SLE
Background
Pathophysiology
- Multi-system, autoimmune condition.
- Cause unknown, but may involve formation of autoantibodies due to defective apoptosis.
Epidemiology
- 10x commoner in women.
- Onset usually in child-bearing years.
- Prevalence by ethnicity: black 1/500, Asian 1/1000, white 1/2000.
Signs and symptoms
- Relapsing-remitting course.
- Wide range of severity.
Symptoms by system:
- Systemic: malaise/fatigue (90%), fever (50%), weight loss, lymphadenopathy.
- Musculoskeletal (90%): arthritis, usually symmetrical, non-erosive polyarthritis with morning stiffness but without swelling. Also: myalgia, tenosynovitis, and tendon rupture.
- Skin: malar rash (60%), photosensitivity (40%), discoid rash (20%), Raynaud's (50%).
- Lupus nephritis (50%): 6 classes from minimal mesangial to advanced sclerosis.
- Serositis (50%): pleurisy, pericarditis. Causes SOB and chest pain.
- Respiratory: pleurisy, interstitial lung disease, pulmonary haemorrhage (causes haemoptysis and anaemia).
- Cardiovascular: IHD (5-fold risk), HTN, vasculitis, pericarditis, myocarditis, endocarditis, antiphospholipid syndrome (causes arterial and venous thrombosis).
- Mouth and face: painless oral and nasal ulcers (30%), alopecia (non-scarring), Sicca.
- GI: diarrhoea, vomiting, abdo pain, splenomegaly (10%), dysphagia (rare).
- Neurological: seizures or psychosis (20%), peripheral neuropathy, transverse myelitis, optic neuritis.
Risk factors
- Genetic: HLA-DR2 and DR3, complement deficiencies (C1q, C2, C4).
- Drugs: minocycline, sulfasalazine, procainamide, isoniazid, phenytoin, carbamazepine.
- Environment: UV light, EBV, smoking.
Investigations and diagnosis
Bloods
- FBC: ↓Hb (of chronic disease or Coomb's +ve hemolytic anaemia), ↓WBC (↓lymphocytes), ↓platelets.
- ↑ESR but CRP may be normal (or raised); do both as this can help distinguish from infection.
- U&E: ↑urea, ↑creatinine.
- Coag: ↑aPTT in APS.
- CK. Check if there is myalgia or weakness.
Immune markers
Anti-nuclear antibodies
Overview:
- Anti-nuclear antibodies (ANA, aka anti-nuclear factor) are autoantibodies which bind to elements of the cell nucleus.
- 95% sensitive – so screen with this first – and 50% specific.
- Mildly +ve in 10% of healthy population.
- Also +ve in systemic sclerosis (plus anti-centromere Ab and Scl70 Ab), polymyositis (plus Jo-1 Ab), dermatomyositis, Sjogren's, and 30% of RA.
Subtypes:
- Double-stranded DNA (dsDNA) Ab is highly specific for SLE, but only 60% sensitive. Especially associated with lupus nephritis. Good for monitoring disease activity.
- Anti-Smith (Sm) Ab. Highly specific for SLE.
- Anti-Ro and anti-La Ab. Can be seen in SLE, but commoner in Sjogren's.
Others
- APS: anti-cardiolipin Ab, lupus anticoagulant, false +ve syphilis serology (rarely done).
- Complement: ↓C3 and ↓C4. Varies with disease activity.
Other tests
- Urinalysis: protein, blood, casts (red cell, tubular, granular).
- Imaging as per symptoms e.g. CXR if CV or resp symptoms.
- BILAG questionnaire for monitoring disease activity.
Diagnostic criteria
- Serositis
- Oral or nasopharyngeal ulcers.
- Arthritis
- Leuco- or lympho-Penia.
- Blood disorder (up to 2): haemolytic anaemia, ↓PLT.
- Renal disease: proteinuria or red cell casts.
- Alopecia (non-scarring).
- Immune markers (up to 6): ANA, dsDNA-Ab, anti-Sm Ab, APS antibodies, ↓C3/↓C4, Coomb's +ve.
- Neuro symptoms: seizures or psychosis.
- Malar rash.
- Discoid rash.
- {Biopsy +ve glomerulonephritis consistent with SLE} plus {ANA or dsDNA Ab}.
Management
Immunomodulation
- Hydroxychloroquine (HCQ) PO 1st line. May be sufficient as monotherapy in mild flares and for patients in stable remission, while part of combination therapy in moderate-severe flares.
- Steroids often required alongside HCQ, but always aim to minimize dose and duration. For mild flares, may be topical or intra-articular only (or none at all), but moderate-severe disease typically requires systemic therapy (PO, IM, or IV).
- Adjuncts if HCQ insufficient and/or for minimizing steroids: methotrexate, azathioprine.
Organ-threatening or resistant disease:
- Renal or resistant non-renal disease: {steroids} plus {cyclophosphamide [CYC] IV pulse or mycophenolate mofetil [MMF] PO}.
- Neuropsychiatric: {steroids} plus {CYC IV pulse}.
- Further options if CYC/MMF ineffective: belimumab IV (B-cell activating factor inhibitor), rituximab IV.
Supportive treatment
- Lifestyle changes: avoid sun exposure (and use SPF >15), smoking cessation.
- Short-term NSAIDs for arthritis.
- Ulcer treatment: chlorhexidine mouthwash, lidocaine ointment.
- Manage CV risk factors as needed: HTN, cholesterol.
- Use low dose estrogen if contraceptive required, as hormones can exacerbate disease.
Monitoring:
- Bloods: FBC (↓Hb), U&E and urinalysis (renal function), LFT (drug side effects).
- Disease activity, BCDE: BILAG questionnaire, C3/4, dsDNA Ab, ESR.
- Monitor side effects: annual visual acuity (HCQ), BP (cyclophosphamide).
Complications and prognosis
- Atherosclerosis: manage cholesterol and BP (aim <130/80). ACEi if proteinuria.
- Antiphospholipid syndrome (25%).
Pregnancy:
- Fetal: miscarriage (especially if APS), IUGR.
- Maternal: pre-eclampsia, VTE, worsening of SLE including nephritis.
Prognosis:
- Poor signs: extensive disease, multiple autoantibodies, neurological or renal disease.
- 90% 10 year survival.
- Causes of death: IHD, renal disease, infection from immunosuppression.
Hydroxychloroquine
Mechanism
- Unclear, but has anti-inflammatory, anti-platelet, and anti-hyperlipidaemic effects.
- Increases effects of MMF.
Side effects
- Nausea, diarrhoea.
- Retinopathy, presenting as blurred vision, field changes, or scotoma. Risk increases with prolonged use, especially >5 years.
- Photosensitive rash, bleaching of hair.
- Headaches
- Tinnitus
Management
- Onset takes up to 3 months, and full effect 9 months.
- Annual visual acuity check.
- Safe in pregnancy.
- Smoking decrease effectiveness.
Cyclophosphamide
Mechanism
Side effects
- Leukopenia (infection, fever), thrombocytopenia (bleeding, bruising).
- GU: haemorrhagic cystitis, bladder cancer.
- Long-term complications: leukaemia, lymphoma, ↓fertility (azoospermia, ovarian dysfunction).
Contraindications
Management
- IV preferred as PO has higher risk of many side effects. Pulsed treatment every 2-4 weeks.
- Reduce dose if age >70 years or renal impairment.
- Check bloods 1 week after each pulse therapy and before next pulse: FBC (pancytopenia), LFT (↑AST/ALT), and U+E.
Antiphospholipid syndrome (APS)
Pathophysiology
Presentation
- Arterial (cerebral, renal) and venous (PE) CLOTs. Recurrent PEs may lead to pulmonary hypertension.
- Coagulation defects.
- Livedo reticularis.
- Obstetric problems: recurrent miscarriage.
- Thrombocytopenia
In most cases it is a standalone condition, but it affects 25% of SLE patients.
Investigations
- Paradoxical ↑aPTT: proteins are anticoagulant in vitro, but pro-thrombotic in vivo. Normal PT. Same pattern seen in heparin use and clotting factor deficiencies.
- Follow with mixing study. In a factor deficiency, clotting will be normalised, but in APS it will remain abnormal.
Antibodies:
- Anti-cardiolipin IgG/M.
- Lupus anticoagulant test: looks for clotting pattern characteristic of presence of lupus anticoagulant IgG/M. 'Anticoagulant' refers to in vitro property, as in vivo it's pro-thrombotic.
- Anti β2-glycoprotein IgG/M.
Diagnosis
Management
- Manage vascular risk factors: smoking cessation, weight loss, exercise, blood pressure and lipid control.
- Aspirin for primary prevention of arterial thrombosis and obstetric complications, though evidence of benefit is mixed.
- If thrombosis occurs, give LMWH followed by long-term warfarin. Prednisolone, IVIG, or rituximab can be used if anticoagulation is insufficient.
- During pregnancy: aspirin once pregnancy confirmed and LMWH once fetal heart visualised.
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