Autoimmune diseases result from the immune system mounting an inappropriate attack against self-tissues. Over 80 recognized autoimmune diseases affect 5–10% of the global population, with a strong female predominance. They can be organ-specific (type 1 diabetes, autoimmune thyroiditis, multiple sclerosis) or systemic (SLE, rheumatoid arthritis, systemic sclerosis).

Diagram of rheumatoid arthritis joint pathology — Illustration of a joint affected by rheumatoid arthritis. Synovial inflammation, pannus formation, and bone erosion are hallmarks of this systemic autoimmune disease. Source: Wikimedia Commons (NIH/NIAMS).

Principles of Autoimmunity

Breakdown of self-tolerance. Central tolerance in the thymus and bone marrow eliminates most self-reactive T and B cells. Peripheral tolerance mechanisms — anergy, deletion, and regulatory T cells (Tregs) — control those that escape. Autoimmunity arises when these mechanisms fail due to genetic susceptibility and environmental triggers.

Genetic factors. HLA alleles are the strongest genetic risk factors: HLA-DR4 in rheumatoid arthritis, HLA-DR2 and DR3 in SLE, HLA-DR3 in Sjögren syndrome. Non-HLA genes (PTPN22, CTLA4, STAT4, IRF5, TNFAIP3) also contribute.

Environmental triggers. Infection (EBV in SLE and MS, molecular mimicry), smoking (RA and SLE), silica exposure (scleroderma, RA), ultraviolet light (SLE), drugs (drug-induced lupus), and hormonal factors (female predominance).

Autoantibodies. Autoantibodies are diagnostic markers and often pathogenic. Examples: anti-dsDNA in SLE, anti-CCP in RA, anti-Scl-70 in systemic sclerosis, anti-SSA/SSB in Sjögren, anti-centromere in limited scleroderma, ANCA in vasculitis.

Spleen anatomy from Gray's Anatomy — The spleen is the largest secondary lymphoid organ and plays a key role in immune surveillance, filtering blood, and mounting immune responses. It is involved in many autoimmune and hematologic disorders. Source: Gray's Anatomy (1918).

Systemic Lupus Erythematosus

SLE is a prototypic systemic autoimmune disease with diverse clinical manifestations caused by immune complex deposition and tissue inflammation. It predominantly affects women of childbearing age, with a 9:1 female-to-male ratio. Incidence and severity are higher in Black, Hispanic, and Asian populations.

Pathophysiology. Loss of tolerance to nuclear antigens (DNA, histones, ribonucleoproteins). Defective clearance of apoptotic debris exposes self-antigens. Plasmacytoid dendritic cells produce type I interferons, driving B-cell activation and autoantibody production. Immune complex deposition in tissues activates complement and recruits inflammatory cells.

Clinical manifestations. Malar (butterfly) rash, discoid rash, photosensitivity, oral ulcers, non-erosive arthritis, serositis (pleuritis, pericarditis), nephritis (proteinuria, hematuria, hypertension), neuropsychiatric lupus (seizures, psychosis, cognitive dysfunction), hematologic cytopenias (anemia, leukopenia, thrombocytopenia), and antiphospholipid antibodies.

Diagnosis. The 2019 EULAR/ACR classification criteria use a weighted scoring system based on clinical domains and antinuclear antibody (ANA) positivity. ANA is the screening test (sensitivity >95%). Anti-dsDNA and anti-Smith are highly specific.

Treatment. Hydroxychloroquine is universal (reduces flares and improves survival). Immunosuppression (corticosteroids, mycophenolate mofetil, azathioprine, cyclophosphamide) for moderate to severe disease. Belimumab (anti-BLyS) is approved for active SLE. Anifrolumab (anti-type I interferon receptor) is approved for moderate to severe disease. For lupus nephritis, mycophenolate mofetil or cyclophosphamide with corticosteroids are first-line, followed by maintenance with mycophenolate or azathioprine.

ⓘ Information

APS is characterized by arterial and venous thrombosis, pregnancy morbidity (recurrent miscarriage, stillbirth, preeclampsia), and the presence of antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, anti-beta2 glycoprotein I). It can occur as primary APS or secondary to SLE. Catastrophic APS (CAPS) is a rare, life-threatening form with widespread microvascular thrombosis. Management: lifelong anticoagulation with warfarin (target INR 2–3) for thrombosis; prophylactic heparin with aspirin during pregnancy.

Systemic Sclerosis (Scleroderma)

A chronic autoimmune disease characterized by fibrosis of the skin and internal organs, vasculopathy, and immune activation. Two major subsets: limited cutaneous (lcSSc, previously CREST syndrome — Calcinosis, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, Telangiectasias) and diffuse cutaneous (dcSSc, with extensive skin thickening and high risk of internal organ involvement).

Complications. Raynaud phenomenon (universal), digital ulcers, pulmonary arterial hypertension (PAH, the leading cause of death in lcSSc), interstitial lung disease (ILD, the leading cause of death in dcSSc), esophageal dysmotility with reflux, scleroderma renal crisis (hypertension, AKI), and cardiac involvement.

Management. No disease-modifying therapy reverses fibrosis. Immunosuppression (mycophenolate, cyclophosphamide) for ILD. Nintedanib (antifibrotic) for ILD. PAH-specific therapy (as discussed in respiratory article). ACE inhibitors are life-saving in renal crisis. Calcium channel blockers and PDE5 inhibitors for Raynaud. PPI for reflux.

Idiopathic Inflammatory Myopathies

Dermatomyositis. Proximal muscle weakness with characteristic skin findings: heliotrope rash (periorbital), Gottron papules (over MCP and IP joints), and nailfold capillary changes. Anti-MDA5 and anti-TIF1-gamma are associated with specific phenotypes. Increased risk of malignancy (ovarian, lung, breast, colorectal) in adult-onset disease.

Polymyositis. Proximal muscle weakness without rash. Diagnosis requires elevated CK, myositis-specific antibodies, MRI (muscle edema), EMG (myopathic changes), and muscle biopsy (CD8+ T-cell infiltration of muscle fibers).

Inclusion body myositis. Slowly progressive weakness of quadriceps and finger flexors, often refractory to immunosuppression.

Treatment. High-dose corticosteroids are first-line. Steroid-sparing immunosuppressants (methotrexate, azathioprine, mycophenolate) and IVIG are used for refractory disease.

Sjögren Syndrome

A chronic autoimmune disease targeting the lacrimal and salivary glands, causing dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia). It occurs as primary Sjögren syndrome or secondary to other autoimmune diseases (RA, SLE, scleroderma). Systemic manifestations include arthritis, Raynaud, interstitial lung disease, renal tubular acidosis, neuropathy, and lymphoma risk (especially MALT lymphoma). Diagnosis by anti-SSA/Ro and anti-SSB/La antibodies, salivary gland biopsy, and objective measures of dryness. Treatment: artificial tears, pilocarpine/cevimeline, hydroxychloroquine, and immunosuppression for systemic disease.

★ Key Concept

Granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA) are necrotizing small vessel vasculitides associated with anti-neutrophil cytoplasmic antibodies (ANCA). GPA targets the respiratory tract and kidneys (c-ANCA/PR3). MPA causes pauci-immune glomerulonephritis and pulmonary capillaritis (p-ANCA/MPO). EGPA has asthma, eosinophilia, and ANCA (50%). Untreated vasculitis is rapidly fatal. Induction therapy: high-dose corticosteroids plus cyclophosphamide or rituximab. Maintenance: rituximab or azathioprine. Plasma exchange is used for severe renal involvement or diffuse alveolar hemorrhage.

Sarcoidosis

A multisystem granulomatous disease of unknown cause, most commonly affecting the lungs (bilateral hilar lymphadenopathy, pulmonary infiltrates), skin (erythema nodosum, lupus pernio), eyes (uveitis), and heart (conduction abnormalities, cardiomyopathy). Non-caseating granulomas are the histologic hallmark. Angiotensin-converting enzyme (ACE) levels are elevated in 60%. Most cases resolve spontaneously. Treatment: corticosteroids (first-line), methotrexate, azathioprine, TNF inhibitors (infliximab) for refractory disease.

Treatment Principles

Immunosuppression. Corticosteroids provide rapid anti-inflammatory effects but cause significant long-term toxicity. Steroid-sparing agents (methotrexate, azathioprine, mycophenolate, cyclophosphamide) and targeted biologics (TNF inhibitors, rituximab, abatacept, tocilizumab, belimumab, anifrolumab) allow dose reduction.

Vaccination. Live vaccines are contraindicated during immunosuppression. Killed vaccines (influenza, pneumococcal, COVID-19, hepatitis B) are recommended. Vaccination ideally precedes immunosuppression.

Monitoring. Disease activity, drug toxicity, and complications (infection, malignancy, organ damage) require regular surveillance by rheumatologists and multidisciplinary specialists.

Summary

Autoimmune diseases collectively affect millions and represent a major cause of chronic disability. SLE is the prototypic systemic autoimmune disease with diverse organ involvement. Systemic sclerosis causes progressive fibrosis with life-threatening pulmonary complications. The inflammatory myopathies, Sjögren syndrome, and vasculitis each have characteristic clinical and serologic profiles. Treatment has advanced dramatically with targeted biologics, though corticosteroids remain a mainstay. The goal of therapy is to achieve remission or low disease activity while minimizing treatment toxicity.