BLISS-BELIEVE study on sequential belimumab and rituximab in SLE reports mixed results but promising disease control benefits

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The phase 3 BLISS-BELIEVE trial provided valuable insights into the efficacy and safety of sequential therapy with subcutaneous belimumab (BEL) and a single cycle of rituximab (RTX) in patients with systemic lupus erythematosus (SLE). The study, designed to explore disease activity control while reducing corticosteroid and immunosuppressant dependence, demonstrated mixed results in achieving its primary objectives. 

The trial included 263 patients with active SLE who were initiated on BEL 200 mg/week for 52 weeks. Participants were randomized into three groups: intravenous placebo (BEL/PBO), intravenous RTX 1000 mg administered at weeks 4 and 6 (BEL/RTX), and a standard therapy arm for reference (BEL/ST). The primary endpoint was the proportion of patients achieving disease control—defined as an SLE Disease Activity Index-2000 (SLEDAI-2K) score ≤2 without immunosuppressants and with prednisone equivalent doses ≤5 mg/day—at week 52. At week 52, 19.4% of BEL/RTX patients achieved disease control, compared to 16.7% in the BEL/PBO group. Although this indicated a numerical advantage, the difference was not statistically significant. Similarly, the major secondary endpoints, including clinical remission at week 64 and disease control at week 104, showed no significant differences between BEL/RTX and BEL/PBO. Despite these findings, BEL/RTX demonstrated meaningful benefits in disease activity markers. Anti-dsDNA antibody levels and most B cell and B-cell subset counts were reduced more effectively with BEL/RTX than with BEL/PBO. Additionally, the duration of disease control through 52 weeks was significantly greater in the BEL/RTX group, suggesting potential clinical advantages in select populations. 

Achieving low disease activity without corticosteroids remains a critical treatment goal for SLE patients. B cells are central to SLE pathogenesis, with B-lymphocyte stimulator (BLyS) driving their activation and differentiation. Elevated serum BLyS levels are linked to increased disease activity, relapses, and higher numbers of autoantibody-secreting plasma cells. BEL is a fully human monoclonal antibody targeting BLyS (BAFF), a cytokine in the TNF superfamily essential for B-cell survival. Overexpression of BLyS supports autoreactive B-cells and contributes to SLE pathogenesis, with elevated levels correlating with disease activity. By binding to soluble BLyS, belimumab promotes autoreactive B-cell apoptosis, aiding in SLE treatment. RTX is a chimeric monoclonal antibody targeting CD20, a transmembrane protein expressed on all B-lineage cells except pro-B cells and plasma cells. Binding to CD20 induces both cell-mediated and antibody-mediated cytotoxicity, leading to the depletion of CD20+ B cells. 

The BLISS-BELIEVE trial marked a historic milestone as the first randomized study in SLE to prospectively investigate a novel treatment regimen incorporating rapid reduction and withdrawal of standard immunosuppressants. This pioneering approach has established a new paradigm for future SLE trials, setting a precedent for targeting the stringent, clinically meaningful endpoint of remission without ongoing therapy. The study’s innovative design and ambitious goals represent a significant advancement in the field of lupus research, despite not achieving its primary endpoint. This landmark study represents a significant step in understanding combination biologic therapy in SLE, highlighting both the challenges and opportunities in developing more effective treatment strategies for this complex autoimmune disease. 

 References 

  1. Aranow C, Allaart CF, Amoura Z, Bruce IN, Cagnoli PC, Chatham WW, et al. Efficacy and safety of sequential therapy with subcutaneous belimumab and one cycle of rituximab in patients with systemic lupus erythematosus: the phase 3, randomised, placebo-controlled BLISS-BELIEVE study. Ann Rheum Dis. 2024 Oct 21;83(11):1502-1512.  
  2. Srivastava A. Belimumab in Systemic Lupus Erythematosus. Indian J Dermatol. 2016 Sep-Oct;61(5):550-3. 
  3. Wise LM, Stohl W. Belimumab and Rituximab in Systemic Lupus Erythematosus: A Tale of Two B Cell-Targeting Agents. Front Med (Lausanne). 2020 Jun 30;7:303.  

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