Medicine chapters
Systemic lupus erythematosus and serum sickness
Two immune complex diseases: systemic lupus erythematosus, a multisystem autoimmune disease of young women with ANA and anti-dsDNA, and serum sickness, a self-limiting reaction to foreign proteins or drugs.
- SLE is a multisystem immune complex disease of young women (about 9:1): arthralgia, malar rash, photosensitivity, mouth ulcers, serositis, cytopenias, nephritis and CNS disease.
- ANA is the best screening test (positive in nearly all); anti-dsDNA and anti-Sm are the most specific; low C3/C4 and high anti-dsDNA mark a flare; CRP often stays normal.
- Treat with hydroxychloroquine for all, NSAIDs and steroids for flares, and mycophenolate or cyclophosphamide plus steroids for nephritis or CNS disease. Serum sickness is a type III reaction 1–2 weeks after foreign serum or drugs: fever, rash, arthralgia, lymphadenopathy, low complement; it settles when the trigger stops.
On this page
Overview
Systemic lupus erythematosus (SLE) is a chronic, relapsing autoimmune disease that can affect almost any organ. Joint pain and rashes are the commonest problems; kidney and brain disease are the most dangerous.
Serum sickness is a short-lived illness caused by immune complexes formed against foreign proteins (antisera, antivenom) or drugs.
Both are classic examples of type III (immune complex) hypersensitivity.
Systemic lupus erythematosus
Epidemiology
- About 9 times more common in women; peak onset 20–40 years (childbearing age).
- More common and more severe in women of African and Asian descent.
Aetiology
- Genetic: higher concordance in identical twins; HLA genes; inherited deficiency of early complement (C1q, C2, C4) carries a high risk.
- Hormonal: mainly pre-menopausal women.
- Ultraviolet light: triggers flares, especially of the skin.
- Viruses: Epstein-Barr virus suggested.
- Drugs: cause drug-induced lupus (see below).
Pathogenesis (brief)
- Dying (apoptotic) cells expose nuclear antigens (DNA, histones). In SLE these remnants are cleared poorly.
- Loss of tolerance → B cells make autoantibodies against nuclear antigens.
- Antibodies form immune complexes that deposit in kidney, skin, joints and vessels, activate complement (so C3 and C4 fall) and attract neutrophils.
- Type I interferon is high in active disease.
- Some autoantibodies attack cells directly (type II): haemolytic anaemia, thrombocytopenia.
Clinical features
| System | Features |
|---|---|
| General | Fatigue (very common), fever, weight loss |
| Joints and muscles | Arthralgia/arthritis in over 90%: symmetrical small joints, like RA but non-erosive; joints may look normal. Jaccoud arthropathy: deformities that correct passively, no erosions. Myalgia; avascular necrosis of the hip (disease or steroids) |
| Skin (about 85%) | Malar (butterfly) rash sparing the nasolabial folds; photosensitivity; discoid lesions (scarring); mouth ulcers (often painless); alopecia; vasculitic lesions, livedo reticularis; Raynaud phenomenon |
| Kidney | Lupus nephritis (clinically about 30%): proteinuria, haematuria, red cell casts, nephrotic or nephritic syndrome, hypertension |
| Nervous system | Depression, psychosis, seizures, stroke, migraine, aseptic meningitis, chorea, neuropathy, cranial nerve lesions |
| Lungs (up to 50%) | Pleurisy and pleural effusion (exudate, often bilateral), pneumonitis, "shrinking lung", rarely alveolar haemorrhage |
| Heart | Pericarditis (commonest cardiac lesion), myocarditis, Libman-Sacks (sterile verrucous) endocarditis of the mitral valve; premature coronary disease |
| Blood | Anaemia of chronic disease, autoimmune haemolytic anaemia (Coombs positive), leucopenia, lymphopenia, thrombocytopenia |
| Eye | Retinal vasculitis (cotton wool spots), secondary Sjogren |
| Gut | Mouth ulcers, mesenteric vasculitis |
Lupus arthritis is non-erosive. Hand deformities that the patient can straighten (Jaccoud) with no erosions on X-ray point to SLE, not RA.
Classic features "SOAP BRAIN MD": Serositis, Oral ulcers, Arthritis, Photosensitivity, Blood disorders, Renal disease, ANA, Immunological antibodies, Neurological disease, Malar rash, Discoid rash.
Investigations
| Test | Finding and meaning |
|---|---|
| ANA | Positive in nearly all patients: best screening test; a negative ANA makes SLE very unlikely. Not specific |
| Anti-dsDNA | About 70%; highly specific; titre rises with activity and nephritis |
| Anti-Sm (Smith) | Only 10–25% (higher in black patients) but most specific |
| Anti-Ro (SS-A) / anti-La (SS-B) | Photosensitive rash, neonatal lupus, secondary Sjogren |
| Anti-histone | Drug-induced lupus |
| Antiphospholipid antibodies | 25–40% of SLE; thrombosis and miscarriage |
| Complement C3, C4 | Low in active disease (consumed) |
| ESR | Raised with activity |
| CRP | Often normal in a flare; a high CRP suggests infection or serositis/arthritis |
| FBC | Leucopenia, lymphopenia, thrombocytopenia, haemolytic anaemia |
| Urine | Protein, blood, red cell casts; urine albumin/creatinine ratio |
| Renal biopsy | Classifies nephritis (class IV diffuse proliferative is the commonest serious type); IgG and complement deposits ("full house" immunofluorescence) |
| Coombs test | Positive in haemolysis |
High anti-dsDNA + low C3 + high ESR = a lupus flare, often renal.
ANA = most sensitive; anti-Sm (and anti-dsDNA) = most specific. Do not mix them up.
A raised ESR with a normal CRP is typical of active SLE. A high CRP in a lupus patient with fever should make you look for infection.
Drug-induced lupus
| Feature | Drug-induced lupus | Idiopathic SLE |
|---|---|---|
| Drugs | Hydralazine, procainamide, isoniazid, penicillamine, minocycline, anti-TNF | None |
| Antibody | Anti-histone | Anti-dsDNA, anti-Sm |
| Kidney and CNS | Usually spared | Often involved |
| Complement | Usually normal | Low in flares |
| Outcome | Settles when the drug is stopped | Chronic, relapsing |
Slow acetylators are at higher risk with hydralazine and procainamide.
Management
General
- Education; sun protection (sunscreen, cover up); stop smoking; control blood pressure and lipids (cardiovascular risk); vaccinations.
Mild disease (skin, joints, fatigue, serositis)
- NSAIDs for arthralgia, fever and serositis.
- Hydroxychloroquine (antimalarial) for all patients unless contraindicated: helps skin, joints and fatigue and reduces flares. Retinal toxicity: baseline and regular eye checks; risk rises above 5 mg/kg per day.
- Topical steroids for skin lesions.
Moderate flares
- Short courses of oral steroids or an intramuscular depot steroid.
- Steroid-sparing drugs: azathioprine, methotrexate, mycophenolate.
Severe organ disease (nephritis, CNS, severe haemolysis or thrombocytopenia)
- High-dose corticosteroids (oral, or IV methylprednisolone pulses).
- Plus mycophenolate mofetil or cyclophosphamide for induction (mycophenolate now often preferred: fewer side effects).
- Azathioprine or mycophenolate for maintenance.
- Refractory disease: rituximab (anti-CD20) or belimumab (blocks B-cell activating factor).
- Exclude infection first in neuropsychiatric lupus.
Pregnancy and SLE
- Fertility is usually normal. Flares are common, especially after delivery.
- Stop mycophenolate (teratogenic) before conception. Hydroxychloroquine, azathioprine and low-dose prednisolone are safe.
- Anti-Ro/anti-La antibodies cross the placenta: about 2% risk of neonatal lupus (rash, hepatitis, congenital heart block).
- Antiphospholipid antibodies → recurrent miscarriage, pre-eclampsia, poor fetal growth.
Antiphospholipid syndrome (APS)
- Diagnosis: arterial or venous thrombosis and/or pregnancy loss, plus persistently positive antiphospholipid antibodies (on two occasions at least 12 weeks apart).
- Antibodies: lupus anticoagulant (prolongs APTT in the test tube but causes clotting in the body), anticardiolipin, anti-beta2-glycoprotein I.
- Other features: thrombocytopenia, livedo reticularis, migraine, chorea, valve disease, false-positive VDRL.
- Can be primary or secondary to SLE. Catastrophic APS: rare multi-organ infarction with high mortality.
- Treatment: after a thrombosis, long-term warfarin. In pregnancy: low-dose aspirin + low-molecular-weight heparin (warfarin is teratogenic).
The lupus anticoagulant is named for a test-tube effect. In the patient it causes thrombosis, not bleeding.
Prognosis
- Relapsing and remitting. 10-year survival is about 90%.
- Early deaths: kidney disease, CNS disease and infection. Late deaths: coronary disease and stroke.
- Increased risk of lymphoma.
Serum sickness
Definition and cause
A systemic type III (immune complex) hypersensitivity reaction to a foreign protein or drug.
Triggers:
- Animal (horse) antisera: antivenom, antitoxins (e.g. diphtheria, tetanus antisera of animal origin), antithymocyte globulin.
- Chimeric or animal-derived monoclonal antibodies.
- Drugs causing a serum sickness-like reaction: penicillins, cephalosporins (especially in children), sulfonamides.
Mechanism
- Foreign antigen is given in a large amount and stays in the blood.
- After about 1–2 weeks, IgG (and IgM) antibodies appear and bind it while antigen is still in excess.
- Small soluble immune complexes deposit in vessel walls, joints, kidneys and skin.
- Complement is activated (C3 and C4 fall), neutrophils are attracted and vessels become inflamed.
- As antigen is cleared, complexes disappear and the illness settles.
Clinical features
- Onset about 1–2 weeks after first exposure (sooner after a repeat exposure).
- Fever and malaise.
- Rash: urticarial or erythematous, often starting at the edges of the palms and soles.
- Arthralgia or arthritis.
- Lymphadenopathy, splenomegaly.
- Oedema; glomerulonephritis with proteinuria (usually mild).
- Settles over days (often about a week or two) once the trigger is removed.
Investigations
- Low C3 and C4 (and CH50); raised ESR.
- Urine: mild proteinuria, microscopic haematuria.
- Circulating immune complexes (not routinely needed).
Management
- Stop the trigger.
- Antihistamines for itch and rash; NSAIDs for fever and joint pain.
- Corticosteroids for severe reactions; plasmapheresis is rarely needed.
- Avoid the agent in future; record it as an allergy.
| Feature | Serum sickness | Anaphylaxis | Arthus reaction |
|---|---|---|---|
| Type | III (systemic) | I (IgE) | III (local) |
| Onset | 1–2 weeks | Minutes | Hours |
| Site | Systemic: skin, joints, kidneys | Systemic | Injection site |
In Pakistan, serum sickness can still follow snake antivenom and anti-rabies serum of equine origin. Ask about these in a patient with fever, rash and joint pain a week or two later.
Expect: young woman with arthralgia, malar rash, photosensitivity, mouth ulcers and cytopenia; ANA as the most sensitive and anti-Sm/anti-dsDNA as the most specific tests; anti-dsDNA and low C3/C4 in flares and nephritis; normal CRP in active lupus; anti-histone in drug-induced lupus (hydralazine, procainamide, isoniazid); anti-Ro and congenital heart block; Jaccoud non-erosive arthropathy; Libman-Sacks endocarditis; hydroxychloroquine and eye checks; mycophenolate or cyclophosphamide for class IV nephritis; APS with aspirin plus heparin in pregnancy; and serum sickness as a type III reaction 1–2 weeks after antivenom or antiserum with low complement.
Quick revision
- SLE: women 9:1, age 20–40; type III hypersensitivity.
- Joints over 90%, non-erosive; malar rash; photosensitivity; serositis.
- ANA most sensitive; anti-dsDNA and anti-Sm most specific.
- Flare: high anti-dsDNA, low C3/C4, high ESR, normal CRP.
- Drug-induced: anti-histone; kidney and brain spared.
- Hydroxychloroquine for all; steroids + mycophenolate/cyclophosphamide for nephritis.
- Anti-Ro: neonatal lupus and congenital heart block.
- APS: thrombosis or miscarriage + antibodies 12 weeks apart; aspirin + LMWH in pregnancy.
- Serum sickness: 1–2 weeks after foreign serum or drug; fever, rash, arthralgia, nodes; low complement; stop trigger.
Written by The House Job from standard references (Kumar and Clark's Clinical Medicine; Katzung's Basic and Clinical Pharmacology; BRS Pathology).
FAQ
Which test should be done first when SLE is suspected?
ANA. It is positive in almost all patients, so a negative result makes SLE unlikely; positive results are followed by anti-dsDNA, anti-Sm and complement levels.
Why is CRP often normal in active lupus?
SLE flares typically raise the ESR but not CRP; a high CRP suggests infection, serositis or arthritis instead.
Which drugs cause drug-induced lupus?
Classically hydralazine, procainamide and isoniazid; it is marked by anti-histone antibodies and usually spares the kidneys and brain.
What is the risk to the baby of a mother with anti-Ro antibodies?
A small risk (about 2%) of neonatal lupus, including congenital complete heart block.
How long after antivenom does serum sickness appear?
Usually about one to two weeks after the first dose, as antibodies form against the foreign horse protein.