What is the cause of lupus and how is it diagnosed and treated?

Cause of Systemic Lupus Erythematosus

Systemic lupus erythematosus is a complex multisystemic autoimmune disease caused by the interplay of genetic predisposition, environmental triggers, and hormonal factors, resulting in loss of self-tolerance, production of autoantibodies, immune complex formation, and multi-organ inflammation. 1, 2, 3

Pathogenic Mechanisms

The disease develops through disrupted molecular pathways involving:

• Genetic susceptibility combined with environmental triggers and hormonal influences that converge to produce the clinical phenotype 1, 2
• Loss of self-tolerance with abnormal immunological function leading to autoantibody production against nuclear and cytoplasmic antigens 2, 4
• Immune complex formation and deposition in tissues causing inflammation and organ damage 4
• Dysregulation of multiple cellular components including innate and adaptive immune systems 2
• Overproduction of type I interferons and other cytokines driving inflammation 2
• Impaired clearance of nucleic acids after cell death, perpetuating autoimmune responses 2
• Complement system activation contributing to tissue injury 2

Epidemiologic Risk Factors

Disease manifestations and severity vary significantly based on:

• Sex: Approximately 90% of patients are female, reflecting hormonal influences 3
• Race/ethnicity: Latin American, North American Mestizo (mixed Amerindian-European ancestry), African descendants, and Native Americans develop lupus earlier, experience more severe disease, higher disease activity, greater organ damage accumulation, and higher mortality rates 1
• Age: Certain populations develop disease at younger ages 1
• Socioeconomic status: Lower SES correlates with worse outcomes, likely due to diagnostic delays, medication access issues, and adherence challenges 1

Diagnosis

The 2019 European Alliance of Associations for Rheumatology/American College of Rheumatology classification criteria are 96.1% sensitive and 93.4% specific for SLE, incorporating: 3

• Clinical manifestations: Fever, cytopenia, rash, arthritis, proteinuria (indicating possible lupus nephritis), serositis, neuropsychiatric symptoms 3, 5
• Immunologic markers: SLE-specific autoantibodies (anti-dsDNA, anti-Smith, antiphospholipid antibodies, anti-Ro/SSA, anti-La/SSB) and low complement levels (C3, C4) 1, 3, 5
• Diagnostic threshold: Meeting at least 4 of 11 American College of Rheumatology criteria yields 95% specificity and 85% sensitivity 5

For suspected lupus nephritis specifically, renal biopsy is essential to confirm diagnosis, evaluate disease activity and chronicity, determine prognosis, and guide appropriate therapy 1, 6

Treatment Approach

Foundation Therapy (Mandatory for All Patients)

Hydroxychloroquine is the cornerstone of therapy for all SLE patients and must be prescribed unless contraindicated, as it reduces disease activity, prevents flares, improves survival, and reduces mortality. 1, 6, 7, 3, 5

• Dose: ≤5 mg/kg actual body weight per day (typically 200-400 mg daily) 6, 7
• Ophthalmological screening required at baseline, after 5 years, then yearly thereafter to monitor for retinal toxicity 6, 7

Glucocorticoid Strategy

• Low-dose glucocorticoids (prednisone ≤7.5 mg/day) added when clinically indicated 1, 6
• IV methylprednisolone pulses (500-1000 mg for 1-3 days) for acute flares provide immediate effect and enable lower starting oral doses 6, 7
• Goal: Minimize to <7.5 mg/day and withdraw when possible to prevent irreversible organ damage 1, 6, 7

Immunosuppressive Therapy Selection by Manifestation

• Musculoskeletal and skin: Methotrexate is preferred first choice due to cost and availability 1, 6, 7
• Lupus nephritis induction: Mycophenolate mofetil OR low-dose IV cyclophosphamide 1, 6, 7
• Lupus nephritis maintenance: Mycophenolate mofetil OR azathioprine 1, 6, 7
• Severe organ-threatening disease: Cyclophosphamide for renal, cardiopulmonary, or neuropsychiatric manifestations 1, 7
• Neuropsychiatric lupus with inflammatory mechanisms: High-dose glucocorticoids plus cyclophosphamide (response rate 95% vs 54% with methylprednisolone alone, p=0.03) 1, 7
• Thrombocytopenia: High-dose glucocorticoids (including IV methylprednisolone pulses) and/or IV immunoglobulin G 7

Biologic Therapies for Inadequate Response

• Belimumab (anti-BAFF antibody): FDA-approved for active extrarenal SLE (2011) and lupus nephritis (2020); add when standard therapy inadequate 6, 7, 8, 3
• Anifrolumab (anti-type I interferon receptor): FDA-approved for moderate-to-severe extrarenal SLE 6, 3
• Voclosporin: FDA-approved for lupus nephritis 6, 3
• Rituximab: Consider for organ-threatening disease refractory to or with intolerance/contraindications to standard immunosuppressants 6, 7

Adjunctive Therapies

• Photoprotection with sunscreens to prevent cutaneous flares 1, 6
• Low-dose aspirin for patients with antiphospholipid antibodies, those receiving corticosteroids, or those with cardiovascular risk factors 1, 6
• Calcium and vitamin D for all patients on long-term glucocorticoids to prevent bone loss 1, 6
• Statins and ACE inhibitors for selected patients with increased cardiovascular disease risk 1

Pregnancy Management

• Safe medications: Hydroxychloroquine, azathioprine, prednisolone (non-fluorinated glucocorticoids), ciclosporin A, low-dose aspirin 1, 6
• Contraindicated medications: Mycophenolate mofetil, cyclophosphamide, methotrexate must be avoided 1, 6
• High-risk patients: Those with lupus nephritis and antiphospholipid antibodies require closer monitoring for preeclampsia, miscarriage, stillbirth, premature delivery (relative risks 2.2-5.8), low birth weight, and intrauterine growth restriction 1
• Fetal congenital heart block occurs in 2-4.5% of SLE pregnancies, associated with anti-Ro/SSA or anti-La/SSB antibodies 1

Monitoring and Comorbidity Screening

SLE patients have a 5-fold increased mortality risk compared to the general population, requiring vigilant screening for life-threatening complications. 1, 6

• Disease activity monitoring: Use validated indices (SLEDAI, BILAG) at each visit; monitor anti-dsDNA, C3, C4, complete blood count, creatinine, proteinuria, and urine sediment regularly 6, 7
• Screen for major comorbidities: Infections, hypertension, coronary heart disease, diabetes mellitus, dyslipidemia, atherosclerosis, osteoporosis, avascular bone necrosis, and malignancies (especially non-Hodgkin's lymphoma, lung cancer, hepatobiliary cancer) 1, 6
• Lupus nephritis monitoring: Changes in serum creatinine, proteinuria, anti-dsDNA, and serum C3 concentrations correlate with renal flares and outcome 1

Critical Pitfalls to Avoid

• Never withhold hydroxychloroquine unless absolute contraindication exists—non-adherence associates with higher flare rates and mortality 6
• Avoid prolonged high-dose glucocorticoids (>7.5 mg/day prednisone equivalent) as they increase irreversible organ damage risk 1, 6, 7
• Do not delay immunosuppressive therapy in organ-threatening disease—early aggressive treatment prevents irreversible damage 6, 7
• Always perform kidney biopsy before treating lupus nephritis—treatment decisions depend on histological classification 1, 6, 7
• Avoid mycophenolate mofetil, cyclophosphamide, and methotrexate during pregnancy—teratogenic risk mandates discontinuation 1, 6