud phenomenon when non-drug measures are insufficient.

Nifedipine modified release

Start 30 mg orally once daily and titrate, commonly to 60 mg once daily, according to Raynaud response, blood pressure and the selected modified-release product.

Monitor headache, flushing, ankle oedema, dizziness, tachycardia and worsening reflux; reduce or stop if symptomatic hypotension occurs. Do not crush modified-release tablets and review CYP3A4 interactions.

Phosphodiesterase-5 inhibition for severe Raynaud or digital ulcers and as part of specialist pulmonary arterial hypertension treatment.

Sildenafil

A common specialist digital-vasculopathy regimen is 20 mg orally three times daily, titrated only under the relevant Raynaud, ulcer or pulmonary-hypertension protocol.

Never combine with nitrates or riociguat. Review hypotension, cardiac risk, renal or hepatic impairment, CYP3A4 interactions, visual or hearing symptoms and prolonged erection.

Suppresses acid to treat gastro-oesophageal reflux and reduce oesophagitis and aspiration-related injury.

Omeprazole

Start 20 mg orally once daily, 30–60 minutes before breakfast; increase to 20 mg twice daily for persistent documented reflux under a reviewed gastroenterology plan.

Persistent dysphagia, weight loss, bleeding or anaemia needs investigation rather than dose escalation alone. Review long-term magnesium, B12, fracture, enteric-infection and interaction risks.

Common immunomodulatory treatment for progressive cutaneous disease and SSc-associated ILD.

Mycophenolate mofetil

Specialist treatment commonly starts at 500 mg orally twice daily and increases toward 1 g twice daily, sometimes 1.5 g twice daily, according to skin or lung response and tolerance.

Monitor FBC, liver and renal function and infection; major teratogenicity requires pregnancy exclusion, effective contraception and pre-conception substitution. Gastrointestinal adverse effects may be especially limiting in systemic sclerosis.

Antifibrotic treatment that slows FVC decline in eligible SSc-ILD but does not reverse established fibrosis.

Nintedanib

For systemic-sclerosis-associated ILD, take the licensed 150 mg oral dose with food every twelve hours; intolerance may require interruption or reduction to 100 mg every twelve hours.

Check liver tests before and during therapy; diarrhoea, nausea, weight loss, bleeding, arterial events and wound-healing concerns require review. Avoid pregnancy and manage P-glycoprotein interactions.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Interstitial lung disease

Fibrotic ILD, particularly with diffuse skin disease or anti-topoisomerase-I, causes cough, restriction, gas-transfer loss, respiratory failure and pulmonary vascular stress.

Pulmonary arterial hypertension

Progressive pulmonary arteriolar disease produces exertional limitation, syncope, right-heart failure and death, sometimes after skin disease has been stable for years.

Renal and vascular injury

Scleroderma renal crisis, digital ulceration, gangrene and calcinosis-related infection arise from severe vasculopathy and may progress rapidly.

Gastrointestinal and cardiac disease

Reflux, strictures, dysmotility, malabsorption, faecal incontinence, arrhythmia, myocarditis and myocardial fibrosis impair nutrition, function and survival.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Check home and clinic blood pressure and renal function more frequently in early diffuse disease, anti-RNA-polymerase-III positivity or any glucocorticoid exposure.
Repeat FVC and DLCO every three to six months in early or progressive ILD and less often only when sustained stability and specialist risk allow.
Perform annual PAH screening with symptoms, examination, DLCO, NT-proBNP and echocardiographic or DETECT pathway, escalating to right-heart catheterisation when indicated.
Track digital attacks, new ulcers, infection, pain, pulses and healing; review vasodilator tolerance and access to urgent iloprost.
Monitor weight, nutrition, haemoglobin, reflux, dysphagia, bowel function and aspiration, involving dietetics and gastroenterology before severe malnutrition develops.
Record skin score, joints, contractures, strength, function, cardiac symptoms, ECG and medicine toxicity at structured multidisciplinary reviews.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Skin labels do not fence organs

Limited cutaneous disease can develop severe PAH and diffuse disease can have modest lung involvement, so surveillance remains individual.

Normal chest radiography is inadequate

Early SSc-ILD may be visible only on HRCT and physiology, well before plain-film change or severe breathlessness.

Echocardiography estimates probability

PAH diagnosis and classification require right-heart catheterisation because lung and left-heart disease can produce similar symptoms and echo findings.

Steroid exposure changes renal vigilance

High glucocorticoid doses increase renal-crisis risk, so every unavoidable course needs a reason, minimum dose and monitoring plan.

Reflux can injure lungs

Oesophageal dysmotility and microaspiration may aggravate respiratory symptoms, making gastrointestinal care part of lung protection.

11Common pitfallsFrequent interpretation and management errors.

01
Calling severe Raynaud primary when puffy fingers, fingertip pits, capillary loss or systemic-sclerosis antibodies are present.
02
Screening ILD with chest radiography alone and waiting for advanced breathlessness before HRCT or pulmonary physiology.
03
Diagnosing PAH from echocardiography without right-heart catheterisation and mechanism classification.
04
Using repeated high-dose glucocorticoid for skin tightness without considering renal-crisis risk and limited benefit.
05
Treating dysphagia or weight loss with escalating PPI alone without investigating stricture, dysmotility, malabsorption or malignancy.
06
Assuming a painful black digit is routine Raynaud and delaying urgent vasodilator and vascular assessment.