Systemic Sclerosis (Scleroderma)

Meet the patient

A 38-year-old woman has had Raynaud for eight years — her fingers go white then blue then red in the cold. Six months ago her fingers began to swell, the skin over them slowly tightening so she can no longer make a fist. She has noticed tiny red spots on her lips and palms, and intermittent heartburn that wakes her at night.[2][4]

Three questions decide her survival, and they decide every scleroderma consult: which subtype, and which antibody? (limited with anti-centromere versus diffuse with anti-Scl-70 or anti-RNA polymerase III — the split that sets the threat), is there organ disease brewing? (annual PFTs and echocardiography find it before symptoms do), and what must I never do? (give high-dose corticosteroids and precipitate renal crisis). The clinical art is not recognising the late, hidebound patient — anyone can. It is recognising Raynaud plus puffy fingers plus abnormal nailfold capillaroscopy plus a disease-specific antibody while disease is still modifiable.[1]

What scleroderma is — three reinforcing processes

Systemic sclerosis is a chronic, multisystem autoimmune disease defined by a pathophysiological triad — microvascular vasculopathy, immune dysregulation, and generalised tissue fibrosis (excess type I and type III collagen and extracellular matrix from activated myofibroblasts). It targets the skin and virtually every internal organ — most lethally the lungs (interstitial lung disease and pulmonary arterial hypertension), kidneys (scleroderma renal crisis), heart (myocardial fibrosis) and gastrointestinal tract (dysmotility and malabsorption).[2][9]

Every clinical feature maps onto one of the three processes — this is the single most useful concept on the page.[3][9]

It is not just "hard skin". The eponymous sclerosis is only the visible surface of a disease whose lethality lives in the lungs, kidneys and heart. It is not localised scleroderma (morphea), which is skin-only with no Raynaud, no internal organ involvement and no scleroderma-specific antibodies. And it is not reversible with steroids — established fibrosis is currently irreversible, and high-dose steroids are actively dangerous here.[2]

The 2013 criteria — and the rule that wins marks

The 2013 ACR/EULAR classification criteria replaced the 1980 criteria (which were insensitive to early disease) with a point-based score. A total of 9 or more classifies definite systemic sclerosis.[5]

[5]

The rule that wins marks: skin thickening proximal to the metacarpophalangeal joints is sufficient alone (9 points). Such a patient has systemic sclerosis by definition. In its absence, the additive domains accumulate — fingertip changes, telangiectasia, abnormal nailfold capillaries, PAH or ILD, Raynaud, and a disease-specific antibody.[1][5]

Limited or diffuse — and why the antibody decides the threat

The clinical classification by the extent of skin thickening is the bedrock of prognosis. It splits the disease into two subtypes with different threats, and the disease-specific autoantibody confirms which threat to watch for.[2]

[2]

The CREST acronym — limited cutaneous disease

CREST describes the cardinal features of limited cutaneous disease and is the most exam-rewarded mnemonic in scleroderma.[2]

The antibody-phenotype map

Each disease-specific autoantibody predicts the clinical course, and they are largely mutually exclusive — a patient has one dominant antibody, not several.[1][2]

[1]

The discriminator line: anti-centromere points to limited disease and late pulmonary arterial hypertension; anti-Scl-70 points to diffuse disease and early interstitial lung disease; anti-RNA polymerase III points to renal crisis and a synchronous cancer. Knowing the antibody tells you which organ to screen hardest.[2]

How common, who, and the silica trigger

Systemic sclerosis is uncommon but not rare — prevalence of approximately 50 to 300 per million and annual incidence around 10 to 20 new cases per million. The female-to-male ratio is about 4 to 1, and the peak age of onset is 30 to 50 years. It carries the highest case fatality of any rheumatic disease.[9]

[9]

Male sex, older age at onset and African ancestry predict worse prognosis, partly through a higher frequency of diffuse cutaneous disease and renal crisis. Genetic susceptibility accounts for only a minority of risk — HLA-DRB1 and HLA-DQB1 haplotypes dominate, with IRF5, STAT4 and CD247 contributing.[2][3]

Environmental and occupational triggers are well documented. The strongest is silica dust (miners, stonemasons, sandblasters) — relative risk in the order of 3 to 25 fold. Others include organic solvents (vinyl chloride — the original "vinyl chloride disease"), epoxy resins, bleomycin (a scleroderma-like syndrome), taxane chemotherapy, radiation therapy, and contaminated L-tryptophan (the eosinophilia-myalgia syndrome).[3]

Anti-RNA polymerase III antibody positivity carries a substantially elevated risk of a synchronous solid malignancy — especially breast and lung — implying that in this subgroup the disease may be paraneoplastic. Age-appropriate cancer screening is recommended at diagnosis and for several years thereafter.[1]

Why the skin hardens and the arteries narrow — the cascade

The cascade proceeds in three reinforcing loops, and understanding the order explains why early therapy matters.[3][9]

Loop 1 — microvascular vasculopathy is the initiating event. The first demonstrable abnormality is injury to the endothelium of small arteries, arterioles and capillaries. Endothelial cells undergo apoptosis, the intima proliferates, and the capillary bed is progressively lost (rarefaction); the survivors dilate into the giant capillaries and microhaemorrhages seen on nailfold capillaroscopy. The injured endothelium produces more endothelin-1 (vasoconstrictor) and less nitric oxide and prostacyclin (vasodilators) — producing fixed structural narrowing plus superimposed vasospasm, the substrate of Raynaud and of the visceral lesions that drive PAH, renal crisis and myocardial ischaemia.[4][9]

Loop 2 — immune dysregulation and autoantibodies. Perivascular CD4 T-cell infiltrates with a Th2-skewed profile (interleukin-4, interleukin-13), B-cell hyperactivity, and autoantibody production define the immune phase. Transforming growth factor-beta (TGF-beta), connective tissue growth factor (CTGF) and interleukin-6 (a tocilizumab target) are the principal drivers of fibroblast activation.[3]

Loop 3 — fibroblast activation and the irreversible end-stage. Quiescent fibroblasts convert to activated myofibroblasts (alpha-smooth muscle actin) that overproduce type I and type III collagen in the dermis, lung interstitium, gut wall, vascular intima and heart. Critically, myofibroblasts become autonomous — they keep producing matrix even after the immune signal is silenced, an epigenetic "imprinting." This is why established fibrosis is currently irreversible, and why no drug reverses it; therapy targets the upstream processes and the organ consequences.[3][7][8]

The clinical sequence — Raynaud first, then puffy fingers, then skin

Systemic sclerosis can present in almost any way, but the classical sequence is Raynaud phenomenon first (often years before other features), followed by puffy fingers, then skin thickening, then organ involvement. The order, tempo and organ pattern are dictated by subtype and antibody.[1]

Raynaud — the first sign

Raynaud is the first manifestation in over 90 percent of patients, and may precede skin disease by years to decades in limited disease, or appear concurrently with skin thickening in diffuse disease. The classical description is the triphasic colour response to cold or stress: pallor (vasospastic ischaemia), then cyanosis (deoxyhaemoglobin in static blood), then erythema (reactive hyperaemia on rewarming).[4]

Primary Raynaud is benign, common in young women, and lacks the nailfold capillary changes, digital ulcers, pitting scars or autoantibodies that mark secondary Raynaud. Any Raynaud onset after age 30, or with any of those accompanying features, demands an autoimmune work-up and nailfold capillaroscopy.[4]

Skin and digital features

The skin evolves through three phases.[2]

1. Oedematous (puffy fingers) phase — early non-pitting swelling of the fingers, often the first objective skin sign and the highest-yield window for diagnosis.
2. Fibrotic (indurated, hidebound) phase — the skin becomes hard, tight, shiny and bound to underlying structures: sclerodactyly (thickening distal to the MCP joints), microstomia (reduced oral aperture), perioral radial furrowing (rhagades), and loss of hair and sweat.
3. Atrophic phase — late thinning of the skin, though the underlying sclerosis persists; in dcSSc the skin often softens after the peak at 1 to 3 years, which can be misread as improvement.[1]

Digital features include digital pitting scars (small depressed atrophic scars at the fingertips — the residue of ischaemic microinfarcts), ischaemic digital ulcers (painful, slow to heal, prone to infection), calcinosis cutis (hard chalky subcutaneous deposits that ulcerate and extrude white material), acral osteolysis (resorption of the terminal phalanges), and in severe cases digital gangrene and auto-amputation. Telangiectasia — mat-shaped dilated capillaries on the face, lips, hands and oral mucosa — is a hallmark of limited disease.[1]

Gastrointestinal — the commonest organ involved

The gastrointestinal tract is involved in up to 90 percent of patients and is the most common organ manifestation overall. The lower two-thirds of the oesophagus (smooth muscle) loses peristalsis and the lower sphincter becomes incompetent — gastro-oesophageal reflux, dysphagia, oesophagitis, strictures and Barrett oesophagus (with a markedly increased risk of oesophageal adenocarcinoma). In the stomach, gastric antral vascular ectasia (GAVE, "watermelon stomach") causes chronic iron-deficiency anaemia from occult bleeding. In the small bowel, dysmotility produces small intestinal bacterial overgrowth — the leading cause of diarrhoea, steatorrhoea and malabsorption — and may progress to intestinal pseudo-obstruction. Primary biliary cholangitis overlaps with limited disease, especially with anti-centromere antibody.[2][9]

The two lethal organs — lung and kidney

The lungs are the leading cause of death in systemic sclerosis, through two distinct mechanisms, and the kidneys deliver the classical emergency. Knowing both is non-negotiable.[1]

Interstitial lung disease — the commonest cause of death

SSc-ILD affects approximately 40 percent of patients and presents with insidious exertional dyspnoea and dry cough, with bibasal fine Velcro-like crackles. The non-specific interstitial pneumonia (NSIP) pattern is commonest (basal subpleural ground-glass, reticulation, traction bronchiectasis) and carries a better prognosis than the usual interstitial pneumonia (UIP) pattern (honeycombing). It is strongly associated with anti-Scl-70 (topoisomerase I).[8]

Pulmonary arterial hypertension — the second commonest cause of death

SSc-PAH affects approximately 10 to 15 percent, mostly in limited cutaneous disease and with anti-centromere antibody. It presents with progressive exertional dyspnoea, fatigue, exertional syncope, chest pain and signs of right heart failure (raised JVP, right ventricular heave, loud P2, tricuspid regurgitation, peripheral oedema).[9]

The screening red flags live in the PFTs. An isolated or disproportionate reduction in DLCO (with relatively preserved FVC) and a raised FVC to DLCO ratio (over 1.6) point to pulmonary vascular disease even before symptoms. A DLCO under 60 percent predicted is a strong independent predictor of PAH.[7]

Scleroderma renal crisis — the classical emergency

Scleroderma renal crisis occurs in approximately 5 to 10 percent, almost always in early diffuse cutaneous disease, and is strongly associated with anti-RNA polymerase III. It presents with new-onset severe (malignant) hypertension, acute kidney injury, microangiopathic haemolytic anaemia (schistocytes on film), thrombocytopenia, raised renin, retinopathy and encephalopathy, and may produce flash pulmonary oedema.[9]

Cardiac involvement — myocardial fibrosis, diastolic dysfunction, arrhythmias and conduction defects — is an independent predictor of mortality. Pericardial effusion is common but usually small and asymptomatic. Cardiac MRI with late gadolinium enhancement is the most sensitive test for subclinical fibrosis.[9]

The mimics — and the bedside discriminator that is essentially diagnostic

The dangerous omission is to label a mimic as systemic sclerosis (or miss true SSc hiding among mimics). The key discriminators are Raynaud, nailfold capillaroscopy, scleroderma-specific antibodies and internal organ involvement.[2]

[2]

The single safest bedside discriminator: Raynaud phenomenon plus abnormal nailfold capillaroscopy plus a disease-specific antibody is essentially diagnostic of systemic sclerosis in the right clinical setting.[6]

The bedside round — and the nailfold capillaroscopy that changes the game

The long-case examination centres on the skin, hands, face, nailfold capillaroscopy, chest and cardiovascular system. The goal is to stage the disease, identify the subtype, detect organ involvement and quantify skin thickening.[1]

The modified Rodnan skin score

The modified Rodnan skin score (mRSS) is the validated, internationally used skin-thickening outcome measure — pinch the skin at 17 body sites and grade thickness from 0 to 3.[9]

[9]

The mRSS tracks disease activity, predicts internal organ involvement (high early scores predict renal crisis and ILD), and is the primary outcome in skin-disease trials.[1]

Nailfold capillaroscopy — the early diagnostic test

Nailfold capillaroscopy is the single most useful early test in suspected scleroderma. Using a dermatoscope, an ophthalmoscope (with the plus-40-dioptre lens) or a dedicated videocapillaroscope with immersion oil on the nailfold, the scleroderma pattern has three components.[6]

• Giant (ectatic, dilated) capillaries — homogeneously enlarged loops, the hallmark.
• Microhaemorrhages — dark blobs from capillary rupture.
• Capillary loss (rarefaction, dropout, avascular areas) — reduced capillary density, late and prognostically adverse.[1]

The disease evolves through early (giant capillaries, no dropout), active (giant capillaries, microhaemorrhages and dropout) and late (predominantly dropout with bushy or ramified capillaries) patterns.[6]

Other bedside must-dos. Measure blood pressure at every visit (renal-crisis surveillance — new or rising BP in early dcSSc is a red flag). Palpate for tendon friction rubs — a leathery crepitus over extensor tendons that is highly specific for active dcSSc and prognostically adverse. Assess functional and nutritional status (grip, oral aperture, weight loss) — malnutrition is common and under-recognised. Listen for fine basal Velcro-like crackles (ILD), a loud P2 and tricuspid regurgitation murmur (PAH), and a right ventricular heave with raised JVP (right heart failure).[1]

Investigations — confirm, subtype, and screen organs annually

There is no single diagnostic test. Investigations confirm the diagnosis and subtype (autoantibodies, capillaroscopy), screen and stage organ involvement (PFTs, HRCT, echocardiography, renal function, GI studies), and monitor disease progression.[1]

Antinuclear antibody is positive in over 95 percent — typically with a speckled, nucleolar or centromere pattern. The disease-specific antibodies are mutually exclusive and predict the phenotype (see the antibody map above).[1][2]

Pulmonary function tests are the cornerstone of ILD and PAH screening — at baseline and annually. A reduced FVC (with preserved or low FVC-to-DLCO ratio) points to interstitial lung disease; a disproportionately reduced DLCO with a raised FVC-to-DLCO ratio (over 1.6) points to pulmonary vascular disease or PAH even before symptoms. A 10 percent or greater fall in FVC or DLCO between visits mandates HRCT and echocardiography.[7][8]

High-resolution CT is the imaging test of choice for interstitial lung disease, showing the pattern (NSIP versus UIP), the extent (over 20 percent is high-risk) and progression. Echocardiography screens for pulmonary hypertension; a tricuspid regurgitant jet velocity over 2.8 m per second and right-heart changes are screening red flags. In high-risk limited disease, the DETECT algorithm is more sensitive than echo alone. Right heart catheterisation is mandatory to confirm PAH (mean pulmonary artery pressure 20 mmHg or higher, wedge pressure 15 mmHg or lower, pulmonary vascular resistance over 3 Wood units).[7][9]

In suspected renal crisis, send urea and electrolytes, creatinine and eGFR (rising), a full blood count and film (schistocytes, thrombocytopenia), LDH and haptoglobin (haemolysis), urinalysis (mild proteinuria and microscopic haematuria), and plasma renin (markedly elevated — the basis for ACE-inhibitor therapy).[1]

The two emergencies — captopril for the kidney, immunosuppression for the lung

Systemic sclerosis is not an ABCDE-resuscitation disease in the classic sense, but two acute, time-critical scenarios demand immediate action: scleroderma renal crisis and acute severe Raynaud or a critically ischaemic digit.[1]

No cure — treat organ by organ

There is no cure for systemic sclerosis. Therapy is organ-targeted and stratified by subtype and antibody, using the 2023 EULAR update as the current framework. No therapy reverses established fibrosis; the goals are to control vascular disease, suppress immune-driven progression, protect organs, and manage complications.[7]

Skin disease

For early diffuse cutaneous disease with rapidly progressive skin thickening (rising mRSS), immunosuppression is offered to attenuate progression: methotrexate 10 to 25 mg weekly, mycophenolate mofetil 1 g twice daily titrated to 2 to 3 g per day, or — for selected patients with early severe rapidly progressive dcSSc unresponsive to standard immunosuppression — autologous haematopoietic stem cell transplant. Physiotherapy, hand therapy and contracture prevention are essential; UVA1 phototherapy helps localised skin disease.[7]

The Raynaud and digital-ulcer ladder

Management of Raynaud and digital ulceration is stepwise, escalating from lifestyle measures through oral vasodilators to intravenous therapy.[4][7]

[1]

Avoid beta-blockers (they worsen peripheral vasospasm) and sympathomimetic decongestants. Smoking cessation is non-negotiable.[1]

Gastrointestinal management

Gastro-oesophageal reflux and dysmotility — a high-dose proton-pump inhibitor (omeprazole 20 to 40 mg daily) plus a prokinetic (metoclopramide 10 mg three times daily); strictures are dilated endoscopically. SIBO and malabsorption are treated with cyclic rotating antibiotics (rifaximin 550 mg twice daily for 2 weeks, alternating with doxycycline, metronidazole or ciprofloxacin) and nutritional support with vitamin and mineral replacement (vitamin D, B12, iron, calcium). GAVE (watermelon stomach) is treated with endoscopic argon plasma coagulation. PBC overlap takes ursodeoxycholic acid 13 to 15 mg per kg per day.[1]

Interstitial lung disease

The goal is to attenuate the inflammatory component and slow fibrosis.[7][8]

• Mycophenolate mofetil 2 to 3 g per day — first-line for SSc-ILD, non-inferior to cyclophosphamide with less toxicity (Scleroderma Lung Study II).
• Cyclophosphamide 600 mg per square metre intravenously monthly for 6 months, then MMF maintenance — for progressive or severe disease (Scleroderma Lung Study I).
• Rituximab 1 g intravenously on days 0 and 14 (repeat 6-monthly) — for refractory or rapidly progressive disease.
• Nintedanib 150 mg twice daily — an antifibrotic tyrosine-kinase inhibitor that slows the rate of FVC decline in SSc-ILD (SENSCIS); monitor LFTs; diarrhoea and transaminitis are the main side-effects.
• Lung transplantation for end-stage disease in selected patients.[1]

Pulmonary arterial hypertension

PAH therapy is specialist-led and now uses upfront combination therapy targeting the three key pathways.[9]

• Endothelin-receptor antagonists — bosentan 62.5 to 125 mg twice daily, ambrisentan 5 to 10 mg daily, macitentan 10 mg daily. Monitor LFTs (bosentan) and haemoglobin; contraindicated in pregnancy.
• PDE-5 inhibitors — sildenafil 20 mg three times daily; tadalafil 40 mg daily.
• Soluble guanylate cyclase stimulator — riociguat 1.0 to 2.5 mg three times daily (riociguat is contraindicated in SSc-ILD and must not be combined with PDE-5 inhibitors).
• Prostacyclin analogues — inhaled iloprost, subcutaneous or inhaled treprostinil, intravenous epoprostenol (for severe WHO functional class IV disease).
• Supportive therapy — oxygen to maintain saturation over 90 percent, diuretics for right heart failure, oral anticoagulation in selected severe cases, avoidance of pregnancy, and vaccination. Lung transplantation for refractory disease.[1]

Scleroderma renal crisis — the ACE-inhibitor rule

Start an ACE inhibitor immediately on suspicion of renal crisis.[9]

Captopril 6.25 to 12.5 mg orally, titrated rapidly to 25 to 50 mg three times daily (the short half-life allows precise titration in the unstable patient). Switch to a longer-acting ACE inhibitor (lisinopril, ramipril) once stable. Add an angiotensin-receptor blocker if the ACE inhibitor alone is insufficient. Renal replacement therapy supports the patient while the ACE inhibitor works — many recover sufficient renal function to come off dialysis; the ACE inhibitor should continue indefinitely even after recovery. Avoid high-dose corticosteroids (over 15 mg per day prednisolone equivalent). Treat the malignant hypertension with slow, controlled BP reduction (intravenous labetalol or nicardipine if oral therapy is insufficient).[1]

Autologous haematopoietic stem cell transplant

For selected patients with early (under 2 to 4 years), severe, rapidly progressive dcSSc unresponsive to standard immunosuppression, AHSCT improves long-term event-free and overall survival compared with cyclophosphamide alone, at the cost of significant early treatment-related mortality (around 5 to 10 percent at one year). The ASTIS and SCOT trials underpin this option; it is offered only in specialist transplant centres and is contraindicated in advanced organ failure.[7]

How scleroderma patients come to harm — the preventable list

• Renal crisis missed or the ACE inhibitor withheld for fear of worsening AKI — the creatinine will rise before it falls; do not stop the ACE inhibitor.[1]
• Renal crisis precipitated by high-dose corticosteroids (over 15 mg per day prednisolone equivalent) given for skin or joint disease.[1]
• ILD missed because PFTs were not done — annual PFTs and HRCT for any decline.[8]
• PAH missed because the echo looked normal — a low isolated DLCO and a raised FVC-to-DLCO ratio are the screening red flags; right heart catheter confirms.[9]
• A mimic labelled as SSc — gadolinium exposure in CKD (NSF) and the groove sign of eosinophilic fasciitis discriminate.[2]
• Beta-blockers given for Raynaud or hypertension — they worsen peripheral vasospasm.[1]
• Malnutrition overlooked — weight loss in SSc is common, multifactorial and under-treated.[1]
• The cancer association forgotten in anti-RNA polymerase III patients — age-appropriate malignancy screening at diagnosis and for 2 to 5 years thereafter.[1]

Prognosis and disposition

Systemic sclerosis has the highest case fatality of any rheumatic disease. Overall 10-year survival is approximately 60 to 70 percent, with a substantial subtype gap — limited cutaneous disease approximately 70 to 80 percent and diffuse cutaneous disease approximately 50 to 60 percent at 10 years.[9]

[9]

Poor-prognosis markers: diffuse subtype, older age at onset, male sex, a high early mRSS, anti-Scl-70 or anti-RNA polymerase III, tendon friction rubs, elevated ESR or CRP, low DLCO (under 60 percent predicted), early ILD, renal crisis, and cardiac involvement.[9]

Disposition — most patients are managed by a rheumatology-led multidisciplinary team with pulmonology, cardiology or pulmonary hypertension, nephrology, gastroenterology, dermatology, hand therapy, dietetics and psychology. Annual PFTs and echocardiography are the backbone of organ surveillance; renal function and BP at every visit in early dcSSc. Admit for renal crisis, severe PAH with right heart failure, respiratory failure from ILD, an acutely ischaemic digit, or severe malnutrition.[1]

Special populations

Pregnancy is higher risk than in the general population but generally feasible in stable disease without severe organ involvement. Avoid ACE inhibitors (fetopathy). Pulmonary arterial hypertension is a contraindication to pregnancy (maternal mortality up to 30 to 50 percent). Early diffuse disease (within the first 4 years) carries a higher risk of renal crisis. Multidisciplinary perinatal care is essential; regional anaesthesia is preferred (microstomia and skin thickening complicate intubation).[9]

Paediatric and localised scleroderma — linear scleroderma in children causes growth arrest of bone and soft tissue (limb-length discrepancy, facial hemiatrophy or Parry-Romberg syndrome); MRI monitors deep involvement; methotrexate and systemic steroids treat active disease, with physiotherapy and occupational therapy.[1]

Elderly male with anti-RNA polymerase III — high risk of renal crisis within months of onset; BP surveillance and age-appropriate malignancy screening.[1]

Pre-operative assessment — assess the airway (microstomia, limited neck movement), cardiac and pulmonary status; avoid hypothermia (worsens Raynaud); avoid vasopressors that worsen digital ischaemia; prefer regional anaesthesia; careful BP control (renal-crisis risk); PPI cover for reflux under anaesthesia.[1]

Renal impairment — avoid NSAIDs and nephrotoxins; avoid high-dose steroids; adjust the methotrexate dose; the ACE inhibitor is still required for renal crisis even in established CKD.[1]

Evidence and regional deltas

The 2013 ACR/EULAR classification criteria replaced the 1980 criteria and are more sensitive to early disease — skin thickening proximal to MCP is sufficient alone (9 points).[5] The EULAR 2023 update is the current European framework: prostacyclin analogues for severe Raynaud and digital ulcers; bosentan to prevent new ulcers; PDE-5 inhibitors for digital ulcers; MMF or cyclophosphamide for SSc-ILD; riociguat contraindicated in SSc-ILD; AHSCT for selected severe early dcSSc.[7]

The landmark trials. Scleroderma Lung Study I showed oral cyclophosphamide modestly improved FVC and skin score versus placebo in SSc-ILD; Scleroderma Lung Study II showed mycophenolate non-inferior to cyclophosphamide with less toxicity, establishing MMF as first-line. SENSCIS showed nintedanib slows the rate of FVC decline in SSc-ILD (approximately 40 ml per year benefit). ASTIS and SCOT showed autologous haematopoietic stem cell transplant improves long-term survival versus cyclophosphamide, at the cost of significant early treatment-related mortality. DETECT is a two-step screening algorithm for PAH more sensitive than echo alone.[7][8]

The mantra, and the antibody map

The mantra: Raynaud first, puffy fingers next, screen the lung and the kidney every year — and never give high-dose steroids.[9]

Ward-round test — three stems, thirty seconds each

Stem 1 — the woman from the top of the topic (answer)

The 38-year-old with eight years of Raynaud, six months of puffy then tightening fingers, lip and palmar red spots, and night-time heartburn. What is the diagnosis, and what three investigations do you send first? Model: This is systemic sclerosis, probably limited cutaneous (CREST) — long-standing Raynaud, puffy fingers progressing to sclerodactyly, telangiectasia on lips and palms, and oesophageal reflux symptoms. Send disease-specific autoantibodies (anti-centromere expected here), nailfold capillaroscopy (giant capillaries, microhaemorrhages, dropout), and baseline organ screening — PFTs (FVC and DLCO) and echocardiography to detect ILD and PAH before symptoms. Add an upper GI endoscopy for reflux and Barrett surveillance. The 2013 ACR/EULAR criteria classify her; the antibody and subtype decide which organ threat to watch — limited with anti-centromere means late PAH, so annual PFTs and echo are non-negotiable.[1][5]

Stem 2 — the malignant hypertension (answer)

A 45-year-old man with three months of rapidly progressive diffuse skin thickening presents with a blood pressure of 210/130, acute kidney injury, confusion, and schistocytes on the blood film. He was started on prednisolone 40 mg daily two weeks ago for "the arthritis". What happened, and what do you do? Model: This is scleroderma renal crisis — new-onset malignant hypertension with AKI and microangiopathic haemolytic anaemia in early diffuse cutaneous disease, precipitated by the high-dose corticosteroid (over 15 mg per day prednisolone equivalent is the trap). Start an ACE inhibitor immediately — captopril 6.25 to 12.5 mg orally, titrated rapidly to 25 to 50 mg three times daily — even though the creatinine is rising and even if dialysis is needed. The ACE inhibitor is life-saving; expect the creatinine to worsen before it improves, and do not stop it for fear of the AKI. Stop the steroids. Support with renal replacement therapy if required; many patients recover sufficient function to come off dialysis, and the ACE inhibitor continues indefinitely.[9]

Stem 3 — the falling DLCO (answer)

A woman with limited scleroderma and anti-centromere antibody has an isolated DLCO of 55 percent predicted with a preserved FVC and a raised FVC-to-DLCO ratio. The chest is clear. What does this mean, and what is the next step? Model: An isolated or disproportionate fall in DLCO with a preserved FVC and a raised FVC-to-DLCO ratio (over 1.6) is the screening red flag for pulmonary vascular disease — pulmonary arterial hypertension — even before symptoms. The clear chest does not exclude it. The next step is echocardiography (tricuspid regurgitant jet velocity, right-heart size and function) and, if confirmed or suspected, right heart catheterisation to confirm pre-capillary PAH (mean pulmonary artery pressure 20 mmHg or higher, wedge 15 mmHg or lower, PVR over 3 Wood units). Begin specialist PAH therapy (endothelin-receptor antagonist plus a PDE-5 inhibitor, plus or minus a prostacyclin). Remember that riociguat is contraindicated in SSc-ILD.[7][9]

References

1. [1]Di Battista M, Lepri G, Codullo V, et al. Systemic sclerosis: one year in review 2025 Clin Exp Rheumatol, 2025.PMID 40737082
2. [2]Jerjen R, Nikpour M, Krieg T, et al. Systemic sclerosis in adults. Part I: Clinical features and pathogenesis J Am Acad Dermatol, 2022.PMID 35131402
3. [3]Rosendahl AH, Schönborn K, Krieg T Pathophysiology of systemic sclerosis (scleroderma) Kaohsiung J Med Sci, 2022.PMID 35234358
4. [4]Herrick AL, Wigley FM. Raynaud's phenomenon Best Pract Res Clin Rheumatol, 2020.PMID 32007400
5. [5]van den Hoogen F, Khanna D, Fransen J, et al. 2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative Ann Rheum Dis, 2013.PMID 24092682
6. [6]Smith V, Ickinger C, Hysa E, et al. Nailfold capillaroscopy Best Pract Res Clin Rheumatol, 2023.PMID 37419757
7. [7]Del Galdo F, Lescoat A, Conaghan PG, et al. EULAR recommendations for the treatment of systemic sclerosis: 2023 update Ann Rheum Dis, 2025.PMID 39874231
8. [8]Maher TM. Interstitial Lung Disease: A Review JAMA, 2024.PMID 38648021
9. [9]Denton CP, Khanna D. Systemic sclerosis Lancet, 2017.PMID 28413064