What is the recommended treatment regimen for systemic lupus erythematosus, including first‑line therapy and stepwise escalation for organ involvement?

Treatment of Systemic Lupus Erythematosus

Foundation Therapy (Mandatory for All Patients)

Hydroxychloroquine is the cornerstone of SLE treatment and must be initiated in all patients unless contraindicated, at a dose not exceeding 5 mg/kg real body weight per day (typically 200-400 mg daily). 1, 2, 3

• Hydroxychloroquine reduces disease activity, prevents flares, improves survival, and reduces mortality in all SLE patients. 1, 2, 4
• Ophthalmological screening is mandatory at baseline, after 5 years of therapy, and yearly thereafter using visual fields examination and/or spectral domain-optical coherence tomography to monitor for retinal toxicity. 1, 2
• Non-adherence to hydroxychloroquine is associated with higher flare rates and mortality—never withhold unless there is a clear contraindication. 2

Additional universal measures include:

• Strict photoprotection with broad-spectrum sunscreens to prevent cutaneous flares. 2, 5
• Low-dose aspirin for patients with antiphospholipid antibodies, those receiving corticosteroids, or those with cardiovascular risk factors. 1, 2
• Calcium and vitamin D supplementation for all patients on long-term glucocorticoids. 1, 2
• Smoking cessation, as smoking reduces antimalarial efficacy and worsens cutaneous lupus. 5

Glucocorticoid Management Strategy

For acute flares or initial presentation, use intravenous methylprednisolone pulse therapy (250-1000 mg daily for 1-3 days) to provide immediate therapeutic effect and enable lower starting doses of oral glucocorticoids. 1, 6

• Oral glucocorticoids should be aggressively tapered with a goal of less than 7.5 mg/day prednisone equivalent for chronic maintenance. 1, 7
• Glucocorticoids must be withdrawn when possible to prevent irreversible organ damage—prolonged high-dose glucocorticoids (>7.5 mg/day) substantially increase damage accrual risk. 1, 2, 7
• Prompt initiation of immunomodulatory agents expedites glucocorticoid tapering and discontinuation. 1, 7

Immunosuppressive Therapy Selection by Manifestation

For mild-to-moderate disease (skin and joint manifestations):

• Methotrexate is the preferred first choice due to cost, availability, and efficacy for musculoskeletal and cutaneous manifestations. 1, 2

For maintenance therapy:

• Azathioprine is recommended, particularly suitable for women contemplating pregnancy. 1, 7

For moderate-to-severe non-renal manifestations:

• Mycophenolate mofetil is recommended for renal and non-renal manifestations (except neuropsychiatric disease). 1, 7

For severe organ-threatening or life-threatening disease:

• Cyclophosphamide is recommended for severe organ-threatening SLE, especially renal, cardiopulmonary, or neuropsychiatric manifestations. 1, 7

Lupus Nephritis Treatment Protocol

Kidney biopsy is essential before initiating therapy to confirm diagnosis and guide treatment planning. 1, 2

Induction therapy (first 3-6 months):

• Mycophenolate mofetil OR low-dose intravenous cyclophosphamide are first-line options with the best efficacy/toxicity ratio. 1, 2, 7
• Low-dose cyclophosphamide is preferred over high-dose cyclophosphamide due to comparable efficacy and lower gonadotoxicity. 1
• Combine with glucocorticoids (IV methylprednisolone pulses followed by oral prednisone with rapid taper). 1, 7

Add-on therapy for lupus nephritis:

• Belimumab should be considered as add-on therapy for active lupus nephritis. 1, 8, 7
• Voclosporin (calcineurin inhibitor) should be considered as add-on therapy for lupus nephritis. 1, 7

Maintenance therapy (after achieving response):

• Mycophenolate mofetil OR azathioprine for long-term maintenance. 1, 2, 7
• Goal is at least partial remission (≥50% reduction in proteinuria to subnephrotic levels) by 6-12 months. 1

Neuropsychiatric Lupus Treatment Algorithm

Perform comprehensive diagnostic workup and exclude infection aggressively before initiating immunosuppressive therapy. 1

For inflammatory/immune-mediated mechanisms:

• High-dose intravenous methylprednisolone PLUS cyclophosphamide is recommended (response rate 95% vs 54% with methylprednisolone alone). 1

For 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. 1

When both mechanisms coexist:

• Combination of immunosuppressive and anticoagulant/antithrombotic therapy. 1

Hematological Manifestations Treatment

For significant thrombocytopenia:

• First-line treatment includes high-dose glucocorticoids (including IV methylprednisolone pulses) combined with immunosuppressive agents (azathioprine, mycophenolate mofetil, or cyclosporine). 1
• Intravenous immunoglobulin G may be considered in the acute phase or with inadequate response to glucocorticoids. 1
• For refractory cases: rituximab or cyclophosphamide. 1

Cutaneous Lupus Treatment Escalation

First-line approach:

• Medium- to high-potency topical corticosteroids (triamcinolone or clobetasol) to affected areas twice daily; use low-potency hydrocortisone on facial lesions. 5
• Topical calcineurin inhibitors (tacrolimus) as alternative for facial involvement to avoid skin atrophy. 5
• Ensure hydroxychloroquine is optimized at ≤5 mg/kg real body weight. 5

For widespread or severe cutaneous disease:

• Add short-term systemic glucocorticoids (prednisone equivalent) with rapid taper. 5

For refractory cutaneous disease:

• Methotrexate is effective for various cutaneous manifestations. 5
• Mycophenolate mofetil is effective for refractory cutaneous disease. 5
• Dapsone is particularly effective for bullous lupus and urticarial vasculitis. 5
• Retinoids are useful for hyperkeratotic and hypertrophic lesions. 5

Biologic Therapies for Inadequate Response to Standard Therapy

Belimumab (anti-BAFF antibody) should be added for patients with inadequate response to standard therapy (hydroxychloroquine + glucocorticoids ± immunosuppressants). 1, 2, 8

• FDA-approved for active extrarenal SLE (2011) and lupus nephritis (2020). 1, 4
• Can be administered intravenously or subcutaneously (200 mg once weekly). 8
• In pediatric SLE, belimumab plus standard therapy achieved 52% SRI-4 response vs 44% with placebo at Week 52. 8

Anifrolumab (anti-type 1 interferon receptor) is FDA-approved for moderate-to-severe extrarenal SLE. 1, 7

Rituximab should be considered for organ-threatening disease refractory to or with intolerance/contraindications to standard immunosuppressive agents. 1, 2, 7

Treatment Goals and Monitoring

Primary treatment goal is achieving remission or low disease activity state while minimizing glucocorticoid exposure to <7.5 mg/day prednisone equivalent. 1, 7

At each visit, monitor:

• Validated activity indices (SLEDAI, BILAG, or ECLAM). 1, 2
• Anti-dsDNA, C3, C4, complete blood count, creatinine, proteinuria, and urine sediment. 1, 2

Comorbidity screening (SLE patients have 5-fold increased mortality risk):

• Screen for infections (including HIV, HCV/HBV, tuberculosis, CMV before immunosuppression). 1, 2
• Screen for cardiovascular disease, hypertension, diabetes, dyslipidemia, atherosclerosis. 1, 2
• Screen for osteoporosis, avascular bone necrosis. 1, 2
• Screen for malignancies (especially non-Hodgkin lymphoma, lung cancer, hepatobiliary cancer). 1, 2

Vaccination:

• Administer inactivated vaccines (influenza, pneumococcus) when SLE is inactive. 2

Special Considerations for Pregnancy

Safe medications during pregnancy:

• Hydroxychloroquine, azathioprine, prednisolone, and low-dose aspirin may be used. 2, 5

Contraindicated medications during pregnancy:

• Mycophenolate mofetil, cyclophosphamide, and methotrexate must be avoided. 2, 5

Pregnancy planning:

• Patients with lupus nephritis and antiphospholipid antibodies have higher risk of preeclampsia and require closer monitoring. 2, 5
• Pregnancy should be postponed for 6 months after withdrawal of bisphosphonates. 1

Critical Pitfalls to Avoid

• Never assume fever is solely due to lupus activity without excluding infection first—infection is the most critical differential diagnosis. 5
• Do not delay immunosuppressive therapy in organ-threatening disease—early aggressive treatment prevents irreversible damage. 2
• Avoid prolonged high-dose glucocorticoids as risks substantially increase above 7.5 mg/day continuous dosing. 2, 7
• Always perform kidney biopsy before treating lupus nephritis—treatment decisions depend on histological classification. 2