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With several targeted therapies demonstrating positive trial results in lupus nephritis, the treatment paradigm appears to be shifting.
Nephritis remains one of the most feared complications of systemic lupus erythematosus. It can be refractory to standard treatment and frequently recurs following initial induction therapy. The price of treatment failure here can be high, with life altering consequences such as end stage renal failure and dialysis dependency a reality for some patients.
For many years, the predominant standard of care has been corticosteroids with cyclophosphamide/mycophenolate mofetil. However, recently several newer treatments have demonstrated positive trial results. One key trial was the successful Belimumab International Study in Lupus Nephritis (BLISS-LN) trial which evaluated the role of belimumab, an anti B-cell activating factor (BAFF) therapy1. This study was the first to show superior renal outcomes when biologic therapy was added on to the standard of care.
In the original BLISS-LN trial, 446 lupus nephritis patients received either 10mg/kg belimumab or placebo in addition to standard of care treatment. Their primary endpoint was primary efficacy renal response (PERR) at week 104. Secondary endpoints included complete renal response (CRR), time to confirmed 30% or 40% decline in epidermal growth factor receptor (eGFR), and sustained 30% and 40% decline in eGFR, among others1,2.
The more recent secondary analysis has provided a deeper dive into the trial outcomes2. The risk of adverse renal related events or death was shown to be significantly lower in belimumab-treated patients (hazard ratio [HR] 0.51, 95% CI 0.34-0.77, P = 0.0014)2. Additionally, Belimumab was shown to reduce the risk of a lupus nephritis flare by 55% relative to placebo. (HR 0.45 95% CI [0.28–0.72]; P = 0.0008)2.
The slope of eGFR decline between weeks 24 and 104 was calculated as an indicator of Belimumab’s potential efficacy in delaying/preventing the onset of end stage renal disease. Belimumab was shown to reduce the risk of having a 30% and 40% eGFR drop within the 104 week follow up relative to placebo. Additionally, there were fewer patients with a sustained 30% and 40% eGFR decline in the Belimumab treated group. These outcomes suggest a possible reduction in longer term progression to end stage renal failure. eGFR was shown to decline in both belimumab treated and untreated patients, but the rate of decline was generally slower in the belimumab treated group.
Although this subgroup analysis yielded largely positive findings, it did demonstrate belimumab’s lack of efficacy in those with non-proliferative class V lupus nephritis and those with nephrotic range proteinuria at baseline. The observed lack of efficacy was felt to be due to pathophysiological differences between non-proliferative and proliferative lupus nephritis. Inefficacy in those with proteinuria ≥3g/g was felt possibly to relate to an increased renal loss of belimumab in early treatment resulting in reduced early systemic drug exposure2,3. Both these negative findings, however, merit further investigation.
With several targeted therapies demonstrating positive trial results in lupus nephritis, the treatment paradigm appears to be shifting. Clearly, the additional cost of these newer add-on therapies will limit their uptake in resource-restricted healthcare systems. However, it will become steadily more difficult to justify standard of care therapy as the evidence base for these increases. Particularly if these add-on therapies demonstrate superior long-term outcomes.
1. Furie R, Rovin BH, Houssiau F, Amoura Z, Santiago M, Contreras G, et al. BLISS-LN: A RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE 3 TRIAL OF INTRAVENOUS BELIMUMAB IN PATIENTS WITH ACTIVE LUPUS NEPHRITIS. Ann Rheum Dis [Internet]. 2020 Jun 1 [cited 2020 Oct 12];79(Suppl 1):103–103. Available from: http://ard.bmj.com/
2. Rovin BH, Furie R, Teng YKO, Contreras G, Malvar A, Yu X, et al. A secondary analysis of the Belimumab International Study in Lupus Nephritis trial examined effects of belimumab on kidney outcomes and preservation of kidney function in patients with lupus nephritis. Kidney Int [Internet]. 2022 Feb 1 [cited 2022 Mar 7];101(2):403–13. Available from: https://pubmed.ncbi.nlm.nih.gov/34560137/
3. Gleeson S, Lightstone L. BLISS-LN trial revisited: function matters. Kidney Int [Internet]. 2022 Feb 1 [cited 2022 Mar 7];101(2):224–6. Available from: http://www.kidney-international.org/article/S0085253821011455/fulltext