Autoimmune diseases are a diverse group of disorders characterized by loss of self-tolerance, leading to immune-mediated attack on healthy tissues. They affect approximately 5-10% of the global population, with a strong female predominance (78% of cases). This article covers common mechanisms, major autoimmune diseases, diagnostic approaches, and treatment principles.
Common Mechanisms of Autoimmunity
Key Concepts in Autoimmune Pathogenesis
| Concept | Description | Examples |
|---|---|---|
| Loss of central tolerance | Failure to eliminate self-reactive T and B cells during development in thymus and bone marrow | AIRE deficiency, APECED |
| Loss of peripheral tolerance | Failure to control self-reactive lymphocytes that escape central selection | FOXP3 mutation, IPEX syndrome |
| Molecular mimicry | Immune response to a pathogen cross-reacts with self-antigens | Rheumatic fever, Guillain-Barre |
| Epitope spreading | Initial immune response spreads to other self-epitopes | RA Citrullination spread |
| Bystander activation | Local inflammation activates self-reactive lymphocytes non-specifically | Post-infectious autoimmune flares |
| Cryptic antigens | Normally hidden self-antigens exposed after tissue damage | Post-traumatic sympathetic ophthalmia |
Autoimmune Disease Groups
| Category | Description | Examples |
|---|---|---|
| Organ-specific | Autoimmunity against a single organ | Type 1 diabetes, Hashimoto, Graves, Addison, myasthenia gravis |
| Systemic | Multiple organs involved | SLE, RA, Sjogren, scleroderma, dermatomyositis, vasculitis |
| Intermediate | Organ-specific with systemic features | IBD, MS, primary sclerosing cholangitis |
Common Autoantibodies
| Autoantibody | Associated Diseases | Sensitivity | Specificity |
|---|---|---|---|
| ANA | SLE, other CTDs | 95% (SLE) | Low |
| Anti-dsDNA | SLE (active nephritis) | 60-80% | >95% |
| Anti-Smith | SLE | 20-30% | >95% |
| Anti-Ro/SSA | Sjogren, SLE (SCLE, neonatal lupus) | 60-70% (Sjogren) | Moderate |
| Anti-La/SSB | Sjogren, SLE | 40-50% (Sjogren) | High |
| Anti-Scl-70 | Systemic sclerosis (diffuse) | 20-30% | >95% |
| Anti-centromere | Limited systemic sclerosis (CREST) | 50-70% | >95% |
| c-ANCA (PR3) | Granulomatosis with polyangiitis | 80-90% | >95% |
| p-ANCA (MPO) | Microscopic polyangiitis | 70-80% | >95% |
| Anti-CCP | Rheumatoid arthritis | 70-80% | 95-98% |
| RF | RA, other CTD, infections | 60-80% (RA) | Low |
| Anti-TPO | Hashimoto (90%), Graves (70%) | >90% | Moderate |
| Anti-thyroglobulin | Hashimoto | 60-80% | Moderate |
Systemic Lupus Erythematosus (SLE)
See Musculoskeletal Disorders article for detailed SLE coverage.
Key Points
- Prototypic systemic autoimmune disease with multi-organ involvement
- F:M ratio 9:1; peak age 15-45
- Loss of tolerance to nuclear antigens (ANA positive in >95%)
- Clinical: malar rash, discoid rash, photosensitivity, arthritis, serositis, nephritis, neuropsychiatric, hematologic
- Treatment: HCQ (all patients), corticosteroids, MMF, cyclophosphamide, azathioprine, belimumab, anifrolumab
Rheumatoid Arthritis (RA)
See Musculoskeletal Disorders article for detailed RA coverage.
Multiple Sclerosis (MS)
See Neurological Disorders article for detailed MS coverage.
Type 1 Diabetes (T1DM)
See Endocrine Disorders article for detailed T1DM coverage.
Hashimoto Thyroiditis
| Parameter | Detail |
|---|---|
| Definition | Chronic autoimmune thyroiditis, most common cause of hypothyroidism in iodine-sufficient areas |
| Prevalence | 5-10% of population; F:M 5-10:1 |
| Pathophysiology | CD4+ and CD8+ T-cell infiltration, Th1 response, gradual destruction of thyroid follicles; autoantibodies to TPO and thyroglobulin |
| Clinical | Goiter (firm, rubbery), hypothyroidism symptoms (fatigue, weight gain, cold intolerance, constipation, dry skin, hair loss, depression) |
| Diagnosis | Elevated TSH, low free T4, positive anti-TPO (>95%) and/or anti-thyroglobulin; ultrasound with diffuse hypoechogenicity |
| Treatment | Levothyroxine lifelong; monitor TSH |
Graves Disease
| Parameter | Detail |
|---|---|
| Definition | Autoimmune hyperthyroidism caused by stimulatory TSH receptor autoantibodies (TSI) |
| Prevalence | 1% of population; F:M 5-10:1 |
| Pathophysiology | TSI binds to TSH receptor, constitutive activation, increased T4/T3 production; stimulates orbital fibroblasts causing ophthalmopathy |
| Clinical | Tachycardia, weight loss, heat intolerance, tremor, anxiety, goiter (diffuse, bruit), ophthalmopathy (proptosis, lid retraction), dermopathy (pretibial myxedema) |
| Diagnosis | Low TSH, high free T4/T3, positive TSI; RAI uptake diffusely increased |
| Treatment | Methimazole (first-line), RAI-131, thyroidectomy; beta-blockers for symptom control |
Sjogren Syndrome
| Parameter | Detail |
|---|---|
| Definition | Chronic autoimmune disorder with lymphocytic infiltration of exocrine glands (sicca syndrome) |
| Prevalence | 0.1-0.5%; F:M 9:1; peak age 40-60 |
| Pathophysiology | Autoimmune attack on salivary and lacrimal glands and systemic involvement |
| Sicca symptoms | Xerophthalmia (dry eyes), xerostomia (dry mouth), parotid enlargement |
| Systemic | Arthralgias, ILD, interstitial nephritis (RTA), peripheral neuropathy, purpura, Raynaud |
| Lymphoma risk | 5-10x increased NHL risk (MALT, DLBCL) |
| Diagnosis | Anti-Ro/SSA antibodies, labial gland biopsy with focus score >=1, ocular staining, Schirmer test |
| Treatment | Artificial tears, pilocarpine/cevimeline for sicca; HCQ, immunosuppression for systemic; rituximab for severe/lymphoma |
Systemic Sclerosis (Scleroderma)
| Parameter | Detail |
|---|---|
| Definition | Chronic autoimmune disease with fibrosis of skin and internal organs, vasculopathy, immune dysregulation |
| Prevalence | 1-3 per 10,000; F:M 3-6:1; peak age 30-60 |
| Subtypes | Limited (lcSSc, distal skin, CREST) vs Diffuse (dcSSc, proximal/truncal skin, more internal organ involvement) |
Scleroderma Subtypes
| Feature | Limited (lcSSc/CREST) | Diffuse (dcSSc) |
|---|---|---|
| Skin distribution | Distal to elbows/knees, face | Proximal to elbows/knees, trunk |
| Calcinosis | Common | Less common |
| Raynaud phenomenon | Nearly universal | Nearly universal |
| Pulmonary fibrosis | Less common | More common |
| Pulmonary hypertension | Late, more common | Can occur |
| Renal crisis | Rare | 15-20% (early) |
| Anti-centromere | 50-70% | <5% |
| Anti-Scl-70 | <10% | 20-30% |
Scleroderma Organ Involvement and Treatment
| Organ | Manifestation | Treatment |
|---|---|---|
| Skin | Fibrosis, thickening, sclerodactyly, digital ulcers | Mycophenolate mofetil, methotrexate, cyclophosphamide; bosentan/iloprost for digital ulcers |
| Raynaud phenomenon | Severe vasospasm, digital ischemia | CCB (nifedipine, amlodipine), PDE5 inhibitors (sildenafil), prostacyclin analogs (iloprost) |
| Pulmonary fibrosis | ILD (most common cause of death in dcSSc) | Cyclophosphamide or mycophenolate mofetil; nintedanib (antifibrotic) |
| Pulmonary hypertension | PAH (most common cause of death in lcSSc) | Bosentan (endothelin receptor antagonist), sildenafil/tadalafil (PDE5i), riociguat, prostacyclin analogs (epoprostenol, treprostinil) |
| GI | Esophageal dysmotility, GERD, dysphagia, pseudo-obstruction, malabsorption, SIBO | PPI, prokinetics (metoclopramide, domperidone), rotating antibiotics for SIBO, nutritional support |
| Renal | Scleroderma renal crisis (sudden severe HTN, AKI, microangiopathy) | ACE inhibitors (first-line, high-dose captopril), dialysis if needed |
| Cardiac | Myocardial fibrosis, diastolic dysfunction, arrhythmias, pericarditis | Management of risk factors, antiarrhythmics, diuretics |
| Calcinosis | Painful calcium deposits in skin | Surgical excision (if symptomatic), minocycline, colchicine |
| Telangiectasias | Dilated superficial capillaries | Laser therapy (if bleeding or cosmetic) |
Vasculitis
Classification by Vessel Size
| Vessel Size | Disease | ANCA | Key Features | Treatment |
|---|---|---|---|---|
| Large vessel | Giant cell arteritis (GCA) | No | Age >50, headache, scalp tenderness, jaw claudication, visual loss; PMR overlap | High-dose corticosteroids (prednisone); tocilizumab |
| Large vessel | Takayasu arteritis | No | Age <40, pulseless, claudication, aortic arch involvement (PANDA) | Corticosteroids, methotrexate, tocilizumab, TNFi |
| Medium vessel | Polyarteritis nodosa (PAN) | No (rarely p-ANCA) | Mononeuritis multiplex, livedo reticularis, renal (ANEURYSMS, not GN), testicular pain, myalgias | Corticosteroids, cyclophosphamide (if severe) |
| Medium vessel | Kawasaki disease | No | Children, fever >5 days, conjunctivitis, rash, strawberry tongue, cervical lymphadenopathy, coronary aneurysms | IVIG + aspirin |
| Small vessel | Granulomatosis with polyangiitis (GPA, Wegener) | c-ANCA (PR3) 90% | Necrotizing granulomatous inflammation: upper/lower respiratory tract (nodules, cavitary lesions, sinusitis, saddle nose), GN, mononeuritis | Corticosteroids + rituximab or cyclophosphamide |
| Small vessel | Microscopic polyangiitis (MPA) | p-ANCA (MPO) 75% | Pauci-immune GN, pulmonary capillaritis (DAH), mononeuritis multiplex | Corticosteroids + rituximab or cyclophosphamide |
| Small vessel | Eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss) | p-ANCA (MPO) 40-50% | Asthma, eosinophilia, sinusitis, pulmonary infiltrates, neuropathy, GN, cardiac involvement | Corticosteroids, mepolizumab (anti-IL5), cyclophosphamide if severe |
| Small vessel | IgA vasculitis (Henoch-Schonlein purpura) | No | Palpable purpura (lower extremities), arthritis, abdominal pain, GN (IgA deposits) | Supportive (self-limited in children); corticosteroids for severe |
| Small vessel | Anti-GBM disease (Goodpasture) | Anti-GBM antibodies | Linear IgG along GBM; RPGN + pulmonary hemorrhage | Plasmapheresis + corticosteroids + cyclophosphamide |
| Small vessel | Cryoglobulinemic vasculitis | Mixed cryoglobulins (type II: IgM RF + HCV) | Palpable purpura, arthritis, neuropathy, GN (membranoproliferative) | Treat HCV (DAAs), rituximab, corticosteroids, plasmapheresis |
Sarcoidosis
| Parameter | Detail |
|---|---|
| Definition | Multi-system granulomatous disorder of unknown cause characterized by non-caseating granulomas |
| Prevalence | 10-40 per 100,000; more common in African Americans (3-4x), Scandinavians; F:M ~2:1 |
| Peak age | 20-40 years |
| Pathophysiology | Unknown trigger (antigen) -> CD4+ Th1 immune response -> macrophage activation -> non-caseating granuloma formation -> fibrosis (chronic) |
Sarcoidosis Organ Involvement
| Organ | Frequency | Manifestations | Treatment |
|---|---|---|---|
| Pulmonary | >90% | Bilateral hilar lymphadenopathy (BHL, stage I), interstitial infiltrates (stage II), fibrosis (stage IV); cough, dyspnea | Observation (stage I often resolves); corticosteroids (first-line), methotrexate, azathioprine, mycophenolate, TNF inhibitors (infliximab) |
| Lymph nodes | 75-90% | Peripheral lymphadenopathy (cervical, axillary, inguinal), BHL | Same as pulmonary |
| Skin | 25-35% | Erythema nodosum (EN, acute, good prognosis), lupus pernio (chronic, disfiguring, poor prognosis), maculopapular lesions, scar infiltration | Topical corticosteroids, hydroxychloroquine, methotrexate, TNF inhibitors; laser for lupus pernio |
| Eyes | 20-30% | Uveitis (anterior > posterior), dry eyes, conjunctival nodules | Topical corticosteroids (anterior); systemic corticosteroids, methotrexate, TNF inhibitors (posterior) |
| Cardiac | 5-10% (subclinical 25%) | Conduction abnormalities (heart block), arrhythmias (VT), heart failure, sudden death | Corticosteroids, methotrexate, biologics; ICD for arrhythmias; cardiac MRI/PET for diagnosis |
| Neurologic | 5-10% | Cranial neuropathies (CN VII most common - Bell palsy), aseptic meningitis, parenchymal brain lesions, myelopathy, hydrocephalus, peripheral neuropathy | High-dose corticosteroids, methotrexate, cyclophosphamide, TNF inhibitors |
| Hepatic | 20-30% | Elevated LFTs (asymptomatic), intrahepatic cholestasis, portal hypertension (rare) | Observation; corticosteroids if severe |
| Hypercalcemia | 10-20% | 1,25-(OH)2 vitamin D produced by activated macrophages | Avoid sunlight/calcium/vitamin D; corticosteroids, hydroxychloroquine, ketoconazole |
| Musculoskeletal | 10-20% | Arthralgias, acute arthritis (Lofgren syndrome: EN + BHL + ankle arthritis - excellent prognosis), chronic arthritis (rare), osseous lesions | NSAIDs, corticosteroids, HCQ |
Sarcoidosis Treatment
| Severity | Treatment | Notes |
|---|---|---|
| Asymptomatic (stage I BHL) | Observation | 60-80% spontaneous remission within 2 years |
| Mild-moderate (symptomatic, no organ-threatening) | NSAIDs, corticosteroids (prednisone 20-40 mg/day, taper over 6-12 months) | First-line for active disease |
| Chronic or corticosteroid-sparing | Methotrexate (first-line steroid-sparing) | Monitor LFTs, CBC, pulmonary function |
| Refractory | Azathioprine, leflunomide, mycophenolate mofetil, hydroxychloroquine | Second-line agents |
| Severe/refractory | TNF inhibitors (infliximab, adalimumab) | For neurologic, cardiac, severe pulmonary, lupus pernio |
| Organ-threatening | Cyclophosphamide | Rare; for life-threatening refractory disease |
Immunosuppressive Treatments
| Drug Class | Examples | Mechanism | Key Uses | Key Toxicities |
|---|---|---|---|---|
| Glucocorticoids | Prednisone, methylprednisolone | Broad anti-inflammatory (NF-kB, AP-1, cytokines) | Induction for most autoimmune diseases | Osteoporosis, diabetes, HTN, weight gain, cataracts, infections, avascular necrosis, mood changes |
| Antimalarials | Hydroxychloroquine | TLR inhibition, antigen presentation modulation | SLE, RA (mild), Sjogren | Retinopathy (dose/duration-related), myopathy |
| Methotrexate | Methotrexate | DHFR inhibition, adenosine, anti-inflammatory | RA, psoriasis, myositis, sarcoidosis | Hepatotoxicity, pneumonitis, myelosuppression, teratogenicity (check T-SPOT-TB, LFTs, CBC) |
| Leflunomide | Leflunomide | DHODH inhibition (pyrimidine synthesis) | RA, psoriatic arthritis | Hepatotoxicity, diarrhea, hypertension, teratogenicity |
| Mycophenolate mofetil | Mycophenolate | IMPDH inhibition (purine synthesis) | Lupus nephritis, myositis, vasculitis, scleroderma ILD | Gastrointestinal (diarrhea, nausea), myelosuppression, teratogenicity |
| Azathioprine | Azathioprine | Purine synthesis inhibition | SLE, RA, vasculitis, myositis, IBD | Hepatotoxicity, myelosuppression, pancreatitis, nausea, lymphoma risk |
| Cyclophosphamide | Cyclophosphamide | DNA alkylation, cell cycle non-specific | Lupus nephritis, vasculitis, myositis | Hemorrhagic cystitis, myelosuppression, infertility, malignancy, teratogenicity |
| Cyclosporine | Cyclosporine | Calcineurin inhibition (T-cell IL-2) | RA, psoriasis, nephrotic syndrome | Nephrotoxicity, HTN, hirsutism, gingival hyperplasia, drug interactions |
| Tacrolimus | Tacrolimus | Calcineurin inhibition | Lupus nephritis, myositis, organ transplant | Nephrotoxicity, HTN, diabetes, neurotoxicity |
| TNF inhibitors | Infliximab, adalimumab, etanercept, certolizumab, golimumab | TNF-alpha neutralization | RA, AS, PsA, psoriasis, IBD, sarcoidosis | TB/HBV reactivation, infections, injection/infusion reactions, demyelinating disease, HF, lymphoma (slight) |
| Rituximab | Rituximab | CD20 B-cell depletion | RA, vasculitis, SLE, pemphigus, myositis | Infusion reactions, HBV reactivation, PML (rare), hypogammaglobulinemia |
| Belimumab | Belimumab | BAFF/BLyS inhibition (B-cell survival) | SLE | Nausea, diarrhea, infections, infusion reactions |
| Anifrolumab | Anifrolumab | IFNAR1 blockade (type I IFN) | SLE | Herpes zoster, URI, infusion reactions |
| Tocilizumab | Tocilizumab | IL-6 receptor blockade | RA, GCA, cytokine release syndrome | Neutropenia, LFT elevation, infections, GI perforation |
| Abatacept | Abatacept | CTLA4-Ig (T-cell costimulation blockade) | RA | Infection risk, infusion reactions |
| JAK inhibitors | Tofacitinib, baricitinib, upadacitinib | JAK-STAT blockade | RA, PsA, IBD, AD | Zoster (VZV), infections, thrombosis, LFT elevation, lipid elevation |