Systemic Sclerosis

Systemic sclerosis (scleroderma) is a multisystem autoimmune connective tissue disease defined by the triad of vasculopathy, immune dysregulation, and progressive fibrosis of skin and internal organs. For NEET PG, the recurring discriminators are the limited-versus-diffuse split, the autoantibody-to-complication mapping, and the life-threatening emergency of scleroderma renal crisis.

Definition and classification

Systemic sclerosis (SSc) is a chronic disorder characterised by excessive deposition of collagen and extracellular matrix in skin and viscera, with an underlying obliterative microvasculopathy. It is distinguished from localised scleroderma (morphoea, linear scleroderma), which is purely cutaneous with no internal organ involvement and no Raynaud phenomenon — a classic distractor.

SSc is divided by the extent of skin involvement (LeRoy classification):

Feature	Limited cutaneous SSc (lcSSc)	Diffuse cutaneous SSc (dcSSc)
Skin involvement	Distal to elbows/knees + face	Proximal to elbows/knees + trunk
Historic name	CREST syndrome	—
Antibody	Anti-centromere (ACA)	Anti-Scl-70 (anti-topoisomerase I)
Raynaud onset	Years before skin changes	Close to / after skin changes
Pulmonary	Late PAH (isolated)	Early ILD (fibrosis)
Renal crisis	Rare	More common
Prognosis	Better	Worse
Pace	Indolent	Rapidly progressive

CREST = Calcinosis cutis, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, Telangiectasia — the components of limited SSc.

High-yield: Anti-centromere antibody → limited (CREST) → late isolated pulmonary arterial hypertension. Anti-Scl-70 (topoisomerase I) → diffuse → early interstitial lung disease and higher renal-crisis risk.

A third entity, sine scleroderma, has internal organ fibrosis and SSc antibodies without skin thickening — a favourite "atypical presentation" stem.

Etiology and pathophysiology

The cause is unknown; genetic susceptibility (HLA associations) plus environmental triggers (silica dust, vinyl chloride, organic solvents, bleomycin, taxanes) are implicated. Three interlocking processes drive disease:

Vascular injury → immune activation → fibrosis is the core sequence.

1. Endothelial injury is the earliest event — intimal proliferation, luminal narrowing, and rarefaction of capillaries produce tissue ischaemia (clinically: Raynaud, digital ulcers, nailfold capillary changes).
2. Immune dysregulation — B-cell and T-cell activation, autoantibody production, and release of profibrotic cytokines (TGF-β, PDGF, IL-6, CTGF).
3. Fibroblast activation — TGF-β drives unchecked collagen (type I and III) deposition with reduced matrix degradation, producing dermal and visceral fibrosis.

High-yield: Endothelial dysfunction (not inflammation alone) is the primary trigger — this explains why Raynaud phenomenon is usually the first manifestation and why vasodilators are central to therapy.

Clinical features

Raynaud phenomenon

Triphasic colour change of digits on cold/stress: white (pallor, vasospasm) → blue (cyanosis) → red (reperfusion hyperaemia). It is the earliest and most common symptom (>90%) and may precede other features by years in limited SSc. SSc-associated (secondary) Raynaud differs from primary Raynaud by abnormal nailfold capillaroscopy, positive ANA, digital pitting/ulcers, and asymmetry.

Skin

Progresses through oedematous → indurative → atrophic phases. Findings: sclerodactyly (tight, shiny, tapered fingers), digital pitting scars and pulp loss, flexion contractures, mask-like facies with reduced oral aperture (microstomia) and perioral furrowing, "salt-and-pepper" dyspigmentation, and calcinosis cutis (subcutaneous calcium deposits, esp. fingertips).

Vascular / extremity

Digital tip ulcers and pitting, gangrene in severe ischaemia, telangiectasiae (mat-like on face/hands).

Gastrointestinal (most commonly involved internal system)

• Oesophageal dysmotility — lower two-thirds hypomotility + incompetent LES → severe GERD, strictures, Barrett oesophagus.
• Watermelon stomach = gastric antral vascular ectasia (GAVE) → chronic GI bleed / iron-deficiency anaemia.
• Small-bowel hypomotility → bacterial overgrowth, malabsorption; "wide-mouthed" colonic pseudodiverticula; pneumatosis cystoides intestinalis.

High-yield: Watermelon stomach (GAVE) is the classic SSc cause of occult/overt GI bleeding and refractory iron-deficiency anaemia; treated endoscopically with argon plasma coagulation.

Pulmonary (leading cause of death overall)

• Interstitial lung disease (ILD) — predominant in diffuse SSc; histology/HRCT pattern is usually NSIP (non-specific interstitial pneumonia) more often than UIP. Presents with exertional dyspnoea and dry cough.
• Pulmonary arterial hypertension (PAH) — predominant in limited SSc, typically late and isolated (without much fibrosis).

Cardiac

Patchy myocardial fibrosis, conduction defects, arrhythmias, pericardial effusion, cor pulmonale secondary to lung disease.

Renal — Scleroderma renal crisis (SRC)

The classic emergency: abrupt malignant hypertension + acute kidney injury (oligo-anuric) + microangiopathic haemolytic anaemia (MAHA). Occurs typically in early diffuse disease, associated with anti-RNA polymerase III antibody and recent high-dose corticosteroid use. Bland urinary sediment; renal biopsy shows onion-skin intimal proliferation of interlobular arteries (thrombotic microangiopathy).

High-yield: Glucocorticoids (especially ≥15 mg/day prednisolone) precipitate scleroderma renal crisis — avoid high-dose steroids in diffuse SSc. Anti-RNA polymerase III is the antibody most strongly linked to SRC (and to malignancy).

Musculoskeletal

Arthralgia, tendon friction rubs (palpable/audible, predict diffuse disease and renal crisis), myopathy.

Diagnosis and investigation of choice

Diagnosis is clinical, supported by autoantibodies, capillaroscopy, and organ screening. The 2013 ACR/EULAR classification criteria use a weighted score (≥9 = SSc); the single sufficient criterion is skin thickening of the fingers extending proximal to the MCP joints.

Antibody	Pattern of disease	Key complication
Anti-centromere (ACA)	Limited (CREST)	Pulmonary arterial hypertension
Anti-Scl-70 (anti-topoisomerase I)	Diffuse	Interstitial lung disease
Anti-RNA polymerase III	Diffuse, rapid skin	Renal crisis, malignancy
Anti-U3-RNP (fibrillarin)	Diffuse	PAH, myositis, cardiac
Anti-Th/To	Limited	PAH, ILD
Anti-PM-Scl	Overlap (myositis)	Calcinosis, myopathy

Workup:

• ANA positive in >90% (screening, but non-specific).
• Nailfold capillaroscopy — giant capillaries, microhaemorrhages, dropout (avascular areas); helps distinguish secondary from primary Raynaud and is an early marker.
• HRCT chest — investigation of choice for ILD; shows basal/subpleural reticulations, ground-glass opacity, traction bronchiectasis, honeycombing in advanced UIP.
• PFTs — restrictive pattern with reduced DLCO; an isolated low DLCO with preserved volumes suggests PAH.
• Echocardiography — screening for PAH (elevated estimated PASP); right heart catheterisation is the confirmatory gold standard for PAH (mean PAP >20 mmHg, PVR ≥3 WU, wedge ≤15).
• Barium swallow / manometry — oesophageal dysmotility.
• Skin biopsy not routinely needed.

High-yield: HRCT chest is the test of choice for SSc-ILD; right heart catheterisation confirms PAH; renal biopsy of SRC shows the onion-skin thrombotic microangiopathy.

Management and drug of choice

There is no cure; treatment is organ-directed, targeting the dominant manifestation.

Approach: screen organs at diagnosis → control vasculopathy → suppress fibrosis in active disease → treat complications aggressively.

Raynaud phenomenon / digital ischaemia

• First line: dihydropyridine calcium-channel blocker (nifedipine / amlodipine).
• Add PDE-5 inhibitors (sildenafil), topical nitrates.
• Active digital ulcers: IV prostacyclin analogues (iloprost); bosentan (endothelin receptor antagonist) to prevent new ulcers.

Skin / progressive diffuse disease

• Methotrexate for early diffuse skin disease; mycophenolate mofetil increasingly preferred (also benefits ILD).
• Cyclophosphamide for severe progressive disease.
• Autologous haematopoietic stem cell transplant for selected rapidly progressive dcSSc.

Interstitial lung disease

• Mycophenolate mofetil or cyclophosphamide as immunosuppressive backbone.
• Nintedanib (antifibrotic tyrosine-kinase inhibitor) is approved for SSc-ILD; tocilizumab (anti–IL-6) preserves lung function in early disease.

Pulmonary arterial hypertension

• Endothelin receptor antagonists (bosentan, ambrisentan, macitentan), PDE-5 inhibitors (sildenafil, tadalafil), prostacyclin pathway agents (epoprostenol), riociguat (soluble guanylate cyclase stimulator).

Scleroderma renal crisis — the exam favourite

• Drug of choice: ACE inhibitor — captopril (short-acting, rapidly titratable), continued even if creatinine rises.
• Avoid corticosteroids and ARBs as first-line; do not use them for BP control here.

High-yield: ACE inhibitors (captopril) transformed SRC from near-uniformly fatal to survivable — start immediately and continue despite worsening renal function; dialysis may be needed but renal recovery can occur over months.

GI

• Proton-pump inhibitors for reflux; prokinetics for dysmotility; cyclical antibiotics (rotating) for small-bowel bacterial overgrowth; argon plasma coagulation for GAVE.

High-yield: Glucocorticoids in SSc are largely avoided (precipitate renal crisis, limited benefit on fibrosis) — a common "which drug to AVOID" item.

Complications

• Digital ulcers, gangrene, autoamputation.
• Pulmonary fibrosis with respiratory failure (commonest cause of death).
• Pulmonary arterial hypertension → right heart failure.
• Scleroderma renal crisis → end-stage renal disease.
• GAVE bleeding, malabsorption, oesophageal stricture/Barrett.
• Conduction defects, arrhythmia, sudden cardiac death.
• Increased malignancy risk (esp. with anti–RNA pol III; lung, breast).

Key differentials

Condition	Distinguishing clue
Eosinophilic fasciitis (Shulman)	"Groove sign", peripheral eosinophilia, spares fingers/face, no Raynaud, ANA negative
Nephrogenic systemic fibrosis	Post-gadolinium in renal failure; spares face
Scleromyxoedema	Papular skin + paraproteinaemia (IgG-λ)
Scleredema (Buschke)	Post-infection or diabetes; upper back/neck induration
Mixed connective tissue disease	Anti-U1-RNP, overlap features, good steroid response
Diabetic cheiroarthropathy	Prayer sign, no Raynaud/visceral disease
Chronic GVHD	Post–stem cell transplant history

High-yield: Eosinophilic fasciitis classically spares the digits and has no Raynaud (versus SSc which begins distally with Raynaud) — and ANA is typically negative.

Recently asked / exam angle

• Single-best discriminator questions on antibody → subtype → complication (ACA/PAH/limited vs Scl-70/ILD/diffuse vs RNA pol III/renal crisis).
• "First manifestation of systemic sclerosis" → Raynaud phenomenon.
• "Most common cause of death in SSc" → pulmonary involvement (ILD then PAH); historically renal crisis but now controlled by ACE inhibitors.
• "Drug of choice in scleroderma renal crisis" → ACE inhibitor (captopril); and "drug to avoid" → high-dose corticosteroids.
• Watermelon stomach = GAVE recognition and its link to GI bleed/anaemia.
• Investigation of choice for ILD = HRCT; isolated reduced DLCO → suspect PAH.
• Image-based: nailfold capillaroscopy, sclerodactyly, calcinosis, telangiectasiae, mask facies.
• Histology: onion-skin renal vessels; HRCT NSIP pattern.
• Differential: eosinophilic fasciitis groove sign / digit sparing.

Rapid revision

1. SSc triad = vasculopathy + autoimmunity + fibrosis; endothelial injury is the primary event.
2. Raynaud phenomenon is the first and commonest manifestation.
3. Limited (CREST) → anti-centromere → late PAH; better prognosis.
4. Diffuse → anti-Scl-70 (topoisomerase I) → early ILD; worse prognosis.
5. Anti–RNA polymerase III → scleroderma renal crisis + malignancy.
6. CREST = Calcinosis, Raynaud, Esophageal dysmotility, Sclerodactyly, Telangiectasia.
7. Watermelon stomach = GAVE → iron-deficiency anaemia / GI bleed; treat with argon plasma coagulation.
8. SSc-ILD is usually NSIP; HRCT is the investigation of choice; reduced DLCO on PFT.
9. Scleroderma renal crisis = malignant HTN + AKI + MAHA; biopsy shows onion-skin vessels.
10. Captopril (ACE inhibitor) is the drug of choice for SRC — continue despite rising creatinine.
11. Avoid high-dose steroids in diffuse SSc — they precipitate renal crisis.
12. Eosinophilic fasciitis spares digits/face, no Raynaud, ANA negative, groove sign — top mimic.