What is the treatment approach for Systemic Lupus Erythematosus (SLE) according to National Institutes of Health (NIH) protocols?

Treatment Approach for Systemic Lupus Erythematosus (SLE)

All patients with SLE should receive hydroxychloroquine at ≤5 mg/kg real body weight as foundational therapy, combined with glucocorticoids tailored to disease severity, with the primary goal of achieving remission or low disease activity while minimizing chronic steroid exposure to <7.5 mg/day prednisone equivalent. 1

Foundation Therapy (All Patients)

• Hydroxychloroquine is mandatory for all SLE patients unless contraindicated, dosed at ≤5 mg/kg real body weight, as it reduces disease activity, prevents flares, and improves survival 1, 2
• Ophthalmological screening must be performed at baseline, after 5 years, then yearly thereafter using visual fields examination and/or spectral domain-optical coherence tomography 1
• Photoprotection with sunscreens prevents 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 3, 4

Glucocorticoid Management Algorithm

Acute/Severe Disease

• 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, 5
• Follow with oral prednisone 0.5-1 mg/kg/day depending on severity 3, 4
• Never exceed prednisone >1 mg/kg/day or >60 mg/day, as higher doses do not improve outcomes and accelerate damage accrual 5

Chronic Maintenance

• Glucocorticoids must be minimized to <7.5 mg/day prednisone equivalent and withdrawn when possible 1
• Prompt initiation of immunomodulatory agents expedites glucocorticoid tapering/discontinuation 1

Immunosuppressive Therapy Selection

Mild-Moderate Disease (Inadequate Response to HCQ + GC)

Add one of the following immunomodulating agents:

• Methotrexate for skin and joint manifestations 1, 3, 4
• Azathioprine for maintenance therapy, particularly suitable for women contemplating pregnancy 1, 3, 4
• Mycophenolate mofetil for renal and non-renal manifestations (except neuropsychiatric disease) 1, 3, 4

Severe Organ-Threatening Disease

• Cyclophosphamide for severe organ-threatening or life-threatening SLE, especially renal, cardiopulmonary, or neuropsychiatric manifestations 1, 3
• Cyclophosphamide also serves as 'rescue' therapy in patients not responding to other immunosuppressive agents 1

Organ-Specific Treatment Protocols

Lupus Nephritis (Class III-IV)

• Kidney biopsy is essential before initiating therapy 1, 3
• Induction therapy: Mycophenolate mofetil (1a/A) or low-dose IV cyclophosphamide (2a/b) as they have the best efficacy/toxicity ratio 1
• For high-risk patients (reduced GFR, fibrous crescents, fibrinoid necrosis, or tubular atrophy/interstitial fibrosis), high-dose IV cyclophosphamide can be used 1
• Maintenance therapy: Mycophenolate mofetil (1a/A) or azathioprine (1a/A) 1
• Mycophenolate may be combined with low-dose calcineurin inhibitor in severe nephrotic syndrome or incomplete renal response, absent uncontrolled hypertension, high chronicity index, or reduced GFR 1

Neuropsychiatric Lupus (NPSLE)

• Attribution to SLE versus non-SLE causes is essential using neuroimaging, cerebrospinal fluid investigation, and exclusion of confounding factors 1
• For inflammatory/immune-mediated mechanisms: High-dose IV methylprednisolone plus cyclophosphamide 3, 5
• For thrombotic/embolic mechanisms: Anticoagulation with warfarin (INR 2.0-3.0 for first venous thrombosis; INR 3.0-4.0 for arterial or recurrent thrombosis) 3
• Rituximab is an alternative for severe acute neurologic manifestations but has lower quality evidence 5

Hematological Manifestations

• Acute lupus thrombocytopenia: High-dose glucocorticoids (including IV methylprednisolone pulses) and/or IV immunoglobulin G 1
• Maintenance: Mycophenolate, azathioprine, or cyclosporine 1
• Refractory cases: Rituximab or cyclophosphamide 1, 5
• For severe hemolytic anemia (hemoglobin ≤8 g/dL): High-dose glucocorticoids alone as first-line, reserving rituximab for refractory cases 5

Cutaneous Manifestations

• First-line: Topical glucocorticoids, topical calcineurin inhibitors, and hydroxychloroquine 1
• Non-responsive cases requiring high-dose GC: Add methotrexate, retinoids, dapsone, or mycophenolate 1

Biologic Therapies for Refractory Disease

When to Consider Biologics

In patients with inadequate response to standard-of-care (HCQ + GC ± immunosuppressive agents), defined as residual disease activity not allowing glucocorticoid tapering and/or frequent relapses 1

Specific Biologic Agents

• Belimumab (anti-BAFF antibody): FDA-approved for active extrarenal SLE and lupus nephritis; add-on treatment should be considered (1a/A) 1, 3
• Anifrolumab (anti-type 1 interferon receptor): FDA-approved for moderate-to-severe extrarenal SLE 3, 4
• Voclosporin: FDA-approved for lupus nephritis 3, 4
• Rituximab: Consider for organ-threatening disease refractory to or with intolerance/contraindications to standard immunosuppressive agents 1, 4

Crisis Management (Life-Threatening Disease)

Diffuse Alveolar Hemorrhage

Add cyclophosphamide and/or IV immunoglobulin and/or therapeutic plasma exchange and/or rituximab to high-dose glucocorticoids, with cost and availability typically favoring glucocorticoids plus cyclophosphamide 5

Severe Acute Neurologic Manifestations

Add cyclophosphamide to glucocorticoids for seizures, psychosis, myelitis, peripheral neuropathy, brain stem disease, or optic neuritis 5

Monitoring Protocol

• Use validated activity indices at each visit 3, 4
• Monitor anti-dsDNA, C3, C4, complete blood count, creatinine, proteinuria, and urine sediment regularly 3, 4
• SLE patients have 5-fold increased mortality risk; screen aggressively for infections, cardiovascular disease, hypertension, diabetes, dyslipidemia, osteoporosis, avascular necrosis, and malignancies (especially non-Hodgkin lymphoma) 3, 4

Pregnancy Considerations

• Safe medications: Prednisolone, azathioprine, hydroxychloroquine, and low-dose aspirin 3, 4
• Contraindicated medications: Mycophenolate mofetil, cyclophosphamide, and methotrexate 3, 4

Critical Pitfalls to Avoid

• Never delay immunosuppressive therapy in organ-threatening disease, as glucocorticoids alone are insufficient and lead to prolonged high-dose steroid exposure 5
• Failure to perform kidney biopsy before treating lupus nephritis leads to suboptimal therapy selection 3, 4
• NSAIDs should only be used judiciously for limited periods in patients at low risk for complications 4
• Consider gonadal toxicity when using cyclophosphamide in reproductive-age patients and counsel about fertility preservation options 5
• Maintain high index of suspicion for infection in immunosuppressed patients; obtain cultures before initiating immunosuppression when infection cannot be excluded 5