Systemic Lupus Erythematosus

Genetic (non-modifiable)

• HLA class II alleles: HLA-DR2 and HLA-DR3 alter self-peptide presentation to autoreactive T cells; strongest common genetic association
• Early classical complement deficiency: C1q, C4, and C2 deficiency impair opsonic clearance of apoptotic debris and immune complexes, leaving nucleosomal antigen available to drive autoantibody formation. Homozygous C1q deficiency is the single strongest known risk factor for SLE, though it is rare
• Interferon-pathway polymorphisms: IRF5, STAT4, and related variants amplify the type I interferon signature described above
• Family history: first-degree relatives have substantially increased risk; concordance is far higher in monozygotic than dizygotic twins

Hormonal and demographic (non-modifiable)

• Female sex during reproductive years: estrogen promotes B-cell survival and autoantibody production; the 9:1 ratio narrows before puberty and after menopause
• X-chromosome dosage: men with Klinefelter syndrome (47,XXY) have markedly increased risk — an examiner favorite showing that gene dosage, not just hormones, matters
• Ancestry: higher incidence and more severe renal disease in Black, Hispanic, and Asian patients

Environmental / modifiable

• Ultraviolet light: UV induces keratinocyte apoptosis and surface translocation of Ro/SSA antigen, triggering cutaneous and systemic flares — hence photoprotection is formal therapy
• Cigarette smoking: associated with SLE onset, more cutaneous disease, and reduced hydroxychloroquine efficacy
• Crystalline silica exposure (sandblasting, mining) and, epidemiologically, Epstein-Barr virus infection through molecular mimicry with Sm/Ro antigens
• Drugs causing drug-induced lupus: hydralazine, procainamide, isoniazid, minocycline, TNF-alpha inhibitors; slow acetylators are at higher risk for the hydralazine/procainamide/isoniazid group
• Exogenous estrogen: combined hormonal contraception is acceptable in stable, antiphospholipid-antibody-negative disease but is avoided when antiphospholipid antibodies are present

• Loss of immune tolerance: Defective T regulatory cells (Tregs), impaired clearance of apoptotic cells, and genetic susceptibility (HLA-DR2, HLA-DR3) lead to breakdown of self-tolerance and activation of autoreactive B and T cells
• Autoantibody production: B cells produce pathogenic autoantibodies including anti-dsDNA (double-stranded DNA), anti-Smith (anti-Sm), anti-histone, and anti-Ro/SSA antibodies; these are directly pathogenic and form circulating immune complexes
• Immune complex deposition: Antibody-antigen complexes deposit in basement membranes (particularly glomerular basement membrane in kidneys, skin, joints, and blood vessel walls), activating complement cascade (especially C3 and C4 consumption) and triggering inflammation
• Type I interferon dysregulation: Elevated interferon-alpha (IFN-α) production by plasmacytoid dendritic cells promotes B cell activation and autoantibody production ("interferon signature")
• Complement activation and deficiency: Classical complement pathway activation leads to chronic C3 and C4 depletion; hereditary complement deficiencies (especially C1q, C2, C4) increase SLE risk by impairing clearance of apoptotic cells and immune complexes
• Endothelial dysfunction and thrombosis: Anticardiolipin and anti-β2 glycoprotein-1 antibodies promote thrombosis; immune complex deposition damages endothelium

Systemic manifestations

• Constitutional symptoms: Fever, malaise, fatigue, weight loss (often precede organ-specific manifestations)
• Photosensitivity: Rash or systemic flare triggered by UV exposure (most common cutaneous manifestation)

Mucocutaneous manifestations (most common; ~85% of patients)

• Malar rash ("butterfly rash"): Erythematous rash across cheeks and bridge of nose, sparing nasolabial folds; classic but NOT specific for SLE
• Discoid rash: Scaly, erythematous plaques on face, ears, scalp; may leave scarring alopecia; suggests cutaneous/discoid lupus (may not progress to SLE)
• Oral ulcers: Usually painless (important distinction from aphthous ulcers)
• Nasopharyngeal ulcers

Musculoskeletal manifestations (~90% of patients)

• Arthralgia and arthritis: Non-erosive (important—unlike rheumatoid arthritis, does NOT cause bone destruction), symmetric polyarthritis affecting small joints of hands, wrists, and knees; "Jaccoud arthropathy" (reversible joint deformities without erosions) is characteristic
• Myositis and myalgia

Hematologic manifestations (~80%)

• Hemolytic anemia (warm-reactive autoimmune hemolytic anemia): Positive direct Coombs test, elevated indirect bilirubin, elevated reticulocyte count, low haptoglobin
• Leukopenia (<4,000/μL): Often lupus lymphopenia
• Thrombocytopenia (<150,000/μL): Usually mild; severe thrombocytopenia should raise suspicion for antiphospholipid syndrome (APS) comorbidity
• Lymphadenopathy

Renal manifestations (30-50%; lupus nephritis)

• WHO Classification:
• Class I: Minimal mesangial
• Class II: Mesangial proliferative
• Class III: Focal proliferative (most common active form; worst prognosis if untreated)
• Class IV: Diffuse proliferative (most severe)
• Class V: Membranous
• Class VI: Advanced sclerosing
• Presents as hematuria, proteinuria, cellular casts (RBC casts particularly specific); can progress to acute kidney injury and chronic kidney disease
• Red flag: Sudden rise in creatinine with active urinary sediment suggests lupus nephritis

Pulmonary manifestations (40-60%)

• Pleuritis ("lupus pleuritis"): Pleuritic chest pain, pleural effusions (typically exudative with low complement levels)
• Pulmonary hemorrhage: Hemoptysis, anemia, infiltrates (life-threatening)
• Interstitial lung disease (ILD): Progressive dyspnea, cough
• Pulmonary hypertension
• Acute respiratory distress syndrome (ARDS)

Cardiac and vascular manifestations

• Pericarditis: Pleuritic chest pain, pericardial effusion, tamponade risk
• Myocarditis and endocarditis ("non-bacterial verrucous endocarditis" or Libman-Sacks endocarditis)
• Coronary artery disease: Accelerated atherosclerosis despite young age (due to chronic inflammation and immune complexes)
• Valvular disease: Mitral regurgitation most common
• Thrombosis: Both arterial and venous (especially if antiphospholipid antibodies present)

Neuropsychiatric manifestations (10-60%; highly variable)

• Cognitive dysfunction ("lupus fog"): Difficulty concentrating, memory problems
• Mood disorders: Depression, anxiety
• Seizures (~5%)
• Psychosis: Acute onset with prominent psychiatric features
• Peripheral neuropathy: Distal, symmetric sensorimotor
• Transverse myelitis (rare but severe)
• Cerebrovascular disease: Stroke (thrombotic or embolic)
• Headaches: May be severe migraines

Ocular manifestations

• Keratoconjunctivitis sicca (dry eyes, often overlap with Sjögren syndrome)
• Lupus retinopathy: "Cotton-wool spots" and retinal hemorrhages

Other manifestations

• Skin photosensitivity (cardinal feature)
• Hair loss (alopecia): Non-scarring in active SLE
• Raynaud phenomenon: ~25% of SLE patients

Important clinical context

• SLE presents highly variably; no two patients are identical
• Flares may be triggered by sunlight, infection, stress, or medication non-compliance
• Drug-induced lupus (from hydralazine, procainamide, isoniazid, TNF inhibitors): Usually resolves with drug discontinuation; anti-histone antibodies positive, anti-dsDNA and anti-Sm typically negative

1. ANA (Antinuclear Antibody) Testing

• Performed via immunofluorescence microscopy or ELISA; >95% sensitivity for SLE
• Homogeneous pattern and speckled pattern most common in SLE
• Positive ANA is prerequisite but NOT specific (also seen in Sjögren, scleroderma, RA, normal subjects ~5%)
• Critical pearl: Negative ANA essentially rules out SLE (NPV >95%)

2. Anti-dsDNA and Anti-Smith (Anti-Sm) Antibodies

• Anti-dsDNA: Highly specific (~99%) for SLE; titers often correlate with disease activity and renal involvement; measured by Farr assay (gold standard) or ELISA
• Anti-Sm: Highly specific (~99%) for SLE; does NOT correlate with disease activity; present in

Immediate stabilisation (organ-threatening disease)

• High-dose IV glucocorticoids: pulse methylprednisolone for diffuse alveolar hemorrhage, rapidly progressive lupus nephritis, lupus cerebritis, myocarditis, or severe cytopenias, with a steroid-sparing agent started simultaneously
• Anticoagulation, not immunosuppression, is the treatment for thrombosis from secondary antiphospholipid syndrome; catastrophic APS additionally requires plasma exchange plus steroids

First-line therapy for all patients

• Antimalarial — hydroxychloroquine: recommended by both the American College of Rheumatology and EULAR for essentially every patient regardless of severity. It blunts endosomal TLR7/9 signalling and the type I interferon axis, reduces flares and organ damage, and improves survival. Dose is capped at ≤5 mg/kg actual body weight per day to limit retinal toxicity (American Academy of Ophthalmology)
• Sun protection and smoking cessation: disease-modifying, not adjunctive
• NSAIDs for arthralgia/serositis and low-dose glucocorticoids for flares, with steroid tapering to the lowest possible dose as an explicit EULAR treatment target

Escalation / steroid-sparing agents

• Antimetabolites: methotrexate or azathioprine for refractory joint and skin disease; mycophenolate mofetil for more severe systemic or renal disease
• Biologics: belimumab (anti-BAFF/BLyS monoclonal antibody) and anifrolumab (type I interferon receptor blocker) for persistently active non-renal disease; rituximab is used off-label in refractory cytopenias and nephritis

Lupus nephritis (proliferative, class III/IV)

• Renal biopsy first — class dictates therapy (ACR and KDIGO glomerular disease guidance)
• Induction: glucocorticoids plus either mycophenolate mofetil or low-dose IV cyclophosphamide (Euro-Lupus regimen), increasingly combined with belimumab or the calcineurin inhibitor voclosporin as triple therapy
• Maintenance: mycophenolate or azathioprine; add an ACE inhibitor or ARB for proteinuria and blood pressure

Contraindicated / avoid

• Mycophenolate, cyclophosphamide, and methotrexate are teratogenic — switch to azathioprine, tacrolimus, or hydroxychloroquine before conception (ACR reproductive health guideline); ACE inhibitors and ARBs are also contraindicated in pregnancy
• Live vaccines during significant immunosuppression
• Sulfonamide antibiotics may precipitate flares and photosensitivity

Disease-related — emergencies

• Diffuse alveolar hemorrhage (emergency): capillaritis causes hemoptysis (may be absent), falling hemoglobin, and diffuse infiltrates; bronchoalveolar lavage returns progressively bloodier aliquots
• Rapidly progressive lupus nephritis (emergency): crescent formation in class III/IV disease; signalled by rising creatinine with an active sediment (dysmorphic RBCs, RBC casts), rising anti-dsDNA, and falling C3/C4 — biopsy urgently
• Neuropsychiatric lupus with seizures or psychosis (emergency): exclude infection, uremia, and steroid psychosis before attributing to disease
• Cardiac tamponade from a large pericardial effusion, and catastrophic antiphospholipid syndrome with multi-organ small-vessel thrombosis (both emergencies)

Disease-related — chronic

• Accelerated atherosclerosis: chronic inflammation plus steroid exposure makes cardiovascular disease the leading late cause of death; myocardial infarction may occur in a woman in her 30s–40s
• Libman-Sacks endocarditis: sterile verrucous vegetations on both surfaces of the mitral valve → mitral regurgitation and embolic stroke; blood cultures are negative
• End-stage renal disease requiring dialysis or transplant
• Obstetric morbidity: anti-Ro/SSA crosses the placenta and can cause neonatal lupus with congenital complete heart block (irreversible); antiphospholipid antibodies cause recurrent fetal loss and preeclampsia

Treatment-related

• Infection (emergency): the leading early cause of death; immunosuppressed patients can present with fever and a normal white count. Distinguishing flare from sepsis is a recurring vignette — a low ESR-to-CRP pattern favors flare, a markedly elevated CRP favors infection
• Hydroxychloroquine retinopathy: dose- and duration-dependent bull's-eye maculopathy; screen with OCT and automated visual fields per the American Academy of Ophthalmology
• Glucocorticoid toxicity: avascular necrosis of the femoral head (new groin pain, normal early radiograph, MRI diagnostic), osteoporosis, hyperglycemia, adrenal suppression
• Cyclophosphamide: hemorrhagic cystitis from acrolein (prevented with mesna and hydration), bladder cancer, and premature ovarian insufficiency
• Azathioprine: severe myelosuppression with TPMT or NUDT15 deficiency — test before starting

• ANA is the screen, not the answer: a negative ANA effectively excludes SLE, but a positive ANA in an asymptomatic patient warrants no further workup. Anti-Sm is the most specific antibody; anti-dsDNA is specific and tracks activity, particularly renal disease
• The flare triad on labs: rising anti-dsDNA titer with falling C3 and C4 (complement consumed by immune complexes) plus active urine sediment. Low complement in a patient with lupus means active disease, not complement deficiency
• Single best next step for proteinuria, hematuria, or rising creatinine in SLE: renal biopsy — class determines whether the patient gets aggressive induction immunosuppression or supportive therapy (ACR/KDIGO)
• Anti-Ro/SSA in a pregnant patient is the association examiners test: neonatal lupus with congenital complete heart block, which is permanent and may require pacing. Continue hydroxychloroquine throughout pregnancy — it lowers flare risk and is not teratogenic
• Prolonged aPTT that fails to correct on mixing study, plus thrombosis or a false-positive RPR/VDRL = lupus anticoagulant. The paradox is the point: prolonged clotting time in vitro, thrombosis in vivo. Treat established thrombosis with warfarin, not a DOAC, in triple-positive antiphospholipid syndrome
• Drug-induced lupus distractor: hydralazine, procainamide, isoniazid, minocycline, TNF inhibitors → anti-histone positive, anti-dsDNA and anti-Sm negative, renal and CNS disease characteristically spared, resolves on drug withdrawal. Note anti-histone antibodies also occur in idiopathic SLE, so their presence alone does not make the diagnosis
• Rash pitfalls: the malar rash spares the nasolabial folds (dermatomyositis gives a heliotrope rash with Gottron papules; rosacea and seborrheic dermatitis involve the folds). SLE arthritis is non-erosive — erosions on hand films point to rheumatoid arthritis
• Cause of death is time-dependent: infection and active disease early, accelerated atherosclerotic cardiovascular disease late. Aggressive lipid and blood pressure control in a young woman with lupus is the correct, counterintuitive answer