Written by: Aki Udupa, Ryan Anderson, Isaac Smith, Poorva Apte, Megan Milne, Catherine Sims, Lisa Criscione-Schreiber, and David Leverenz

Based on: Furie et al. NEJM.2020;383(12):1117-28

Topic Overview

Are you ready for a BLySfull scouting report? Don’t look so BAFFled! You’ve come to the right place! With the burden of disease unacceptably high and so few tolerable and effective current therapies available for our patients, the urgency to identify novel therapeutic targets to treat systemic lupus erythematous cannot be overstated. Comprising up to half of this at-risk population is a particularly vulnerable subset of patients with lupus nephritis, who, left untreated, are at high risk for progression to ESRD and death¹.

B cells are key orchestrators of the abnormal immune response in lupus and lupus nephritis; they facilitate the activation of autoreactive T cells via self-antigen presentation, promote the release of inflammatory cytokines, and produce harmful autoantibodies². Autoreactive B cells are, at least in part, enabled by B-lymphocyte stimulator (BLyS), a cytokine which promotes B cell proliferation, differentiation, and survival^2,3. BLyS is elevated in lupus patients, is locally expressed at the level of the kidney in lupus nephritis, and levels may correlate with disease activity ^1-4.

Belimumab, a fully human monoclonal IgG1 antibody, neutralizes BLyS and subsequently depletes the autoreactive B cell pool contributing to the pathogenic autoimmune milieu of lupus. This medication has been FDA approved for the treatment of serologically and clinically active lupus since 2011 and has recently been awarded the title of the first FDA approved treatment for lupus nephritis. Approval was based on the results of a two year phase III double blind randomized placebo controlled trial by Furie and colleagues titled BLISS-LN¹. This study sought to examine the effect of adding intravenous belimumab to standard of care lupus nephritis induction and maintenance regimens on renal response in patients with serologically and clinically active lupus plus biopsy proven active lupus nephritis¹. Remarkably, the use of belimumab significantly improved the primary efficacy renal response, with a significantly greater proportion of patients in the belimumab group achieving reduced proteinuria, stable renal function, and less need for rescue therapy such as steroids.

Implications for Patients, Providers, & Researchers

Current implications: Previously, belimumab was primarily shown to work for patients with milder forms of lupus activity, such as skin and joint disease. The BLISS-LN study proves that belimumab also works for lupus nephritis when added on to standard induction regimens, and the recent FDA stamp of approval means that this treatment option is available right now! This is a huge win for patients with lupus nephritis.

Future implications: While we are excited about a new FDA-approved medication for SLE nephritis, this study also makes us wonder what other SLE manifestations may benefit from belimumab (i.e. neuropsychiatric). As with all other rheumatologic medications, trials of belimumab with pregnant women have not yet been performed. If this medication were studied and deemed safe in pregnant women, it would be wonderful to have an alternative to Azathioprine (AZA) for SLE nephritis during pregnancy. It will also be interesting to see if initiation of belimumab prior to pregnancy improves maternal and/or fetal outcomes (pregnancy loss, HTN, pre-eclampsia, heart block etc.) as compared to AZA/hydroxychloroquine. Another natural next step is to evaluate the effectiveness of this medication in children to see if belimumab may prevent progression of renal disease. Long term data will need to be evaluated in the future focusing on outcome measures such as proteinuria, serum creatinine, and new dependence on hemodialysis (HD). This will be important to know for patient expectations, anticipatory guidance, and financial burden of care. Finally, prior studies have suggested a possible increase in depression in patients treated with belimumab, though this was not seen in BLISS-LN. We would like to see additional studies that have a baseline assessment of depression prior to belimumab initiation. Lupus patients have a higher rate of depression than the general public and the addition of a weekly injection or monthly infusion may increase burden of care and make depression worse. These confounding variables are important to stratify before determining that belimumab is the cause of depression as opposed to a potential bystander.

Will BLISS-LN Win its First Round Match-up?

Belimumab is the clear favorite in the first-round match-up against anifrolumab. Though its competitors are often “BLYS”-fully ignorant, when it comes to shooting “BAFF”-kets, there is none better than belimumab. Leading experts in the field have been keeping a close eye on the upcoming match-up, and in the words of one prominent lupologist, “What is anifrolumab anyway? Only FDA-approved medications should be allowed to compete.” While it is true that anifrolumab isn’t even a prescribable medication, supporters of the drug turn to sports history to defend their position. “Our inspiration for TULIP 2 came from one of the greatest athletes of all time, Tom Brady. If you’re not getting the results you want, deflate the endpoint, and you’ll be sure to score a win.” Reviewers and practitioners of evidence-based medicine alike will need to be vigilant to ensure the goal-posts aren’t moved again leading up to the first round match-up. In spite of these concerns, APRIL showers are just around the corner, and belimumab is expected to rain destruction on its competitor. After all is said and done, belimumab will reign supreme.

Could BLISS-LN Win it All?

The BLISS-LN trial is a strong contender to win the tournament. Other trials in this tournament may boast that their interventions significantly limit steroid exposure. BLISS-LN demonstrates that belimumab is both a steroid-sparing agent and an effective disease-modifying agent in controlling a major rheumatic disease. Belimumab does not just have the potential to be steroid-sparing. It is potentially life-sparing. Belimumab decreased renal-related events or death in a well-selected treatment group of lupus nephritis patients. The same cannot be said for trials that had to alter primary endpoints or did not find positive results in the initial study population. BLISS-LN clearly represents a new frontier for the treatment of lupus nephritis. The discerning rheumatologist can easily foresee that belimumab, which has already undergone the rigors of FDA-approval, will change the management of lupus nephritis. The well-designed, clinically meaningful BLISS-LN trial is responsible for this major innovation.

References:

1. Furie, Richard, et al. “Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis.” The New England Journal of Medicine, vol. 383, no. 12, 2020, pp. 1117–1128., doi:10.1056/NEJMoa2001180. Accessed 7 Mar. 2021.
2. Furie, Richard et al. “Biologic activity and safety of belimumab, a neutralizing anti-B-lymphocyte stimulator (BLyS) monoclonal antibody: a phase I trial in patients with systemic lupus erythematosus.” Arthritis research & therapy vol. 10,5 (2008): R109. doi:10.1186/ar2506
3. Furie, Richard et al. “A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus.” Arthritis and rheumatism vol. 63,12 (2011): 3918-30. doi:10.1002/art.30613
4. Neusser, M., Lindenmeyer, M., Edenhofer, I. et al. Intrarenal production of B-cell survival factors in human lupus nephritis. Mod Pathol 24, 98–107 (2011). https://doi.org/10.1038/modpathol.2010.184

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