Systemic sclerosis is a chronic autoimmune connective tissue disease characterized by widespread vascular dysfunction, fibrosis of the skin and internal organs, and immune dysregulation.

Systemic Sclerosis (SSc) — Scleroderma

Parameter	Details
Peak age of onset	30–50 years ^[1]
Sex ratio	Female : Male = 4 : 1 ^[1]
Prevalence	10–20 per 100,000 ^[1]
Annual incidence	1–2 per 100,000 ^[1]
Geography	Unrestricted (no specific geographic predilection) ^[1]
Genetic predisposition	?HLA-DR5, DRw52, DR4 ^[1]^[3]

Additional epidemiological points

SSc is relatively rare compared to RA or SLE, but has the highest case fatality rate among the connective tissue diseases ^[3]
Hong Kong context: SSc is uncommon but not rare. The local prevalence mirrors global figures. HKU rheumatology sees a steady flow of cases. Awareness matters because late diagnosis → organ damage → poor outcomes
Ethnicity: African Americans and Choctaw Native Americans have higher incidence and more severe disease (especially dcSSc with pulmonary fibrosis). In Asian populations, limited cutaneous SSc (lcSSc) is relatively more common
Environmental exposures that may trigger SSc-like syndromes:
- Silica dust (occupational — construction, mining) — this is a recognized risk factor and is relevant in Hong Kong's construction industry
- Organic solvents (trichloroethylene, vinyl chloride)
- Contaminated rapeseed oil (toxic oil syndrome, Spain 1981)
- L-tryptophan (eosinophilia-myalgia syndrome)
- Bleomycin

HK Clinical Pearl

In Hong Kong, always ask about occupational silica exposure (construction workers, quarry workers). Silicosis is a notifiable occupational disease in HK and is a recognized risk factor for systemic sclerosis. The GC slide on "Shortness of breath in a construction site worker" ^[4] discusses pneumoconiosis including silicosis — remember that silica exposure can also trigger autoimmunity and SSc.

3. Relevant Anatomy and Function

To understand SSc, you need to appreciate the anatomy of the structures it damages:

4. Etiology and Pathophysiology

Initiating event: Unclear, but endothelial injury (possibly from viral infection, oxidative stress, or environmental toxin) exposes neoantigens
Innate immunity: Activated macrophages and dendritic cells release TGF-β, PDGF, IL-4, IL-6, IL-13 → these are all pro-fibrotic cytokines
Adaptive immunity:
- T cells: CD4+ T-helper cells (especially Th2 subtype) dominate → produce IL-4 and IL-13 → stimulate fibroblast collagen production
- B cells: Produce disease-specific autoantibodies:
  - Anti-centromere antibody (ACA): targets centromere proteins (CENP-A, -B, -C) → associated with limited cutaneous SSc ^[1]^[2]
  - Anti-Scl-70 (anti-topoisomerase I): targets DNA topoisomerase I → associated with diffuse cutaneous SSc and ILD ^[1]^[2]
  - Anti-RNA polymerase III: associated with diffuse SSc and scleroderma renal crisis ^[1]^[2]
- These autoantibodies are not just markers — they may directly activate fibroblasts and endothelial cells

Autoantibody Table — High Yield for Exams

Antibody	SSc Subtype	Clinical Association
Anti-centromere	Limited SSc	PAH (isolated, late), better prognosis
Anti-Scl-70 (anti-topoisomerase I)	Diffuse SSc	ILD, poor prognosis
Anti-RNA polymerase III	Diffuse SSc	Scleroderma renal crisis, rapid skin progression

These antibodies are mutually exclusive — a patient almost never has more than one. This helps predict prognosis and organ involvement.

5. Classification

SSc is divided into Limited cutaneous SSc (lcSSc) and Diffuse cutaneous SSc (dcSSc). ^[1]

Feature	Limited Cutaneous SSc (lcSSc, ~70%)	Diffuse Cutaneous SSc (dcSSc, ~30%)
Skin involvement	Confined to areas below elbows and below knees + head/neck ^[1]^[3]	Proximal extremities (above elbow) or trunk below clavicles ^[1]^[3]
Skin progression	Slow over years	Rapid, can progress within months
Raynaud's	Long preceding history (may precede by years or decades) ^[2]	Sudden onset, close to or concurrent with skin changes ^[2]
Organ involvement	Less extensive, late ^[1]	Higher risk for major organ involvement, esp pulmonary fibrosis and renal crisis ^[1]
Key antibody	Anti-centromere ^[1]	Anti-Scl-70, anti-RNA polymerase III ^[1]
Prognosis	Comparatively better ^[1]	Poor prognosis ^[1]
Former name	Previously known as CREST syndrome ^[1]	—

The acronym CREST captures the hallmark features of limited cutaneous SSc ^[2]:

Letter	Feature	Pathological Pillar
C	Calcinosis (subcutaneous calcium deposits)	Fibrosis/tissue damage
R	Raynaud's phenomenon	Vasculopathy
E	Esophageal dysmotility	Fibrosis (smooth muscle)
S	Sclerodactyly (tight, thickened skin on fingers)	Fibrosis
T	Telangiectasia	Vasculopathy (compensatory capillary dilation)

The 2013 (not 2017 as stated in some older notes) EULAR/ACR classification criteria use a scoring system ^[2]:

Criterion	Score
Skin thickening of fingers of both hands extending proximal to MCPJs	9 (sufficient alone)
Skin thickening of fingers: puffy fingers (2) or sclerodactyly (4) — count higher	2 or 4
Fingertip lesions: digital tip ulcers (2) or pitting scars (3) — count higher	2 or 3
Telangiectasia	2
Abnormal nailfold capillaries	2
Pulmonary arterial hypertension and/or ILD	2
Raynaud's phenomenon	3
SSc-related autoantibodies (anti-centromere, anti-Scl-70, anti-RNA pol III) — max 3	3

Total ≥ 9 = classified as SSc
Note: Skin thickening proximal to MCPJs alone is sufficient (scores 9 by itself)
These are classification criteria (for research), not diagnostic criteria — clinical diagnosis relies on the overall clinical picture

Exam Pearl

Don't confuse the EULAR/ACR classification criteria with diagnostic criteria. A patient can have SSc without meeting classification criteria (e.g., early disease). Conversely, these criteria are designed for research cohort uniformity. In clinical practice, diagnosis is clinical + serological + organ assessment.

6. Clinical Features

6.3 Symptoms (with pathophysiological basis)

Symptom	Pathophysiological Basis
Skin tightening (fingers → hands → proximal)	Fibrosis: excessive collagen deposition in dermis → loss of elasticity, tethering to subcutaneous tissue
Skin dryness and pruritus	Fibrosis of sweat glands and sebaceous glands → reduced secretion
Difficulty opening mouth (microstomia)	Fibrosis of perioral skin → restricted mouth opening
Difficulty making a fist	Fibrosis of skin over fingers + flexion contractures of MCPJs/IPJs
Color changes in fingers (Raynaud's) — cold triggers	Vasculopathy: exaggerated vasoconstriction → pallor (ischaemia) → cyanosis (deoxygenated stagnant blood) → rubor (reactive hyperaemia)
Finger tip pain / ulcers	Vasculopathy: critical digital ischaemia → ischaemic ulceration at fingertips
Finger shortening	Acro-osteolysis: chronic ischaemia → bone resorption of distal phalanges

Phases of skin involvement ^[3]:
1. Early: puffy oedema — swollen fingers and hands
2. Advanced: sclerosis — dry, thickened, shiny skin, "salt and pepper" appearance (areas of hypo- and hyperpigmentation due to melanocyte damage)

Symptom	Pathophysiological Basis
Arthralgia / polyarthritis	Immune-mediated synovitis (20–30% have erosive arthritis) ^[3]
Joint stiffness and contractures	Fibrosis around tendons, joint capsules, and periarticular structures
Tendon friction rubs (palpable crepitus over tendons)	Fibrous deposits on tendon sheaths — almost pathognomonic for dcSSc
Muscle weakness	Fibrotic myopathy (non-inflammatory) or overlap inflammatory myositis
Carpal tunnel syndrome	Fibrosis of carpal tunnel contents → median nerve compression

The GI tract is the most commonly involved internal organ (up to 90% of patients). Virtually any segment can be affected.

Symptom	Pathophysiological Basis
Dysphagia	Fibrosis and atrophy of oesophageal smooth muscle → dysmotility of lower 2/3 of oesophagus
Heartburn / regurgitation (GERD)	Loss of LOS tone (fibrosis) → gastro-oesophageal reflux ^[2]
Odynophagia	Reflux oesophagitis → erosion and ulceration of oesophageal mucosa
Early satiety, nausea, vomiting, bloating	Gastroparesis — fibrosis of gastric smooth muscle → delayed gastric emptying ^[3]
Bloating, flatulence, diarrhoea	Small intestinal bacterial overgrowth (SIBO) — intestinal hypomotility allows bacterial proliferation → fermentation → gas and malabsorption ^[3]
Chronic abdominal pain, distension	Small bowel hypomotility → pseudo-obstruction ^[3]
Constipation	Large bowel fibrosis → colonic hypomotility
Faecal incontinence	Fibrosis of internal anal sphincter
Weight loss / malnutrition	Malabsorption (SIBO + reduced absorptive surface area)

GC slide: GI involvement management includes "H2 blockers; proton pump inhibitor; drugs that improve gut motility; antibiotics for bowel flora overgrowth." ^[1]

The lungs are the leading cause of death in SSc. Two major pulmonary complications:

Symptom	Pathophysiological Basis
Progressive dyspnoea on exertion (SOBOE) + dry cough	ILD: fibrosis of alveolar interstitium → reduced gas exchange surface → restrictive physiology
Rapidly progressive SOBOE	PAH: obliterative vasculopathy of pulmonary arterioles → ↑pulmonary vascular resistance → right heart strain
Exertional chest pain	PAH → RV subendocardial ischaemia from ↑wall stress
Exertional syncope	PAH → inability to ↑cardiac output during exercise

ILD is more common in dcSSc (>50%) and is associated with anti-Scl-70 ^[3]
PAH can occur in both subtypes: in lcSSc as isolated Group 1 PAH (late); in dcSSc as secondary to ILD (Group 3) ^[2]

Symptom	Pathophysiological Basis
Palpitations	Arrhythmias from myocardial fibrosis → conduction system disruption
Dyspnoea, orthopnoea, PND	Heart failure — either HFrEF or HFpEF from myocardial fibrosis
Chest pain	Pericarditis (immune-mediated) or myocardial ischaemia (coronary microvascular disease)

Cardiovascular involvement is associated with poor prognosis (60% 2-year mortality) ^[3]

Symptom	Pathophysiological Basis
Often asymptomatic initially	Microalbuminuria from early glomerular and vascular damage
Headache, visual disturbance, seizures	Scleroderma renal crisis (SRC): malignant hypertension from RAAS activation
Oliguria/anuria	SRC → acute kidney injury (can progress to ESRD in 1–2 months) ^[2]

SRC occurs in 10–15% of SSc patients, predominantly dcSSc ^[2]
Risk factor: steroid use (especially in diffuse SSc) — steroids can precipitate renal crisis ^[2]

Symptom	Pathophysiological Basis
Dry eyes, dry mouth	Secondary Sjögren syndrome — lymphocytic infiltration of lacrimal and salivary glands
Erectile dysfunction	Penile vascular fibrosis and neuropathy
Depression, fatigue	Chronic disease burden, pain, disability
Trigeminal neuropathy	Fibrosis around trigeminal nerve branches → numbness in V2/V3 distribution

6.4 Signs (with pathophysiological basis)

Sign	Description	Pathophysiological Basis
Sclerodactyly	Tight, thickened, shiny skin over fingers ^[2]^[3]	Dermal collagen deposition (fibrosis)
Puffy fingers	Sausage-like swollen fingers (early phase)	Oedema from vascular leak + early inflammation
Digital ulcers	Painful ulcers at fingertips or over bony prominences	Critical ischaemia from obliterative vasculopathy
Digital gangrene	Necrosis of fingertips	Severe vasculopathy → complete vascular occlusion
Pitting scars	Small depressed scars at fingertips	Healed digital ulcers
Calcinosis cutis	Hard subcutaneous calcium deposits (often over fingers, elbows, knees)	Dystrophic calcification in damaged/ischaemic tissue; calcium hydroxyapatite deposits
Atrophic nails	Thin, ridged nails	Chronic ischaemia of nail matrix
Shortening of fingers	Digits appear shortened	Acro-osteolysis: distal phalangeal resorption from chronic ischaemia ^[2]
Flexion contractures	Fixed flexion of fingers	Periarticular fibrosis + skin tightening
Telangiectasia	Dilated capillaries visible on skin (especially fingers, face, lips)	Usually at nailfold capillaries ^[2] — compensatory capillary dilation proximal to obliterated downstream vessels
Tendon friction rubs	Palpable/audible crepitus over tendons during movement	Fibrous deposits on tendon sheaths — highly specific for dcSSc
Non-pitting oedema	Firm oedema of hands/fingers	Fibrotic tissue is not compressible (unlike cardiac/renal pitting oedema)

Sign	Description	Pathophysiological Basis
Microstomia	Small, constricted mouth opening	Perioral skin fibrosis → reduced oral aperture
Radial furrows	Vertical wrinkles radiating from lips	Fibrosis of perioral skin → puckering
Pinched "beak-like" nose	Thin, sharp nose	Skin tightening + nasal cartilage resorption
Thin lips	Lips appear narrowed	Perioral fibrosis
Mask-like facies	Loss of facial expression	Skin tightness limits facial muscle movement
Telangiectasia on face	Red spots on face, lips, tongue	Vasculopathy (see above)

Nailfold capillaroscopy: abnormal capillary loops indicate connective tissue disease ^[5]^[6]

Finding	Significance
Dilated capillary loops (giant capillaries)	Early SSc pattern — endothelial damage
Capillary drop-out (avascular areas)	Late SSc pattern — progressive vasculopathy
Microhaemorrhages	Active vascular damage
Bushy/ramified capillaries	Attempted neovascularization (compensatory)

Nailfold capillaroscopy is the single most important non-invasive test to differentiate primary from secondary Raynaud's:
- Normal capillaroscopy → likely primary Raynaud's → reassurance
- Abnormal capillaroscopy → secondary Raynaud's → investigate for CTD (especially SSc)

Sign	Pathophysiological Basis
Bibasal fine inspiratory crackles (Velcro crackles)	ILD: fibrotic lung tissue creates crackling sounds as stiff alveoli pop open on inspiration
Signs of pulmonary hypertension: loud P2, RV heave, elevated JVP, peripheral oedema	PAH → RV pressure overload → right heart failure
Reduced chest expansion	Skin fibrosis over chest wall (in dcSSc) + restrictive lung disease

Sign	Pathophysiological Basis
Abdominal distension	Intestinal pseudo-obstruction from bowel dysmotility
Reduced bowel sounds	Intestinal smooth muscle atrophy and fibrosis
Hepatomegaly (if right heart failure present)	Hepatic congestion from elevated right-sided pressures

Sign	Pathophysiological Basis
"Salt and pepper" skin	Patchy hypo- and hyperpigmentation from melanocyte damage in fibrotic skin
Tight, shiny skin	Dermal fibrosis — skin cannot be pinched
Skin thickening extending proximal to MCPJs	The hallmark finding that separates SSc from localized scleroderma
Clubbing	Can occur with ILD (though less common than in IPF)

System	Limited SSc (lcSSc)	Diffuse SSc (dcSSc)
Skin	Distal to elbows and knees, slow ^[2]	Proximal, rapid and progressive ^[2]
Raynaud's	Long preceding history ^[2]	Sudden onset ^[2]
GI	GERD common, a/w PBC ^[2]	GERD, malabsorption ^[2]
Lung	Type 1 PAH ± ILD (late) ^[2]	ILD ± secondary PAH ^[2]
Renal	Uncommon ^[2]	Scleroderma renal crisis ^[2]
Cardiac	Less severe ^[2]	More severe: pericarditis, arrhythmia ^[2]
Antibody	Anti-centromere ^[2]	Anti-Scl-70, anti-RNA polymerase III ^[2]
Other	CREST syndrome features prominent	Tendon friction rubs, flexion contractures more common

6.6 Organ Involvement — Detailed Breakdown

7. Investigations (Overview — for context before DDx section)

This section provides the investigative framework. Detailed diagnostic criteria and algorithm will follow in the next response.

X-ray hands: acro-osteolysis, calcinosis, soft tissue wasting
Nailfold capillaroscopy: dilated loops, avascular areas
CXR, HRCT, PFT (for ILD)
Doppler echocardiogram (for pulmonary hypertension screening — estimated RVSP)
OGD / manometry (for oesophageal involvement)

GC slide: Investigations should include assessment for organ involvement including lung (HRCT, PFT), heart (echo), GI (OGD/manometry), and kidney (RFT, urinalysis). ^[1]

High Yield Summary

Definition: SSc is a generalised CTD characterised by (1) immune activation, (2) obliterative vasculopathy, and (3) tissue fibrosis affecting skin and internal organs.

Epidemiology: Peak onset 30–50y, F:M = 4:1, prevalence 10–20/100k, incidence 1–2/100k.

Two main subtypes:

Limited SSc (70%): skin below elbows/knees, anti-centromere Ab, CREST features, late PAH, better prognosis.
Diffuse SSc (30%): skin proximal, anti-Scl-70/anti-RNA pol III, early ILD and renal crisis, poor prognosis.

Three pathological pillars: Immune activation → Vasculopathy → Fibrosis. Every feature maps to one or more.

Key clinical features:

Raynaud's (virtually 100%) — vasculopathy
Sclerodactyly, microstomia, mask-like facies — fibrosis
Digital ulcers/gangrene, telangiectasia, PAH — vasculopathy
Oesophageal dysmotility/GERD — smooth muscle fibrosis
ILD (bibasal fine crackles) — pulmonary fibrosis
Scleroderma renal crisis — vasculopathy → RAAS activation (risk factor: steroids)

Key antibodies: Anti-centromere (lcSSc), Anti-Scl-70 (dcSSc/ILD), Anti-RNA pol III (dcSSc/renal crisis).

ANA is 95% sensitive — if negative, reconsider diagnosis.

Lungs are #1 cause of death (ILD > PAH).

Nailfold capillaroscopy differentiates primary from secondary Raynaud's.

Active Recall - Systemic Sclerosis (Definition, Epidemiology, Etiology, Pathophysiology, Classification, Clinical Features)

Differential Diagnosis of Systemic Sclerosis

Raynaud's is the gateway symptom. The critical first question is: is this primary or secondary?

Connective tissue diseases associated with Raynaud's phenomenon: Systemic sclerosis, MCTD, Undifferentiated CTD, Sjögren's syndrome, Poly-/dermato-myositis, Systemic lupus erythematosus, Necrotising vasculitis e.g. polyarteritis nodosa, Rheumatoid arthritis. ^[1]

Diagnosis	Key Differentiating Features	Why it's different from SSc
Primary Raynaud's disease	15–30y onset, F > M, no associated secondary causes, bilateral, symmetric, no tissue injury, normal nailfold capillaroscopy ^[6]^[10]	No skin changes, no digital ulcers, no ANA/SSc antibodies, no nailfold capillary abnormality. SSc has abnormal nailfold capillaroscopy with dilated loops and avascular areas
SLE	Inflammatory rashes (malar rash), inflammatory arthritis, immune complex disease, multi-system involvement, multi-autoantibodies ^[1] — Raynaud's in ~50% of SLE but rarely severe	SLE is inflammation-dominant; SSc is fibrosis-dominant. SLE has anti-dsDNA, anti-Sm; SSc has anti-centromere/anti-Scl-70. SLE skin is inflammatory (rash), not fibrotic (tight skin)
MCTD	Raynaud's, scleroderma changes, inflammatory rashes, inflammatory myositis, oesophageal involvement, lung involvement, anti-RNP ^[1]^[5]	Overlaps extensively with SSc but must have anti-U1 RNP. MCTD classically has features of SLE + SSc + polymyositis. Characteristically NO severe renal involvement (cf. SRC in dcSSc) ^[5]
uCTD	Early Raynaud + nonspecific features that don't meet criteria for any defined CTD ^[12]	A "holding diagnosis" — may evolve into SSc, SLE, MCTD over time. Key is follow-up
PM/DM	Proximal muscle weakness, Gottron's papules, heliotrope rash, anti-Jo-1/anti-MDA-5	Raynaud's is less prominent; myositis dominates. Can overlap with SSc (scleromyositis)
Drug-induced	Beta-blockers, bleomycin ^[6]^[10]	Temporal association with drug. Reversible on cessation
Vibration white finger	Occupational — use of vibrating tools (e.g., jackhammers, chainsaws) ^[6]^[10]	Occupational history; no autoantibodies; nailfold capillaroscopy normal
Haematological	Cold haemagglutinins, cryoglobulinaemia, paraproteinaemia ^[6]^[10]	Triggered by cold but mechanism is intravascular (RBC agglutination or cryoprecipitation), not vasospasm. Check cold agglutinins, cryoglobulins, serum protein electrophoresis
Hypothyroidism	Cold intolerance, weight gain, bradycardia, ↑TSH	Hypothyroidism causes peripheral vasoconstriction. TFTs distinguish
Atherosclerosis / thoracic outlet syndrome	Older patient, vascular risk factors; or positional symptoms with arm elevation	Asymmetric, large vessel disease. No autoantibodies. Imaging differentiates

The 'Red Flags' for Secondary Raynaud's — Must Know!

Suspect secondary Raynaud's (and thus investigate for SSc/CTD) when:

Age > 40 at onset (primary is typically young)
Male sex
Severe with tissue ischaemia (digital ulcers, gangrene)
Asymmetric (primary is usually symmetric bilateral)
Associated CTD symptoms (skin changes, arthritis, sicca, dysphagia)
Abnormal nailfold capillaroscopy — this is the single best non-invasive differentiator ^[6]^[10]
Positive ANA or SSc-specific antibodies

When a patient presents with tight, thickened skin, SSc is the most likely diagnosis but several mimics exist:

Diagnosis	Key Differentiating Features	Why it's different from SSc
Morphoea (localised scleroderma)	Circumscribed patches or plaques of skin fibrosis — can be plaque, linear, or generalised morphoea	No internal organ involvement, no Raynaud's, no SSc-specific antibodies. Morphoea is a skin-only disease. ANA may be positive but anti-centromere/anti-Scl-70 are negative
Eosinophilic fasciitis (Shulman syndrome)	Symmetric induration of limbs (forearms, legs) with "peau d'orange" skin texture, peripheral eosinophilia, ↑ESR	Spares hands and feet (cf. SSc starts with hands). No Raynaud's. Skin biopsy shows fascial inflammation/fibrosis with eosinophils. Responds well to steroids
Chronic GvHD (sclerotic form)	Post-allogeneic HSCT; sclerotic features — firm hyper/hypopigmented shiny plaques with hair loss ^[11]; may mimic SSc with skin thickening, oesophageal webs, bronchiolitis obliterans	History of transplant is key. No SSc-specific antibodies. Different pathogenesis (donor T cells vs host)
Scleroedema (scleredema of Buschke)	Woody induration of posterior neck/upper back; associated with DM, post-streptococcal, paraproteinaemia	Spares hands (cf. SSc = acral predominance). No Raynaud's. Skin biopsy: mucin deposition in dermis, not collagen fibrosis
Scleromyxoedema	Waxy papules and diffuse skin thickening; associated with paraproteinaemia (IgG-lambda)	Papular lesions (not smooth shiny skin). No Raynaud's. Monoclonal gammopathy on SPEP
Nephrogenic systemic fibrosis	Gadolinium exposure in patients with renal impairment; fibrosis of skin, subcutaneous tissue, and sometimes viscera	History of gadolinium-based contrast in CKD/dialysis patient. Rapid onset after MRI. No SSc antibodies
Diabetic cheiroarthropathy	Waxy skin thickening of hands in long-standing diabetes; "prayer sign" (cannot fully extend fingers)	History of diabetes. No Raynaud's, no visceral involvement. No autoantibodies
Amyloidosis (systemic AL)	Skin thickening, macroglossia, carpal tunnel, nephrotic syndrome, heart failure	Multi-organ involvement but different pattern. Congo red stain positive on biopsy. No Raynaud's
Toxic/environmental exposure	Vinyl chloride, organic solvents, silica, contaminated rapeseed oil, L-tryptophan	Occupational/exposure history. May cause SSc-like syndrome but usually with different antibody profile

Exam Pearl: Morphoea vs SSc

A common mistake is confusing morphoea (localised scleroderma) with SSc. They are completely different diseases:

Morphoea = skin only, no Raynaud's, no visceral involvement, no SSc antibodies
SSc = systemic disease with skin + visceral involvement + Raynaud's + specific antibodies The word "scleroderma" can refer to both, which causes confusion. In clinical practice, specify whether it is localised (morphoea) or systemic.

When a patient with possible SSc presents with SOBOE and bibasal crackles, you must differentiate SSc-ILD from other causes of ILD:

"Exclusion of collagen vascular diseases" is listed as a potential pitfall in making a diagnosis of IPF ^[4]. This means: before labelling someone as IPF, you must rule out CTD-ILD (including SSc-ILD), because the treatment and prognosis are different.

Diagnosis	Key Differentiating Features
IPF	Older (typically > 50y), no CTD features, UIP pattern on HRCT (basal, peripheral honeycombing + traction bronchiectasis), ANA/SSc antibodies negative, male predominance. Must exclude CTD-ILD before diagnosing IPF ^[4]^[7]
SSc-ILD	Most commonly UIP and NSIP patterns ^[7]; younger, female, with SSc skin/vascular features, anti-Scl-70 positive. NSIP pattern (GGO, less honeycombing) more responsive to immunosuppression
RA-ILD	Joint symptoms first (symmetric small joint polyarthritis), RF/ACPA positive, rheumatoid nodules ^[7]
PM/DM-ILD	Proximal weakness, CK elevation, anti-Jo-1 or anti-MDA-5. Anti-MDA-5 associated with rapidly progressive ILD ^[7]
Pneumoconiosis (silicosis, asbestosis)	Occupational exposure history: silicosis (construction, mining — upper lobe predominant); asbestosis (construction, shipyard — lower lobe predominant, pleural plaques) ^[4]^[8]
Hypersensitivity pneumonitis	Organic dust exposure (birds, mouldy hay), predominantly upper/mid zone, often GGO + mosaic attenuation on HRCT ^[8]
Drug-induced ILD	Amiodarone, methotrexate, bleomycin, nitrofurantoin ^[7]^[8] — temporal relationship with drug
Sarcoidosis	Bilateral hilar lymphadenopathy on CXR, upper/middle zone predominance, non-caseating granulomas on biopsy, ↑serum ACE

SSc characteristically causes dysmotility of the lower 2/3 of the oesophagus. Differentials for oesophageal dysphagia include ^[13]:

Diagnosis	Key Differentiating Features
SSc oesophagus	Hx or features of systemic sclerosis, e.g. Calcinosis, Raynaud's, (Esophageal dysmotility), Sclerodactyly, Telangiectasia ^[13]. Manometry: absent peristalsis in lower oesophagus + low LOS pressure
Achalasia	Dysphagia to both solids and liquids, regurgitation, weight loss. Manometry: absent peristalsis + high LOS pressure (cf. SSc = low LOS pressure). Barium swallow: "bird's beak" at LOS
GERD (without SSc)	Heartburn dominant. No skin/vascular features. Normal manometry (or mild dysmotility). Responds to PPI
Oesophageal stricture	Progressive dysphagia to solids > liquids. History of chronic GERD, caustic ingestion, or radiation
Oesophageal malignancy	Progressive dysphagia, weight loss, older age. OGD with biopsy diagnostic
Eosinophilic oesophagitis	Young atopic male, intermittent dysphagia, food impaction. Eosinophils on biopsy

Achalasia vs SSc Oesophagus — A Classic Exam Question

Both cause dysphagia and absent peristalsis on manometry. The key discriminator is LOS pressure:

Achalasia: LOS pressure is HIGH (LOS fails to relax — the sphincter is too tight)
SSc: LOS pressure is LOW (LOS is fibrosed and atonic — the sphincter is too loose → reflux) This makes physiological sense: in achalasia, the problem is failure of inhibitory neurons (ganglion cell degeneration in Auerbach's plexus); in SSc, the problem is smooth muscle fibrosis and atrophy.

SRC presents as acute onset malignant hypertension + AKI ± MAHA. DDx includes other causes of thrombotic microangiopathy (TMA) and malignant hypertension ^[2]^[11]:

Diagnosis	Key Differentiating Features
Scleroderma renal crisis	dcSSc (esp. anti-RNA pol III), risk factor: steroid use, malignant HTN + AKI + MAHA. Vasculopathy → intra-renal arterial stenosis → activates RAAS ^[2]
TTP	ADAMTS13 activity < 10%, pentad (MAHA, thrombocytopaenia, AKI, fever, neuro Sx). No SSc features. Treat with plasma exchange
Typical HUS	Post-diarrhoeal (Shiga toxin-producing E. coli), predominantly in children. Bloody diarrhoea → AKI + MAHA
Atypical HUS (complement-mediated TMA)	Complement dysregulation. No diarrhoeal prodrome. Treat with eculizumab
Malignant hypertension (other causes)	Essential HTN, phaeochromocytoma, renal artery stenosis. No SSc features. No SSc antibodies
Secondary TMA: HELLP, SLE, antiphospholipid syndrome ^[11]	HELLP in pregnancy; SLE with lupus nephritis; APS with thrombosis + pregnancy morbidity

The spectrum of connective tissue disorders ranges from SSc (predominant fibrosis) through uCTD/MCTD (overlap) to SLE (predominant inflammation). ^[1]^[12]

This is the most important conceptual framework for the in-house exam:

Feature	SSc	MCTD	SLE
Dominant process	Predominant fibrosis ^[1]	Overlap (inflammation + fibrosis)	Predominant inflammation ^[1]
Raynaud's	Virtually 100%, severe	Common, can be severe	~50%, usually milder
Skin	Severe scleroderma ^[1]	Scleroderma + lupus rashes	Inflammatory rashes (malar, discoid) ^[1]
Arthritis	Fibrotic contractures, less inflammatory	Erosive (RA-like) ^[5]	Non-erosive, non-deforming (Jaccoud's)
Lung	ILD (NSIP/UIP) + PAH	ILD + pHTN ^[5]	Pleuritis > ILD
Kidney	Scleroderma renal crisis (vasculopathy)	Characteristically NO severe renal involvement ^[5]	Lupus nephritis (immune complex GN)
Key antibodies	Anti-centromere, anti-Scl-70 ^[1]	Anti-U1 RNP ^[1]^[5]	Anti-dsDNA, anti-Sm
Steroid response	Generally poor (and steroids may precipitate SRC)	Classically very responsive to steroid ^[5]	Generally responsive

High Yield — SSc vs SLE: The Fibrosis-Inflammation Spectrum

SSc sits at the fibrosis-dominant end of the CTD spectrum; SLE sits at the inflammation-dominant end. MCTD/uCTD sits in the middle with overlap features. ^[1]^[12]

This conceptual framework directly guides management:

Inflammatory disease (SLE) → immunosuppression works well
Fibrotic disease (SSc) → immunosuppression has limited benefit for established fibrosis; treatment is largely symptomatic + organ-specific

"No drug has been proven to be totally useless until it has been tried in systemic sclerosis" — this GC slide quote ^[1] humorously captures the difficulty of treating a predominantly fibrotic disease.

Presenting Feature	Top DDx to Consider	Key Investigation to Differentiate
Raynaud's phenomenon	Primary Raynaud's, SSc, SLE, MCTD, uCTD, PM/DM, drug-induced, vibration, haematological	Nailfold capillaroscopy, ANA, SSc-specific antibodies
Skin thickening / sclerosis	SSc (lcSSc/dcSSc), morphoea, eosinophilic fasciitis, chronic GvHD, scleroedema, nephrogenic systemic fibrosis, diabetic cheiroarthropathy	Clinical pattern, ANA/SSc Ab, skin biopsy, history
ILD (SOBOE + bibasal crackles)	SSc-ILD, IPF, RA-ILD, PM/DM-ILD, pneumoconiosis, HP, drug-induced, sarcoidosis	HRCT pattern, autoantibodies (must exclude CTD-ILD before diagnosing IPF ^[4]), occupational history
Oesophageal dysmotility	SSc oesophagus, achalasia, GERD, stricture, malignancy, eosinophilic oesophagitis	Manometry (LOS pressure: low in SSc, high in achalasia), OGD
Malignant HTN + AKI + MAHA	SRC, TTP, HUS, aHUS, HELLP, malignant HTN (other)	SSc features/antibodies, ADAMTS13, complement studies, blood film
Polyarthritis + skin changes	SSc, SLE, MCTD, overlap syndromes, RA, PM/DM	Antibody profile (anti-centromere, anti-Scl-70, anti-dsDNA, anti-RNP, RF/ACPA), clinical pattern

When you suspect SSc in a patient, the clinical reasoning proceeds as follows:

Is Raynaud's primary or secondary? → Nailfold capillaroscopy + ANA + clinical features
If secondary, is the underlying cause SSc or another CTD? → Antibody panel (anti-centromere, anti-Scl-70, anti-RNA pol III, anti-dsDNA, anti-RNP, anti-Jo-1) + clinical pattern
If SSc, is it limited or diffuse? → Extent of skin involvement (below vs above elbows/knees) ^[1]
What organ involvement is present? → Systematic screening (PFT + HRCT for ILD, echo for PAH, RFT + urinalysis for renal, OGD/manometry for GI)
Are there mimics of SSc that need exclusion? → Morphoea, eosinophilic fasciitis, GvHD, nephrogenic systemic fibrosis, etc.

High Yield Summary — DDx of Systemic Sclerosis

Raynaud's DDx: Primary (young, female, no tissue injury, normal capillaroscopy) vs Secondary (SSc most common cause; also SLE, MCTD, PM/DM, Sjögren's, PAN, RA, drugs, vibration, haematological).

Skin thickening DDx: SSc vs morphoea (localised, no visceral/no Raynaud's) vs eosinophilic fasciitis (spares hands, eosinophilia) vs GvHD (post-HSCT) vs scleroedema/scleromyxoedema vs nephrogenic systemic fibrosis (gadolinium + CKD).

ILD DDx: Must exclude CTD-ILD (SSc, RA, PM/DM) before diagnosing IPF. Also consider pneumoconiosis (occupational) and drug-induced ILD.

Oesophageal dysmotility DDx: SSc (low LOS) vs achalasia (high LOS) — manometry differentiates.

SRC DDx: vs TTP (ADAMTS13 < 10%), HUS (diarrhoeal prodrome), other TMA causes.

CTD spectrum: SSc (fibrosis-dominant) ↔ MCTD (overlap) ↔ SLE (inflammation-dominant). Antibody profile and clinical pattern differentiate.

Active Recall - Differential Diagnosis of Systemic Sclerosis

References

^[1] Lecture slides: GC 053. Fingers turn white and blue.pdf ^[2] Senior notes: Maksim Medicine Notes.pdf (Rheumatology section, p.316–318) ^[3] Senior notes: Ryan Ho Rheumatology.pdf (Systemic Sclerosis section, p.83–85) ^[4] Lecture slides: GC 083. Shortness of breath in a construction site worker.pdf ^[5] Senior notes: Ryan Ho Rheumatology.pdf (MCTD section, p.86–87) ^[6] Senior notes: Ryan Ho Fundamentals.pdf (Raynaud Phenomenon section, p.411) ^[7] Senior notes: Ryan Ho Respiratory.pdf (ILD section, p.120–121) ^[8] Senior notes: Maksim Medicine Notes.pdf (ILD classification, p.303–305) ^[10] Senior notes: Ryan Ho Rheumatology.pdf (Raynaud Phenomenon section, p.81) ^[11] Senior notes: Ryan Ho Haemtology.pdf (TMA/MAHA section, p.137; GvHD section, p.158) ^[12] Senior notes: Ryan Ho Rheumatology.pdf (Overview on CTD section, p.82) ^[13] Senior notes: Ryan Ho GI.pdf (Dysphagia approach, p.35)

Sclerodactyly extending proximal to MCPJ alone is a sufficient criterion ^[2]

These criteria were developed for classification (not diagnosis), but they are the best standardised framework we have. A total score ≥ 9 classifies a patient as having SSc.

Criterion	Sub-items	Score
Skin thickening of fingers of both hands extending proximal to MCPJs	—	9 (sufficient alone)
Skin thickening of fingers (count only higher score)	Puffy fingers	2
	Sclerodactyly (distal to MCPJs only)	4
Fingertip lesions (count only higher score)	Digital tip ulcers	2
	Fingertip pitting scars	3
Telangiectasia	—	2
Abnormal nailfold capillaries	—	2
Pulmonary involvement	PAH and/or ILD	2
Raynaud's phenomenon	—	3
SSc-related autoantibodies (maximum 3)	Anti-centromere, anti-Scl-70, or anti-RNA polymerase III	3

How to use: Add up the scores from applicable items (use the higher score when sub-items are mutually exclusive). Total ≥ 9 = classified as SSc.

Understanding the Scoring Logic — Why These Weights?

The criteria weights reflect specificity for SSc:

Skin thickening proximal to MCPJs = 9 points alone because this is virtually pathognomonic. No other common disease causes bilateral symmetric proximal scleroderma.
Raynaud's = 3 points — very common (up to 5% of the general population have primary Raynaud's), so less specific. But it's highly sensitive for SSc.
SSc-specific antibodies = 3 points — these are disease-defining markers.
Pitting scars > digital ulcers (3 > 2) — pitting scars represent healed chronic ischaemic injury, more specific to SSc; active digital ulcers can have other causes (vasculitis, etc.).

A patient with Raynaud's (3) + sclerodactyly (4) + abnormal nailfold capillaries (2) = 9 → classified as SSc even without proximal skin thickening.

Classification vs Diagnosis

These are classification criteria, not diagnostic criteria. Important implications:

A patient with early SSc (e.g., just Raynaud's + abnormal capillaroscopy + positive anti-Scl-70 but no skin thickening yet) scores only 3 + 2 + 3 = 8 → does NOT meet classification criteria, but the clinical diagnosis of very early SSc is appropriate.
Conversely, someone with SSc sine scleroderma (internal organ involvement without skin changes — rare) may not meet criteria either.
In clinical practice, use the criteria as a guide, not a rigid gate.

3. Investigation Modalities — Detailed Breakdown

Test	Expected Finding in SSc	Interpretation / Why
CBC ^[2]	Anaemia (normocytic or iron-deficiency from GAVE); MAHA if renal crisis	Iron deficiency → think GAVE (watermelon stomach, chronic GI blood loss). MAHA + thrombocytopaenia → think scleroderma renal crisis (TMA)
RFT ^[2]	Usually normal unless renal crisis	Baseline for monitoring. Rising creatinine = red flag for SRC
ESR ^[2]	↑ESR, ↑IgG, normal CRP ^[3]	SSc is a fibrotic, not primarily inflammatory disease → CRP often normal. Elevated CRP suggests co-existing infection, overlap myositis, or serositis
LFT	May show ↑ALP	Consider associated PBC (especially in lcSSc). Check anti-mitochondrial antibody (AMA) if ALP elevated
CK	May be mildly elevated	Overlap myositis (especially in dcSSc or scleromyositis). If CK significantly ↑, consider PM/DM overlap
Urinalysis	Microalbuminuria, haematuria	Early renal involvement. Proteinuria + active sediment in SRC

Test	Finding	Clinical Significance
ANA	Positive in 95% of SSc ^[2]	Highly sensitive screening test. Reconsider diagnosis if negative ^[2]. ANA pattern: centromere (lcSSc), nucleolar (dcSSc), speckled (consider MCTD)
Anti-centromere	Present in ~70% lcSSc ^[3]	Associated with limited SSc ^[1], PAH (isolated, late), oesophageal disease. Better prognosis
Anti-Scl-70 (anti-topoisomerase I)	Present in ~30% dcSSc ^[3]	Associated with diffuse SSc ^[1], pulmonary fibrosis ^[3]. Poor prognosis
Anti-RNA polymerase III	Present in ~20–35% dcSSc ^[3]	Associated with diffuse SSc, scleroderma renal crisis, rapid skin progression, malignancy ^[3]
Anti-U1 RNP	Positive in MCTD	If positive, consider MCTD (features of SLE + SSc + PM) ^[5]
RF, anti-CCP	May be positive in overlap	Rule out RA ^[3]
Anti-dsDNA, anti-Sm	Negative in pure SSc	Rule out SLE ^[3]
AMA (anti-mitochondrial)	May be positive in lcSSc	Associated PBC — check if cholestatic LFT pattern

Antibody Profile Predicts Everything

The SSc-specific antibody is one of the most clinically useful antibody tests in rheumatology because it simultaneously tells you:

Subtype (limited vs diffuse)
Organ risk (ILD, PAH, renal crisis)
Prognosis (better vs worse)

Antibody	Subtype	Major Organ Risk	Prognosis
Anti-centromere	lcSSc	Isolated PAH (late)	Better
Anti-Scl-70	dcSSc	ILD	Poor
Anti-RNA pol III	dcSSc	Renal crisis, malignancy	Poor

These are mutually exclusive — if a patient has anti-centromere, they almost certainly don't have anti-Scl-70.

Principle: A non-invasive technique using a dermatoscope or stereomicroscope to visualise capillary loops at the nailfold (the area where the cuticle meets the nail plate)
Why the nailfold? Because capillaries here run parallel to the skin surface → easily visualised. In most body sites, capillaries are perpendicular and cannot be seen
Abnormal capillary loops indicate connective tissue disease ^[6]^[10]

Pattern	Findings	Stage of SSc
Early	Dilated capillaries (giant loops), few microhaemorrhages, relatively preserved architecture	Early vascular damage
Active	Frequent giant capillaries, frequent microhaemorrhages, moderate avascular areas, mild architectural disorganization	Active vasculopathy
Late	Severe avascular areas (capillary drop-out), irregular capillary architecture, bushy/ramified capillaries (neoangiogenesis)	Advanced obliterative vasculopathy

Clinical utility: The single best non-invasive test to differentiate primary from secondary Raynaud's. If abnormal → high probability of CTD (especially SSc)
Can also be used for serial monitoring — progression from early to late pattern predicts worsening disease

Modality	Findings	Interpretation
X-ray hands ^[2]	Acro-osteolysis: resorption of distal phalangeal tufts	Chronic ischaemia from Raynaud's → bone resorption. The distal phalanx "pencils down"
	Calcinosis: dense, irregular calcifications in soft tissues	Dystrophic calcification in damaged tissue
	Soft tissue wasting/atrophy	Loss of finger pulp from chronic ischaemia
	Juxta-articular osteopaenia	Disuse + inflammatory arthritis (if present)
	Joint space narrowing, erosions (in 20–30%)	Erosive arthritis component

3.5 Pulmonary Investigations — ILD and PAH

This is arguably the most important organ screen because lungs are the #1 cause of SSc-related death.

Modality	Findings	Interpretation
CXR ^[2]	Bibasal reticular opacities; may be normal in early disease	Low sensitivity for early ILD. Always follow up with HRCT if suspicious
HRCT chest ^[2]	NSIP pattern (more common in SSc): bibasal ground-glass opacities (GGO) ± reticular changes, traction bronchiectasis, sparing subpleural region, honeycombing RARE ^[7]^[14]	GGO = potentially reversible (inflammatory). Reticular/honeycombing = established fibrosis (irreversible). NSIP has better prognosis than UIP
	UIP pattern: bibasal, peripheral, subpleural reticular opacities, traction bronchiectasis, honeycombing ^[7]^[15]	UIP pattern in SSc is less common but carries worse prognosis
PFT (Pulmonary Function Tests) ^[2]	Restrictive pattern: ↓FVC, ↓TLC; normal or ↑FEV₁/FVC ratio; ↓DLCO ^[7]	↓DLCO is the most sensitive early marker of ILD. DLCO < 70% predicted is significant. In SSc, ↓DLCO can also reflect PAH or both

DLCO is non-specific to ILD → consider other causes, e.g. pHTN (in scleroderma), PE, emphysema ^[7]

HRCT Pattern in SSc-ILD — NSIP vs UIP

SSc-ILD most commonly shows UIP and NSIP patterns ^[7]. Why does this matter?

NSIP (bibasal GGO, sparing subpleural zone, rare honeycombing): More responsive to immunosuppression. Better prognosis (5-year mortality < 15%) ^[14]
UIP (basal honeycombing, traction bronchiectasis): Less responsive to immunosuppression. Worse prognosis
Unlike IPF (where UIP = poor prognosis and antifibrotics are first-line), SSc-ILD with NSIP pattern responds to cyclophosphamide/MMF + nintedanib

Exclusion of collagen vascular diseases is listed as a potential pitfall in making a diagnosis of IPF ^[4]. Always check for CTD features before labelling ILD as "idiopathic."

Modality	Findings	Interpretation
Doppler echocardiogram ^[2]	Estimated RVSP (tricuspid regurgitation velocity) → suggests PAH if RVSP > 35–40 mmHg	Screening tool. If RVSP elevated → proceed to right heart catheterisation for confirmation
	RV dilatation, RV hypokinesis, RA dilatation, D-shaped septum	Signs of RV pressure overload
Right heart catheterisation	mPAP > 20 mmHg, PAWP ≤ 15 mmHg, PVR ≥ 3 WU = pre-capillary PH (Group 1 PAH)	Gold standard for diagnosing PAH. Required for definitive diagnosis and to guide specific PAH therapy
NT-proBNP	Elevated	RV strain marker. Used for screening and monitoring
6-minute walk test	Reduced distance, desaturation	Functional assessment and serial monitoring

Screening protocol: Current guidelines (EUSTAR/ERS) recommend annual echocardiography in all SSc patients. The DETECT algorithm (for lcSSc > 3 years) uses FVC/DLCO ratio, ECG, NT-proBNP, serum urate, and echo to identify patients needing right heart catheterisation
FVC/DLCO ratio > 1.6 suggests isolated PAH (DLCO disproportionately reduced compared to FVC) — because PAH affects gas transfer at the alveolar-capillary membrane without restricting lung volumes

Modality	Findings	Interpretation
OGD (upper endoscopy) ^[2]	Oesophagitis, Barrett's oesophagus, oesophageal stricture, GAVE (watermelon stomach)	Assesses reflux complications. GAVE = longitudinal red antral stripes → chronic GI bleeding → iron deficiency anaemia
Oesophageal manometry ^[2]	Hypotensive LOS, absent/reduced peristalsis in lower 2/3 of oesophagus, normal proximal oesophagus and UES ^[13]	SSc specifically affects smooth muscle (lower 2/3). Hypotensive LOS + distal hypoperistalsis + normal proximal oesophagus and UES is the SSc manometric signature ^[13]
Barium swallow	Dilated oesophagus, aperistalsis, free reflux	Less commonly used now; manometry is more informative
Glucose hydrogen breath test	Positive (early rise in hydrogen)	Confirms SIBO — bacterial overgrowth from intestinal hypomotility
CT abdomen	Wide-mouth diverticula (colonic), pseudo-obstruction	Colonic fibrosis complications

SSc Oesophageal Manometry vs Achalasia

Both show absent peristalsis. The key difference is LOS pressure:

SSc: Hypotensive LOS (smooth muscle fibrosis → sphincter cannot contract → reflux)
Achalasia: Hypertensive LOS (loss of inhibitory neurons → sphincter cannot relax → obstruction) This distinction has direct therapeutic implications: SSc patients need aggressive anti-reflux therapy; achalasia patients need procedures to lower LOS pressure (pneumatic dilatation or Heller myotomy).

Modality	Findings	Interpretation
ECG	Conduction blocks, arrhythmias (atrial/ventricular), low voltage	Myocardial fibrosis disrupts conduction pathways
Echocardiogram	Pericardial effusion, LV/RV dysfunction, diastolic dysfunction	Myocardial fibrosis → HFpEF or HFrEF. Pericarditis → effusion
Cardiac MRI	Myocardial fibrosis (late gadolinium enhancement)	Most sensitive for detecting subclinical myocardial involvement. Use with caution in CKD (gadolinium risk)
Holter monitor	Arrhythmias over 24 hours	High prevalence of silent arrhythmias in dcSSc

Modality	Findings	Interpretation
RFT (creatinine, urea) ^[2]	Rising creatinine in SRC	Baseline for monitoring. Monitor frequently in dcSSc (weekly in early disease, especially if on steroids)
Urinalysis	Proteinuria, haematuria, casts	Active renal involvement
Blood pressure monitoring	Home BP monitoring recommended in dcSSc	Early detection of SRC — can present with sudden severe hypertension. All dcSSc patients should own a BP cuff
Blood film	Schistocytes, fragmented RBCs	MAHA in SRC (thrombotic microangiopathy)
Renal biopsy	Intimal proliferation "onion-skin" lesion of interlobular arteries, fibrinoid necrosis, thrombotic microangiopathy	Usually not needed for diagnosis (clinical picture + blood film sufficient) but done if diagnosis uncertain

SRC Monitoring — Practical Pearl

Scleroderma renal crisis can progress to ESRD within 1–2 months ^[2]. Risk factor: steroid use (esp. in diffuse SSc) ^[2].

Every dcSSc patient should:

Own a home blood pressure monitor
Check BP regularly (at least weekly in the first 3–5 years)
Know to seek immediate medical attention if BP suddenly rises
Avoid steroids > 15 mg/day prednisolone (or at all, if possible) — steroids can precipitate SRC

Once SSc is diagnosed, all patients need baseline screening for organ involvement, regardless of symptoms:

Organ System	Investigation	Frequency
Lungs (ILD)	HRCT chest + PFT (FVC, DLCO) ^[2]	Baseline → repeat PFT every 3–12 months (more frequently in dcSSc with anti-Scl-70)
Lungs (PAH)	Doppler echocardiogram ^[2] + NT-proBNP	Baseline → annually in all SSc. RHC if echo suggestive
Heart	ECG + Echocardiogram	Baseline → annually or if symptoms
Kidneys	RFT, urinalysis, BP monitoring ^[2]	Baseline → BP monitored regularly, RFT every 3–6 months in dcSSc
GI	OGD ± manometry ^[2]	If symptoms (dysphagia, GERD). Not routine if asymptomatic
Skin	Modified Rodnan Skin Score	Every visit — to track progression
Hands	X-ray hands ^[2] + nailfold capillaroscopy	Baseline. Capillaroscopy can be repeated to track vascular damage

Clinical Scenario	Key Investigation	Expected Finding
Raynaud's — primary vs secondary?	Nailfold capillaroscopy	Normal → primary; abnormal → secondary (investigate for CTD)
Suspect SSc — screening test?	ANA	95% sensitive. If negative → reconsider
Confirmed SSc — subtype?	Anti-centromere / anti-Scl-70 / anti-RNA pol III	Mutually exclusive; predict subtype + organ risk
SSc + dyspnoea — ILD?	HRCT + PFT (DLCO)	NSIP/UIP pattern; ↓FVC, ↓DLCO
SSc + dyspnoea — PAH?	Echo → RHC if suspicious	↑RVSP, mPAP > 20 mmHg
SSc + malignant HTN — renal crisis?	RFT + blood film + BP	↑Creatinine, schistocytes (MAHA), severe HTN
SSc + dysphagia — oesophageal?	Manometry ± OGD	Hypotensive LOS, absent distal peristalsis
SSc + iron deficiency — GAVE?	OGD	Watermelon stomach (red antral stripes)
SSc + ↑ALP — PBC?	AMA	Anti-mitochondrial antibody positive

The diagnosis of SSc is predominantly clinical ^[3]. Investigations confirm, subtype, and stage — but the clinical eye comes first.

High Yield Summary — Diagnosis of SSc

Classification: EULAR/ACR 2013 criteria, score ≥ 9. Skin thickening proximal to MCPJs alone = 9 (sufficient).

Diagnosis is predominantly clinical: Raynaud's + skin changes + organ involvement + autoantibodies.

Key investigations:

Nailfold capillaroscopy: First-line to differentiate primary vs secondary Raynaud's
ANA: 95% sensitive screening test — if negative, reconsider diagnosis
SSc-specific antibodies: Anti-centromere (lcSSc), anti-Scl-70 (dcSSc/ILD), anti-RNA pol III (dcSSc/renal crisis) — mutually exclusive, predict subtype and organ risk
HRCT + PFT: Screen for ILD (DLCO most sensitive early marker)
Echocardiogram: Annual screening for PAH (proceed to RHC if suspicious)
OGD/manometry: SSc oesophagus = hypotensive LOS + absent distal peristalsis (cf. achalasia = hypertensive LOS)
RFT + BP monitoring: Monitor for scleroderma renal crisis (especially dcSSc, especially if on steroids)
X-ray hands: Acro-osteolysis, calcinosis, soft tissue atrophy

Inflammatory markers: ↑ESR, ↑IgG, normal CRP (fibrotic, not inflammatory disease).

Organ screening: All SSc patients need baseline lung (HRCT + PFT), heart (echo + ECG), kidney (RFT + BP), and GI (if symptomatic) assessment.

Active Recall - Diagnostic Criteria, Algorithm, and Investigations for Systemic Sclerosis

Management of Systemic Sclerosis

These apply to every SSc patient regardless of subtype or organ involvement:

Measure	Rationale
Patient education	Chronic disease; patients must understand the nature, prognosis, and importance of monitoring (home BP, recognising new symptoms)
Multidisciplinary team	Rheumatologist (lead), respirologist, cardiologist, gastroenterologist, nephrologist, dermatologist, physiotherapist, occupational therapist, psychologist
Physiotherapy and occupational therapy	Maintain joint range of motion (prevent contractures), hand exercises (counteract sclerodactyly), respiratory physiotherapy
Good skin hygiene	Emollients for dry skin (sweat/sebaceous gland fibrosis → dryness). Avoid trauma to fingers. Moisturise regularly
Smoking cessation	Smoking worsens vasospasm (nicotine is a vasoconstrictor) → aggravates Raynaud's and digital ischaemia. Also worsens ILD
Vaccination	Influenza and pneumococcal vaccination — immunosuppressed patients are at higher infection risk ^[7]
Psychological support	Chronic, disfiguring, incurable disease → high rates of depression and anxiety

This is often the first and most persistent symptom. The goal is to reduce vasospasm, prevent digital ischaemia, and heal ulcers.

"Raynaud's phenomenon: Keep warm; avoid cigarettes and vasoconstrictors; vasodilators (calcium channel blockers, PGI₂ / analogues / phosphodiesterase inhibitors)" ^[1]

Step-wise Approach

Step	Treatment	Mechanism	Notes
Non-pharmacological	Keep warm ^[1]; hand/foot warmers; avoid cigarettes and vasoconstrictors ^[1]; avoid beta-blockers ^[2]^[6]	Beta-blockers block β₂-mediated vasodilation → worsen vasospasm. Cold triggers vasospasm. Smoking causes vasoconstriction via nicotine	Also avoid caffeine. Gloves, thermal socks, heated gloves
1st line	Calcium channel blockers (CCBs) — nifedipine (most evidence) or amlodipine ^[1]^[2]	Dihydropyridine CCBs block L-type calcium channels in vascular smooth muscle → vasodilation → counteract vasospasm	"Nifedipine" → nife = from the chemical name nifedipine (a 1,4-dihydropyridine). Start low, titrate up. SE: headache, ankle oedema, flushing, hypotension
2nd line	PDE5 inhibitors — sildenafil, tadalafil ^[1]^[2]	PDE5 breaks down cGMP (vasodilator). Inhibiting PDE5 → ↑cGMP → sustained vasodilation. Also reduces pulmonary vascular resistance	"Sildenafil" → same drug as Viagra. Useful in SSc because it helps both Raynaud's AND PAH. SE: headache, flushing. Contraindicated with nitrates (profound hypotension)
2nd line	PGI₂ (prostacyclin) analogues — iloprost (IV), epoprostenol, treprostinil ^[1]^[3]	Prostacyclin (PGI₂) is a potent vasodilator + antiplatelet. In SSc, endogenous PGI₂ production is reduced (endothelial damage). Replacing it restores vasodilation	IV iloprost is used for severe Raynaud's / active digital ulcers. Typically given as an infusion over 3–5 days. SE: flushing, headache, jaw pain, hypotension, nausea
3rd line / refractory	Endothelin receptor antagonists (ERAs) — bosentan ^[1]^[3]	Endothelin-1 is ↑↑ in SSc → vasoconstriction + pro-fibrotic. Bosentan blocks ET-A and ET-B receptors → vasodilation.	"Bosentan" → bos from bosentan, an ET receptor antagonist. Licensed specifically for prevention of new digital ulcers (not healing existing ones). SE: hepatotoxicity (monitor LFTs monthly), teratogenic, fluid retention
Adjuncts	Topical GTN patches; ARBs (losartan); fluoxetine (SSRIs may reduce vasospasm); aspirin (if digital ischaemia); wound care for ulcers	Various — GTN is a nitric oxide donor → vasodilation. ARBs block angiotensin II-mediated vasoconstriction	Avoid trauma to digits (including fingerstick glucose monitoring → use alternative sites) ^[2]. Aggressive wound care for digital ulcers

Why Avoid Beta-Blockers in SSc?

Beta-blockers (especially non-selective ones like propranolol) block β₂-adrenergic receptors on vascular smooth muscle. β₂ stimulation normally causes vasodilation — blocking it removes this vasodilatory mechanism → worsening vasospasm → worsening Raynaud's → risk of digital ischaemia. Stop beta-blockers ^[2] if a patient develops SSc or severe Raynaud's. If a BB is essential (e.g., for rate control in AF), use a cardioselective one (bisoprolol) with caution.

"Cutaneous involvement: Penicillamine; colchicine; γ-interferon – None has been proven" ^[1]

This is the most frustrating area of SSc management. Once skin fibrosis is established, no drug reliably reverses it.

Treatment	Mechanism	Evidence	Notes
Skin hygiene, emollients	Maintain skin moisture and integrity	Standard care	Fibrosis of sweat glands → dryness → cracking → infection risk
Physiotherapy, hand exercises	Prevent contractures	Standard care	Active and passive ROM exercises daily
Methotrexate (MTX)	Immunosuppressant; may help in the early inflammatory (oedematous) phase before established fibrosis ^[2]^[3]	Modest evidence — may improve mRSS in early dcSSc	Only useful in the "window of opportunity" — early disease when inflammation predominates over fibrosis
Mycophenolate mofetil (MMF)	Inhibits lymphocyte proliferation (blocks IMPDH → purine synthesis)	Some evidence for skin improvement, especially in early dcSSc	Often chosen because it also treats ILD (dual benefit)
Penicillamine ^[1]	Putative anti-fibrotic (interferes with collagen cross-linking)	None has been proven ^[1]. Now largely abandoned due to toxicity and lack of efficacy	Historical — was once the "standard" but RCTs showed no benefit. SE: nephrotic syndrome, bone marrow suppression, autoimmune syndromes
Colchicine ^[1]	Inhibits microtubule assembly → may inhibit fibroblast activity	None has been proven ^[1]	Limited evidence
γ-interferon ^[1]	Putative anti-fibrotic (counteracts TGF-β-driven fibrosis)	None has been proven ^[1]	Studied but not adopted into practice
Low-dose steroids	Anti-inflammatory — may help in the early inflammatory phase	Used cautiously — never high dose (risk of renal crisis) ^[2]^[3]	Avoid high dose steroid (prednisolone > 10mg/day) ^[2] — especially in dcSSc

Potential disease-remitting drugs: Endothelial modulators e.g. PGI₂, tPA; Immune modulators for inflammatory complications e.g. methotrexate, mycophenolate, cyclosporin A, tacrolimus (watch out for renal toxicity); Anti-fibrotic agents with limited evidence e.g. penicillamine, colchicine, γ-interferon, anti-TGFβ; Specific inhibitors – endothelin receptor antagonists ^[1]

Watch Out for Renal Toxicity

The GC slide specifically warns: "Immune modulators for inflammatory complications e.g. methotrexate, mycophenolate, cyclosporin A, tacrolimus (watch out for renal toxicity)" ^[1]. Calcineurin inhibitors (cyclosporin A, tacrolimus) cause afferent arteriolar vasoconstriction → can worsen renal ischaemia in SSc (which already has intrarenal arterial stenosis) → risk of precipitating or worsening renal crisis. Use with extreme caution and close RFT monitoring.

"Gastrointestinal involvement: H2 blockers; proton pump inhibitor; drugs that improve gut motility; Antibiotics for bowel flora overgrowth" ^[1]

GI Problem	Treatment	Mechanism	Specific Notes
GERD / Oesophagitis	PPI (omeprazole, lansoprazole) ^[1]^[2]; H2 blockers (ranitidine, famotidine) ^[1]	PPI blocks H⁺/K⁺ ATPase (proton pump) in parietal cells → ↓acid secretion. H2 blockers block histamine H2 receptors on parietal cells → ↓acid	PPI is preferred over H2 blockers (more potent). Use high-dose PPI as SSc GERD is severe (hypotensive LOS → constant reflux). Elevate head of bed, small frequent meals
Oesophageal dysmotility	Prokinetics (metoclopramide, domperidone) ^[1]^[3]	Metoclopramide: D2 antagonist + 5-HT4 agonist → ↑gastric motility + ↑LOS tone. Domperidone: peripheral D2 antagonist (less CNS SE than metoclopramide)	Limited efficacy once smooth muscle is replaced by fibrosis. More helpful early. SE of metoclopramide: tardive dyskinesia (avoid long-term), drowsiness
Gastroparesis	Prokinetics; small frequent meals; dietitian input	See above	May need enteral feeding (jejunostomy) if severe
GAVE (watermelon stomach)	Argon plasma coagulation (APC) endoscopically; iron supplementation	APC cauterises the ectatic antral vessels → stops bleeding	Presents with chronic iron deficiency anaemia from occult GI blood loss
SIBO	Antibiotics for bowel flora overgrowth ^[1] — rotating antibiotics (e.g., ciprofloxacin, metronidazole, rifaximin) ^[3]	Intestinal hypomotility → stasis → bacterial proliferation → fermentation (bloating, gas) + bile acid deconjugation (malabsorption)	Rotate antibiotics to prevent resistance. Typical regimen: 7–14 day courses, rotating every 1–2 months
Intestinal pseudo-obstruction	Conservative (NG decompression, IV fluids, correct electrolytes); prokinetics; parenteral nutrition if severe	Fibrosis of intestinal smooth muscle → complete dysmotility → functional obstruction	Surgical intervention generally NOT helpful (fibrosis, not mechanical obstruction)
Constipation	Osmotic laxatives (macrogol), stool softeners, dietary fibre	Colonic hypomotility from fibrosis	Avoid stimulant laxatives long-term
Faecal incontinence	Pelvic floor exercises, loperamide, biofeedback	Internal anal sphincter fibrosis → loss of tone	Refractory cases: sacral nerve stimulation

This is where management has improved most in recent years. The GC lecture highlights this:

"Systemic sclerosis associated interstitial lung disease: Systemic corticosteroids and cyclophosphamide / mycophenolate mofetil; Nintedanib – tyrosine kinase inhibitor; Tocilizumab – Anti-IL6 receptor monoclonal Ab" ^[1]

And:

"Lung fibrosis – steroid and immunosuppressive for early disease" ^[1]

Treatment Algorithm for SSc-ILD

Treatment	Mechanism	Evidence / Indication	Practical Notes
Mycophenolate mofetil (MMF) ^[1]^[2]	Inhibits inosine monophosphate dehydrogenase (IMPDH) → blocks de novo purine synthesis → selectively inhibits T and B lymphocyte proliferation (lymphocytes depend on de novo pathway, unlike other cells which can use salvage pathway)	SLS II trial: MMF non-inferior to CYC for SSc-ILD with better safety profile. Now considered first-line	Dose: 2–3g/day. SE: GI upset (nausea, diarrhoea), cytopaenias, infection. Teratogenic — contraception required
Cyclophosphamide (CYC) ^[1]^[2]	Alkylating agent → cross-links DNA → kills rapidly dividing cells (lymphocytes) → potent immunosuppression	SLS I trial: IV CYC improved FVC at 12 months (but benefit waned after stopping). Used for severe/rapidly progressive ILD	"Cyclophosphamide" → cyclo = cyclic, phosph = phosphorus-containing. IV pulse monthly × 6–12 months. SE: haemorrhagic cystitis (give mesna), bone marrow suppression, infection, gonadal toxicity, bladder cancer (long-term). Cumulative dose limit
Nintedanib ^[1]^[2]	Tyrosine kinase inhibitor (TKI) — blocks PDGFR, FGFR, VEGFR → inhibits fibroblast proliferation, migration, and differentiation → anti-fibrotic	SENSCIS trial: Nintedanib slowed FVC decline in SSc-ILD (regardless of background immunosuppression). Now approved for SSc-ILD	"Nintedanib – tyrosine kinase inhibitor" ^[1]. Dose: 150mg BD. SE: diarrhoea (most common), hepatotoxicity (monitor LFTs). Can be combined with MMF. Originally developed for IPF
Tocilizumab ^[1]	Anti-IL-6 receptor monoclonal antibody → blocks IL-6 signalling → ↓inflammation and ↓fibroblast activation (IL-6 drives both inflammation and fibrosis in SSc)	focuSSced trial: Tocilizumab preserved FVC in early dcSSc (though primary skin endpoint not met). Now used off-label for SSc-ILD	"Tocilizumab – Anti-IL6 receptor monoclonal Ab" ^[1]. Dose: 162mg SC weekly. SE: infection risk, GI perforation (rare), neutropaenia, ↑lipids
Systemic corticosteroids ^[1]	Anti-inflammatory — may help in the early inflammatory phase of ILD (when GGO predominates over fibrosis)	"Steroid and immunosuppressive for early disease" ^[1]. Used as adjunct, NOT monotherapy. Avoid high dose	Avoid prednisolone > 10–15mg/day in dcSSc (risk of scleroderma renal crisis) ^[2]^[3]. Use lowest effective dose
Rituximab	Anti-CD20 monoclonal antibody → depletes B cells → ↓autoantibody production + ↓B-cell-mediated fibroblast activation	Emerging evidence for refractory SSc-ILD. Used as rescue therapy	2nd/3rd line. Dose: 1g IV × 2 doses, 2 weeks apart
Lung transplant	Replaces fibrotic lungs	Consider early referral in progressive ILD despite maximal therapy ^[7]	SSc patients can undergo lung transplantation. Outcomes are similar to IPF transplant recipients in experienced centres

Why Does Immunosuppression Work in SSc-ILD but Not in IPF?

In IPF, the fibrotic process is predominantly non-inflammatory — there is a self-sustaining fibrotic loop driven by epithelial cell injury and aberrant wound healing. Immunosuppression (the PANTHER-IPF trial with prednisone + azathioprine + NAC) actually worsened outcomes in IPF.

In SSc-ILD, there is a significant inflammatory component (especially in early NSIP-pattern disease) — immune activation drives fibroblast activation. Targeting this immune component (with MMF, CYC) can slow fibrosis. However, once fibrosis is established, immunosuppression alone is insufficient → hence the addition of nintedanib (anti-fibrotic) for additive benefit.

"Pulmonary hypertension – vasodilators as per for RP; O₂, endothelin-1 antagonists, phosphodiesterase 5 inhibitors" ^[1]

SSc-PAH is Group 1 PAH (when isolated) or Group 3 PH (when secondary to ILD). Treatment follows PAH guidelines:

Treatment	Mechanism	Notes
General measures	O₂ therapy (if hypoxaemic); diuretics (for fluid overload); supervised exercise rehabilitation	Supplemental O₂ prevents hypoxic pulmonary vasoconstriction
Endothelin receptor antagonists (ERAs) — bosentan, ambrisentan, macitentan ^[1]	Block endothelin-1 receptors (ET-A ± ET-B) → pulmonary vasodilation + anti-proliferative effect on vascular smooth muscle	"Endothelin-1 antagonists" ^[1]. Bosentan (dual ERA): SE = hepatotoxicity, teratogenic. Ambrisentan (selective ET-A): less hepatotoxicity. Macitentan (dual ERA, newer): SERAPHIN trial — reduced morbidity/mortality
PDE5 inhibitors — sildenafil, tadalafil ^[1]	Inhibit PDE5 → ↑cGMP → pulmonary vasodilation	"Phosphodiesterase 5 inhibitors" ^[1]. Dual benefit: helps both Raynaud's and PAH. SE: headache, flushing. Contraindicated with nitrates
Soluble guanylate cyclase (sGC) stimulator — riociguat ^[2]	Sensitises sGC to NO + directly stimulates sGC → ↑cGMP → vasodilation	Used instead of PDE5i (NOT combined — risk of hypotension). PATENT trial evidence. Cannot combine riociguat with PDE5i
Prostacyclin analogues — epoprostenol (IV), iloprost (inhaled), treprostinil (SC/IV/inhaled) ^[1]	PGI₂ analogues → potent vasodilation + antiplatelet + antiproliferative	IV epoprostenol for severe PAH (functional class III–IV). Continuous infusion via Hickman line. SE: jaw pain, flushing, diarrhoea, catheter-related infection
Selexipag	Selective prostacyclin IP receptor agonist (oral)	Oral prostacyclin pathway agonist. GRIPHON trial evidence
Combination therapy	ERA + PDE5i (or sGC stimulator) ± prostacyclin pathway agent	AMBITION trial: upfront combination (ambrisentan + tadalafil) superior to monotherapy in PAH. Current guidelines favour early combination therapy
Atrial septostomy / Lung transplant	Last resort for refractory severe PAH	Creates R-to-L shunt to decompress RV (septostomy) or replaces lungs

Riociguat vs PDE5i — Understand the Mechanism

Both riociguat and PDE5 inhibitors increase cGMP, but by different mechanisms:

PDE5i (sildenafil): Prevents breakdown of cGMP (inhibits the enzyme that degrades cGMP)
Riociguat: Increases cGMP production (stimulates guanylate cyclase directly, even in absence of NO)

They must NEVER be used together because the combined effect on cGMP → profound systemic hypotension.

"Renal involvement: Accelerated hypertension – ACEI" ^[1]

This is a rheumatologic emergency. SRC occurs in 10–15% of SSc (predominantly dcSSc), and can progress to ESRD within 1–2 months ^[2].

Aspect	Details
Pathology	Vasculopathy → intra-renal arterial stenosis → activates RAAS → malignant hypertension ^[2]
Risk factor	Steroid use (especially in diffuse SSc) ^[2]. Also: anti-RNA polymerase III antibody, early dcSSc ( < 4 years), rapidly progressive skin disease
Prevention	Avoid high-dose steroid (prednisolone > 10mg/day) ^[2]. Home BP monitoring in all dcSSc patients
Treatment	ACEI (captopril) ^[1]^[2]^[3] — the cornerstone of SRC treatment
Why ACEi?	RAAS is the driver: renal ischaemia → ↑renin → ↑angiotensin II → vasoconstriction + aldosterone → worsening HTN. ACEi blocks ACE → ↓angiotensin II → vasodilation + ↓aldosterone → BP drops + renal perfusion improves
Drug choice	Captopril — short-acting ACEi, allows rapid dose titration (start 6.25–12.5mg TDS, titrate up every 8–24 hours to control BP)
Target	BP < 130/80 mmHg (or at least 20mmHg drop per 24 hours initially). Continue ACEi even if creatinine initially rises or dialysis is needed — some patients recover renal function months later
What NOT to do	Do NOT use ARBs instead of ACEi (less evidence). Do NOT stop ACEi even if creatinine rises. Do NOT use corticosteroids (they precipitated the crisis)
Dialysis	If ESRD develops — temporary haemodialysis. ~50% of SRC patients who need dialysis may eventually recover enough renal function to stop dialysis (if ACEi continued)
Prognosis	Pre-ACEi era: 90% mortality. Post-ACEi era: ~75% 1-year survival. ACEi revolutionised SRC outcomes

ACEi in SRC — One of Medicine's Greatest Success Stories

Before ACE inhibitors, scleroderma renal crisis was almost uniformly fatal. The introduction of captopril in the 1980s transformed SRC from a death sentence to a manageable emergency. This is why "Accelerated hypertension – ACEI" ^[1] is the single most important management point for SSc renal disease.

Key practical point: Continue ACEi even during dialysis. Some patients who are dialysis-dependent for months can eventually recover renal function if ACEi is maintained — because the renal vasculopathy can partially reverse with sustained RAAS blockade.

Steroids and SRC — A Dangerous Combination

High-dose steroid is generally avoided due to risk of precipitating renal crisis ^[3]. The mechanism is thought to involve steroid-induced fluid retention and hypertension in the setting of already compromised renal vasculature, tipping the balance into malignant hypertension. Never use prednisolone > 10–15mg/day in dcSSc unless absolutely necessary (e.g., life-threatening overlap myositis), and if you must, monitor BP and RFT extremely closely.

"Dysrhythmia – anti-arrhythmic drugs" ^[1]

Problem	Treatment	Notes
Arrhythmias	Anti-arrhythmic drugs ^[1] — amiodarone (but watch for pulmonary toxicity in patients who may already have ILD), beta-blockers with caution (worsen Raynaud's), calcium channel blockers	ECG and Holter monitoring. Treat based on arrhythmia type
Pericarditis	NSAIDs first-line ^[3]; colchicine; avoid steroids if possible (renal crisis risk) ^[3]	Low-dose prednisolone only if NSAID-refractory and no renal risk factors
Heart failure	Standard HF management (diuretics, ACEi — beneficial for both HF and renal protection, beta-blockers cautiously)	Myocardial fibrosis → HFrEF or HFpEF. Consider cardiac MRI for assessment
Myocardial ischaemia	Anti-anginals (CCBs preferred — dual benefit for Raynaud's)	Coronary microvascular disease from vasculopathy

"Polyarthritis – NSAID; anti-malarials" ^[1] "Low grade myositis – low dose prednisolone" ^[1]

Problem	Treatment	Mechanism / Notes
Polyarthritis	NSAIDs ^[1]^[3]; antimalarials (hydroxychloroquine) ^[1]^[3]	HCQ inhibits TLR signalling → ↓immune activation. Anti-inflammatory. Low toxicity profile
	± MTX if refractory ^[3]	Steroid-sparing agent for inflammatory arthritis
Low-grade myositis	Low-dose prednisolone ^[1]^[3] ± MTX, azathioprine ^[3]	Non-inflammatory fibrotic myopathy → usually mild. If CK significantly elevated (overlap PM) → treat as polymyositis with higher-dose immunosuppression
Joint contractures	Physiotherapy, occupational therapy, splinting	Prevention > treatment. Once established, contractures are very difficult to reverse
Tendon friction rubs	No specific treatment; physiotherapy	Marker of dcSSc; associated with worse organ prognosis
Calcinosis	No reliably effective treatment. Options with limited evidence: colchicine, diltiazem, minocycline, surgical excision of symptomatic deposits	Dystrophic calcification is notoriously resistant to treatment

Problem	Treatment	Notes
Sicca symptoms (secondary Sjögren's)	Artificial tears, saliva substitutes, pilocarpine (muscarinic agonist → stimulates secretion)	Present in ~20% of SSc patients
Erectile dysfunction	PDE5 inhibitors (sildenafil, tadalafil)	Triple benefit in SSc: Raynaud's + PAH + ED
Associated PBC	Ursodeoxycholic acid (UDCA)	Screen with ALP + AMA in lcSSc patients

"Newer treatment: Autologous HSCT if severe / refractory" ^[2]

Treatment	Mechanism	Indication	Evidence
Autologous HSCT	Harvest patient's stem cells → high-dose immunoablation (cyclophosphamide + ATG) → re-infuse stem cells → "reset" the immune system	Severe, rapidly progressive dcSSc with organ involvement (ILD), refractory to conventional immunosuppression	ASTIS and SCOT trials: HSCT improved event-free survival vs CYC alone at 4 years, but with significant treatment-related mortality (~10% in first year). Selected patients only. Must have adequate cardiac function
Anti-TGFβ strategies	Block the master fibrotic cytokine	Experimental / clinical trials	"Anti-fibrotic agents with limited evidence e.g. anti-TGFβ" ^[1]. Fresolimumab studied but not yet in clinical use
JAK inhibitors (tofacitinib)	Block JAK-STAT signalling → ↓cytokine-driven inflammation and fibrosis	Emerging evidence for SSc skin and ILD	Very early evidence. Watch this space

Organ	Key Treatments	Key Contraindications/Cautions
Raynaud's	CCB → PDE5i → prostacyclin analogues → bosentan	Avoid beta-blockers ^[2]; avoid smoking
Skin	Emollients, physiotherapy; MTX/MMF for early inflammatory phase	None proven for fibrosis ^[1]; avoid high-dose steroids
GI	PPI, H2 blockers; prokinetics; antibiotics for SIBO ^[1]	—
ILD	MMF or CYC; ± nintedanib; ± tocilizumab ^[1]	Avoid prednisolone > 10–15mg/day
PAH	ERAs + PDE5i + prostacyclin pathway agents; O₂ ^[1]	Riociguat + PDE5i contraindicated together
Renal crisis	ACEI (captopril) ^[1]	Avoid high-dose steroids ^[2]; do NOT substitute ARB for ACEi
Cardiac	Anti-arrhythmics; NSAIDs for pericarditis ^[1]	Amiodarone caution with ILD; BB caution with Raynaud's
MSK	NSAIDs, antimalarials; low-dose prednisolone for myositis ^[1]	—
Severe/refractory	Autologous HSCT ^[2]	~10% treatment-related mortality; requires adequate cardiac function

High Yield Summary — Management of Systemic Sclerosis

Overall principle: "Treatment is largely symptomatic" ^[1]. Organ-by-organ approach. No single drug treats all of SSc.

Raynaud's: Keep warm, stop smoking/BBs → CCBs (1st line) → PDE5i/prostacyclin analogues → bosentan (digital ulcer prevention).

Skin: No proven drug reverses fibrosis. MTX/MMF may help early inflammatory phase. Avoid high-dose steroids.

GI: PPI (high dose) for GERD; prokinetics for dysmotility; rotating antibiotics for SIBO; APC for GAVE.

ILD: MMF or CYC + nintedanib ± tocilizumab ^[1]. Steroid low dose only. Consider lung transplant for refractory cases.

PAH: Combination therapy: ERA + PDE5i ± prostacyclin pathway agents. O₂ therapy.

Renal crisis: ACEI (captopril) ^[1] — the single most important drug. AVOID high-dose steroids ^[2]. Continue ACEi even on dialysis.

Cardiac: Anti-arrhythmics; NSAIDs for pericarditis (avoid steroids if possible).

MSK: NSAIDs + antimalarials for arthritis; low-dose prednisolone for myositis.

Severe/refractory: Autologous HSCT (selected patients).

Three drugs to AVOID in SSc:

High-dose corticosteroids (precipitate renal crisis)
Beta-blockers (worsen Raynaud's)
Calcineurin inhibitors with caution (renal toxicity)

Active Recall - Management of Systemic Sclerosis

References

^[1] Lecture slides: GC 053. Fingers turn white and blue.pdf ^[2] Senior notes: Maksim Medicine Notes.pdf (Rheumatology section, p.316–319) ^[3] Senior notes: Ryan Ho Rheumatology.pdf (Systemic Sclerosis management, p.85) ^[6] Senior notes: Ryan Ho Fundamentals.pdf (Raynaud Phenomenon section, p.411) ^[7] Senior notes: Ryan Ho Respiratory.pdf (ILD general management, p.121–122) ^[14] Senior notes: Ryan Ho Respiratory.pdf (NSIP section, p.123)

Complications of Systemic Sclerosis

SSc is unique among autoimmune diseases in that it relentlessly damages virtually every organ system through three simultaneous pathological processes — immunological activation, occlusive vasculopathy, and tissue fibrosis ^[2]. Unlike SLE, where flares and remissions occur, SSc tends to be progressive and cumulative. Complications are therefore not "occasional bad luck" but rather the natural history of untreated or undertreated disease.

Understanding complications requires mapping each one back to which pathological pillar is responsible:

Pathological Pillar	Complications Driven
Vasculopathy	Digital ulcers/gangrene, PAH, scleroderma renal crisis, GAVE, coronary microvascular disease
Fibrosis	ILD, oesophageal dysmotility/stricture, intestinal pseudo-obstruction, myocardial fibrosis, joint contractures, skin contractures
Immune activation	Pericarditis, overlap myositis, secondary Sjögren's, associated malignancy
Combined	Most organ damage involves > 1 pillar working together

Mortality in SSc is 4× that of the general population, with the majority related to cardiopulmonary involvement ^[3]

Poor prognostic factors: male sex, early onset, extensive skin or pulmonary involvement ^[3]

1. Pulmonary Complications — The #1 Cause of Death

The lungs are the leading cause of SSc-related mortality, accounting for approximately 35% of SSc deaths. There are two major pulmonary complications, and they can coexist or occur independently.

Feature	Details
Prevalence	ILD: 50% in dcSSc, 25% in lcSSc ^[3]^[16]
Histological pattern	Most commonly associated with fibrotic NSIP ^[16]; UIP also occurs
Antibody association	Anti-Scl-70 (anti-topoisomerase I) — strongly associated with ILD risk ^[2]^[3]
Pathophysiology	Fibrosis of alveolar interstitium → thickened gas-exchange barrier → ↓diffusion capacity → restrictive physiology. Early: GGO (inflammation) → Late: honeycombing (irreversible fibrosis)
Clinical features	Progressive SOBOE, non-productive cough, bibasal fine Velcro crackles
Monitoring	PFT (FVC, DLCO) every 3–12 months. ↓FVC > 10% or ↓DLCO > 15% over 12 months = clinically significant progression
Complications of ILD	Respiratory failure (Type 1 → Type 2 in end-stage), secondary pulmonary hypertension (Group 3), recurrent lower respiratory tract infections, cor pulmonale

Why does SSc-ILD carry a different prognosis than IPF?

SSc-ILD with NSIP pattern has a better prognosis than IPF (UIP): 5-year mortality < 15% for NSIP vs ~50% for IPF ^[14]
SSc-ILD with NSIP responds to immunosuppression (MMF, CYC) — because there is a significant inflammatory component driving fibroblast activation. IPF does not respond to immunosuppression
However, SSc-ILD with UIP pattern carries a worse prognosis, closer to IPF

Feature	Details
Prevalence	PAH occurs in 10–15% of SSc, especially in lcSSc with CREST syndrome and anti-centromere antibody +ve patients ^[16]
Type	Group 1 PAH (isolated vasculopathy of pulmonary arterioles) in lcSSc; Group 3 PH (secondary to ILD/hypoxia) in dcSSc
Pathophysiology	Obliterative vasculopathy of pulmonary arterioles → ↑pulmonary vascular resistance → RV pressure overload → RV failure. Same vasculopathic process as Raynaud's and digital ulcers, but in the pulmonary vasculature
Clinical features	Rapidly progressive SOBOE with ↓exercise tolerance, right heart failure, angina ^[3]
Why does RV fail?	The RV is a thin-walled chamber designed for low-pressure circulation. When PVR rises chronically, the RV hypertrophies initially (compensated) but eventually dilates and fails (decompensated) → tricuspid regurgitation → systemic venous congestion (↑JVP, oedema, ascites, hepatomegaly)
Screening	Annual echocardiography in all SSc patients. FVC/DLCO ratio > 1.6 suggests isolated PAH (DLCO disproportionately low because the vascular bed is destroyed while lung parenchyma is relatively preserved)
Prognosis	SSc-PAH has a worse prognosis than idiopathic PAH (1-year mortality ~30% vs ~15%). This is because SSc-PAH often has coexistent myocardial fibrosis and diastolic dysfunction, limiting RV adaptation

Feature	Details
Pathophysiology	Recurrent aspiration due to oesophageal dysmotility ^[16] — hypotensive LOS + absent peristalsis → chronic reflux → silent aspiration of gastric contents into the lungs
Clinical features	Recurrent episodes of cough, fever, consolidation (especially RLL — because the right main bronchus is more vertical) ^[13]
Consequence	Repeated aspiration → chemical pneumonitis → accelerates ILD progression → worsens prognosis
Prevention	Aggressive anti-reflux measures: high-dose PPI, elevate head of bed, small frequent meals, prokinetics. Consider fundoplication in selected cases

The Lung in SSc — A Double Hit

SSc patients' lungs face a "double hit": (1) ILD from fibrosis destroying the parenchyma, AND (2) PAH from vasculopathy destroying the vascular bed. These can occur independently (isolated PAH in lcSSc; predominant ILD in dcSSc) or together (ILD → hypoxic vasoconstriction → secondary PH). Additionally, chronic aspiration from oesophageal dysmotility adds a "third hit" — silently accelerating lung damage. This is why pulmonary complications dominate SSc mortality.

This is a rheumatologic emergency and one of the most feared complications.

Feature	Details
Prevalence	Found in 10–15% of scleroderma patients ^[2]
Subtype	Predominantly dcSSc ^[1]^[2]. Higher risk for renal crisis in dcSSc ^[1]
Antibody association	Anti-RNA polymerase III — strongest predictor
Risk factors	Steroid use (especially in diffuse SSc) ^[2]; early dcSSc ( < 4 years from onset); rapidly progressive skin disease; new anaemia; pericardial effusion
Pathophysiology	Vasculopathy → intra-renal arterial stenosis → activates RAAS ^[2]. The renal afferent arterioles develop intimal hyperplasia ("onion-skin" lesion) → luminal narrowing → renal ischaemia → ↑renin release → ↑angiotensin II → malignant hypertension → further renal damage (vicious cycle). TMA develops with fibrin deposition → MAHA + thrombocytopaenia
Presentation	Abrupt onset malignant hypertension (often > 180/120, can be > 220/130); oliguric renal failure ^[3]; headache, visual disturbance, seizures (hypertensive encephalopathy); flash pulmonary oedema
Laboratory	↑↑creatinine (rapidly rising); urinalysis: mild proteinuria, few cells/casts ^[3]; CBC: MAHA (schistocytes) + thrombocytopaenia ^[3]; ↑LDH, ↑reticulocytes, ↓haptoglobin
Prognosis	Can progress to ESRD within 1–2 months ^[2]. Pre-ACEi era: 90% mortality. Post-ACEi era: ~75% 1-year survival. ~50% of those requiring dialysis may recover renal function if ACEi is continued
Treatment	ACEI (captopril) ^[1]. Never stop ACEi even during dialysis. Avoid ARBs as substitute (less evidence). AVOID high-dose steroids

SRC Can Be Normotensive

About 10% of SRC cases present without hypertension ("normotensive SRC"). These are particularly dangerous because the diagnosis is delayed — the physician may not think of SRC without elevated BP. Suspect normotensive SRC if a dcSSc patient develops unexplained acute kidney injury ± MAHA, even with normal BP. Check blood film for schistocytes.

GI involvement is the most common internal organ involvement (up to 90% of SSc patients) and encompasses a cascade of complications from mouth to anus.

Complication	Pathophysiology	Clinical Significance
GERD and reflux oesophagitis	Hypotensive LOS (fibrosis) → chronic acid reflux → erosive oesophagitis	Can progress to Barrett's oesophagus (intestinal metaplasia → ↑risk of oesophageal adenocarcinoma). All SSc patients need aggressive PPI therapy
Barrett's oesophagus	Chronic acid exposure → squamous epithelium replaced by columnar epithelium (metaplasia) → dysplasia → carcinoma	Surveillance OGD recommended. SSc patients have very high rates of Barrett's due to the severity and chronicity of reflux
Oesophageal stricture	Chronic reflux → fibrosis and scarring of oesophageal wall → luminal narrowing	Progressive dysphagia to solids. May need endoscopic dilatation
Aspiration pneumonia	Oesophageal dysmotility + LOS incompetence → silent aspiration	See pulmonary complications section above
GAVE (watermelon stomach) ^[3]	Gastric antral vascular ectasia — dilated ectatic capillaries in the gastric antrum. Unique endoscopic appearance of "watermelon stomach" ^[3]. Mechanism unclear but likely related to vasculopathy	May present with GI bleeding ^[3] → chronic occult blood loss → iron deficiency anaemia. Treat with argon plasma coagulation (APC). More common in lcSSc
Gastroparesis	Gastric smooth muscle fibrosis → delayed emptying	Early satiety, nausea, vomiting, bloating. May compromise oral medication absorption. Treat with prokinetics
SIBO	Small intestinal hypomotility → bacterial overgrowth	Bloating, flatulence, diarrhoea, malabsorption (fat-soluble vitamins A, D, E, K; B12; iron) → malnutrition, weight loss
Pseudo-obstruction ^[3]	Small bowel fibrosis → complete hypomotility mimicking mechanical obstruction	Chronic abdominal pain, cramps, distension ^[3]. Dilated loops on AXR but no transition point. Conservative management (NG decompression, IV fluids). Surgery is NOT helpful
Malnutrition	Cumulative effect of dysphagia + gastroparesis + SIBO + malabsorption	Cachexia, vitamin deficiencies, sarcopenia. May need supplemental enteral or parenteral nutrition
Diverticulosis and faecal incontinence	Large bowel fibrosis → constipation, diverticulosis, incontinence ^[3]	Wide-mouth diverticula (characteristic of SSc — unlike typical diverticula). Internal anal sphincter fibrosis → incontinence

Cardiovascular involvement: associated with poor prognosis (60% 2-year mortality) ^[3]

Cardiac involvement is probably underdiagnosed because much of it is subclinical. It can involve any cardiac structure.

Complication	Pathophysiology	Details
Myocardial fibrosis ^[3]	Patchy replacement fibrosis of the myocardium from both direct fibroblast activation and coronary microvascular ischaemia (vasculopathy of intramyocardial arterioles)	Leads to HFrEF/HFpEF ^[3]. Detected by cardiac MRI (late gadolinium enhancement). Restrictive cardiomyopathy pattern ^[17]
Arrhythmias ^[3]	Fibrosis disrupts the cardiac conduction system → re-entrant circuits or conduction blocks	Atrial fibrillation, ventricular tachycardia, conduction blocks. Sudden cardiac death is a recognised complication
Symptomatic pericarditis (7–20%) ^[3]	Immune-mediated inflammation of the pericardium	Pericardial effusion; rarely tamponade. Treat with NSAIDs (avoid steroids if possible due to renal crisis risk). Pericardial effusion is a poor prognostic marker
↑Risk of MI ^[3]	Coronary microvascular disease (vasculopathy → intimal hyperplasia of small coronary arteries) → supply-demand mismatch	Epicardial coronary arteries often normal on angiography. The problem is at the microvascular level — similar to cardiac syndrome X

Why is the prognosis so poor with cardiac involvement? Because myocardial fibrosis is irreversible and impairs both systolic and diastolic function simultaneously. Combined with the additional haemodynamic burden from PAH (RV pressure overload) and possible pericardial disease, the heart faces a triple insult: myocardial fibrosis + pulmonary hypertension + pericardial constriction. 60% 2-year mortality ^[3] reflects this relentless multimodal cardiac damage.

Complication	Pathophysiology	Details
Digital ulcers	Severe vasospasm (Raynaud's) + obliterative vasculopathy → critical digital ischaemia → tissue necrosis at fingertips or over bony prominences	Painful, often multiple. Heal slowly due to poor perfusion. Prevent with vasodilators (CCB, PDE5i, iloprost). Bosentan for prevention of new ulcers
Digital gangrene and autoamputation	End-stage digital ischaemia → complete arterial occlusion → dry gangrene → spontaneous loss of distal phalanx	Devastating functionally and psychologically. May require surgical amputation if wet gangrene/infection develops
Secondary infection of digital ulcers	Ischaemic tissue is poorly perfused → impaired immune response → prone to bacterial colonisation (often Staph aureus)	Osteomyelitis of the distal phalanx can occur. Needs aggressive antibiotic therapy ± surgical debridement
Acro-osteolysis	Chronic ischaemia → resorption of the distal phalangeal tufts ^[2]	Fingers appear shortened. Visible on X-ray hands. Irreversible
Calcinosis cutis	Dystrophic calcification — calcium hydroxyapatite deposits in damaged subcutaneous tissue	Can ulcerate through the skin → secondary infection. Can discharge chalky white material. Very difficult to treat

Complication	Pathophysiology	Details
Joint contractures	Fibrosis around tendons and other periarticular structures ^[3] → fixed flexion deformities	Hands, wrists, elbows most affected. Prevention with physiotherapy is key — once established, contractures are very difficult to reverse
Tendon friction rubs	Fibrous deposits on tendon sheaths	Palpable/audible crepitus. Highly specific for dcSSc. Associated with more severe organ involvement
Polyarthritis (20–30% with erosions) ^[3]	Immune-mediated synovitis	Can be erosive. May mimic RA. Treat with NSAIDs, antimalarials ± MTX
Digital tuft resorption	Due to long-standing Raynaud ^[3] — chronic ischaemia → bone resorption	See acro-osteolysis above
Myopathy	Fibrotic myopathy (non-inflammatory) or overlap inflammatory myositis (with PM/DM features)	Proximal weakness. Check CK. If elevated → overlap myositis → treat as PM. If normal CK → fibrotic myopathy (less responsive to treatment)
Carpal tunnel syndrome	Fibrosis of carpal tunnel contents → median nerve compression	Tingling/numbness in median nerve distribution. May need surgical release

Feature	Details
↑Risk of CA lung (5×) ^[3]	Chronic ILD → scarring → scar carcinoma (typically adenocarcinoma or squamous cell carcinoma arising in fibrotic lung). Also, SSc itself is a risk factor independent of ILD
↑Risk of oesophageal adenocarcinoma	Barrett's oesophagus from chronic severe GERD → metaplasia → dysplasia → carcinoma
Anti-RNA polymerase III and malignancy	Anti-RNA pol III is associated with a paraneoplastic form of SSc — screening for synchronous malignancy (breast, lung, ovarian) is recommended at diagnosis if this antibody is positive. SSc may be a paraneoplastic phenomenon in some of these patients
Other malignancies	Slightly increased risk of breast cancer, haematological malignancies, and tongue/oral cancers (chronic mucosal irritation from microstomia and dryness)

Anti-RNA Polymerase III and Cancer Screening

There is growing evidence that SSc with anti-RNA polymerase III antibody (especially in older patients with rapid-onset skin thickening) may represent a paraneoplastic phenomenon. Cancer and SSc onset are often temporally related (within 1–3 years). Current recommendations suggest age-appropriate cancer screening at diagnosis in all SSc patients, with intensified screening (CT chest/abdomen/pelvis, mammography, colonoscopy) in anti-RNA pol III-positive patients.

These are iatrogenic complications that arise from the drugs used to manage SSc:

Drug	Complication	Why
Corticosteroids	Scleroderma renal crisis ^[2]; osteoporosis; diabetes; Cushingoid features; infections	Steroids cause fluid retention + HTN in a patient with already compromised renal vasculature → precipitate SRC. Avoid prednisolone > 10–15mg/day in dcSSc
Cyclophosphamide	Haemorrhagic cystitis; bone marrow suppression; gonadal toxicity; bladder cancer (long-term); infection	Acrolein (CYC metabolite) is toxic to bladder urothelium. Give mesna to bind acrolein. Monitor CBC
MMF	GI upset; cytopaenias; infection; teratogenicity	Effective contraception required
Cyclosporin A / Tacrolimus	Renal toxicity ^[1] — can worsen renal ischaemia in SSc	"Watch out for renal toxicity" ^[1]. Calcineurin inhibitors cause afferent arteriolar vasoconstriction → dangerous in SSc renal vasculopathy
Bosentan	Hepatotoxicity; teratogenicity; fluid retention	Monitor LFTs monthly. Contraindicated in pregnancy
Methotrexate	Hepatotoxicity; bone marrow suppression; pneumonitis (rare but dangerous in SSc-ILD)	Monitor CBC, LFTs. Supplement with folic acid
Nintedanib	Diarrhoea (very common); hepatotoxicity	Monitor LFTs
Beta-blockers (if inadvertently used)	Worsening Raynaud's → digital ischaemia	Block β₂ vasodilation → worsen vasospasm

Often overlooked but profoundly impactful:

Complication	Pathophysiology / Mechanism
Depression and anxiety	Chronic, progressive, incurable, disfiguring disease. Pain from digital ulcers. Loss of hand function. Facial changes (microstomia, mask-like facies) → social withdrawal
Body image disturbance	Facial skin changes, hand deformities, calcinosis, telangiectasia
Sexual dysfunction	Erectile dysfunction (penile vascular fibrosis) in men; vaginal dryness and dyspareunia (mucosal fibrosis) in women. Both sexes: reduced libido from chronic illness
Functional disability	Loss of hand dexterity (sclerodactyly, contractures, digital amputation) → cannot work, dress, cook, write
Social isolation	Microstomia → difficulty eating in public; facial changes → self-consciousness
Financial burden	Chronic disease + multiple specialist visits + expensive medications (PAH drugs, biologics)

Factor	Impact
Overall mortality	4× general population ^[3]
Major causes of death	Cardiopulmonary involvement ^[3]: ILD (#1) > PAH (#2) > cardiac (#3) > renal crisis (#4)
Subtype	dcSSc: poor prognosis ^[1]; lcSSc: comparatively better prognosis ^[1]
Antibody	Anti-centromere → better; Anti-Scl-70 → worse (ILD); Anti-RNA pol III → worse (renal crisis, malignancy)
Poor prognosticators	Male sex, early onset, extensive skin involvement, extensive pulmonary involvement ^[3]. Cardiac involvement (60% 2-year mortality). Anti-Scl-70 or anti-RNA pol III positivity
10-year survival	lcSSc: ~70–80%; dcSSc: ~55–65% (improved with modern therapy)
Causes of death over time	Early ( < 5 years): renal crisis, rapidly progressive ILD, cardiac. Late ( > 5 years): PAH, progressive ILD, malignancy

Organ	Key Complications	Driven By	Subtype Predilection
Lung	ILD, PAH, aspiration pneumonia, CA lung	Fibrosis + vasculopathy	ILD: dcSSc; PAH: lcSSc
Kidney	Scleroderma renal crisis, CKD	Vasculopathy	dcSSc
Heart	Myocardial fibrosis, arrhythmias, pericarditis, HF	Fibrosis + vasculopathy	dcSSc (more severe)
GI	GERD, Barrett's, stricture, GAVE, SIBO, pseudo-obstruction, malnutrition	Fibrosis	Both subtypes
Vascular	Digital ulcers, gangrene, acro-osteolysis, calcinosis	Vasculopathy	Both subtypes
MSK	Contractures, erosive arthritis, myopathy, tendon friction rubs	Fibrosis + immunity	Both subtypes
Malignancy	CA lung (5×), oesophageal adenoCA, paraneoplastic SSc	Chronic fibrosis + immunity	Anti-RNA pol III
Iatrogenic	Renal crisis (steroids), infections (immunosuppression), drug toxicity	Treatment-related	dcSSc (steroids)
Psychosocial	Depression, body image, sexual dysfunction, disability	Chronic disease burden	Both subtypes

High Yield Summary — Complications of Systemic Sclerosis

#1 cause of death: Pulmonary complications — ILD (dcSSc, anti-Scl-70) and PAH (lcSSc, anti-centromere).

Scleroderma renal crisis: 10–15%, dcSSc, anti-RNA pol III. Vasculopathy → RAAS activation → malignant HTN → ESRD in 1–2 months. Treat with ACEi. AVOID high-dose steroids.

Cardiac involvement: 60% 2-year mortality. Myocardial fibrosis → HF, arrhythmias; pericarditis.

GI complications: GERD → Barrett's → adenoCA; GAVE (watermelon stomach) → IDA; SIBO → malabsorption; pseudo-obstruction.

Digital complications: Ulcers → gangrene → autoamputation → osteomyelitis.

Malignancy: ↑CA lung (5×); Barrett's adenoCA; paraneoplastic SSc (anti-RNA pol III).

Treatment complications: Steroids → SRC; calcineurin inhibitors → renal toxicity; CYC → haemorrhagic cystitis.

Prognosis: Overall mortality 4× general population. Poor prognosticators: male, early onset, extensive skin, extensive lung involvement, cardiac involvement.

Active Recall - Complications of Systemic Sclerosis

References

^[1] Lecture slides: GC 053. Fingers turn white and blue.pdf ^[2] Senior notes: Maksim Medicine Notes.pdf (Rheumatology section, p.316–319) ^[3] Senior notes: Ryan Ho Rheumatology.pdf (Systemic Sclerosis section, p.83–85) ^[7] Senior notes: Ryan Ho Respiratory.pdf (ILD general management, p.121–122) ^[13] Senior notes: Ryan Ho GI.pdf (Dysphagia approach, p.35) ^[14] Senior notes: Ryan Ho Respiratory.pdf (NSIP section, p.123) ^[16] Senior notes: Ryan Ho Respiratory.pdf (Respiratory Manifestations of Rheumatic Diseases, p.127) ^[17] Senior notes: Ryan Ho Cardiology.pdf (Restrictive Cardiomyopathy, p.170)

High Yield Summary

Definition: SSc is a generalised CTD characterised by (1) immune activation, (2) obliterative vasculopathy, and (3) tissue fibrosis affecting skin and internal organs.

Epidemiology: Peak onset 30–50y, F:M = 4:1, prevalence 10–20/100k, incidence 1–2/100k.

Two main subtypes:

Limited SSc (70%): skin below elbows/knees, anti-centromere Ab, CREST features, late PAH, better prognosis.
Diffuse SSc (30%): skin proximal, anti-Scl-70/anti-RNA pol III, early ILD and renal crisis, poor prognosis.

Three pathological pillars: Immune activation → Vasculopathy → Fibrosis. Every feature maps to one or more.

Key clinical features:

Raynaud's (virtually 100%) — vasculopathy
Sclerodactyly, microstomia, mask-like facies — fibrosis
Digital ulcers/gangrene, telangiectasia, PAH — vasculopathy
Oesophageal dysmotility/GERD — smooth muscle fibrosis
ILD (bibasal fine crackles) — pulmonary fibrosis
Scleroderma renal crisis — vasculopathy → RAAS activation (risk factor: steroids)

Key antibodies: Anti-centromere (lcSSc), Anti-Scl-70 (dcSSc/ILD), Anti-RNA pol III (dcSSc/renal crisis).

ANA is 95% sensitive — if negative, reconsider diagnosis.

Lungs are #1 cause of death (ILD > PAH).

Nailfold capillaroscopy differentiates primary from secondary Raynaud's.

High Yield Summary — DDx of Systemic Sclerosis

Raynaud's DDx: Primary (young, female, no tissue injury, normal capillaroscopy) vs Secondary (SSc most common cause; also SLE, MCTD, PM/DM, Sjögren's, PAN, RA, drugs, vibration, haematological).

ILD DDx: Must exclude CTD-ILD (SSc, RA, PM/DM) before diagnosing IPF. Also consider pneumoconiosis (occupational) and drug-induced ILD.

Oesophageal dysmotility DDx: SSc (low LOS) vs achalasia (high LOS) — manometry differentiates.

SRC DDx: vs TTP (ADAMTS13 < 10%), HUS (diarrhoeal prodrome), other TMA causes.

CTD spectrum: SSc (fibrosis-dominant) ↔ MCTD (overlap) ↔ SLE (inflammation-dominant). Antibody profile and clinical pattern differentiate.

High Yield Summary — Diagnosis of SSc

Classification: EULAR/ACR 2013 criteria, score ≥ 9. Skin thickening proximal to MCPJs alone = 9 (sufficient).

Diagnosis is predominantly clinical: Raynaud's + skin changes + organ involvement + autoantibodies.

Key investigations:

Nailfold capillaroscopy: First-line to differentiate primary vs secondary Raynaud's
ANA: 95% sensitive screening test — if negative, reconsider diagnosis
SSc-specific antibodies: Anti-centromere (lcSSc), anti-Scl-70 (dcSSc/ILD), anti-RNA pol III (dcSSc/renal crisis) — mutually exclusive, predict subtype and organ risk
HRCT + PFT: Screen for ILD (DLCO most sensitive early marker)
Echocardiogram: Annual screening for PAH (proceed to RHC if suspicious)
OGD/manometry: SSc oesophagus = hypotensive LOS + absent distal peristalsis (cf. achalasia = hypertensive LOS)
RFT + BP monitoring: Monitor for scleroderma renal crisis (especially dcSSc, especially if on steroids)
X-ray hands: Acro-osteolysis, calcinosis, soft tissue atrophy