The Role of Anti-B Cell Activating Factor Therapy for Treating Lupus Nephritis

Lupus nephritis is among the most common and dreaded manifestations of SLE. It is frequently present at the time of SLE diagnosis, and depending on the cohort studied, more than half of all patients with SLE will develop lupus nephritis over their lives (1). The prognosis of lupus nephritis depends on several factors, including histologic subtype, degree of proteinuria, and response to therapy. In a large contemporary cohort of patients with SLE, those with lupus nephritis had a 10% risk of reaching kidney failure within 10 years of diagnosis (2). With respect to the pathophysiology of SLE, multiple components of the innate and adaptive immune systems appear to be dysregulated and contribute to end-organ manifestations of the disease, including lupus nephritis. Genetic susceptibility, combined with an environmental second hit, are thought to be initial events leading to immunologic dysregulation and subsequent clinical disease. Autoantibodies against nuclear material are a hallmark of the disease, as is deposition of immune complexes. B cell dysfunction, a key aspect of pathogenesis of lupus nephritis, appears to be driven by multiple factors, including alterations in immature B cell selection and abnormal cellular signaling pathways. The B cell activating factor (BAFF) is a cytokine that both promotes B cell survival and stimulates cell proliferation; BAFF levels are elevated in patients with SLE, and mice with induced overexpression of BAFF develop an SLE-like syndrome (3,4). In addition to alterations in B cell function, dysregulation of T cells, the classic complement pathway, neutrophil activation, antigen-presenting cells, and cytokine production are all implicated in the pathogenesis of SLE (5). The treatment of active lupus nephritis had long been limited to a handful of immunomodulatory agents. In the most recent Kidney Disease Improving Global Outcomes guidelines, hydroxychloroquine was recommended for all patients, and for patients with active class III/IV lupus nephritis, the recommended initial immunosuppression is a combination of corticosteroids and either mycophenolate or cyclophosphamide (6). There are a number of suggested criteria to define complete and partial response to initial therapy, revolving around degree of reduction in proteinuria and serum creatinine. In the major trials of lupus nephritis initial therapy with cyclophosphamide and mycophenolate, complete and partial response were achieved in approximately 65% of patients (7). On the basis of recent data, the addition of calcineurin inhibitors (notably voclosporin) or biologics (such as belimumab, obinutuzumab, or rituximab) to standard therapy have been included in the 2021 Kidney Disease Improving Global Outcomes treatment guidelines as emerging options. In 2021, both belimumab and voclosporin received Food and Drug Administration (FDA) approval for treating lupus nephritis, the first such approvals in several decades; obinutuzumab is in phase 3 testing. Belimumab is a monoclonal antibody targeting BAFF. It was initially tested in active nonkidney SLE (8,9), producing improvements in the SLE Responder Index compared with placebo, leading to FDA approval in 2011 for use in SLE as an add-on to standard immunomodulatory therapy. In 2020, the Belimumab International Study in Lupus Nephritis (BLISS-LN) trial demonstrated the benefit of belimumab therapy in active lupus nephritis (10). The trial enrolled adult patients with biopsy-proven active lupus nephritis and a urinary protein-creatinine ratio (UPCR) ≥1 g/g. Exclusion criteria included recent B cell targeted therapy, recent cyclophosphamide before trial enrollment, prior failure of mycophenolate or cyclophosphamide, eGFR <30 ml/min, or recent requirement of KRT. In the intention-to-treat analysis, 223 patients were randomized to receive belimumab 10 mg/kg intravenously every 14 days for three doses, then every 28 days for a total treatment duration of 2 years (104 weeks); 223 patients received placebo on the same dosing schedule. Standard initial therapy with corticosteroids, mycophenolate, or cyclophosphamide, was instituted no more than 60 days before starting belimumab or placebo. The primary kidney efficacy end point was UPCR <0.7 g/g, eGFR >60 ml/min, or <20% below initial baseline, and no need for rescue immunosuppression. At the 2-year mark, 43% of patients treated with belimumab met the primary kidney efficacy end point, compared with 32% of patients treated with placebo (odds ratio, 1.6; 95% confidence interval, 1.0 to 2.3, P=0.03). Similarly, a greater proportion of patients treated with belimumab achieved a complete kidney response, defined as a UPCR <0.5 g/g and eGFR >90 ml/min, or <10% below baseline (30% in the belimumab group, 20% in the placebo group; odds ratio, 1.7; 95% confidence interval, 1.1 to 2.7, P=0.02). Safety outcomes, including all-cause mortality and infection-related mortality, were similar between patients who were treated with belimumab and placebo. On the strength of these data, belimumab received FDA approval for the treatment of lupus nephritis in patients already on standard initial immunosuppression. In this issue of CJASN, Furie et al. present the open-label 28-week extension of the BLISS-LN trial. At the conclusion of BLISS-LN, all eligible patients (regardless of initial randomization) were treated with belimumab 10 mg/kg intravenously every 28 days for a total of 24 weeks, with a final follow-up visit on week 28 (11). Patients who had been randomized to the placebo arm in the original BLISS-LN trial were denoted as belonging to the "placebo-to-belimumab" group, whereas patients who had received belimumab from the original randomization comprised the "belimumab-to-belimumab" group. Of the 279 patients who completed the initial 2-year randomized portion of the study, 254 were enrolled in the open-label 28-week extension and included in the modified intention-to-treat analysis. The primary goal of this open-label extension was to assess safety outcomes and adverse events. Because the study was open label and all patients were treated with belimumab, no comparative statistics were used. Baseline demographic characteristics between the placebo-to-belimumab and belimumab-to-belimumab groups were similar at the beginning of the open-label phase, with approximately 90% of participants in both groups being female, with a mean age of 36 years. Presumably reflecting the effect of preceding belimumab treatment, the median baseline UPCR was lower in the belimumab-to-belimumab group (0.3 g/g versus 0.4 g/g in the placebo-to-belimumab group), the average corticosteroid dose was lower (5-mg daily prednisone equivalent versus 7.5-mg daily), and fewer patients had positive anti-dsDNA, anti-C1q, and hypocomplementemia. During the 28-week open-label phase, the most common treatment-related adverse event was infection, occurring in 13% of the patients in the belimumab-to-belimumab group and 14% of the patients who were in the placebo-to-belimumab group. Serious adverse events occurred in 8% of patients in the belimumab-to-belimumab group and 4% of those in the placebo-to-belimumab group. There was one death (in the placebo-to-belimumab group), and five patients discontinued treatment due to adverse events (four in the belimumab-to-belimumab group, one in the placebo-to-belimumab group). Efficacy end points were also assessed. Using the same primary kidney efficacy end point as the original randomized study (although with a relaxed requirement for meeting criteria on consecutive visits, and no restriction on patients' additional medications), proportions of patients achieving the end point increased in both placebo-to-belimumab (60%–67%) and belimumab-to-belimumab (70%–75%) groups over the 28-week extension phase. Similar increases were seen in complete kidney response (36%–48% in patients in the placebo-to-belimumab group, 48%–62% in patients in the belimumab-to-belimumab group). A post hoc analysis using the original criteria for primary kidney efficacy and complete kidney response (requiring consecutive measurements meeting laboratory criteria, and counting use of certain additional medications as a treatment failure) showed a reduction in rates of the primary kidney efficacy end point and complete kidney response in the belimumab-to-belimumab group (66% and 46%, respectively, to 52% and 41%), although this was reportedly driven mainly by use of medications (primarily prednisone) for nonkidney reasons, or by discontinuation from the study (four patients for adverse events, and four for reasons such as protocol deviation or loss to follow-up). Measurements of proteinuria, eGFR, and average corticosteroid dosing showed consistent patterns over the 28-week open-label phase, with stable median UPCR and eGFR, and nearly all patients required <10-mg/day prednisone equivalent. Patients in the placebo-to-belimumab group had a greater median reduction in anti-dsDNA titer, and larger median increase in C4 than the belimumab-to-belimumab group. In summary, we are amid a revolution in the treatment of lupus nephritis, with belimumab being one of several promising new therapies for this devastating disease. By extending the original 2-year BLISS-LN trial for an additional 28 weeks, Furie et al. have provided further data regarding the sustained safety and efficacy profile for belimumab. The decision to treat all patients (regardless of original randomization assignment) with belimumab prohibits a meaningful statistical comparison between the placebo-to-belimumab and belimumab-to-belimumab groups in terms of adverse events rates and efficacy, but provides an exploratory glimpse into two intriguing questions (1): what is the safety and utility of adding belimumab for patients who have already completed 2 years of standard immunosuppression, and (2) does continuation of belimumab therapy for >2 years show any signal for changes in safety and efficacy? In terms of safety, neither the placebo-to-belimumab nor the belimumab-to-belimumab group showed a striking increase in treatment-related adverse events relative to the original randomized phase of the study. Efficacy is more nuanced, because the authors report two sets of criteria—one using the strict requirements of the randomized phase (including the prohibition of certain medication changes which were not mandated in the study protocol for the open-label phase), and one using a relaxed set, solely on the basis of laboratory parameters of disease activity. The strict criteria showed a decrease in the rate of kidney response in the belimumab-to-belimumab group, and essentially unchanged rates in the placebo-to-belimumab group. However, the authors note that a substantial number of participants were classified as not achieving kidney response due to study withdrawal or use of steroids for reasons unrelated to lupus nephritis, and when including those patients in the analysis, the rates of kidney response increased in both groups, even over the relatively short 28-week timeline. Ultimately, these data are exploratory but indicate that extending belimumab beyond 2 years is likely safe and imply that adding belimumab to standard therapy may be beneficial, even in patients who have completed a course of standard initial immunosuppression for active lupus nephritis. Several important questions remain unanswered. Is belimumab effective for people who fail standard initial therapy, is it superior to standard maintenance therapy in preventing relapse, could glucocorticoid exposure be minimized/eliminated, what is the role of concomitant anti-CD20 and anti-BAFF therapy, and finally, are there subsets of patients who would particularly benefit from BAFF suppression? Future research will hopefully answer these questions. Disclosures B. Wooden reports having an ownership interest in Coca Cola. J. Radhakrishnan reports having consultancy agreements with Angion Biomedica, Ani Pharmaceuticals, Aurinia Pharmaceuticals, Equillium Bio, GlaxoSmithKline, Reata Pharmaceuticals, Reistone Biopharma, Sanofi Genzyme, and Travere Therapeutics; reports receiving research funding from Bayer, Goldfinch Bio, and Travere Therapeutics; reports receiving honoraria from Angion Biomedica, Aurinia Pharmaceuticals, Equillium Bio, GlaxoSmithKline, Reistone Biopharma, Reata Pharmaceuticals, Sanofi Genzyme, and Travere Therapeutics; reports serving on Data Safety Monitoring Board for Novartis; and reports having advisory or leadership roles for Kidney International and Kidney International Reports. Funding None.