What are the symptoms and treatment options for a Systemic Lupus Erythematosus (SLE) nephritis flare?

From the Guidelines

A lupus nephritis flare requires prompt treatment with immunosuppressive therapy, and the standard approach involves a combination of high-dose corticosteroids plus either mycophenolate mofetil (MMF) or cyclophosphamide, as recommended by the most recent guidelines 1. The treatment of lupus nephritis flare should be based on the severity of the flare and the patient's specific factors, such as the class of lupus nephritis and the presence of other organ involvement.

• The initial therapy should include high-dose corticosteroids, typically prednisone 0.5-1 mg/kg/day, plus either MMF at 2-3 g/day or cyclophosphamide (either IV pulses of 500-750 mg/m² monthly or lower-dose Euro-Lupus regimen of 500 mg every 2 weeks for 6 doses) 1.
• For severe flares, methylprednisolone pulse therapy (500-1000 mg IV daily for 3 days) may be given initially, as recommended by the 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus 1.
• The induction therapy typically continues for 3-6 months, followed by maintenance therapy with lower-dose prednisone (≤10 mg/day) plus either MMF (1-2 g/day) or azathioprine (1.5-2.5 mg/kg/day) 1.
• Hydroxychloroquine (5 mg/kg/day) should be continued or initiated as background therapy, as it has been shown to be effective in reducing the risk of flares and improving patient outcomes 1.
• Blood pressure control with ACE inhibitors or ARBs is essential, targeting <130/80 mmHg, to reduce the risk of kidney damage and improve patient outcomes.
• Regular monitoring of kidney function, urinary protein, complete blood count, and lupus serologies is necessary to assess response and adjust treatment as needed. The goal of treatment is to rapidly suppress inflammation and prevent permanent kidney damage, as persistent inflammation leads to fibrosis and irreversible nephron loss.
• Treatment adjustments may be needed based on the class of lupus nephritis, severity of the flare, and patient-specific factors, and the treatment should be individualized to each patient's needs.
• The most recent guidelines from the KDIGO 2024 clinical practice guideline for the management of lupus nephritis recommend that LN relapse should be treated with the same initial therapy used to achieve the original response, or an alternative recommended therapy 1.

From the FDA Drug Label

The proportion of patients having at least 1 severe flare over 52 weeks was not consistently significantly different for BENLYSTA plus standard therapy relative to placebo plus standard therapy in both trials In Trial 2,18% of patients receiving BENLYSTA 10 mg/kg plus standard therapy and 16% of patients receiving BENLYSTA 1 mg/kg plus standard therapy had a severe flare compared with 24% of patients receiving placebo plus standard therapy. In Trial 3,14%, 18%, and 23% of patients receiving BENLYSTA 10 mg/kg, BENLYSTA 1 mg/kg and placebo, respectively, plus standard therapy had a severe flare. The primary efficacy endpoint was Primary Efficacy Renal Response (PERR) at Week 104, defined as a response at Week 100 confirmed by a repeat measurement at Week 104 of the following parameters: urine protein:creatinine ratio (uPCR) ≤0.7 g/g and estimated glomerular filtration rate (eGFR) ≥60 mL/min/1. 73 m2 or no decrease in eGFR of >20% from pre-flare value. The proportion of patients achieving PERR at Week 104 was significantly higher in patients receiving BENLYSTA plus standard therapy compared with placebo plus standard therapy

Lupus Nephritis Flare:

• The drug label does provide information on the effect of belimumab on lupus nephritis flare.
• Severe SLE Flares were not consistently significantly different for BENLYSTA plus standard therapy relative to placebo plus standard therapy in both trials.
• Primary Efficacy Renal Response (PERR) at Week 104 was significantly higher in patients receiving BENLYSTA plus standard therapy compared with placebo plus standard therapy.
• The use of belimumab may help reduce the risk of lupus nephritis flare, as evidenced by the significant improvement in PERR at Week 104. 2

From the Research

Definition and Prevalence of Lupus Nephritis Flare

• Lupus nephritis (LN) flares are defined as an increase in disease activity, characterized by an increase in proteinuria and/or serum creatinine concentration, abnormal urine sediment, or a reduction in creatinine clearance rate as a result of active disease 3.
• Relapses or flares of systemic lupus erythematosus (SLE) are frequent and observed in 27-66% of patients 3.
• Renal flares are independently associated with an increased risk of deterioration in renal function; prevention of renal flares might decrease long-term morbidity and mortality 3.

Treatment and Management of Lupus Nephritis Flare

• Current induction treatment protocols achieve remission in the majority of patients with lupus nephritis; however, few studies focus on treatment interventions for renal flares in these patients 3.
• The available data suggest that remission can be induced again in a substantial percentage of patients experiencing a lupus nephritis flare 3.
• Appropriate immunosuppressive maintenance therapy might lead to a decrease in the occurrence of renal and extrarenal flares in patients with SLE, and monitoring for the early detection and treatment of renal flares could improve their outcomes 3.
• The APLAR consensus recommends a combination of glucocorticoids with cyclophosphamide, mycophenolate mofetil, or calcineurin inhibitors as first-line options for initial treatment of LN 4.
• Mycophenolate mofetil has been shown to be more effective than intravenous cyclophosphamide in inducing remission of lupus nephritis and has a more favorable safety profile 5.

Risk Factors and Outcomes of Lupus Nephritis Flare

• Low C4 at the time of response and African American ethnicity are significant independent risk factors for renal flare 6.
• Nephritic flares are common in patients with proliferative lupus nephritis, even in those with a complete response to therapy, but they do not necessarily result in loss of renal function if treated with additional immunosuppressive agents 6.
• Within 10 years of an initial SLE diagnosis, 5-20% of patients with LN develop end-stage kidney disease, and multiple comorbidities associated with immunosuppressive treatment remain a concern 7.