Rheumatology:Connective tissue diseases

• Lupus and antiphospholipid syndrome: Approach to Connective Tissue Disease | SLE — Clinical Features | SLE — Diagnosis and Monitoring | Lupus Nephritis and Severe Organ Disease | Treating SLE | Drug-induced and Cutaneous Lupus | Antiphospholipid Syndrome
• Sjögren's and systemic sclerosis: Sjögren's Disease | Raynaud's Phenomenon | Systemic Sclerosis — Types and Features | Systemic Sclerosis — Organ Complications and Screening | Treating Systemic Sclerosis
• Myositis and overlap: Dermatomyositis and Polymyositis | Other Myopathies | Mixed and Overlap Connective Tissue Disease
• Revision: Connective Tissue Diseases at a Glance | Spot the Diagnosis | Exam-style Scenarios | Key Points | Guidelines and Further Reading

🩺 Connective tissue diseases — page 4 of the Rheumatology chapter. Connective tissue diseases (CTDs) are multi-system autoimmune diseases — SLE, antiphospholipid syndrome, Sjögren's disease, systemic sclerosis and myositis. They mostly affect women, often of childbearing age, and can quietly damage the kidneys, lungs and heart. The key clinical habits are: dipstick the urine and check the BP, ask about Raynaud's, and match the autoantibody to the clinical picture. Drug details are on the Assessment, Investigations and Drugs page; vasculitis is on the next page.
Your four questions for every patient: Which organs are involved — skin, joints, kidneys, lungs, heart, blood, brain? Which autoantibody fits — and does it predict a complication? Is any organ in danger now (nephritis, ILD, renal crisis, clots)? Is there a pregnancy plan, and are hydroxychloroquine, bone and cardiovascular health covered?

Approach to Connective Tissue Disease

• Suspect a CTD with combinations of — Raynaud's, inflammatory joint pain, rashes (especially photosensitive), mouth ulcers, dry eyes and mouth, hair loss, tight or thick skin, muscle weakness, serositis (pleurisy, pericarditis), unexplained cytopenias, proteinuria or haematuria, breathlessness (ILD, pulmonary hypertension), recurrent miscarriage or clots, fatigue and fever.
• Screening tests — FBC, U&E, CRP and ESR, urine dipstick and protein–creatinine ratio, ANA (with titre and pattern); if ANA positive — ENA panel (Ro, La, Sm, RNP, Scl-70, Jo-1, centromere), anti-dsDNA, complement (C3, C4); CK; antiphospholipid antibodies if clots or pregnancy loss.
• A negative ANA makes SLE very unlikely; a positive ANA alone does not mean disease.
• Antibody–disease links (see page 1 for the full table):
  • Anti-dsDNA, anti-Sm — SLE.
  • Anti-Ro, anti-La — Sjögren's, SLE, congenital heart block.
  • Anti-centromere — limited systemic sclerosis; anti-Scl-70 — diffuse; anti-RNA polymerase III — renal crisis.
  • Anti-Jo-1 — antisynthetase syndrome.
  • Anti-U1 RNP — mixed connective tissue disease.
• Nailfold capillaroscopy — enlarged, dilated or missing capillaries mean secondary Raynaud's from a CTD (systemic sclerosis, dermatomyositis).

SLE — Clinical Features

• Systemic lupus erythematosus — autoimmune disease with immune complexes and autoantibodies against nuclear material.
• Who — women 9 times more than men, onset usually 15–45; more common and more severe in people of African, Caribbean, Asian and Hispanic descent.
• Triggers — UV light, infections, pregnancy and post-partum, oestrogens, stopping treatment, some drugs.

SLE — Diagnosis and Monitoring

• EULAR/ACR 2019 classification criteria — entry requirement ANA at 1:80 or more; then weighted points across clinical domains (fever, cytopenias, skin, serositis, joints, neuro, kidney) and immunology (antiphospholipid antibodies, low complement, anti-dsDNA or anti-Sm); a score of 10 or more classifies SLE. Clinical diagnosis uses the whole picture.
• Key tests:
  • ANA — positive in over 95%.
  • Anti-dsDNA — specific; levels track activity (nephritis).
  • Anti-Sm — very specific but less common.
  • Complement C3 and C4 — low in active disease.
  • ESR high, CRP often normal — a high CRP suggests infection or serositis.
  • FBC, U&E, urine dipstick and protein–creatinine ratio, antiphospholipid antibodies, anti-Ro and anti-La (pregnancy).
• Monitoring — disease activity scores (SLEDAI, BILAG), anti-dsDNA, complement, FBC, kidney function, urine at every visit, BP.
• Flare or infection? — both cause fever; CRP is usually high in infection and normal in lupus flares (except serositis); low complement and rising anti-dsDNA suggest a flare.
• Long-term risks — cardiovascular disease (major cause of death — manage risk factors aggressively), infections, osteoporosis, avascular necrosis, lymphoma, cervical cancer (screening), steroid damage.

Lupus Nephritis and Severe Organ Disease

• Lupus nephritis — affects up to about half of people with SLE (more in non-white groups); often no symptoms until advanced.
• Suspect it with proteinuria (PCR over 50 mg/mmol), haematuria with red cell casts, hypertension, oedema, rising creatinine, rising anti-dsDNA and low complement.
• Kidney biopsy — essential — ISN/RPS classes:
  • Class I–II — mesangial (mild).
  • Class III (focal) and class IV (diffuse proliferative — commonest and most severe; "wire-loop" lesions).
  • Class V — membranous (nephrotic syndrome).
  • Class VI — advanced sclerosis.
• Treatment of class III–IV (± V):
  • Induction — steroids (IV methylprednisolone pulses then oral) plus mycophenolate or low-dose IV cyclophosphamide (Euro-Lupus); add belimumab or a calcineurin inhibitor (voclosporin, tacrolimus) in many patients.
  • Maintenance — mycophenolate (or azathioprine in pregnancy) for several years; hydroxychloroquine for all.
  • ACE inhibitor or ARB for proteinuria, BP control, statins.
  • Rituximab for refractory disease.
• Other severe or organ-threatening lupus — neuropsychiatric lupus (seizures, psychosis — exclude infection, metabolic causes, drugs and APS-related stroke), severe haemolysis or thrombocytopenia, myocarditis, pulmonary haemorrhage, transverse myelitis — high-dose steroids, cyclophosphamide or rituximab, plasma exchange or IVIG in some.
• Macrophage activation syndrome — high fever, cytopenias, very high ferritin, liver dysfunction — emergency (see page 6).

Treating SLE

• For everyone:
  • Hydroxychloroquine (unless contraindicated) — reduces flares, organ damage, clots and death; continue in pregnancy; eye screening.
  • Sun protection — high-factor broad-spectrum sunscreen, covering up.
  • Vitamin D (sun avoidance), bone protection with steroids.
  • Cardiovascular risk management — stop smoking, BP, lipids, weight.
  • Vaccinations (inactivated), fatigue management, mental health support, cervical screening.
  • Contraception and pre-pregnancy planning (avoid oestrogen-containing contraception with antiphospholipid antibodies).
• Mild disease (skin, joints) — hydroxychloroquine, NSAIDs (caution with kidneys), topical steroids, short steroid courses.
• Moderate disease — steroid-sparing immunosuppressants — methotrexate (joints and skin), azathioprine, mycophenolate; belimumab or anifrolumab for persistent activity (NICE TAs).
• Severe disease — IV methylprednisolone, mycophenolate or cyclophosphamide, rituximab.
• Steroids — use the lowest dose; aim to reduce to 5 mg prednisolone or less daily and stop if possible (steroids drive long-term damage).
• Treat to target — remission or low disease activity.

💡 Clinical Pearl — in a known lupus patient with fever, a high CRP suggests infection rather than a flare. Don't simply increase steroids — culture and treat infection first.

Drug-induced and Cutaneous Lupus

• Drug-induced lupus:
  • Drugs — hydralazine, procainamide, isoniazid, minocycline, methyldopa, quinidine, anti-TNF drugs, terbinafine, carbamazepine, phenytoin.
  • Features — arthralgia, myalgia, fever, serositis, rash; kidney and brain involvement are rare.
  • Anti-histone antibodies (over 90%); anti-dsDNA usually negative (except anti-TNF); complement usually normal.
  • Resolves within weeks to months of stopping the drug.
• Cutaneous lupus (skin-limited):
  • Discoid lupus — red scaly plaques on the face, scalp and ears that scar and cause permanent hair loss; only about 5–10% develop SLE.
  • Subacute cutaneous lupus — annular or psoriasis-like rash on sun-exposed areas; anti-Ro positive; often drug-triggered (PPIs, thiazides, terbinafine, ACE inhibitors).
  • Treatment — sun protection, topical steroids or calcineurin inhibitors, hydroxychloroquine, stop smoking (reduces hydroxychloroquine effect).
• Neonatal lupus — babies of mothers with anti-Ro/anti-La: rash, cytopenias, liver problems and congenital heart block (about 2% — fetal heart monitoring from 16–26 weeks; hydroxychloroquine reduces risk).

Antiphospholipid Syndrome

• Antiphospholipid syndrome (APS) — autoantibodies causing thrombosis and pregnancy complications; primary or with SLE (secondary).
• Clinical features:
  • Venous thrombosis (DVT, PE, unusual sites — cerebral venous sinus, hepatic vein).
  • Arterial thrombosis — stroke or TIA in young people, MI, limb ischaemia.
  • Pregnancy morbidity — 3 or more miscarriages before 10 weeks, fetal death at 10 weeks or later, early severe pre-eclampsia or placental insufficiency causing birth before 34 weeks.
  • Other — livedo reticularis, thrombocytopenia, heart valve disease, migraine, cognitive problems, kidney thrombotic microangiopathy.
• Laboratory criteria — one or more of lupus anticoagulant (prolongs APTT — a paradox: "anticoagulant" in the lab, clotting in the body), anticardiolipin or anti-beta-2 glycoprotein I antibodies, positive on two occasions at least 12 weeks apart. Triple-positive patients have the highest risk.
• Treatment:
  • After venous thrombosis — warfarin (INR 2–3) long-term.
  • After arterial thrombosis — warfarin (some use INR 2–3 plus aspirin, or a higher INR target — specialist).
  • DOACs are not recommended in APS, especially triple-positive or arterial disease (more clots than warfarin — MHRA).
  • Pregnancy — low-dose aspirin plus prophylactic LMWH (obstetric APS); treatment-dose LMWH if previous thrombosis (warfarin is teratogenic — switch before 6 weeks).
  • Antibodies without clots — consider low-dose aspirin (high-risk profile); avoid oestrogen contraceptives and HRT; thromboprophylaxis in high-risk situations.
  • Hydroxychloroquine may help in SLE-associated APS.
• Catastrophic APS — rapid clots in 3 or more organs within a week (kidneys, lungs, brain, skin), often triggered by infection, surgery or stopping anticoagulation — high mortality — anticoagulation plus high-dose steroids plus plasma exchange and/or IVIG (ICU).

Sjögren's Disease

• Autoimmune inflammation of exocrine glands (tear and salivary glands) — primary, or secondary to RA, SLE or systemic sclerosis; mostly women aged 40–60.
• Sicca symptoms:
  • Dry eyes — gritty, burning, red (keratoconjunctivitis sicca).
  • Dry mouth — difficulty swallowing dry food, needing water to eat, dental decay, oral candida.
  • Dry skin, dry vagina (painful intercourse), dry cough.
  • Parotid gland swelling (recurrent or persistent).
• Systemic features — fatigue (prominent), arthralgia, Raynaud's, peripheral neuropathy, renal tubular acidosis (distal, type 1 — low potassium), interstitial nephritis, ILD, vasculitis (purpura — cryoglobulinaemia), cytopenias.
• Lymphoma — increased risk (about 5–10% over a lifetime, mostly MALT lymphoma of the parotid) — warning signs: persistent parotid enlargement, lymphadenopathy, purpura, low C4, cryoglobulins, monoclonal protein.
• Investigations — anti-Ro (± anti-La), ANA, RF (often positive), high immunoglobulins (raised ESR); Schirmer's test (under 5 mm wetting of filter paper in 5 minutes); salivary flow; ultrasound of salivary glands; lip (minor salivary gland) biopsy (focal lymphocytic sialadenitis) if antibodies negative.
• Treatment — symptomatic: artificial tears (preservative-free), lubricating ointments, punctal plugs; saliva substitutes, sugar-free gum, pilocarpine (sweating, flushing); dental care with high-fluoride toothpaste; hydroxychloroquine for joint pain and fatigue; immunosuppression (rituximab, steroids) for serious organ disease.
• Pregnancy — anti-Ro — risk of congenital heart block and neonatal lupus.
• Other causes of dry eyes and mouth — ageing, anticholinergic drugs (antidepressants, antihistamines), radiotherapy, sarcoidosis, hepatitis C, HIV, IgG4-related disease.

Raynaud's Phenomenon

• Episodic colour changes of the fingers (and toes) with cold or stress — white (vasospasm), blue (deoxygenation), red (reperfusion), with numbness and pain.
• Primary Raynaud's — common (about 5% of adults), young women, onset in teens to 20s, symmetrical, no tissue damage, normal nailfold capillaries, negative ANA.
• Secondary Raynaud's — warning signs:
  • Onset after age 30–40; men; asymmetrical.
  • Digital ulcers, pitting scars, gangrene; severe pain.
  • Features of CTD (sclerodactyly, puffy fingers, rash, joint pain), abnormal nailfold capillaries, positive ANA.
• Causes of secondary Raynaud's — systemic sclerosis (over 95% have it — often the first sign), SLE, Sjögren's, myositis, MCTD; drugs (beta-blockers, ergotamine, triptans, chemotherapy — bleomycin, cisplatin; stimulants); vibrating tools (hand-arm vibration syndrome); cervical rib; cryoglobulinaemia; hypothyroidism.
• Investigations — FBC, ESR, CRP, ANA, TFTs (secondary features), nailfold capillaroscopy.
• Treatment:
  • Keep warm (whole body, gloves, heated gloves), stop smoking, avoid triggering drugs, stress management.
  • Nifedipine (modified-release) first-line (headaches, flushing, ankle swelling); alternatives — amlodipine, diltiazem, losartan, fluoxetine.
  • Specialist — sildenafil (PDE5 inhibitor), IV iloprost (severe attacks or ulcers), bosentan (prevents new digital ulcers in systemic sclerosis), botulinum toxin, sympathectomy.
  • Critical digital ischaemia (persistent white or blue finger, pain) — emergency admission: iloprost, antiplatelets, analgesia, look for clots or vasculitis.

Systemic Sclerosis — Types and Features

• Systemic sclerosis (scleroderma) — autoimmune disease with vasculopathy (Raynaud's), fibrosis of skin and organs, and autoantibodies; women 4 times more than men; onset 30–50.
• Skin — puffy swollen fingers early, then tight, thick, shiny skin (sclerodactyly); fixed flexion contractures; microstomia (small mouth with radial furrows), beaked nose; telangiectasia; calcinosis; digital ulcers and pitting scars; pigment changes.

• Morphoea (localised scleroderma) — skin-only patches of thickening; no Raynaud's or organ disease; not the same as systemic sclerosis.
• Mimics — eosinophilic fasciitis (spares fingers, "groove sign", eosinophilia), scleredema (diabetes), nephrogenic systemic fibrosis (gadolinium in kidney failure), diabetic cheiroarthropathy.

Systemic Sclerosis — Organ Complications and Screening

• Lungs — the leading cause of death:
  • Interstitial lung disease (NSIP pattern) — breathlessness, dry cough, fine basal crackles; HRCT, falling FVC and TLCO.
  • Pulmonary arterial hypertension — breathlessness, falling TLCO with preserved FVC, raised NT-proBNP; echo, then right heart catheter.
• Gut (about 90%) — GORD and oesophageal dysmotility (dysphagia, strictures, Barrett's), gastroparesis, GAVE ("watermelon stomach" — iron deficiency anaemia), small intestinal bacterial overgrowth (bloating, diarrhoea, malabsorption), pseudo-obstruction, faecal incontinence, malnutrition.
• Kidneys — scleroderma renal crisis:
  • Sudden severe hypertension (sometimes normotensive), AKI, microangiopathic haemolytic anaemia, headache, visual change, seizures, pulmonary oedema.
  • Risk — early diffuse disease, anti-RNA polymerase III, high-dose steroids (prednisolone over 15 mg daily — avoid).
  • Treatment — ACE inhibitor (e.g. captopril, rapidly increased) even if creatinine rises; dialysis if needed (kidneys may recover over months).
• Heart — myocardial fibrosis, arrhythmias, conduction block, pericardial effusion, heart failure.
• Musculoskeletal — arthralgia, tendon friction rubs (diffuse disease — poor sign), contractures, myopathy.
• Screening — at diagnosis and annually: PFTs (FVC and TLCO), echocardiogram (PAH), NT-proBNP; HRCT at baseline; BP and kidney function (home BP monitoring in early diffuse disease); urine; FBC (GAVE).

Treating Systemic Sclerosis

• No cure — treatment targets each organ in a specialist centre.
• Skin (early diffuse) — mycophenolate or methotrexate; rituximab; autologous stem cell transplant for rapidly progressive disease in selected patients.
• ILD — mycophenolate; cyclophosphamide; rituximab; tocilizumab; nintedanib (antifibrotic) for progressive fibrosis; lung transplant.
• Pulmonary arterial hypertension — endothelin receptor antagonists (bosentan, ambrisentan, macitentan), PDE5 inhibitors (sildenafil, tadalafil), riociguat, prostacyclin analogues (iloprost, epoprostenol, selexipag); oxygen, diuretics, anticoagulation in some (see the Respiratory chapters).
• Raynaud's and digital ulcers — nifedipine, sildenafil, IV iloprost, bosentan (prevents new ulcers); wound care; treat infection.
• Gut — high-dose PPI, prokinetics (metoclopramide, domperidone), rotating antibiotics for SIBO, nutritional support; GAVE — endoscopic laser therapy.
• Renal crisis — ACE inhibitors (see above); prevention — avoid high-dose steroids, monitor BP at home.
• Calcinosis and contractures — physiotherapy, occupational therapy, hand exercises, surgery for troublesome calcinosis.
• Avoid — high-dose steroids; beta-blockers (worsen Raynaud's).

Dermatomyositis and Polymyositis

• Idiopathic inflammatory myopathies — autoimmune muscle inflammation causing symmetrical proximal muscle weakness (difficulty climbing stairs, rising from a chair, lifting arms above the head), developing over weeks to months; muscle pain is less prominent than weakness.
• Dermatomyositis — myositis with characteristic skin signs:
  • Heliotrope rash — violet discolouration of the upper eyelids with swelling.
  • Gottron's papules — red or violet scaly bumps over the knuckles (MCP and IP joints), elbows and knees.
  • Shawl sign (upper back and shoulders) and V sign (front of the chest) — photosensitive.
  • Nailfold changes — ragged cuticles, dilated capillaries.
  • Mechanic's hands — cracked, rough skin on the sides of the fingers (antisynthetase syndrome).
  • Calcinosis (especially in juvenile dermatomyositis).
  • Can be amyopathic (skin only).
• Cancer link — dermatomyositis (especially in older adults, and with anti-TIF1-gamma or anti-NXP2) is associated with cancer (ovary, lung, breast, GI, nasopharyngeal) — screen for malignancy at diagnosis (CT chest, abdomen and pelvis; age- and sex-specific screening; consider PET-CT) and for 3 years.
• Other organ involvement — ILD, dysphagia (pharyngeal muscle weakness — aspiration risk), respiratory muscle weakness, myocarditis, arthritis, Raynaud's.
• Investigations:
  • CK — raised (can be normal in dermatomyositis); also ALT, AST, LDH and aldolase (muscle sources — don't mistake for liver disease).
  • Myositis-specific antibodies — anti-Jo-1, anti-Mi-2 (classic DM with good prognosis), anti-MDA5 (rapidly progressive ILD, skin ulcers), anti-TIF1-gamma (cancer), anti-SRP and anti-HMGCR (necrotising myopathy).
  • MRI of muscles (oedema — guides biopsy), EMG (myopathic pattern), muscle biopsy (diagnostic), PFTs and HRCT, swallowing assessment, ECG and troponin.
• Treatment — high-dose steroids (oral or IV pulses) plus a steroid-sparing drug early (methotrexate, azathioprine, mycophenolate); IVIG (refractory disease, severe dysphagia); rituximab; cyclophosphamide or tacrolimus for ILD; physiotherapy; sun protection for skin disease; treat any cancer.
• Polymyositis (without skin signs) is now diagnosed less often — many such cases are inclusion body myositis, necrotising myopathy or antisynthetase syndrome.

Other Myopathies

• Antisynthetase syndrome — anti-Jo-1 (and others): myositis, ILD (often the main problem), arthritis, mechanic's hands, Raynaud's, fever.
• Immune-mediated necrotising myopathy:
  • Anti-HMGCR — linked with statin use; weakness and very high CK persisting after stopping the statin — needs immunosuppression (unlike ordinary statin myalgia).
  • Anti-SRP — severe, rapidly progressive weakness; cardiac involvement.
• Inclusion body myositis — men over 50; slowly progressive, asymmetrical weakness of the finger flexors (weak grip) and quadriceps (falls), dysphagia; CK normal or mildly raised; doesn't respond to steroids or immunosuppression; physiotherapy.
• Statin-associated muscle symptoms — myalgia with normal CK (common); myopathy with raised CK; rhabdomyolysis (rare — fibrates, high doses, interacting drugs such as clarithromycin, ciclosporin). Stop the statin; most settle within weeks.
• Other causes of proximal weakness and high CK — hypothyroidism, steroid myopathy (normal CK), Cushing's, osteomalacia, hypokalaemia, alcohol, drugs (colchicine, zidovudine), viral myositis, muscular dystrophies, metabolic myopathies (McArdle's).
• Polymyalgia rheumatica — pain and stiffness (not weakness), normal CK (see the next page).

Mixed and Overlap Connective Tissue Disease

• Mixed connective tissue disease (MCTD) — features of SLE, systemic sclerosis and myositis together, with high-titre anti-U1 RNP antibodies:
  • Raynaud's, puffy hands, arthritis, myositis, sclerodactyly, oesophageal dysmotility.
  • Risk of pulmonary arterial hypertension (main cause of death) and ILD — annual echo and PFTs.
  • Kidney and brain involvement are less common than in SLE.
• Overlap syndromes — features of two or more CTDs (e.g. systemic sclerosis with myositis — anti-PM-Scl, anti-Ku).
• Undifferentiated connective tissue disease — CTD features (e.g. Raynaud's, arthralgia, positive ANA) that don't meet criteria for one disease; many stay stable; some evolve into a defined CTD — monitor.
• Treatment — according to the organs involved (hydroxychloroquine, steroids, immunosuppressants, PAH therapy).

Connective Tissue Diseases at a Glance

Spot the Diagnosis