Autoimmunity
Autoimmune diseases result from loss of immunological self-tolerance, leading to immune-mediated attack on self-antigens. They can be organ-specific or systemic.
Key Facts
Autoimmune diseases affect approximately 5-8% of the UK population, with a female predominance (3:1 ratio overall) HLA associations are the strongest genetic risk factors: HLA-B27 (ankylosing spondylitis), HLA-DR4 (rheumatoid arthritis), HLA-DQ2/DQ8 (coeliac disease) Molecular mimicry — immune response to pathogen cross-reacts with self-antigens (e.g., rheumatic fever, Guillain-Barré) Central tolerance (thymic deletion of self-reactive T cells) and peripheral tolerance (Tregs, anergy, deletion) prevent autoimmunity ANA is positive in >95% of SLE but is non-specific; anti-dsDNA and anti-Sm are more specific for SLE ANCA: c-ANCA/anti-PR3 (granulomatosis with polyangiitis), p-ANCA/anti-MPO (microscopic polyangiitis, EGPA) Autoimmune diseases frequently cluster — patients with one autoimmune condition are at increased risk of developing others Immune checkpoint inhibitors can trigger de novo autoimmune disease (immune-related adverse events)
Overview
Key Facts
Autoimmune diseases arise when the immune system mounts a response against self-antigens. They are classified as organ-specific (targeting a single organ) or systemic (affecting multiple organs).
Epidemiology
- Prevalence: ~5-8% of the UK population
- Female:male ratio varies: SLE 9:1, RA 3:1, ankylosing spondylitis 3:1 male predominance
- Peak onset varies: Type 1 diabetes (childhood/adolescence), RA (30-50 years), SLE (15-45 years)
- Autoimmune diseases are the third most common disease category after cardiovascular disease and cancer
Aetiology
Multifactorial — genetic susceptibility + environmental triggers:
- Genetic: HLA associations, AIRE gene (APECED syndrome), FoxP3 (IPEX syndrome), CTLA-4, PTPN22
- Environmental: Infections (molecular mimicry), smoking (RA, Graves'), UV light (SLE), drugs (drug-induced lupus), gut microbiome dysbiosis
- Hormonal: Oestrogen promotes immune activation — explaining female predominance
Pathophysiology
Mechanisms of tolerance breakdown:
- Molecular mimicry: Pathogen antigens share epitopes with self-antigens
- Bystander activation: Tissue damage releases sequestered self-antigens
- Epitope spreading: Immune response extends from initial epitope to other self-antigens
- Failure of regulatory mechanisms: Treg dysfunction, defective apoptosis (Fas/FasL)
- Superantigen-mediated: Non-specific T cell activation
Clinical Presentation
Organ-Specific Autoimmune Diseases
- Hashimoto's thyroiditis: Hypothyroidism, goitre, anti-TPO antibodies
- Graves' disease: Thyrotoxicosis, ophthalmopathy, TSH receptor antibodies
- Type 1 diabetes: Hyperglycaemia, anti-GAD/anti-IA2 antibodies
- Pernicious anaemia: Megaloblastic anaemia, anti-intrinsic factor antibodies
- Myasthenia gravis: Fatigable weakness, anti-AChR antibodies
- Autoimmune hepatitis: Chronic hepatitis, anti-smooth muscle/anti-LKM antibodies
Systemic Autoimmune Diseases
- SLE: Butterfly rash, arthritis, serositis, renal disease, cytopenias
- Rheumatoid arthritis: Symmetrical polyarthritis, morning stiffness
- Systemic sclerosis: Raynaud's, skin thickening, pulmonary fibrosis
- Sjögren's syndrome: Dry eyes, dry mouth, parotid enlargement
Red Flags
- Multi-system disease with constitutional symptoms
- Renal involvement (proteinuria, haematuria, rising creatinine)
- Pulmonary haemorrhage (Goodpasture's, ANCA vasculitis)
- Rapidly progressive neurological deficit
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| SLE | Multi-system, butterfly rash, photosensitivity | ANA, anti-dsDNA, complement (C3/C4 low) |
| Rheumatoid arthritis | Symmetrical small joint arthritis, morning stiffness >30 min | RF, anti-CCP, X-rays hands/feet |
| Vasculitis | Purpura, organ ischaemia, constitutional symptoms | ANCA, biopsy |
| Infection | Fever, localised signs, acute onset | Blood cultures, CRP, imaging |
| Malignancy | Weight loss, lymphadenopathy, night sweats | CT, biopsy, LDH |
| Fibromyalgia | Widespread pain, fatigue, normal investigations | Clinical diagnosis, exclude autoimmune |
Diagnosis / Investigation
Bedside
- Urinalysis: Proteinuria, haematuria (renal involvement)
- Blood pressure: Hypertension in renal disease
Bloods
- Autoantibodies:
- ANA (screening), anti-dsDNA (SLE activity), anti-Sm (SLE specific)
- RF, anti-CCP (RA)
- ANCA (vasculitis)
- Anti-TPO (Hashimoto's), TSH receptor Ab (Graves')
- Anti-GBM (Goodpasture's)
- Anti-centromere (limited systemic sclerosis), anti-Scl-70 (diffuse systemic sclerosis)
- Complement: C3, C4 (low in active SLE, Type II/III hypersensitivity)
- ESR and CRP: Inflammatory markers (ESR often raised more than CRP in SLE)
- Immunoglobulins: Polyclonal elevation common in autoimmune disease
Imaging
- X-rays: Joint erosions (RA), sacroiliac joint changes (AS)
- USS/CT/MRI: Organ-specific assessment
- HRCT chest: Pulmonary fibrosis (systemic sclerosis), alveolar haemorrhage
Special Tests
- Biopsy: Renal (lupus nephritis classification), skin, salivary gland (Sjögren's)
- Schirmer's test: Dry eye assessment (Sjögren's)
- HLA typing: HLA-B27 (spondyloarthropathy), HLA-DQ2/DQ8 (coeliac disease)
- Nerve conduction studies: Myasthenia gravis, GBS
Management
Non-pharmacological
- Patient education and self-management support
- Sun protection (SLE)
- Smoking cessation (particularly important in RA)
- Exercise and physiotherapy
- Psychological support
Pharmacological
General principles:
- Mild disease: NSAIDs, hydroxychloroquine
- Moderate disease: Conventional DMARDs (methotrexate 7.5-25mg weekly, azathioprine 1-3mg/kg/day, mycophenolate 1-3g/day)
- Severe/refractory disease: Biological DMARDs (rituximab, belimumab, TNF inhibitors), cyclophosphamide
- Acute flares: Corticosteroids (prednisolone 0.5-1mg/kg/day) — taper to lowest effective dose
Specific therapies:
- SLE: Hydroxychloroquine (all patients), mycophenolate for nephritis (ALMS trial)
- RA: Methotrexate first-line DMARD; biologics (anti-TNF, rituximab, JAK inhibitors) for inadequate response
- ANCA vasculitis: Cyclophosphamide + corticosteroids for induction; azathioprine/rituximab for maintenance (RAVE, RITUXVAS trials)
Referral Criteria
- Suspected autoimmune disease → rheumatology or relevant specialist
- Multi-system disease → urgent assessment
- Renal involvement → nephrology
- Pregnancy planning in autoimmune disease → specialist pre-conception counselling
Prognosis
- SLE: 10-year survival >90%; lupus nephritis is the main cause of morbidity and mortality
- RA: Life expectancy reduced by 3-10 years; early DMARD therapy improves outcomes
- Type 1 diabetes: Lifelong insulin dependence; complications relate to glycaemic control
- Systemic sclerosis: 5-year survival 80-85%; diffuse cutaneous form has worse prognosis
- ANCA vasculitis: 5-year survival ~75-80% with treatment; relapse rate 50% over 5 years
- Cardiovascular disease is a major cause of mortality across all autoimmune conditions
Other Relevant Information
Key Autoantibody Associations
| Antibody | Condition | Specificity |
|---|---|---|
| Anti-dsDNA | SLE | High — correlates with disease activity |
| Anti-Sm | SLE | Very high specificity |
| Anti-CCP | Rheumatoid arthritis | >95% specific |
| Anti-TPO | Hashimoto's thyroiditis | Present in >90% |
| Anti-GBM | Goodpasture's syndrome | Diagnostic |
| c-ANCA (anti-PR3) | GPA (Wegener's) | ~90% in active disease |
| p-ANCA (anti-MPO) | MPA, EGPA | ~70% in MPA |
| Anti-centromere | Limited systemic sclerosis (CREST) | Highly specific |
| Anti-Scl-70 (anti-topoisomerase I) | Diffuse systemic sclerosis | Indicates pulmonary fibrosis risk |
HLA Associations
| HLA Type | Condition |
|---|---|
| HLA-B27 | Ankylosing spondylitis (>90%), reactive arthritis, anterior uveitis |
| HLA-DR4 | Rheumatoid arthritis, Type 1 diabetes |
| HLA-DQ2/DQ8 | Coeliac disease (>99% have DQ2 or DQ8) |
| HLA-DR3 | SLE, Graves', Type 1 diabetes, Sjögren's |
| HLA-B51 | Behçet's disease |