Autoimmune Diseases

Autoimmune diseases arise when immunological tolerance breaks down and the immune system attacks self-antigens. For NEET PG the single most reliable yield is autoantibody–disease matching, so this note is organised around antibody profiles, pathogenesis, and histopathology of the classic connective tissue diseases — SLE, Sjögren syndrome, systemic sclerosis, dermatomyositis/polymyositis, and mixed connective tissue disease (MCTD).

Definition and classification

Autoimmunity = immune responses against self-antigens causing tissue injury. It is distinguished from a normal protective response by persistence, self-directed targeting, and demonstrable tissue damage. Mere presence of autoantibodies (e.g. low-titre ANA in 5–15% of healthy elderly) is NOT enough; the antibody/T-cell response must cause disease.

Two broad categories:

Type	Target	Examples
Organ-specific	One organ/antigen	Hashimoto thyroiditis, Graves, type 1 DM, pernicious anaemia, myasthenia gravis, Goodpasture, pemphigus
Systemic (non-organ-specific)	Widespread (nuclear, vascular) antigens	SLE, systemic sclerosis, Sjögren, dermatomyositis, MCTD, RA

High-yield: SLE is the prototype systemic autoimmune disease and the prototype type III (immune-complex) hypersensitivity disorder. Hashimoto and type 1 DM are prototype organ-specific autoimmune diseases.

Etiology and pathophysiology

Loss of self-tolerance is central. Mechanisms tested:

1. Failure of central tolerance — defective negative selection (e.g. AIRE gene mutation → APECED/autoimmune polyendocrinopathy).
2. Failure of peripheral tolerance — defective regulatory T cells (FOXP3 mutation → IPEX syndrome), failed anergy, defective Fas–FasL apoptosis (ALPS).
3. Molecular mimicry — microbial antigens resembling self (rheumatic fever, GBS).
4. Defective clearance of apoptotic debris — exposes nuclear antigens; central to SLE. Deficiency of early complement (C1q, C2, C4) impairs clearance and is the strongest inherited risk for SLE.
5. Genetic susceptibility — HLA associations and non-HLA genes.

High-yield: Strongest genetic SLE risk = homozygous C1q deficiency (>90% develop SLE). Most common complement abnormality clinically = C2/C4 deficiency.

Tolerance breakdown → autoantibody/autoreactive T cell generation → tissue injury via:

• Type II (cytotoxic): autoimmune haemolytic anaemia, Goodpasture, pemphigus, myasthenia.
• Type III (immune complex): SLE, post-streptococcal GN.
• Type IV (T cell): type 1 DM, Hashimoto, RA synovitis.

HLA associations (recurring MCQ)

Disease	HLA
Ankylosing spondylitis, reactive arthritis	HLA-B27
Rheumatoid arthritis	HLA-DR4 (DRB1)
SLE	HLA-DR2, DR3
Type 1 DM	HLA-DR3/DR4
Coeliac disease	HLA-DQ2/DQ8
Sjögren	HLA-DR3
Behçet	HLA-B51
Narcolepsy	HLA-DR2
Goodpasture	HLA-DR15

Autoantibody profiles — the core table

High-yield: This table is the single most rewarding thing to memorise for the topic.

Autoantibody	Disease association	Notes / specificity
ANA	SLE (sensitive, ~95%), many CTDs	Best screening test; not specific
Anti-dsDNA	SLE	Specific; correlates with lupus nephritis & activity
Anti-Smith (anti-Sm)	SLE	Most specific for SLE; not for monitoring
Anti-histone	Drug-induced lupus	Procainamide, hydralazine, isoniazid
Anti-Ro (SSA) / Anti-La (SSB)	Sjögren, SCLE, neonatal lupus	Anti-Ro → congenital heart block, ANA-negative SLE
Anti-U1 RNP	MCTD (high titre, defining)	Also in SLE
Anti-centromere	Limited SSc (CREST)	Better prognosis
Anti-Scl-70 (anti-topoisomerase I)	Diffuse SSc	Lung fibrosis risk
Anti-RNA polymerase III	Diffuse SSc	Renal crisis & malignancy risk
Anti-Jo-1 (anti-histidyl tRNA synthetase)	Polymyositis / antisynthetase syndrome	ILD, mechanic's hands
Anti-Mi-2	Dermatomyositis	Good prognosis, skin
Anti-TIF1-γ / anti-NXP2	Dermatomyositis	Malignancy association (adult)
Anti-MDA5	Amyopathic DM	Rapidly progressive ILD
Anti-CCP, RF	Rheumatoid arthritis	Anti-CCP most specific
Anti-mitochondrial (AMA)	Primary biliary cholangitis	M2 subtype
Anti-smooth muscle	Autoimmune hepatitis type 1

Mnemonic for SSc antibodies: "Centromere = CREST (limited); Scl-70 = Skin diffuse + Scarring lung."

Systemic Lupus Erythematosus (SLE)

A multisystem type III disease, classically young woman of reproductive age (F:M ~9:1), more severe in Afro-Caribbean and Asian populations.

Clinical features

• Constitutional: fatigue, fever, weight loss.
• Malar (butterfly) rash sparing nasolabial folds; photosensitivity; discoid rash; oral ulcers (painless).
• Non-erosive arthritis (Jaccoud arthropathy = reducible deformity).
• Serositis — pleuritis, pericarditis.
• Renal — lupus nephritis (ISN/RPS class IV = diffuse proliferative, worst).
• Neuropsychiatric — seizures, psychosis.
• Haematological — haemolytic anaemia, leucopenia, lymphopenia, thrombocytopenia.
• Libman–Sacks endocarditis — sterile, non-bacterial verrucous vegetations on both surfaces of valves (mitral).

Diagnosis

• ANA = screening (high sensitivity); anti-dsDNA & anti-Sm confirm.
• Low C3/C4 during flares (consumed by immune complexes).
• 2019 EULAR/ACR criteria: entry criterion = ANA ≥1:80, then weighted clinical/immunological domains, score ≥10 classifies.
• Renal biopsy guides nephritis class.

High-yield: Falling complement (C3/C4) + rising anti-dsDNA = active disease / impending flare. Anti-Sm and anti-dsDNA are specific; anti-dsDNA tracks nephritis.

Drug-induced lupus

• Drugs: procainamide (highest), hydralazine, isoniazid, minocycline, anti-TNF, quinidine.
• Anti-histone antibodies positive; anti-dsDNA usually negative; renal & CNS spared; resolves on stopping drug.

Mnemonic (SLE criteria — "SOAP BRAIN MD"): Serositis, Oral ulcers, Arthritis, Photosensitivity, Blood disorders, Renal, ANA, Immunologic (dsDNA/Sm/APLA), Neurologic, Malar rash, Discoid rash.

Antiphospholipid syndrome (APLA)

• Antibodies: lupus anticoagulant, anti-cardiolipin, anti-β2-glycoprotein I.
• Features: recurrent arterial/venous thrombosis, recurrent miscarriage, thrombocytopenia.
• Paradox: prolonged aPTT in vitro but thrombosis in vivo; false-positive VDRL.

Sjögren syndrome

Lymphocytic destruction of exocrine (lacrimal & salivary) glands → "sicca complex."

• Primary (alone) or secondary (with RA, SLE).
• Features: dry eyes (keratoconjunctivitis sicca), dry mouth (xerostomia), parotid enlargement, dental caries.
• Antibodies: anti-Ro (SSA) and anti-La (SSB); RF often positive.
• Diagnosis: Schirmer test (↓tear wetting <5 mm/5 min), rose-bengal staining, labial minor salivary gland biopsy = focal lymphocytic sialadenitis (focus score ≥1 = ≥50 lymphocytes/4 mm²).
• Complication: ~40× increased risk of MALT (marginal zone) B-cell lymphoma of parotid — suspect if persistent unilateral glandular swelling.

High-yield: Sjögren → anti-Ro/La, biopsy shows focal lymphocytic infiltrate, dreaded complication = MALT lymphoma.

Systemic sclerosis (scleroderma)

Excess collagen deposition / fibrosis of skin and internal organs with obliterative vasculopathy. Pathogenesis: endothelial injury → fibroblast activation (TGF-β, PDGF) → fibrosis.

Feature	Limited (CREST)	Diffuse
Skin	Distal to elbows/knees + face	Proximal + trunk
Antibody	Anti-centromere	Anti-Scl-70, anti-RNA pol III
Pulmonary	Pulmonary arterial hypertension (late)	Interstitial lung disease
Renal	Rare	Scleroderma renal crisis
Onset/progression	Slow, better prognosis	Rapid, worse

CREST = Calcinosis, Raynaud, Esophageal dysmotility, Sclerodactyly, Telangiectasia.

• Raynaud phenomenon is often the first manifestation.
• Scleroderma renal crisis: malignant hypertension + acute kidney injury; ACE inhibitors are drug of choice (life-saving). Risk ↑ with anti-RNA pol III and high-dose steroids.
• Most common cause of death = pulmonary (ILD/PAH).

High-yield: Anti-centromere → limited/CREST (PAH); anti-Scl-70 → diffuse (ILD); ACE inhibitor for renal crisis; avoid high-dose steroids (precipitate crisis).

Dermatomyositis and polymyositis

Inflammatory myopathies with symmetrical proximal muscle weakness (difficulty climbing stairs, combing hair).

Feature	Dermatomyositis	Polymyositis
Skin signs	Heliotrope rash, Gottron papules, shawl sign	Absent
Mechanism	Humoral, perimysial, perifascicular atrophy, CD4/B around vessels	Cell-mediated, endomysial CD8+ invading non-necrotic fibres
Vessels	Complement (MAC) on capillaries	—
Malignancy	Strong (esp. anti-TIF1-γ)	Weaker
Antibody	Anti-Mi-2, anti-Jo-1, anti-MDA5	Anti-Jo-1

• Investigations: ↑CK (most useful enzyme), EMG (myopathic), muscle biopsy = confirmatory, MRI to localise.
• Gottron papules (scaly violaceous over MCP/PIP) and heliotrope rash (periorbital violaceous) are pathognomonic of DM.
• Antisynthetase syndrome (anti-Jo-1): myositis + ILD + mechanic's hands + Raynaud + arthritis.
• Management: corticosteroids first line; add methotrexate/azathioprine/IVIG. Screen for occult malignancy in adult DM (ovary, lung, GI, breast, nasopharynx).

High-yield: Perifascicular atrophy = dermatomyositis; endomysial CD8+ infiltrate = polymyositis. Adult DM mandates malignancy screen.

Mixed connective tissue disease (MCTD)

An overlap of SLE + systemic sclerosis + polymyositis features.

• Defining antibody: high-titre anti-U1 RNP (anti-Sm typically absent).
• Features: Raynaud, swollen "puffy" hands/sausage fingers, arthralgia, myositis, oesophageal dysmotility; renal disease is characteristically uncommon/mild.
• Pulmonary hypertension is the leading cause of death.
• Generally steroid-responsive.

High-yield: Puffy hands + Raynaud + high-titre anti-U1 RNP + renal sparing = MCTD.

Diagnostic approach — stepwise flow

Suspect CTD → ANA by immunofluorescence (screen) → if positive, characterise ANA pattern → order specific antibodies (ENA panel: dsDNA, Sm, Ro, La, RNP, Scl-70, Jo-1, centromere) → complement (C3/C4) + organ workup (renal biopsy, PFTs/HRCT, CK, salivary biopsy) → classify disease & assess activity.

ANA immunofluorescence patterns

Pattern	Antibody / association
Homogeneous (diffuse)	Anti-dsDNA, anti-histone (SLE, drug-induced)
Rim/peripheral	Anti-dsDNA (most specific for SLE)
Speckled	Sm, RNP, Ro, La (SLE, MCTD, Sjögren)
Nucleolar	Scl-70 (systemic sclerosis)
Centromere	Limited SSc (CREST)

Management / drug of choice (quick reference)

• SLE: hydroxychloroquine (backbone for all), steroids for flares; mycophenolate or cyclophosphamide for proliferative lupus nephritis; belimumab/anifrolumab as add-ons.
• Lupus nephritis class IV: induction with mycophenolate mofetil or IV cyclophosphamide + steroids.
• Scleroderma renal crisis: ACE inhibitor (captopril).
• Raynaud: calcium channel blockers (nifedipine).
• Sjögren: artificial tears, pilocarpine/cevimeline (secretagogues).
• Myositis: corticosteroids → steroid-sparing immunosuppressants/IVIG.
• APLA syndrome: lifelong warfarin after thrombosis; LMWH + aspirin in pregnancy.

Complications

• SLE: lupus nephritis (leading cause of morbidity), accelerated atherosclerosis (leading cause of late death), infection (immunosuppression), APLA thrombosis, neonatal lupus/congenital heart block (anti-Ro).
• Sjögren: MALT lymphoma, dental caries, corneal ulceration.
• Systemic sclerosis: renal crisis, ILD/PAH, GI malabsorption, watermelon stomach (GAVE).
• DM/PM: aspiration (pharyngeal weakness), respiratory failure, underlying malignancy, ILD.

Key differentials

• Malar rash: SLE vs rosacea (involves nasolabial folds) vs dermatomyositis (involves them too, more violaceous).
• Raynaud: primary (benign) vs secondary (SSc, MCTD, SLE).
• Proximal weakness: inflammatory myopathy vs inclusion body myositis (older men, distal + proximal, finger flexors, poor steroid response, rimmed vacuoles) vs statin myopathy vs hypothyroid myopathy.
• Dry eyes/mouth: Sjögren vs sarcoidosis vs IgG4-related disease vs anticholinergic drugs.
• Drug-induced lupus vs idiopathic SLE (anti-histone vs anti-dsDNA; organ sparing).

Recently asked / exam angle

• Antibody → disease single-best-answer is the dominant format: anti-Sm (specific SLE), anti-dsDNA (nephritis/activity), anti-histone (drug-induced), anti-Scl-70 vs anti-centromere (diffuse vs limited SSc), anti-Jo-1 (antisynthetase/ILD), anti-U1 RNP (MCTD), anti-Ro (neonatal lupus/heart block).
• "Most specific ANA pattern for SLE" → peripheral/rim.
• "Drug of choice in scleroderma renal crisis" → ACE inhibitor.
• Image-based: Gottron papules / heliotrope rash → dermatomyositis; malar rash → SLE.
• Histology: perifascicular atrophy (DM) vs endomysial CD8 (PM); Libman–Sacks vegetations on both valve surfaces; focal lymphocytic sialadenitis (Sjögren).
• Complement: low C3/C4 in active lupus; C1q deficiency strongest genetic risk.
• Sjögren complication → MALT lymphoma.
• Adult dermatomyositis → screen for malignancy.

Rapid revision

1. ANA = best screening test for SLE; anti-dsDNA & anti-Sm = most specific.
2. Anti-dsDNA + low C3/C4 = active lupus nephritis.
3. Anti-histone = drug-induced lupus (procainamide > hydralazine > INH).
4. Anti-centromere → limited SSc/CREST (PAH); anti-Scl-70 → diffuse SSc (ILD).
5. ACE inhibitor is life-saving in scleroderma renal crisis; avoid high-dose steroids.
6. Anti-Jo-1 = antisynthetase syndrome (myositis + ILD + mechanic's hands).
7. Anti-U1 RNP (high titre) = MCTD; puffy hands, renal sparing.
8. Anti-Ro/La → Sjögren, SCLE, neonatal lupus & congenital heart block.
9. Sjögren biopsy = focal lymphocytic sialadenitis; complication = MALT lymphoma.
10. Perifascicular atrophy = dermatomyositis; endomysial CD8 = polymyositis.
11. C1q deficiency = strongest inherited SLE risk; defective apoptotic debris clearance.
12. Libman–Sacks = sterile verrucous endocarditis on both surfaces of the mitral valve in SLE.