B-Cell Targeted Therapeutics in Systemic Lupus Erythematosus: From Paradox to Synergy?

Abstract

Systemic lupus erythematosus (SLE) is a complex, multisystem autoimmune disease characterized by a wide range of clinical manifestations—from rashes and joint swelling to life-threatening organ involvement—and a chronic course subject to unpredictable flares. Few therapeutic agents have been approved by the U.S. Food and Drug Administration for SLE since the 1950s, despite advancements in the understanding of SLE pathophysiology and promising candidates for new therapeutic options. These disappointing results are at least partly attributable to small sample sizes, trial design challenges, and disease heterogeneity. Antinuclear antibodies and antibodies against specific nuclear antigens, such as double-stranded DNA (anti-dsDNA), are hallmarks of SLE; sharp increases in autoantibody titers accompany flares. The predominance of autoantibodies in SLE and their correlation with disease flares provided the basis for investigating therapeutic strategies targeting antibody-producing B cells, with paradoxical results. Rituximab is a chimeric monoclonal antibody that targets the CD20 antigen, which results in B-cell depletion. Belimumab is a recombinant human monoclonal antibody that binds and neutralizes the B-cell activating factor (BAFF), blocking pathways for B-cell activation and survival. Despite rituximab s greater ability to deplete B cells and promising uncontrolled and retrospective studies, rituximab failed to achieve primary clinical end points in 2 independent randomized clinical trials in patients with SLE (1, 2). As a result, use of rituximab remains off-label in SLE. In contrast, belimumab achieved its primary clinical end point in 4 phase 3 clinical trials (3–5) and became the first drug approved for SLE inmore than half a century. One proposed mechanistic explanation for the failed rituximab trials in SLE is that BAFF levels increase after Bcell depletion with rituximab, promoting maturation of the surviving autoreactive B cells and B-cell reconstitution (6), which correlates with increased SLE disease activity and elevated anti-dsDNA levels (7). Targeting soluble BAFF with belimumab may prevent this reemergence of autoreactive B cells. Thus, there is active debate regarding a potential synergistic effect of belimumab administration after rituximab for improved control of clinical SLE disease activity, as well as the safety of administering 2 biologic agents. A phase 2 multicenter, randomized, open-label, placebo-controlled trial (CALIBRATE [Combination of Antibodies in Lupus Nephritis: Belimumab and Rituximab Assessment of Tolerance and Efficacy]) did not show improved clinical efficacy of belimumab after cyclophosphamide and rituximab in patients with severe, refractory lupus nephritis but did demonstrate safety of belimumab after rituximab. Notably, the data from CALIBRATE showed a greater reduction in autoreactive B cells in the belimumab group (8). In their article, Shipa and colleagues report the results of the BEAT-LUPUS (BElimumab After b cell depletion Therapy in patients with systemic LUPUS erythematosus) trial (9). This investigator-initiated phase 2, double-blind, placebo-controlled study of SLE that was refractory to conventional treatment randomly assigned 52 patients to belimumab versus placebo 4 to 8 weeks after treatment with rituximab. The primary end point was serum IgG anti-dsDNA antibody levels at 52 weeks; secondary outcomes included incidence of disease flares, defined using a clinical SLE disease activity index (British Isles Lupus Assessment Group – 2004 index [BILAG2004]), and adverse events. Belimumab-treated patients had lower antibody levels than placebo recipients (geometric mean, 47 [95% CI, 25 to 88] vs. 103 [CI, 49 to 213] IU/mL). They also had fewer severe flares (hazard ratio, 0.27 [CI, 0.07 to 0.98]; log-rankP= 0.033). Six patients (23%) in each group reported serious adverse events, of which 3 in the belimumab group and 4 in the placebo group were infectionrelated. Caution is needed in interpretation of these findings because of limitations in the data and study design. First, the primary outcome compared anti-dsDNA levels at 52 weeks in patients randomly assigned to belimumab versus placebo after treatment with rituximab. The use of a biomarker as the primary outcome differs frommost similar trials, which used validated clinical end points. Anti-dsDNA is clinically used to assess SLE disease activity, but it is not used in isolation; levels are informative only in the context of other clinical signs and symptoms. The lower anti-dsDNA levels among patients randomly assigned to belimumab are difficult to interpret—there are no clinically defined anti-dsDNA levels to determine SLE disease activity. In addition, a few patients had undetectable anti-dsDNA at screening, raising questions about the use of this biomarker as a surrogate for disease activity. In summary, the clinical significance of a reduced but persistently positive anti-dsDNA IgG level is not certain. Although the investigators showed a reduction in flares in their secondary analysis, use of a primary clinical composite end point may provide better clinical interpretability and improve the ability to compare results with those of other SLE trials. Generalizability may also be compromised by the small sample size, the variation in SLE disease presentation (38% of patients had renal disease), the lack of racial diversity (only 12% of participants were Black), and the requirement for dose restriction of concomitant immunosuppressive medications—the latter potentially ensuring that patients with more severe, refractory SLE were excluded. The protocol for use of rituximab in the United Kingdom, where the study was conducted, differs from that used in theUnited States, which also limits generalizability. On balance, and acknowledging the many challenges in studying SLE, this study sheds light on the potential synergy between rituximab and belimumab in this population of patients with SLE. Data from this study may complement