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

Management of Systemic Lupus Erythematosus

Core Treatment Foundation

All patients with SLE should receive hydroxychloroquine as the cornerstone of therapy at a dose not exceeding 5 mg/kg real body weight, unless specifically contraindicated, as this reduces disease activity, flares, organ damage, and mortality. 1, 2

• Hydroxychloroquine is standard of care and has been associated with significant reduction in mortality 2
• Regular ophthalmological screening is mandatory at baseline, after 5 years, and yearly thereafter to monitor for retinal toxicity 1
• Never discontinue hydroxychloroquine unless there is a specific contraindication, as it improves survival even in severe disease 3

Treatment Goals

Aim for clinical remission or low disease activity state, defined as minimal symptoms, low autoimmune inflammatory markers, and glucocorticoid requirement ≤7.5 mg/day prednisone equivalent. 1, 3, 2

• The primary goal is achieving disease remission or quiescence while minimizing organ damage from both disease activity and treatment toxicity 2
• Prevention of disease exacerbations, hospitalizations, and organ damage are critical secondary goals 2

Initial Evaluation and Monitoring

Perform comprehensive baseline assessment including clinical manifestations, laboratory markers, and immunological tests to establish disease activity and guide treatment intensity. 1

Baseline Assessment Must Include:

• Clinical signs: skin lesions, arthritis, serositis, neurological manifestations 1
• Laboratory tests: complete blood count, serum creatinine, proteinuria, urine sediment 1
• Immunological tests: C3/C4, anti-dsDNA, anti-Ro/SSA, anti-La/SSB, antiphospholipid antibodies, anti-RNP 1

Ongoing Monitoring:

• Use validated disease activity indices (SLEDAI, BILAG, or ECLAM) to objectively track disease activity and detect flares early 1, 3
• Monitor every 3 months for stable patients with clinical examination, complete blood count, serum creatinine, urinalysis with microscopy, C3/C4 levels, and anti-dsDNA antibodies 3

Pharmacological Treatment Algorithm

Mild to Moderate Disease (Mucocutaneous, Musculoskeletal):

Start with hydroxychloroquine plus topical glucocorticoids for localized manifestations. 1

• For widespread or severe cutaneous disease, add short-term systemic glucocorticoids (prednisone equivalent) 1
• For refractory cases, add immunomodulatory agents: methotrexate (effective for various cutaneous manifestations), azathioprine, or mycophenolate mofetil 1, 2
• Methotrexate is on par with azathioprine for moderate disease 4

Moderate to Severe Disease (Organ-Threatening):

Initiate glucocorticoids plus immunosuppressive agents (mycophenolate mofetil, azathioprine, or cyclophosphamide for life-threatening situations). 2, 4

• Cyclophosphamide is reserved only for life-threatening situations such as lupus nephritis or CNS vasculitis, and in drastically reduced doses compared to historical protocols 4
• Mycophenolate mofetil is effective for lupus nephritis and refractory disease 1, 4
• Azathioprine is used for maintenance therapy after achieving initial response in organ-threatening disease, or as a glucocorticoid-sparing agent 5

Refractory Disease:

For cases unresponsive to standard immunosuppressive therapy, add belimumab or consider rituximab off-label. 1, 6, 4

• Belimumab (10 mg/kg IV at 2-week intervals for first 3 doses, then every 4 weeks) is FDA-approved for active SLE and demonstrated 49% response rate versus 42% placebo in clinical trials 6
• Belimumab can be added to standard therapy and has shown efficacy in reducing disease activity 6
• Rituximab is used off-label in refractory disease courses 4
• Anifrolumab is another FDA-approved option for active SLE 2

Lupus Nephritis-Specific Management

For active proliferative and/or membranous lupus nephritis (Class III, IV, V), use glucocorticoids plus either mycophenolate or cyclophosphamide for induction, followed by maintenance immunosuppression. 6, 2

• Belimumab 10 mg/kg IV is FDA-approved for lupus nephritis, showing 43% primary efficacy renal response at Week 104 versus 32% placebo 6
• Voclosporin is FDA-approved specifically for lupus nephritis 2
• Renal biopsy, urine sediment analysis, proteinuria, and renal function have independent predictive value for clinical outcome 1
• Approximately 40% of people with SLE develop lupus nephritis, and 10% progress to end-stage kidney disease after 10 years 2

Glucocorticoid Management

Minimize chronic glucocorticoid exposure to <7.5 mg/day prednisone equivalent and withdraw when possible to reduce risks of infection, osteoporosis, and cardiovascular disease. 1, 3

• Systemic glucocorticoids should be minimized to less than 7.5 mg/day for chronic maintenance 1
• Prompt initiation of immunomodulatory agents can expedite the tapering/discontinuation of glucocorticoids 1
• Avoid prolonged high-dose glucocorticoids (>7.5 mg/day prednisone for >3 months) to minimize treatment-related complications 3

Non-Pharmacological Management

All patients must implement strict photoprotection, achieve smoking cessation, engage in regular physical activity, and maintain optimal cardiovascular risk factor control. 7, 5

Photoprotection:

• Use SPF 60+ broad-spectrum sunscreen daily, avoid sun exposure during peak hours, and wear protective clothing 5
• Photoprotection prevents development of new skin lesions and is beneficial for all patients with cutaneous manifestations 1, 5

Smoking Cessation:

• Achieve complete smoking cessation immediately, as smoking impairs response to antimalarial therapy, increases disease activity, and accelerates cardiovascular damage 5
• Assess smoking status at baseline and annually 5

Physical Activity:

• Engage in regular physical activity to reduce disease activity and improve outcomes 5
• Patients should be offered education and support for physical exercise 7

Cardiovascular Risk Management:

• Assess and aggressively manage all modifiable cardiovascular risk factors at baseline and annually: blood pressure, LDL cholesterol, fasting glucose, and body mass index 5
• Consider low-dose aspirin for primary prevention in patients with antiphospholipid antibodies, those on chronic glucocorticoids, or those with multiple traditional cardiovascular risk factors 5

Management of Comorbidities

Screen for and aggressively manage comorbidities including infections, atherosclerosis, hypertension, dyslipidemia, diabetes, and osteoporosis. 1, 5

Infection Prevention:

• Screen for latent infections at baseline: HIV, hepatitis B and C, tuberculosis, and CMV in immunosuppressed patients 5, 3
• Vaccinate according to guidelines for immunocompromised patients: annual influenza, pneumococcal, and COVID-19 vaccines 5
• Consider Pneumocystis jirovecii prophylaxis (trimethoprim-sulfamethoxazole) if using high-dose glucocorticoids or multiple immunosuppressants 3
• Live vaccines should not be given concurrently with belimumab or other immunosuppressive therapy 6

Bone Health:

• Ensure adequate calcium intake and vitamin D supplementation for all patients, particularly those on glucocorticoids 5
• Assess calcium and vitamin D intake, weight-bearing exercise habits, and smoking status at baseline and annually 5

Cardiovascular Disease:

• Patients with SLE have increased risk for atherosclerosis, hypertension, and dyslipidemia 1
• Aggressively manage traditional cardiovascular risk factors, as cumulative damage compounds the inflammatory burden of SLE itself 5

Special Populations

Antiphospholipid Antibody-Positive Patients:

• Consider low-dose aspirin for primary prevention of thrombosis and pregnancy loss 1
• Evaluate other risk factors for thrombosis 1
• Avoid estrogen-containing contraceptives due to increased thrombosis risk 1, 5
• For non-pregnant patients with antiphospholipid-associated thrombosis, use long-term anticoagulation with oral anticoagulants for secondary prevention 1

Pregnancy:

• Pregnancy can increase SLE disease activity, but flares are usually mild 1
• Patients with lupus nephritis and antiphospholipid antibodies have higher risk of preeclampsia and require closer monitoring 1
• Safe medications during pregnancy: prednisolone, azathioprine, hydroxychloroquine, and low-dose aspirin 1
• Avoid during pregnancy: mycophenolate mofetil, cyclophosphamide, and methotrexate 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 and must be ruled out before attributing symptoms to lupus activity alone 1, 3
• Do not escalate immunosuppression empirically for fever alone without comprehensive infectious workup 1
• Never discontinue hydroxychloroquine unless there is a specific contraindication 3
• Avoid prolonged high-dose glucocorticoids - risks substantially increase above 7.5 mg/day continuous dosing 1, 3
• Do not overlook cardiovascular risk factors - cumulative damage from inadequately controlled traditional risk factors compounds the inflammatory burden of SLE 5