What is the treatment approach for a patient with systemic lupus erythematosus (SLE)?

Treatment of Systemic Lupus Erythematosus

Foundation Therapy: Universal for All Patients

All patients with SLE must receive hydroxychloroquine at ≤5 mg/kg real body weight unless absolutely contraindicated, as this reduces disease activity, prevents flares, improves survival, and reduces mortality. 1, 2, 3

• The dose must not exceed 5 mg/kg of real body weight to minimize retinal toxicity risk, which exceeds 10% after 20 years of continuous use 2, 4
• Ophthalmological screening is mandatory at baseline, after 5 years, then yearly thereafter using visual fields examination and/or spectral domain-optical coherence tomography 2, 4
• Hydroxychloroquine is safe during pregnancy and should be continued 1, 4

Glucocorticoid Management Algorithm

Glucocorticoids must be minimized to <7.5 mg/day prednisone equivalent and withdrawn when possible to prevent organ damage. 1, 2

• For acute flares or severe presentations: IV methylprednisolone pulse therapy (250-1000 mg daily for 1-3 days) provides immediate therapeutic effect and enables lower starting doses of oral glucocorticoids 1, 2
• Promptly add immunosuppressive agents to expedite glucocorticoid tapering and discontinuation 2
• The chronic maintenance goal is <7.5 mg/day prednisone equivalent 1, 2

Immunosuppressive Therapy Selection by Disease Severity

Mild Disease (Skin and Joint Manifestations Without Major Organ Involvement)

Add methotrexate if hydroxychloroquine and low-dose glucocorticoids are insufficient. 1, 2, 4

• NSAIDs may be used judiciously for limited periods in patients at low risk for complications 1
• Azathioprine is an alternative, particularly suitable for women contemplating pregnancy 2, 4

Moderate Disease Requiring Glucocorticoid-Sparing

Add azathioprine or mycophenolate mofetil when patients fail to respond to hydroxychloroquine alone or cannot reduce steroids below acceptable doses for chronic use. 1, 2

• Azathioprine is preferred for women contemplating pregnancy 2, 4
• Mycophenolate mofetil is effective for renal and non-renal manifestations except neuropsychiatric disease 2, 4

Severe Organ-Threatening Disease

Initiate cyclophosphamide or mycophenolate mofetil for severe organ-threatening or life-threatening SLE, especially renal, cardiopulmonary, or neuropsychiatric manifestations. 2, 4

Organ-Specific Treatment Protocols

Lupus Nephritis

Kidney biopsy is essential before initiating therapy, as histological classification determines treatment selection and prognosis. 2, 4

Induction therapy: Mycophenolate mofetil or low-dose IV cyclophosphamide (Euro-Lupus regimen) are first-line agents with the best efficacy/toxicity ratio 2, 4

• Low-dose cyclophosphamide is preferred over high-dose due to comparable efficacy and lower gonadotoxicity 1

Maintenance therapy: Mycophenolate mofetil or azathioprine after achieving initial response 2, 4

• Treatment goals include at least partial remission (≥50% reduction in proteinuria to subnephrotic levels and serum creatinine within 10% of baseline) by 6-12 months 2, 4

Neuropsychiatric Lupus

Treatment depends on the underlying pathophysiological mechanism—exclude infection aggressively before initiating immunosuppressive therapy. 1, 4

For inflammatory/immune-mediated mechanisms: High-dose IV methylprednisolone plus cyclophosphamide 1, 2

• Major inflammatory manifestations include optic neuritis, acute confusional state/coma, cranial or peripheral neuropathy, psychosis, and transverse myelitis/myelopathy 1

For thrombotic/embolic mechanisms: Anticoagulation with warfarin (target INR 2.0-3.0 for first venous thrombosis; 3.0-4.0 for arterial or recurrent thrombosis) 2, 4

When both mechanisms coexist: Combination of immunosuppressive and anticoagulant/antithrombotic therapy 1, 2

Hematological Manifestations

For significant thrombocytopenia (platelets <30,000/mm³): initiate IV methylprednisolone pulses plus an immunosuppressive agent (azathioprine, mycophenolate mofetil, or cyclosporine). 2, 5

• IVIG may be considered in the acute phase or with inadequate response to glucocorticoids 2, 5
• For refractory cases: rituximab or cyclophosphamide 2

Cutaneous Manifestations

First-line treatment includes topical glucocorticoids, topical calcineurin inhibitors, and hydroxychloroquine. 2

• Photo-protection with sunscreens is mandatory to prevent cutaneous flares 1, 4

Biologic Therapies for Refractory Disease

Belimumab (anti-BAFF antibody) is FDA-approved as add-on treatment for active extrarenal SLE and lupus nephritis when standard therapy is insufficient. 2, 4, 6, 3

• Dosing for adults with SLE: 10 mg/kg IV at 2-week intervals for the first 3 doses, then at 4-week intervals thereafter, or 200 mg subcutaneously once weekly 6
• Dosing for adults with lupus nephritis: 400 mg subcutaneously (two 200-mg injections) once weekly for 4 doses, then 200 mg once weekly thereafter 6

Rituximab should be considered for organ-threatening disease refractory to standard immunosuppressive agents, particularly for hematological manifestations. 2, 4

Anifrolumab (anti-type 1 interferon receptor) is approved for moderate-to-severe extrarenal SLE. 2, 4, 3

Voclosporin is FDA-approved for lupus nephritis. 2, 3

Adjunctive Therapies and Comorbidity Prevention

Low-dose aspirin for patients with antiphospholipid antibodies, those receiving corticosteroids, or those with cardiovascular risk factors. 2, 4

Calcium and vitamin D supplementation for all patients on long-term glucocorticoids to prevent osteoporosis. 2, 4

Lifestyle modifications (smoking cessation, weight control, exercise) should be encouraged. 1

Monitoring Parameters

Use validated activity indices (BILAG, ECLAM, or SLEDAI) at each visit. 1, 2

Monitor at every visit: Anti-dsDNA, C3, C4, complete blood count, creatinine, proteinuria, and urine sediment 1, 2, 4

Screen aggressively for comorbidities: SLE patients have a 5-fold increased mortality risk; screen for infections, cardiovascular disease, hypertension, diabetes, dyslipidemia, osteoporosis, avascular necrosis, and malignancies (especially non-Hodgkin lymphoma) 1, 2, 4

Critical Pitfalls to Avoid

Do not use mycophenolate mofetil, cyclophosphamide, or methotrexate in women who are pregnant or contemplating pregnancy—azathioprine, hydroxychloroquine, and prednisolone are safe alternatives 1, 4

Do not attribute all neuropsychiatric symptoms to SLE without excluding infection (especially in immunosuppressed patients), metabolic causes, or medication side effects (steroid-induced psychosis) 4

Do not delay kidney biopsy in suspected lupus nephritis—histological classification is essential for treatment selection and prognosis 2, 4

Do not overlook antiphospholipid antibody syndrome—it requires anticoagulation in addition to immunosuppression 2, 4, 5

Live vaccines should not be given concurrently with immunosuppressive therapy or belimumab. 6