What is the initial treatment approach for a patient with Systemic Lupus Erythematosus (SLE)?

Treatment for Systemic Lupus Erythematosus (SLE)

Foundation Therapy - Universal for All SLE Patients

Hydroxychloroquine at ≤5 mg/kg real body weight is mandatory for all SLE patients unless contraindicated and must be started immediately upon diagnosis, as it reduces disease activity, prevents flares, improves survival, and reduces mortality. 1

• 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
• Ophthalmological screening is required at baseline, after 5 years, then yearly thereafter using visual fields examination and/or spectral domain-optical coherence tomography 1, 2
• Hydroxychloroquine should never be discontinued unless there is a specific contraindication 3

Glucocorticoid Management Strategy

Glucocorticoids must be aggressively tapered with a goal of <7.5 mg/day prednisone equivalent and withdrawn when possible to prevent organ damage. 1

• For acute flares or initial presentation, use IV methylprednisolone pulse therapy (250-1000 mg daily for 1-3 days), which provides immediate therapeutic effect and enables lower starting doses of oral glucocorticoids 1
• Prompt initiation of immunomodulatory agents expedites glucocorticoid tapering/discontinuation 1
• Risks substantially increase above 7.5 mg/day continuous dosing 3

Immunosuppressive Agent Selection Algorithm

The choice of immunosuppressive agent depends on organ involvement and disease severity:

For Mild Disease (Skin and Joint Manifestations)

• Methotrexate is the preferred agent for skin and joint manifestations when hydroxychloroquine and low-dose glucocorticoids are insufficient 1, 2
• For discoid lupus specifically: topical agents and hydroxychloroquine first-line, then azathioprine, then mycophenolate 4
• For arthritis: hydroxychloroquine and/or glucocorticoids first, then methotrexate, then rituximab 4

For Moderate Disease Requiring Glucocorticoid-Sparing

• Azathioprine is recommended for maintenance therapy and is particularly suitable for women contemplating pregnancy 1, 2
• Mycophenolate mofetil is recommended for renal and non-renal manifestations except neuropsychiatric disease 1, 2

For Severe Organ-Threatening Disease

• Cyclophosphamide is recommended for severe organ-threatening or life-threatening SLE, especially renal, cardiopulmonary, or neuropsychiatric manifestations 1, 2

Organ-Specific Treatment Protocols

Lupus Nephritis

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

• Induction therapy: Mycophenolate mofetil or low-dose IV cyclophosphamide (Euro-Lupus regimen) are first-line agents with the best efficacy/toxicity ratio 1, 2
• Maintenance therapy: Mycophenolate mofetil or azathioprine after achieving initial response 1, 2
• 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

Neuropsychiatric Lupus (NPSLE)

Treatment depends on the underlying pathophysiological mechanism - never assume neuropsychiatric symptoms are due to SLE without excluding infection, metabolic causes, or medication side effects. 2

• For inflammatory/immune-mediated mechanisms: high-dose IV methylprednisolone plus cyclophosphamide 1, 4
• For embolic/thrombotic/ischemic mechanisms: anticoagulation with warfarin (target INR 2.0-3.0 for first venous thrombosis, 3.0-4.0 for arterial or recurrent thrombosis) 1, 2
• For mononeuritis multiplex and CNS vasculitis: glucocorticoids and cyclophosphamide first-line, then maintenance with azathioprine or mycophenolate, then rituximab, IVIG, or plasmapheresis 4

Hematological Manifestations

• For significant thrombocytopenia: high-dose glucocorticoids (including IV methylprednisolone pulses) and/or IV immunoglobulin G 1
• For refractory cases: rituximab or cyclophosphamide 1

Cutaneous Manifestations

• First-line: topical glucocorticoids or calcineurin inhibitors plus hydroxychloroquine 1, 3
• For widespread or severe disease: add short-term systemic glucocorticoids 3
• For refractory cases: methotrexate, azathioprine, or mycophenolate mofetil 3

Biologic Therapies for Refractory Disease

When there is inadequate response to standard therapy, residual disease activity, or frequent relapses, biologics should be considered. 1

• Belimumab (anti-BAFF antibody) is FDA-approved as add-on treatment for active extrarenal SLE and lupus nephritis when standard therapy is insufficient 1, 2, 5
• Rituximab should be considered for organ-threatening disease refractory to standard immunosuppressive agents, particularly for hematological manifestations 1, 2
• Anifrolumab (anti-type 1 interferon receptor) is approved for moderate-to-severe extrarenal SLE 1, 2
• Voclosporin is FDA-approved for lupus nephritis 1

Adjunctive Therapies - Essential for All Patients

• 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 to prevent osteoporosis 1, 2
• Photoprotection with sunscreens to prevent cutaneous flares 1, 2

Monitoring and Comorbidity Screening

Use validated disease activity indices (SLEDAI, BILAG, or ECLAM) at each visit. 1, 3

• Monitor anti-dsDNA, C3, C4, complete blood count, creatinine, proteinuria, and urine sediment at each visit 1, 3
• SLE patients have a 5-fold increased mortality risk - screen aggressively for infections, cardiovascular disease, hypertension, diabetes, dyslipidemia, osteoporosis, and malignancies (especially non-Hodgkin lymphoma) 1, 3

Critical Pitfalls to Avoid

• Never attribute fever solely 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 3
• Do not escalate immunosuppression empirically for fever alone without comprehensive infectious workup 3
• Do not use mycophenolate mofetil, cyclophosphamide, or methotrexate in women who are pregnant or contemplating pregnancy - azathioprine, hydroxychloroquine, and prednisolone are safe alternatives 3, 2
• Do not delay kidney biopsy in suspected lupus nephritis - histological classification is essential for treatment selection 2
• Do not overlook antiphospholipid antibody syndrome - requires anticoagulation in addition to immunosuppression 2
• Live vaccines should not be given concurrently with belimumab or other immunosuppressive therapy 5