Systemic sclerosis, mixed connective tissue disease and Sjogren syndrome

Overview

These three autoimmune connective tissue diseases often overlap:

• Systemic sclerosis (SSc, scleroderma): small-vessel damage plus fibrosis of skin and internal organs. It has the highest mortality of the autoimmune rheumatic diseases.
• Mixed connective tissue disease (MCTD): an overlap of SLE, scleroderma and polymyositis features with anti-U1-RNP antibodies.
• Sjogren syndrome: lymphocytes destroy the tear and salivary glands, causing dry eyes and dry mouth.

Systemic sclerosis

Epidemiology and risk factors

• Women about 3 times more than men; peak onset 30–50 years.
• Scleroderma-like illness can follow silica dust, vinyl chloride, trichloroethylene and bleomycin.

Pathogenesis (brief)

1. Vascular damage first: endothelial injury in small arteries and capillaries; endothelin-1 causes vasoconstriction → Raynaud, digital ulcers, renal crisis, pulmonary hypertension.
2. Immune activation: T cells and cytokines (TGF-beta, PDGF).
3. Fibrosis: fibroblasts lay down excess collagen (types I and III) in skin, lungs, gut, heart and kidneys.

Classification

CREST describes limited disease:

• Calcinosis (calcium deposits in the fingers).
• Raynaud phenomenon.
• O: oesophageal dysmotility.
• Sclerodactyly (tight, shiny finger skin with flexion deformity).
• Telangiectasia (face, lips, hands).

Systemic sclerosis sine scleroderma: internal organ disease without skin thickening (rare).

Localised scleroderma (morphoea, linear scleroderma): skin patches only; no Raynaud or internal disease; mainly children; does not progress to SSc.

Clinical features

Scleroderma renal crisis

• Usually early diffuse disease, especially with anti-RNA polymerase III antibodies and rapidly spreading skin.
• Sudden severe hypertension, acute kidney injury, headache, visual change, seizures; microangiopathic haemolytic anaemia (fragmented red cells) and low platelets.
• Corticosteroids raise the risk: prednisolone doses over 10 mg a day are best avoided.
• Treatment: ACE inhibitor (e.g. captopril), titrated up even if creatinine rises; dialysis if needed. ACE inhibitors changed renal crisis from the main killer into a treatable problem.

Investigations

Lung function and echocardiography are repeated every year to catch lung fibrosis and pulmonary hypertension early.

Management

There is no cure; treatment is organ-based. Steroids and immunosuppressants are used mainly for lung fibrosis.

Prognosis

• Limited disease: better (about 70% 10-year survival); late pulmonary hypertension is the main killer.
• Diffuse disease: early deaths from lung, heart and kidney involvement.

Mixed connective tissue disease (brief)

• An overlap syndrome with features of SLE, systemic sclerosis and polymyositis in one patient.
• Mostly women (about 80%), often in their 30s.
• Typical features:
  • Raynaud phenomenon (very common).
  • Puffy, swollen hands and sausage fingers.
  • Arthralgia or non-erosive arthritis.
  • Myositis (proximal weakness).
  • Oesophageal hypomotility.
  • Pulmonary hypertension (main cause of death) and lung fibrosis.
• Kidney disease is uncommon and CNS disease is rare, unlike SLE.
• Antibodies: high-titre speckled ANA with anti-U1-RNP; anti-dsDNA and anti-Sm usually negative.
• Treatment: by organ, as for each disease: NSAIDs or hydroxychloroquine for joints, calcium-channel blockers for Raynaud, steroids for myositis, and specific therapy for pulmonary hypertension.
• Undifferentiated connective tissue disease: some autoimmune features (e.g. Raynaud, arthralgia, positive ANA) but not enough to name one disease; often stays mild.

Sjogren syndrome (brief)

Definition

A chronic autoimmune disease in which lymphocytes infiltrate exocrine glands, mainly the lacrimal and salivary glands.

• Primary: occurs alone. Linked with HLA-B8/DR3. Mostly middle-aged women.
• Secondary: with another autoimmune disease, most often rheumatoid arthritis, also SLE, systemic sclerosis, primary biliary cholangitis.

Clinical features

Glandular (sicca) features

• Dry eyes (keratoconjunctivitis sicca): gritty, burning eyes.
• Dry mouth (xerostomia): difficulty with dry food, altered taste, dental caries at the gum line, oral candida.
• Parotid or salivary gland swelling.
• Dry skin, dry vagina (dyspareunia), dry cough.
• Fatigue is common.

Systemic features (minority)

• Arthralgia or non-erosive arthritis; Raynaud phenomenon.
• Distal (type 1) renal tubular acidosis (hypokalaemia, kidney stones), interstitial nephritis, nephrogenic diabetes insipidus.
• Interstitial lung disease, neuropathy, vasculitis.
• Other autoimmune diseases: thyroid, primary biliary cholangitis, autoimmune hepatitis.
• B-cell non-Hodgkin lymphoma (often MALT, in the parotid): suspect with persistent, firm parotid enlargement, lymphadenopathy, falling C4 or a monoclonal band.

Investigations

Management

• Artificial tears and saliva substitutes; good dental care.
• Pilocarpine (muscarinic agonist) stimulates remaining salivary and tear flow.
• Hydroxychloroquine for fatigue and arthralgia.
• Steroids or immunosuppression only for systemic features (vasculitis, neuropathy, persistent gland swelling).
• Monitor for lymphoma.

Pregnancy

Anti-Ro and anti-La cross the placenta and can cause neonatal lupus and congenital heart block in the baby.

Quick revision

• SSc: Raynaud first; skin and organ fibrosis; women 30–50.
• Limited (CREST): anti-centromere; late pulmonary hypertension.
• Diffuse: anti-Scl-70; early lung fibrosis; renal crisis (anti-RNA polymerase III).
• Renal crisis: ACE inhibitor; avoid high-dose steroids.
• Raynaud: nifedipine first; iloprost for severe ischaemia.
• Lung disease causes about half of deaths.
• MCTD: SLE + SSc + myositis; anti-U1-RNP; kidneys spared.
• Sjogren: dry eyes and mouth; anti-Ro/La; Schirmer under 10 mm in 5 minutes; lip biopsy; lymphoma.

Written by The House Job from standard references (Kumar and Clark's Clinical Medicine; BRS Pathology).

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