Autoimmune Diseases

Genetic / non-modifiable

• HLA class II alleles: shape which self-peptides are presented to CD4+ T cells — HLA-DR3 (SLE, Sjögren, type 1 diabetes, Graves), HLA-DR4/DRB1 shared epitope (RA, T1DM), HLA-B27 (spondyloarthritis, class I–restricted).
• Non-HLA immune-regulatory genes: PTPN22 (altered TCR/BCR signaling thresholds), complement deficiencies (C1q, C2, C4 — impaired clearance of immune complexes and apoptotic debris, paradoxically causing lupus), AIRE and FOXP3 (tolerance failure).
• Female sex and sex hormones: X-chromosome dosage effects on TLR7 and incomplete X inactivation; note Klinefelter syndrome (47,XXY) carries markedly increased SLE risk, and Turner syndrome associates with autoimmune thyroid disease — the classic stem clue that sex chromosomes, not estrogen alone, drive risk.
• Family history and ancestry: clustering of multiple autoimmune diseases in one family; African American, Hispanic, and Asian ancestry carry higher SLE incidence and severity.

Infection-triggered (molecular mimicry, bystander activation, epitope spreading)

• Group A Streptococcus → rheumatic carditis (M protein vs. cardiac myosin) and post-streptococcal glomerulonephritis.
• Campylobacter jejuni → Guillain–Barré (lipooligosaccharide vs. gangliosides); Chlamydia/Shigella/Yersinia → reactive arthritis; EBV → SLE and multiple sclerosis association.

Modifiable exposures

• Cigarette smoking: activates peptidylarginine deiminase → citrullinated proteins → anti-CCP antibodies; the strongest modifiable RA risk factor and a driver of seropositive, erosive disease. Periodontal P. gingivalis acts by the same citrullination mechanism.
• Ultraviolet light: induces keratinocyte apoptosis and surface expression of Ro/La, precipitating cutaneous lupus flares — photoprotection is standard ACR-endorsed counseling.
• Drugs: hydralazine, procainamide, isoniazid, minocycline, TNF inhibitors → drug-induced lupus; immune checkpoint inhibitors (anti–CTLA-4, anti–PD-1) unmask peripheral tolerance and cause thyroiditis, colitis, hypophysitis.
• Occupational silica, obesity, and intestinal dysbiosis: promote Th17 skewing and chronic innate activation.
• Vitamin D deficiency is epidemiologically associated, though causality is unproven.

• Central tolerance failure: Defective negative selection in the thymus (T cells) and bone marrow (B cells) allows autoreactive lymphocytes to escape deletion; mutations in AIRE gene exemplify this mechanism in autoimmune polyendocrine syndrome (APS)

• Peripheral tolerance mechanisms disrupted: Reduced regulatory T cell (Treg) function, impaired CTLA-4 and PD-1 checkpoint signaling, and defective Fas-mediated apoptosis (as in autoimmune lymphoproliferative syndrome) allow autoreactive cells to persist and expand

• Breach of epithelial barriers: Loss of intestinal epithelial tight junctions ("leaky gut"), compromised skin and mucosal barriers increase pathogen and antigen exposure; molecular mimicry allows cross-reactive immune responses

• Th1 and Th17 predominance: Dysregulation of T helper cell differentiation favors pro-inflammatory responses; IL-17 and TNF-α drive chronic tissue inflammation and autoantigen presentation

• Hyperactive B cell response: Production of pathogenic autoantibodies (anti-dsDNA, anti-tissue-specific antigens) that form immune complexes, activate complement, and cause tissue-specific damage through type II (cytotoxic) and type III (immune complex) hypersensitivity

• Genetic predisposition: Strong associations with HLA alleles (e.g., HLA-DR3/DR4 in type 1 diabetes, HLA-B27 in ankylosing spondylitis); non-HLA susceptibility genes (PTPN22, IL23R) affect immune regulation

• Environmental triggers: Infections (EBV, molecular mimicry), UV exposure, smoking, medications (drug-induced lupus), and intestinal dysbiosis contribute to loss of tolerance in genetically susceptible individuals

• Constitutional symptoms: Fatigue, malaise, low-grade fever, and weight loss are near-universal features due to chronic inflammatory cytokine production; these often precede organ-specific manifestations

• Systemic polyarticular arthritis: Symmetric joint involvement (especially small joints of hands), morning stiffness >1 hour, and progressive joint swelling/deformity; classic in rheumatoid arthritis but seen across multiple autoimmune conditions

• Skin and mucosal manifestations: Malar rash (lupus), photosensitivity, oral/genital ulcers, Raynaud's phenomenon, and dry eyes/mouth; often provide diagnostic clues to underlying systemic disease

• Organ-specific involvement: Target organ damage varies—thyroiditis causes hypothyroidism, glomerulonephritis causes hematuria/proteinuria/renal failure, myositis causes proximal muscle weakness, pulmonary fibrosis causes dyspnea and restrictive physiology

• Insidious vs. acute onset: Most autoimmune diseases develop insidiously over weeks to months, but some (particularly drug-induced lupus) can present acutely; flare-remit pattern is typical for SLE and other systemic diseases

• Clinical pearls: Younger age at onset (reproductive years), female predominance (10:1 in SLE), family history of autoimmunity, and concurrent autoimmune conditions strongly suggest autoimmune etiology; ethnic/ancestry differences exist (African Americans and Hispanics have higher lupus prevalence and severity)

• ANA (Antinuclear Antibody) screening: Most sensitive test for systemic autoimmune disease (95%+ sensitivity in SLE); positive ANA is common in general population (up to 5%), so clinical context is essential; patterns (homogeneous, speckled, centromere, nucleolar) can suggest specific diagnoses but lack specificity

• Disease-specific autoantibodies: Anti-dsDNA and anti-Smith (highly specific for SLE), anti-TPO/anti-thyroglobulin (Hashimoto's), anti-GAD65 and anti-IA2 (type 1 diabetes), anti-CCP (cyclic citrullinated peptide) and rheumatoid factor (rheumatoid arthritis—anti-CCP is more specific), anti-ANCA (vasculitis), anti-mitochondrial (primary biliary cholangitis)

• Complement levels (C3, C4): Hypocomplementemia indicates active immune complex disease and correlates with lupus nephritis activity; low C4 is particularly sensitive for SLE activity

• Inflammatory markers: ESR and CRP elevation confirms inflammation but lack specificity; some conditions (SLE) may have normal CRP with high ESR; CRP typically normal in SclerodermaRA

• Tissue biopsy: Essential for diagnosis in organ-specific autoimmunity (kidney biopsy for lupus nephritis, thyroid biopsy for thyroiditis, skin biopsy for bullous diseases); immunofluorescence patterns are diagnostic

• Organ-specific functional tests: TSH/free T4 (thyroid), urinalysis with proteinuria/hematuria (kidney), EMG/muscle biopsy (myositis), pulmonary function tests (interstitial lung disease)

• Important diagnostic consideration: Meeting classification criteria (e.g., EULAR/ACR criteria for SLE, RA, vasculitis) is useful for research and communication but should not replace clinical judgment; seronegative presentations (negative ANA, negative RF) occur in 20-30% of RA cases

• First-line approaches vary by disease: NSAIDs for mild arthritis; corticosteroids (prednisone 0.5-1 mg/kg/day) remain the most rapid anti-inflammatory agent for acute flares and induction therapy (tapered to lowest effective maintenance dose, typically <7.5 mg/day); glucocorticoids should never be monotherapy long-term due to toxicity

• Disease-modifying antirheumatic drugs (DMARDs):
• Conventional synthetic DMARDs: Methotrexate (15-25 mg weekly, gold standard for RA and many systemic diseases), hydroxychloroquine (200-400 mg daily, particularly for SLE skin/joint manifestations), sulfasalazine, leflunomide
• Biologic DMARDs: TNF-α inhibitors (infliximab, etanercept, adalimumab—highly effective for RA but increase infection risk, especially TB), IL-6 inhibitors (tocilizumab), B cell depletion (rituximab), T cell co-stimulation blockade (abatacept)
• Targeted synthetic DMARDs: JAK inhibitors (baricitinib, tofacitinib) increasingly used for RA

• Additional immunosuppressants: Azathioprine, mycophenolate mofetil, and cyclophosphamide reserved for severe, refractory disease (especially active lupus nephritis, vasculitis); calcineurin inhibitors (cyclosporine, tacrolimus) for selected cases

• Organ-protective therapy: ACE inhibitors/ARBs for lupus nephritis and diabetic kidney disease, hydroxychloroquine to reduce SLE flares and thrombosis risk, antimalarials for cutaneous lupus

• Special populations:
• Pregnancy: Methotrexate, mycophenolate, cyclophosphamide are teratogenic—switch to safer agents (sulfasalazine, azathioprine, most biologic agents, corticosteroids); hydroxychloroquine and NSA

Disease-driven — emergencies first

• Rapidly progressive glomerulonephritis / proliferative lupus nephritis (emergency): immune-complex deposition with crescent formation; signaled by rising creatinine, active urine sediment (dysmorphic RBCs, RBC casts), new proteinuria, falling C3/C4 with rising anti-dsDNA. ACR and KDIGO glomerular disease guidance make kidney biopsy the step that determines induction therapy.
• Diffuse alveolar hemorrhage (emergency): hemoptysis (may be absent), dropping hematocrit, diffuse infiltrates, rising DLCO.
• Catastrophic antiphospholipid syndrome (emergency): multi-site small-vessel thrombosis over days with thrombocytopenia.
• Macrophage activation syndrome/secondary HLH (emergency): cytokine-driven macrophage activation — falling counts, paradoxically falling ESR with high ferritin, hypertriglyceridemia, hypofibrinogenemia.
• Scleroderma renal crisis (emergency): abrupt severe hypertension plus MAHA; treat with an ACE inhibitor (captopril), not other antihypertensives.
• Pericardial tamponade, transverse myelitis/seizures in CNS lupus, and atlantoaxial subluxation in RA (airway risk at intubation) round out the acute list.

Chronic disease complications

• Accelerated atherosclerosis: chronic inflammation plus steroid exposure; MI in a young woman with SLE is a classic stem. EULAR recommends formal cardiovascular risk assessment in inflammatory arthritis and SLE.
• Secondary amyloidosis (AA), interstitial lung disease, and lymphoma in Sjögren (parotid MALT lymphoma from chronic B-cell stimulation).

Treatment complications

• Glucocorticoids: osteoporotic fracture and osteonecrosis (new groin pain with normal radiographs → MRI), hyperglycemia, cataract, myopathy, and adrenal crisis on abrupt withdrawal (emergency). ACR glucocorticoid-induced osteoporosis guidance directs calcium/vitamin D and bisphosphonate risk stratification.
• Opportunistic infection: TNF inhibitors reactivate latent TB (granuloma maintenance requires TNF) — screen with IGRA/PPD and hepatitis B before starting; rituximab causes HBV reactivation and hypogammaglobulinemia; high-dose steroids/cyclophosphamide warrant Pneumocystis prophylaxis.
• Hydroxychloroquine: bull's-eye maculopathy; AAO screening advises weight-based dosing plus baseline and periodic ophthalmologic exams.
• Cyclophosphamide: hemorrhagic cystitis and bladder cancer (acrolein; mitigate with hydration/mesna), premature ovarian insufficiency.
• Methotrexate: transaminitis, macrocytic anemia (give folic acid), hypersensitivity pneumonitis.
• JAK inhibitors: FDA boxed warnings for thrombosis, major cardiovascular events, malignancy; herpes zoster is common.

• ANA is a screening test, not a diagnosis: highly sensitive but positive in a meaningful fraction of healthy people, especially older women. ACR Choosing Wisely advises against ordering ANA panels for nonspecific fatigue or diffuse pain — the distractor answer in a stem describing fibromyalgia-type symptoms.
• Specificity lives in the sub-serologies: anti-dsDNA (tracks nephritis activity) and anti-Smith are specific for SLE; anti-histone with anti-dsDNA typically absent points to drug-induced lupus (hydralazine, procainamide, isoniazid, minocycline) — renal and CNS involvement are characteristically spared and the disease remits when the drug is stopped, which is the single best next step.
• Low C3/C4 plus rising anti-dsDNA plus new proteinuria = active lupus nephritis; the next step is kidney biopsy to define ISN/RPS class before immunosuppression, not empiric pulse steroids alone.
• ESR/CRP dissociation: SLE flares often raise ESR with a relatively normal CRP. A high CRP in a febrile lupus patient should raise suspicion for infection rather than flare — the classic trap, since the management diverges (antibiotics/workup vs. more immunosuppression).
• Anti-CCP beats RF: more specific for RA, predicts erosive disease, and links mechanistically to smoking-induced citrullination plus HLA-DRB1 shared epitope. RF is also positive in Sjögren, hepatitis C–associated cryoglobulinemia, and endocarditis.
• The one association examiners love: anti-SSA (Ro) crosses the placenta and causes neonatal lupus and congenital complete heart block; ACOG-endorsed practice is serial fetal cardiac surveillance in anti-Ro–positive pregnancies. Hydroxychloroquine is continued through pregnancy.
• Antiphospholipid clues: false-positive VDRL/RPR, prolonged aPTT that does not correct with mixing study, recurrent fetal loss, Libman–Sacks verrucous endocarditis. Confirm with persistent positivity on repeat testing weeks later; anticoagulate with warfarin after thrombosis — DOACs are inferior in triple-positive/arterial APS.
• Before any biologic: screen for latent TB and hepatitis B, and give indicated inactivated vaccines first — ACIP considers live vaccines contraindicated during significant immunosuppression.