Systemic Lupus Erythematosus: Diagnosis and Management
Diagnosis
All patients with suspected SLE should be evaluated using the 2019 EULAR/ACR classification criteria, which are 96.1% sensitive and 93.4% specific, incorporating both clinical manifestations (fever, cytopenia, rash, arthritis, proteinuria) and immunologic markers (SLE-specific autoantibodies, low complement levels). 1
Key Diagnostic Elements
Clinical manifestations to assess: Constitutional symptoms (fatigue), mucocutaneous features (lupus-specific rash, mouth ulcers, alopecia), musculoskeletal symptoms (joint pain, myalgia), serositis, hematologic abnormalities (cytopenia), and renal involvement (proteinuria). 1, 2
Essential laboratory tests: Complete blood count, serum creatinine, proteinuria, urine sediment, anti-dsDNA antibodies, anti-Sm antibodies, C3/C4 complement levels, and antiphospholipid antibodies. 3, 4
Kidney biopsy is mandatory before initiating therapy for suspected lupus nephritis to confirm diagnosis, determine histological class (III, IV, or V), and guide treatment planning. 3, 5
Foundation Therapy (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. 3, 5, 1
Hydroxychloroquine Protocol
Dosing: ≤5 mg/kg real body weight per day (typically 200-400 mg daily). 3, 5
Ophthalmological monitoring: Baseline screening, repeat after 5 years, then yearly thereafter using visual fields examination and/or spectral domain-optical coherence tomography to detect retinal toxicity. 3, 5
Additional Foundation Measures
Photoprotection with sunscreens to prevent cutaneous flares. 3, 4
Low-dose aspirin for patients with antiphospholipid antibodies, those receiving corticosteroids, or those with cardiovascular risk factors. 3, 4
Calcium and vitamin D supplementation for all patients on long-term glucocorticoids to prevent osteoporosis. 6, 3
Glucocorticoid Management Algorithm
For acute flares or initial presentation, administer IV methylprednisolone pulse therapy (500-1000 mg daily for 1-3 days) to provide immediate therapeutic effect and enable lower starting doses of oral glucocorticoids. 3, 5
Chronic Glucocorticoid Strategy
Target dose: Minimize to <7.5 mg/day prednisone equivalent and withdraw when possible to prevent irreversible organ damage. 3, 5
Steroid-sparing approach: Promptly initiate immunomodulatory agents to expedite glucocorticoid tapering and discontinuation. 5
Critical threshold: Risks substantially increase above 7.5 mg/day continuous dosing. 3, 4
Treatment Algorithm by Disease Severity
Mild Disease (Mucocutaneous and Musculoskeletal)
Start with hydroxychloroquine plus low-dose glucocorticoids (if needed), adding methotrexate as the preferred first-choice immunosuppressant for skin and joint manifestations due to cost and availability. 3, 5
Topical therapy: Topical glucocorticoids or calcineurin inhibitors for localized cutaneous lesions. 4
Alternative agents for refractory cutaneous disease: Retinoids for hyperkeratotic lesions, dapsone for bullous lupus or urticarial vasculitis, or mycophenolate mofetil. 4
Moderate Disease Requiring Immunosuppression
When patients fail to respond to hydroxychloroquine alone or in combination with glucocorticoids, or cannot reduce glucocorticoids below 7.5 mg/day, add immunosuppressive agents. 5
Azathioprine: For maintenance therapy, particularly suitable for women contemplating pregnancy. 5, 7
Mycophenolate mofetil: For renal and non-renal manifestations (except neuropsychiatric disease). 5
Severe Organ-Threatening Disease
Cyclophosphamide is indicated for severe organ-threatening or life-threatening SLE, especially renal, cardiopulmonary, or neuropsychiatric manifestations. 5
Lupus Nephritis Treatment Protocol
Induction Therapy
Mycophenolate mofetil (Level of Evidence 1a/A) or low-dose IV cyclophosphamide (Level of Evidence 2a/b) are first-line options, with mycophenolate mofetil preferred due to the best efficacy/toxicity ratio. 3, 5
- Low-dose cyclophosphamide is preferred over high-dose cyclophosphamide due to comparable efficacy and lower gonadotoxicity. 5
Maintenance Therapy
Mycophenolate mofetil (Level of Evidence 1a/A) or azathioprine (Level of Evidence 1a/A) should be used for long-term maintenance. 3, 5
Monitoring Targets
Partial remission goal: ≥50% reduction in proteinuria to subnephrotic levels by 6-12 months. 4
Predictive markers: Renal biopsy, urine sediment analysis, proteinuria, and renal function have independent predictive value for clinical outcome. 4
Biologic Therapies for Refractory Disease
Belimumab (FDA-Approved)
Belimumab should be added for patients with inadequate response to standard therapy (hydroxychloroquine + glucocorticoids ± immunosuppressants) in both active extrarenal SLE and lupus nephritis. 3, 8
Efficacy in lupus nephritis: 43% of patients achieved Primary Efficacy Renal Response at Week 104 versus 32% with placebo (OR 1.6,95% CI 1.0-2.3, p=0.031). 8
Dosing: 10 mg/kg IV on Days 0,14,28, then every 28 days. 8
Indication: Patients ≥5 years of age with active SLE or active lupus nephritis receiving standard therapy. 8
Limitation: Not recommended for severe active CNS lupus. 8
Rituximab
Rituximab should be considered for organ-threatening disease refractory to or with intolerance/contraindications to standard immunosuppressive agents. 3, 5
Anifrolumab
Anifrolumab (anti-type 1 interferon receptor) is FDA-approved for moderate-to-severe extrarenal SLE. 3
Voclosporin
Voclosporin is FDA-approved specifically for lupus nephritis. 3, 1
Neuropsychiatric Lupus (NPSLE) Management
Treatment depends on the underlying pathophysiological mechanism, which must be determined through comprehensive diagnostic workup with aggressive exclusion of infection before initiating immunosuppressive therapy. 5, 4
Inflammatory/Immune-Mediated Mechanisms
High-dose IV methylprednisolone plus cyclophosphamide is recommended, with a response rate of 95% (18/19 patients) compared to 54% (7/13) with methylprednisolone alone (p=0.03). 3
Thrombotic/Embolic Mechanisms
Anticoagulation with warfarin is recommended, with target INR 2.0-3.0 for first venous thrombosis and 3.0-4.0 for arterial or recurrent thrombosis. 3
Combined Mechanisms
Use combination of immunosuppressive and anticoagulant/antithrombotic therapy when both mechanisms coexist. 5
Hematological Manifestations
Acute Lupus Thrombocytopenia
First-line treatment includes high-dose glucocorticoids (including IV methylprednisolone pulses) and/or IV immunoglobulin G. 5
Maintenance therapy: Moderate/high doses of glucocorticoids in combination with immunosuppressive agents (azathioprine, mycophenolate mofetil, or cyclosporine). 5
Refractory cases: Rituximab or cyclophosphamide. 5
Critical Monitoring and Comorbidity Management
Disease Activity Monitoring
Use validated activity indices (SLEDAI, BILAG) at each visit, monitoring anti-dsDNA, C3, C4, complete blood count, creatinine, proteinuria, and urine sediment regularly. 3, 4
Mortality and Comorbidity Risk
SLE patients have a 5-fold increased mortality risk compared to the general population, requiring systematic screening for infections, cardiovascular disease, hypertension, diabetes, dyslipidemia, atherosclerosis, osteoporosis, avascular bone necrosis, and malignancies (especially non-Hodgkin lymphoma, lung cancer, hepatobiliary cancer). 3, 4
Infection Prevention
Screening before immunosuppression: HIV (based on risk factors), HCV/HBV (especially before high-dose glucocorticoids), tuberculosis (according to local guidelines), and CMV (in selected patients during treatment). 6
Vaccination: Inactivated vaccines (influenza and pneumococcus) should be strongly encouraged in patients on immunosuppressive drugs, preferably administered when SLE is inactive. 6
Infection risk assessment: Monitor for severe neutropenia (<500 cells/mm³), severe lymphopenia (<500 cells/mm³), and low IgG (<500 mg/dl). 6
Osteoporosis Management
All patients should be assessed for adequate calcium and vitamin D intake, regular exercise, and smoking habits, with screening and follow-up according to existing guidelines for postmenopausal women and patients on steroids. 6
Cancer Screening
Cancer screening is recommended according to guidelines for the general population, including cervical smear tests. 6
Special Populations: Pregnancy
Safe Medications During Pregnancy
Hydroxychloroquine, azathioprine, prednisolone, and low-dose aspirin are safe medications during pregnancy. 3, 4
Contraindicated Medications
Mycophenolate mofetil, cyclophosphamide, and methotrexate must be avoided during pregnancy. 3, 4
High-Risk Monitoring
Patients with lupus nephritis and antiphospholipid antibodies have higher risk of preeclampsia and require closer monitoring. 4
Pregnancy can increase SLE disease activity, but flares are usually mild. 4
SLE can affect the fetus, especially if the mother has history of lupus nephritis, antiphospholipid antibodies, anti-Ro, and/or anti-La. 4
Non-Pharmacological Management
Non-pharmacological management should be tailored, person-centered, and participatory, complementing rather than replacing pharmacotherapy. 6
Patient education and support for self-management. 6
Physical exercise programs. 6
Smoking cessation interventions. 6
Avoidance of cold exposure (particularly important in SSc, but relevant for Raynaud's in SLE). 6
Psychosocial interventions for SLE patients. 6
Treatment Goals
The primary goal is to achieve remission or low disease activity state, defined by minimal symptoms, low levels of autoimmune inflammatory markers, and minimal systemic glucocorticoid requirement (<7.5 mg/day) while on maintenance immunomodulatory therapy. 1, 2
Reduce disease exacerbations and hospitalizations. 1
Prevent organ damage due to disease or treatment toxicity. 1, 2
Minimize damage accrual and drug side-effects. 4
Common Pitfalls to Avoid
Never withhold hydroxychloroquine unless there is a clear contraindication—non-adherence is associated with higher flare rates and mortality. 3, 4
Avoid prolonged high-dose glucocorticoids (>7.5 mg/day prednisone equivalent) as they increase irreversible organ damage risk. 3, 4
Do not delay immunosuppressive therapy in organ-threatening disease—early aggressive treatment prevents irreversible damage. 3
Always perform kidney biopsy before treating lupus nephritis—treatment decisions depend on histological classification. 3, 5
Never assume fever is solely due to lupus activity without excluding infection first—infection is the most critical differential diagnosis and must be ruled out before attributing fever to lupus activity alone. 4
Do not escalate immunosuppression empirically for fever alone without comprehensive infectious workup. 4
Do not discontinue hydroxychloroquine unless there is a specific contraindication. 4