Clinical Immunology: Autoimmunity, autoantibodies and complement

🛡️ Autoimmunity, autoantibodies and complement - page 5 of the Clinical Immunology chapter. Autoimmune diseases affect about 1 in 10 people in the UK, mostly women. Autoantibody tests are ordered every day - but many are positive in healthy people, and a test sent without a clear question often causes more confusion than help. This page is a practical guide to which antibody to request, what a result means, and the complement and immune complex diseases that cross every specialty. Detailed disease management is in the Rheumatology, Renal, Neurology and other chapters.
Your four questions for every autoantibody result: What clinical question was it sent to answer? How specific is this antibody, and at what titre? Does it fit the clinical picture? Will the result change management - or should it be repeated, confirmed or ignored?

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How Autoimmunity Develops

• Loss of tolerance - failure of central (thymic and bone marrow) or peripheral (regulatory T cells, anergy, checkpoints) tolerance allows self-reactive lymphocytes to cause damage.
• Genetic susceptibility - HLA genes (e.g. HLA-DR3, DR4, DQ2, B27) and many non-HLA genes (PTPN22, CTLA4); rare single-gene causes (AIRE, FOXP3, complement deficiency).
• Environmental triggers:
  • Infection - molecular mimicry (e.g. rheumatic fever after group A streptococcus; Guillain–Barré after Campylobacter), bystander activation; EBV (multiple sclerosis, SLE).
  • Smoking - rheumatoid arthritis (anti-CCP), Goodpasture's syndrome.
  • UV light - lupus flares.
  • Drugs - drug-induced lupus (hydralazine, procainamide, isoniazid, minocycline, anti-TNF), drug-induced ANCA vasculitis (propylthiouracil, hydralazine, levamisole-contaminated cocaine), checkpoint inhibitors, alemtuzumab, interferon.
  • Hormones - female predominance (SLE about 9:1), flares in pregnancy or postpartum (thyroiditis).
• Mechanisms of damage - autoantibodies against cells or receptors (type II - ITP, myasthenia, Graves'), immune complexes (type III - SLE), T-cell destruction (type IV - type 1 diabetes, multiple sclerosis).
• Clustering - one autoimmune disease raises the risk of others (e.g. type 1 diabetes with coeliac and thyroid disease; autoimmune polyglandular syndromes).
• Autoantibodies often precede disease by years (anti-CCP before RA; islet antibodies before type 1 diabetes; ANA and dsDNA before SLE).

Organ-specific and Systemic Autoimmune Disease

Type	Examples
Organ-specific	Hashimoto's thyroiditis, Graves' disease, type 1 diabetes, Addison's disease, pernicious anaemia, coeliac disease, autoimmune hepatitis, primary biliary cholangitis, myasthenia gravis, multiple sclerosis, vitiligo, pemphigus, membranous nephropathy
Systemic	SLE, Sjögren's disease, systemic sclerosis, myositis, rheumatoid arthritis, ANCA vasculitis, antiphospholipid syndrome, mixed connective tissue disease
Cytopenias	Immune thrombocytopenia, autoimmune haemolytic anaemia, Evans syndrome, autoimmune neutropenia, acquired haemophilia (factor VIII inhibitor), pure red cell aplasia
Autoinflammatory (innate, no autoantibodies)	Periodic fever syndromes, adult-onset Still's disease, gout, Behçet's (overlap), VEXAS

• Associations to remember:
  • Type 1 diabetes - screen for coeliac disease and thyroid disease.
  • Autoimmune thyroid disease - pernicious anaemia, vitiligo, coeliac disease.
  • Sjögren's - lymphoma (MALT), primary biliary cholangitis.
  • Myasthenia gravis - thymoma, thyroid disease.
  • Addison's disease - other endocrine autoimmunity (polyglandular syndrome type 2 - Addison's with thyroid disease and/or type 1 diabetes).

Using Autoantibody Tests Well

• Request targeted tests for a specific clinical question - e.g. ANA for suspected connective tissue disease, ANCA for suspected vasculitis with renal or lung involvement, anti-tTG for suspected coeliac disease.
• Pre-test probability matters - a positive ANA in a well woman with tiredness and no other features is likely a false positive (low positive predictive value).
• Sensitivity vs specificity:
  • Sensitive but not specific - ANA (SLE about 95% positive, but positive in many healthy people), rheumatoid factor.
  • Specific but less sensitive - anti-dsDNA and anti-Sm (SLE), anti-CCP (RA), anti-centromere (limited systemic sclerosis), anti-GBM.
• Titre and pattern - higher titres are more meaningful (ANA 1:160 or more); patterns (homogeneous, speckled, centromere, nucleolar) suggest specific antibodies.
• Monitoring - only some antibodies track disease activity: anti-dsDNA (with complement) in SLE, anti-GBM, anti-PLA2R (membranous), anti-TSH receptor; ANA, ANCA and RF titres usually don't guide treatment - don't repeat ANA routinely once positive.
• False results - infections (endocarditis, HIV, hepatitis C, TB) and cancer can produce autoantibodies; IVIG and blood products can cause passive positivity; IgA deficiency gives false-negative IgA-based tests.
• Treat the patient, not the test - a negative test doesn't exclude disease (seronegative RA, ANCA-negative vasculitis) and a positive test doesn't confirm it.

ANA and Extractable Nuclear Antigens

• Antinuclear antibodies (ANA) - screened by indirect immunofluorescence on HEp-2 cells (or immunoassay):
  • Positive in about 95% of SLE - a negative ANA makes SLE unlikely.
  • Also positive in Sjögren's, systemic sclerosis, myositis, MCTD, drug-induced lupus, autoimmune hepatitis, autoimmune thyroid disease, juvenile idiopathic arthritis (uveitis risk).
  • Positive in up to 10–20% of healthy people (low titre), more in older women; also infections and cancer.
• If ANA is positive - the lab tests for extractable nuclear antigens (ENA) and dsDNA:

  Antibody	Association
  Anti-Ro (SSA)	Sjögren's disease, SLE (photosensitive subacute cutaneous lupus); in pregnancy - neonatal lupus and congenital heart block (fetal heart monitoring; hydroxychloroquine reduces risk)
  Anti-La (SSB)	Sjögren's disease, SLE, neonatal lupus
  Anti-Sm	Highly specific for SLE (low sensitivity)
  Anti-U1 RNP	Mixed connective tissue disease (high titre), SLE
  Anti-Scl-70 (topoisomerase I)	Diffuse cutaneous systemic sclerosis - interstitial lung disease
  Anti-centromere	Limited cutaneous systemic sclerosis (CREST) - pulmonary arterial hypertension
  Anti-RNA polymerase III	Diffuse systemic sclerosis - scleroderma renal crisis, cancer association
  Anti-Jo-1 (and other anti-synthetase)	Anti-synthetase syndrome - myositis, ILD, arthritis, mechanic's hands, Raynaud's
  Anti-histone	Drug-induced lupus (also in SLE)
  Anti-ribosomal P	SLE - neuropsychiatric lupus

• ANA patterns - homogeneous (dsDNA, histone - SLE, drug-induced), speckled (ENA), centromere (limited SSc), nucleolar (systemic sclerosis), DFS70 pattern (dense fine speckled - usually not associated with systemic autoimmune disease - reassuring).

Lupus Serology - dsDNA and Complement

• Anti-double-stranded DNA (dsDNA) - specific for SLE (about 60–70% sensitive); associated with lupus nephritis; levels rise with disease activity (with falling complement).
• Complement C3 and C4 - low in active SLE (classical pathway consumption), especially nephritis and haematological disease; normalise with treatment.
• Monitoring SLE activity - dsDNA, C3, C4, FBC (cytopenias), U&E, urine dipstick and protein:creatinine ratio (nephritis), ESR (CRP usually normal unless infection or serositis).
• Classification - EULAR/ACR 2019 criteria require ANA 1:80 or more as an entry criterion, then weighted clinical (fever, cytopenias, rash, arthritis, serositis, nephritis, neuropsychiatric) and immunological domains (antiphospholipid antibodies, low complement, anti-dsDNA or anti-Sm).
• Drug-induced lupus - arthralgia, serositis, rash; anti-histone positive, dsDNA usually negative (except anti-TNF-induced), kidneys and brain spared; resolves after stopping the drug.
• Coombs-positive haemolysis, lymphopenia and thrombocytopenia are typical lupus blood findings.
• Pregnancy in SLE - check anti-Ro/La and antiphospholipid antibodies; continue hydroxychloroquine; low-dose aspirin (pre-eclampsia prevention).

Antiphospholipid Antibodies

• Antiphospholipid syndrome (APS) - thrombosis and/or pregnancy morbidity with persistent antiphospholipid antibodies.
• Tests (repeat after at least 12 weeks to confirm persistence):
  • Lupus anticoagulant (clotting-based - dilute Russell's viper venom time - affected by anticoagulants; paradoxically prolongs APTT in the lab but causes thrombosis).
  • Anticardiolipin antibodies (IgG or IgM, moderate to high titre).
  • Anti-beta-2 glycoprotein I antibodies.
  • "Triple positivity" - highest thrombotic risk.
• Clinical features:
  • Venous thrombosis (DVT, PE, unusual sites - cerebral venous sinus, Budd–Chiari) and arterial thrombosis (stroke or TIA in young people, MI).
  • Pregnancy morbidity - recurrent early miscarriage (3 or more before 10 weeks), fetal death after 10 weeks, early severe pre-eclampsia or placental insufficiency before 34 weeks.
  • Other - livedo reticularis, thrombocytopenia, heart valve thickening (Libman–Sacks), nephropathy, cognitive problems.
  • Catastrophic APS - rapid multi-organ microvascular thrombosis - anticoagulation, steroids, plasma exchange or IVIG.
• Primary APS or secondary (with SLE in about a third of cases).
• Treatment:
  • Thrombosis - long-term warfarin (INR 2–3); DOACs are not recommended in APS, especially triple-positive or arterial disease (MHRA - higher recurrence).
  • Obstetric APS - low-dose aspirin plus prophylactic LMWH in pregnancy; warfarin is teratogenic (switch to LMWH before 6 weeks).

ANCA and Anti-GBM Antibodies

• Anti-neutrophil cytoplasmic antibodies (ANCA) - tested by immunoassay for PR3 and MPO (immunofluorescence patterns c-ANCA and p-ANCA):

  ANCA	Associations
  PR3-ANCA (c-ANCA)	Granulomatosis with polyangiitis (GPA) - sinusitis, nasal crusting, saddle nose, lung nodules and cavities, glomerulonephritis
  MPO-ANCA (p-ANCA)	Microscopic polyangiitis (kidneys and lungs - alveolar haemorrhage), EGPA (asthma, eosinophilia - ANCA positive in under half), renal-limited vasculitis; drug-induced (propylthiouracil, hydralazine, cocaine/levamisole)
  Atypical p-ANCA (not MPO)	Ulcerative colitis, primary sclerosing cholangitis, autoimmune hepatitis - no vasculitis

• Request ANCA urgently in suspected rapidly progressive glomerulonephritis (rising creatinine with blood and protein on dipstick) or pulmonary–renal syndrome (haemoptysis plus AKI) - many labs offer same-day results.
• Anti-GBM antibodies - anti-GBM disease (Goodpasture's) - antibodies against type IV collagen (alpha-3 chain) in glomerular and alveolar basement membranes:
  • Rapidly progressive glomerulonephritis ± pulmonary haemorrhage (more in smokers); linear IgG on renal biopsy.
  • Double-positive (anti-GBM plus ANCA) in up to a third - behaves like anti-GBM acutely but may relapse like vasculitis.
  • Treatment - plasma exchange, steroids and cyclophosphamide - an emergency.
• ANCA vasculitis treatment - steroids plus rituximab or cyclophosphamide; avacopan (C5a receptor inhibitor) as a steroid-sparing option; plasma exchange in selected cases (see Rheumatology and Renal chapters).

⚠️ Safety Pearl: Haemoptysis with AKI, or a rising creatinine with blood and protein on the dipstick, is a renal emergency. Send ANCA and anti-GBM antibodies urgently, phone the lab and nephrology the same day - waiting days for a routine result can cost the kidneys.

Rheumatoid, Myositis and Scleroderma Antibodies

• Rheumatoid factor (IgM against IgG Fc) - positive in about 70% of RA but not specific - also Sjögren's, cryoglobulinaemia (hepatitis C), endocarditis, older age, chronic infection.
• Anti-cyclic citrullinated peptide (anti-CCP) - highly specific for RA (about 95%); predicts erosive disease; can appear years before arthritis (especially in smokers).
• Myositis-specific antibodies:

  Antibody	Association
  Jo-1, PL-7, PL-12	Anti-synthetase syndrome - ILD, myositis, arthritis, mechanic's hands, fever
  Mi-2	Classic dermatomyositis - good prognosis
  TIF1-γ	Dermatomyositis with cancer in adults - screen for malignancy
  NXP2	Dermatomyositis - calcinosis; cancer in adults
  MDA5	Amyopathic dermatomyositis with rapidly progressive ILD, skin ulcers
  SRP and HMGCR	Immune-mediated necrotising myopathy - very high CK; anti-HMGCR after statins

• Systemic sclerosis antibodies - anti-centromere (limited - PAH), anti-Scl-70 (diffuse - ILD), anti-RNA polymerase III (renal crisis, rapid skin progression, cancer), anti-PM/Scl (overlap with myositis).
• Sjögren's disease - anti-Ro and anti-La, RF, ANA; hypergammaglobulinaemia; lymphoma risk (parotid swelling, low C4, cryoglobulins).
• Seronegative spondyloarthritis - RF and anti-CCP negative; HLA-B27 associated.

Gut and Liver Autoantibodies

• Coeliac disease:
  • IgA tissue transglutaminase (tTG) - first-line test, with total IgA (IgA deficiency gives false negatives - then use IgG tTG, IgG DGP or IgG EMA).
  • IgA endomysial antibodies (EMA) - very specific - confirms weakly positive tTG.
  • The patient must be eating gluten (at least one meal a day for 6 weeks) before testing.
  • Children with tTG over 10 times the upper limit plus positive EMA on a second sample can be diagnosed without biopsy (BSPGHAN); adults usually need duodenal biopsy (a no-biopsy pathway is used in some adults - local policy).
• Pernicious anaemia - intrinsic factor antibodies (specific - about 50% sensitive) and gastric parietal cell antibodies (sensitive, not specific).
• Autoimmune hepatitis - anti-smooth muscle (anti-actin) and ANA (type 1 - adults); anti-LKM-1 (type 2 - children); anti-SLA (severe); raised IgG; interface hepatitis on biopsy.
• Primary biliary cholangitis - anti-mitochondrial antibody (AMA M2) (over 90%), raised IgM and ALP; anti-gp210 and anti-sp100 (AMA-negative PBC).
• Primary sclerosing cholangitis - atypical p-ANCA (not diagnostic); diagnosis by MRCP; associated with ulcerative colitis.
• Inflammatory bowel disease - atypical p-ANCA (UC), ASCA (Crohn's) - limited clinical use.
• Autoimmune gastritis - parietal cell antibodies; B12 and iron deficiency; gastric NET risk.

Endocrine Autoantibodies

• Thyroid:
  • Anti-thyroid peroxidase (TPO) - Hashimoto's thyroiditis (and many with Graves'); predicts progression to hypothyroidism in subclinical disease; postpartum thyroiditis risk.
  • TSH receptor antibodies (TRAb) - Graves' disease (stimulating) - diagnosis, predicting relapse after antithyroid drugs, and in pregnancy (cross the placenta - fetal and neonatal thyrotoxicosis - check in the third trimester if positive or previous Graves' treated with radioiodine or surgery).
  • Anti-thyroglobulin - interferes with thyroglobulin as a thyroid cancer marker.
• Type 1 diabetes - GAD, IA-2, ZnT8 and insulin autoantibodies - support type 1 or LADA (latent autoimmune diabetes in adults - slim adults with diabetes progressing to insulin dependence); teplizumab (anti-CD3) can delay onset in antibody-positive people (approved in the US; UK availability under review).
• Addison's disease - 21-hydroxylase (adrenal cortex) antibodies - the commonest cause of primary adrenal insufficiency in the UK.
• Hypophysitis - pituitary antibodies (limited use); immune checkpoint inhibitors cause hypophysitis (see page 6).
• Premature ovarian insufficiency - adrenal and ovarian antibodies (autoimmune cause in some).
• Autoimmune polyglandular syndromes - type 1 (APECED - candidiasis, hypoparathyroidism, Addison's) and type 2 (Addison's with thyroid disease and/or type 1 diabetes - adults, HLA-associated).

Neurological Autoantibodies

Antibody	Condition and clues
Acetylcholine receptor	Myasthenia gravis (about 85% of generalised); thymoma - CT chest
MuSK	Seronegative myasthenia - bulbar and neck weakness, poorer response to pyridostigmine; rituximab works well
Voltage-gated calcium channel (P/Q)	Lambert–Eaton myasthenic syndrome - proximal weakness improving with exercise, autonomic symptoms, absent reflexes; small cell lung cancer in about half
Aquaporin-4 (AQP4)	Neuromyelitis optica spectrum disorder - severe optic neuritis, longitudinally extensive transverse myelitis, area postrema syndrome (intractable hiccups and vomiting)
MOG	MOG antibody-associated disease - optic neuritis, ADEM (children), myelitis
NMDA receptor	Autoimmune encephalitis - young women, psychiatric symptoms, seizures, dyskinesias, autonomic instability, reduced consciousness; ovarian teratoma
LGI1 (VGKC complex)	Limbic encephalitis in older men - memory loss, faciobrachial dystonic seizures, hyponatraemia
CASPR2	Neuromyotonia, Morvan syndrome, limbic encephalitis
GAD (high titre)	Stiff person syndrome, cerebellar ataxia, epilepsy
Anti-Hu (ANNA-1)	Paraneoplastic sensory neuronopathy, encephalomyelitis - small cell lung cancer
Anti-Yo (PCA-1)	Paraneoplastic cerebellar degeneration - ovarian and breast cancer
Anti-Ri (ANNA-2)	Opsoclonus–myoclonus - breast and lung cancer
Anti-Ma2	Limbic and brainstem encephalitis - testicular germ cell tumour
Anti-ganglioside (GQ1b, GM1)	Miller Fisher syndrome (GQ1b - ophthalmoplegia, ataxia, areflexia); multifocal motor neuropathy (GM1); axonal GBS
Anti-MAG	Demyelinating neuropathy with IgM paraprotein

• Paraneoplastic antibodies - a positive result means search for cancer (CT chest, abdomen and pelvis; PET-CT; mammography; testicular or pelvic ultrasound) and repeat screening if negative.
• Autoimmune encephalitis - test serum and CSF; treat early (steroids, IVIG, plasma exchange; rituximab or cyclophosphamide); remove a tumour if found.

Kidney, Skin and Blood Autoantibodies

• Kidney:
  • Anti-phospholipase A2 receptor (PLA2R) - primary membranous nephropathy (about 70–80%) - supports diagnosis without biopsy in some, tracks activity and treatment response (rituximab).
  • Anti-THSD7A - some PLA2R-negative membranous nephropathy (cancer association).
  • ANCA and anti-GBM (above); anti-dsDNA and complement (lupus nephritis); C3 nephritic factor (C3 glomerulopathy); anti-factor H antibodies (atypical HUS).
• Skin (with skin biopsy and direct immunofluorescence):
  • Pemphigus vulgaris - anti-desmoglein 3 (and 1) - fragile flaccid blisters and mucosal erosions; Nikolsky sign positive; intraepidermal; "chicken wire" IgG on DIF.
  • Bullous pemphigoid - anti-BP180 and BP230 (hemidesmosome) - tense blisters on itchy urticarial plaques in older people; mucosa usually spared; linear IgG and C3 at the basement membrane (subepidermal); gliptins can trigger it.
  • Dermatitis herpetiformis - anti-tTG and epidermal transglutaminase - itchy vesicles on extensor surfaces - coeliac disease; dapsone and gluten-free diet.
  • Linear IgA disease, epidermolysis bullosa acquisita (anti-type VII collagen).
• Blood:
  • Direct antiglobulin (Coombs) test - warm (IgG - SLE, CLL, drugs, idiopathic) or cold (IgM, complement - Mycoplasma, EBV, lymphoma - cold agglutinin disease) autoimmune haemolytic anaemia.
  • Immune thrombocytopenia - a diagnosis of exclusion (platelet antibody tests have limited value).
  • Acquired haemophilia A - factor VIII inhibitor - sudden extensive bruising in older people or postpartum with an isolated prolonged APTT that doesn't correct on mixing.
  • Heparin-induced thrombocytopenia - anti-PF4/heparin antibodies; vaccine-induced thrombotic thrombocytopenia (VITT) - anti-PF4.
  • Acquired TTP - anti-ADAMTS13 antibodies (ADAMTS13 under 10%) - plasma exchange, caplacizumab, rituximab.

Complement-mediated Diseases

• Atypical haemolytic uraemic syndrome (aHUS) - uncontrolled alternative pathway activation (variants in factor H, factor I, CD46, C3; or anti-factor H antibodies) - microangiopathic haemolytic anaemia, thrombocytopenia and AKI without Shiga toxin E. coli; triggers - pregnancy, infection, drugs; ADAMTS13 normal (excludes TTP) - eculizumab or ravulizumab.
• C3 glomerulopathy (dense deposit disease and C3 glomerulonephritis) - low C3, C3 nephritic factor; C3-dominant staining on biopsy; iptacopan and other complement inhibitors emerging.
• Paroxysmal nocturnal haemoglobinuria - acquired PIGA variant in stem cells - loss of CD55 and CD59 - complement-mediated intravascular haemolysis (dark morning urine, raised LDH, haemosiderinuria), thrombosis in unusual sites (hepatic, mesenteric, cerebral veins), marrow failure - flow cytometry (FLAER) - C5 inhibitors (eculizumab, ravulizumab), proximal inhibitors (pegcetacoplan, iptacopan).
• Post-infectious glomerulonephritis - low C3 (normal C4) after streptococcal throat or skin infection - recovers in 6–8 weeks (persistently low C3 - think C3 glomerulopathy).
• Lupus nephritis - low C3 and C4.
• Membranoproliferative glomerulonephritis - immune complex (hepatitis C, cryoglobulins, SLE, paraproteins) or complement-mediated.
• Age-related macular degeneration - complement factor H variants (pegcetacoplan for geographic atrophy - approved in some countries).
• Myasthenia gravis and NMOSD - complement inhibitors (eculizumab, ravulizumab, zilucoplan) for refractory AChR-positive myasthenia and AQP4-positive NMOSD.
• Meningococcal risk with all complement inhibitors - vaccinate (ACWY and B) and give prophylactic antibiotics.

Cryoglobulinaemia

• Cryoglobulins - immunoglobulins that precipitate in the cold (sample must be kept at 37°C from collection to the laboratory).
• Types:
  • Type I - monoclonal (myeloma, Waldenström's, MGUS) - hyperviscosity and thrombosis (Raynaud's, digital ischaemia, livedo).
  • Types II and III (mixed) - monoclonal or polyclonal IgM rheumatoid factor bound to IgG - immune complex vasculitis - hepatitis C (most), Sjögren's, SLE, lymphoma, HIV, hepatitis B.
• Mixed cryoglobulinaemic vasculitis - palpable purpura (legs), arthralgia, weakness (Meltzer's triad), peripheral neuropathy, MPGN glomerulonephritis, leg ulcers.
• Tests - cryoglobulins (warm sample), very low C4 (with normal or low C3), positive rheumatoid factor, hepatitis C serology and RNA, protein electrophoresis.
• Treatment - treat the cause (direct-acting antivirals for hepatitis C - often curative); rituximab for vasculitis; plasma exchange for severe disease; avoid cold.

IgG4-related Disease

• A fibro-inflammatory condition - often in older men - forming tumour-like masses in one or more organs (often mistaken for cancer).
• Organs:
  • Pancreas - autoimmune pancreatitis type 1 - painless obstructive jaundice, "sausage-shaped" pancreas, diabetes.
  • Biliary tree - IgG4-related sclerosing cholangitis (mimics PSC and cholangiocarcinoma).
  • Salivary and lacrimal glands - bilateral swelling (formerly Mikulicz's disease), orbital disease.
  • Retroperitoneal fibrosis - ureteric obstruction and AKI, aortitis.
  • Kidneys (tubulointerstitial nephritis), lungs, thyroid (Riedel's thyroiditis), lymph nodes, meninges.
• Tests - raised serum IgG4 (supportive but neither sensitive nor specific), raised IgE and eosinophils, low complement in some; biopsy - dense IgG4-positive plasma cell infiltrate, storiform fibrosis, obliterative phlebitis; exclude cancer and lymphoma.
• Treatment - glucocorticoids (rapid response - e.g. prednisolone 0.6 mg/kg tapering); rituximab for relapse; inebilizumab (anti-CD19) reduces flares; biliary stenting if obstructed.

Principles of Treating Autoimmune Disease

• Induction then maintenance - control active disease quickly (often with high-dose steroids plus another agent), then maintain remission with the lowest effective treatment and taper steroids.
• Glucocorticoids - rapid and broad; side effects (infection, diabetes, osteoporosis, hypertension, weight gain, mood, cataracts, adrenal suppression) - use bone protection, PCP prophylaxis when indicated, and steroid-sparing agents; steroid emergency card for long-term use.
• Conventional immunosuppressants - methotrexate, azathioprine (check TPMT), mycophenolate (teratogenic), cyclophosphamide (infertility, bladder toxicity, infection), hydroxychloroquine (SLE backbone - annual retinal screening after 5 years), calcineurin inhibitors.
• Targeted biologics - anti-CD20 (rituximab), anti-BAFF (belimumab - SLE), anti-IFN receptor (anifrolumab - SLE), IL-6, IL-17 and TNF inhibitors, complement inhibitors, JAK inhibitors (see page 6).
• Removing antibodies:
  • Plasma exchange - rapid removal of pathogenic antibodies or complexes - anti-GBM disease, TTP, myasthenic crisis, Guillain–Barré, hyperviscosity, catastrophic APS, severe ANCA vasculitis (selected).
  • FcRn inhibitors (efgartigimod, rozanolixizumab) - increase IgG breakdown - myasthenia gravis.
• High-dose IVIG (immunomodulation, 2 g/kg over 2–5 days) - ITP, Guillain–Barré, CIDP, multifocal motor neuropathy, Kawasaki disease, myasthenic crisis, dermatomyositis, autoimmune encephalitis - NHS England commissioning criteria apply.
• Vaccination and screening before immunosuppression (see page 3); reproductive planning (teratogenic drugs - methotrexate, mycophenolate, cyclophosphamide, leflunomide).
• Shared care - specialist initiation, GP monitoring (blood tests) under agreed protocols.

Autoantibodies at a Glance

Antibody	Disease
ANA	Screen for SLE (95%) and CTDs - non-specific
dsDNA, Sm	SLE (dsDNA - nephritis and activity)
Ro, La	Sjögren's, SLE, neonatal lupus, congenital heart block
U1 RNP	Mixed connective tissue disease
Histone	Drug-induced lupus
Centromere / Scl-70 / RNA pol III	Limited SSc (PAH) / diffuse SSc (ILD) / renal crisis
Jo-1	Anti-synthetase syndrome
HMGCR	Statin-associated necrotising myopathy
Anti-CCP / RF	Rheumatoid arthritis (CCP specific)
PR3 / MPO ANCA	GPA / MPA and EGPA
Anti-GBM	Goodpasture's disease
Lupus anticoagulant, anticardiolipin, beta-2 GP1	Antiphospholipid syndrome
tTG, EMA	Coeliac disease (check total IgA)
Intrinsic factor	Pernicious anaemia
Smooth muscle / LKM-1	Autoimmune hepatitis type 1 / type 2
AMA M2	Primary biliary cholangitis
TPO / TRAb	Hashimoto's / Graves'
GAD, IA-2, ZnT8	Type 1 diabetes, LADA
21-hydroxylase	Addison's disease
AChR / MuSK / VGCC	Myasthenia gravis / MuSK myasthenia / Lambert–Eaton
AQP4 / MOG	NMOSD / MOGAD
NMDAR / LGI1	Autoimmune encephalitis (teratoma) / limbic encephalitis with hyponatraemia
Hu / Yo / Ma2	Paraneoplastic - SCLC / ovary and breast / testis
GQ1b	Miller Fisher syndrome
PLA2R	Membranous nephropathy
Desmoglein / BP180	Pemphigus / bullous pemphigoid
ADAMTS13 antibody	Acquired TTP

Spot the Diagnosis

Clue	Diagnosis
Positive ANA 1:80 in a well woman with fatigue and no other features	Likely incidental - don't chase
Arthralgia and pleurisy on hydralazine; anti-histone positive	Drug-induced lupus
Baby with complete heart block; mother has dry eyes and mouth	Neonatal lupus - maternal anti-Ro
Rising dsDNA and falling C3 and C4 with proteinuria	Lupus nephritis flare
Three early miscarriages and a lupus anticoagulant on two tests 12 weeks apart	Obstetric antiphospholipid syndrome
Young stroke, livedo reticularis and triple-positive aPL	Antiphospholipid syndrome - warfarin (not DOAC)
Haemoptysis, AKI and PR3-ANCA with nasal crusting	Granulomatosis with polyangiitis
Pulmonary haemorrhage and RPGN in a smoker; linear IgG on biopsy	Anti-GBM disease
MPO-ANCA vasculitis in a woman on propylthiouracil	Drug-induced ANCA vasculitis
ILD, myositis and cracked fingertips	Anti-synthetase syndrome (Jo-1)
Proximal weakness and CK 9,000 on atorvastatin that persists after stopping	Anti-HMGCR necrotising myopathy
Heliotrope rash, Gottron's papules and TIF1-γ antibodies in a 60-year-old	Dermatomyositis - screen for cancer
Negative tTG-IgA with low total IgA in suspected coeliac disease	Use IgG-based coeliac tests
Itch, raised ALP and IgM, AMA positive	Primary biliary cholangitis
Ptosis worse in the evening; anterior mediastinal mass	Myasthenia gravis with thymoma
Proximal weakness improving after exercise, dry mouth, heavy smoker	Lambert–Eaton syndrome - SCLC
Intractable hiccups, then longitudinal transverse myelitis	NMOSD (AQP4)
Young woman with psychosis, seizures and orofacial dyskinesias	Anti-NMDA receptor encephalitis - look for ovarian teratoma
Faciobrachial dystonic seizures and sodium 126 in a 65-year-old	LGI1 limbic encephalitis
Subacute cerebellar ataxia in a woman; anti-Yo positive	Paraneoplastic - ovarian or breast cancer
Tense blisters on itchy plaques in an 85-year-old on sitagliptin	Bullous pemphigoid
Oral erosions and flaccid blisters; Nikolsky positive	Pemphigus vulgaris
Purpura, arthralgia, neuropathy, very low C4 and hepatitis C	Mixed cryoglobulinaemic vasculitis
Dark morning urine, raised LDH and hepatic vein thrombosis	Paroxysmal nocturnal haemoglobinuria
MAHA, low platelets and AKI with normal ADAMTS13 and no diarrhoea	Atypical HUS - eculizumab
Painless jaundice, sausage-shaped pancreas and raised IgG4	Autoimmune pancreatitis (IgG4-related disease)

Exam-style Scenarios

1. A 28-year-old woman has a malar rash, painful joints and ankle swelling. Urine: blood 2+, protein 3+. ANA 1:640, dsDNA strongly positive, C3 and C4 low.
Answer: SLE with probable lupus nephritis.

• Urine protein:creatinine ratio, U&E, BP; urgent nephrology referral for renal biopsy (class guides treatment).
• Induction - steroids plus mycophenolate (or cyclophosphamide); hydroxychloroquine for all; consider belimumab or voclosporin.
• Check antiphospholipid and anti-Ro/La antibodies; contraception and pregnancy planning; bone and PCP protection.

2. A 65-year-old man has haemoptysis, fatigue and a creatinine of 380 µmol/L (normal 3 months ago). Urine dipstick: blood 3+, protein 2+.
Answer: Pulmonary–renal syndrome - ANCA vasculitis or anti-GBM disease.

• Urgent ANCA (PR3, MPO) and anti-GBM - phone the lab; urgent nephrology.
• Chest imaging; assess for alveolar haemorrhage (falling Hb, hypoxia); renal biopsy.
• Treatment - high-dose steroids plus rituximab or cyclophosphamide; plasma exchange if anti-GBM positive (and selected ANCA cases); dialysis if needed.

3. A 32-year-old woman has had a DVT and two miscarriages at 9 and 11 weeks. Lupus anticoagulant and anti-beta-2 GP1 are positive and still positive at 14 weeks.
Answer: Antiphospholipid syndrome (thrombotic and obstetric).

• Long-term warfarin (INR 2–3) - not a DOAC.
• Pre-conception planning - switch to LMWH before 6 weeks of pregnancy, plus low-dose aspirin; joint obstetric haematology care.
• Screen for SLE (ANA, dsDNA, complement).

4. A 24-year-old woman develops anxiety, hallucinations and insomnia over 2 weeks, then seizures, abnormal mouth movements and fluctuating BP. MRI is normal; CSF shows lymphocytes.
Answer: Anti-NMDA receptor encephalitis.

• Serum and CSF NMDA receptor antibodies; EEG; pelvic ultrasound or MRI for ovarian teratoma.
• Early immunotherapy - IV methylprednisolone, IVIG or plasma exchange; rituximab or cyclophosphamide if poor response.
• Remove a teratoma if found; critical care support; good recovery is possible but slow.

5. A 55-year-old man with hepatitis C has palpable purpura on his legs, joint pains, numb feet and proteinuria. C4 is very low; rheumatoid factor positive.
Answer: Mixed cryoglobulinaemic vasculitis.

• Cryoglobulins (sample kept at 37°C), HCV RNA, protein electrophoresis, renal function and urine PCR.
• Direct-acting antivirals for hepatitis C; rituximab for active vasculitis; plasma exchange if severe.
• Renal biopsy if significant kidney involvement (MPGN); monitor for lymphoma.

Key Points

• Autoimmunity = genetic susceptibility plus triggers (infection, smoking, UV, drugs, hormones, checkpoint inhibitors).
• Request autoantibodies to answer a clinical question - low-titre ANA is common in healthy people.
• ANA is sensitive for SLE; dsDNA and Sm are specific; dsDNA and complement track activity.
• Anti-Ro in pregnancy - congenital heart block; anti-histone - drug-induced lupus.
• APS - confirm antibodies at 12 weeks; warfarin, not DOACs; LMWH and aspirin in pregnancy.
• PR3-ANCA - GPA; MPO-ANCA - MPA and EGPA; anti-GBM - Goodpasture's - urgent tests and plasma exchange.
• Anti-CCP is specific for RA; RF is not.
• Myositis antibodies define phenotype and cancer risk (TIF1-γ) - anti-HMGCR after statins.
• Coeliac - tTG-IgA with total IgA, while eating gluten.
• Paraneoplastic antibodies - search for cancer (Hu - SCLC; Yo - ovary and breast; NMDAR - teratoma).
• Complement diseases - aHUS, C3G, PNH - complement inhibitors; vaccinate against meningococcus.
• Cryoglobulinaemia - hepatitis C, very low C4, warm sample.
• IgG4-related disease - tumour-like masses, raised IgG4, steroid-responsive.

Guidelines and Further Reading

• EULAR/ACR 2019 classification criteria for SLE; EULAR recommendations for SLE and lupus nephritis
• British Society for Rheumatology: Guidelines for SLE, ANCA vasculitis, systemic sclerosis and myositis
• British Society for Haematology: Guidelines on the investigation and management of antiphospholipid syndrome
• KDIGO: Glomerular diseases guideline (2021) and lupus nephritis update
• NICE NG20: Coeliac disease - recognition, assessment and management
• Association of British Neurologists: Autoimmune encephalitis and myasthenia gravis guidance
• Royal College of Pathologists / UK NEQAS: Autoantibody testing and interpretation
• BNF - for current doses