Combined effect of belimumab and hydroxychloroquine treatment : results from the phase 3 belimumab clinical trials in patients with SLE

Combined effect of belimumab and hydroxychloroquine treatment : results from the phase 3 belimumab clinical trials in patients with SLE

Systemic lupus erythematosus (SLE) is a chronic disease affecting the immune system characterized by phases of activity with high level of inflammation and alternating periods of remission. SLE can potentially affect any organ with skin, joint, renal, respiratory, cardiovascular, hematological, and neurological manifestations. Until recently, the treatment and management of SLE were based mainly on non-steroidal anti-inflammatory drugs, glucocorticoids, hydroxychloroquine, and immunosuppressive agents. Progress in the treatment of SLE has resulted in a significant improvement in prognosis. Nonetheless, SLE management is challenging because of the adverse effects of conventional therapies and the occurrence of refractory disease. Thus, the search for new therapeutic strategies is relentless. SLE may affect almost any organ during the disease course, and several pathogenic pathways drive SLE inflammation in affected tissues. To date, the majority of studies have focused on targeting selected sub-population of the immune system, such as the lymphocytes B. Undoubtedly, B lymphocytes play a crucial role in the pathogenesis of SLE and several mechanisms related to inflammation and development of autoimmunity have been identified as key players in the pathogenesis of SLE. In particular, therapy targeting B lymphocyte stimulator (the molecule targeted by belimumab) has been shown to be able to reduce SLE disease activity compared with standard therapy alone and to reduce the level of pathogenic antibodies, to include antiphospholipid and anti-DNA antibodies. While the direct effect of therapies targeting B lymphocytes, including belimumab, is well-recognized, the hypothesis of a synergic action of belimumab and hydroxycloroquine (HCQ) is a matter of discussion. The potential beneficial effect of combining HCQ in addition to belimumab in reducing some mediators of inflammation (including the B- cell activating factor, BAFF) throws light on the importance of considering this therapeutic combination. In fact, different cellular and molecular pathways of synergic interaction between HCQ and belimumab in altering the immune response (including the production of antibodies at the base of SLE pathogenesis) can be identified. HCQ might indeed improve the control of SLE, when administered in combination with belimumab, reducing the level of inflammation mediators (including BAFF).In this study, we aim to investigate the potential synergetic role of HCQ and belimumab therapy in a post-hoc analysis on the 2 randomized controlled trials BLISS-52 and BLISS-76.These trials featured a pragmatic design whereby background medications could be adjusted to some extent, based on the patient's condition. Thus, not all patients treated with belimumab were treated with HCQ as well. This flexibility in the BLISS-52 and BLISS-76 trial designs supports a post hoc analysis of the combined data set to examine the overall synergic effect of HCQ combined to belimumab in reduced SLE disease activity and antibodies reduction. Furthermore, this study might demonstrate whether there was a difference between patients who received belimumab alone and those who received belimumab and HCQ. We anticipate an overall reduction in SLE activity and antibodies production in the belimumab and HCQ group, and hypothesize that belimumab combined with HCQ would permit a greater reduction of SLE activity when compared to belimumab alone.

[{ "PostingID": 1416, "Title": "GSK-HGS1006-C1056", "Description": "A Phase 3, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, 76-Week Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006, LymphoStat-B™), a Fully Human Monoclonal Anti-BLyS Antibody, in Subjects with Systemic Lupus Erythematosus (SLE)" },{ "PostingID": 1417, "Title": "GSK-HGS1006-C1057", "Description": "A Phase 3, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, 52-Wk Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006, LymphoStat-B™), a Fully Human Monoclonal Anti-BLyS Antibody, in Subjects With Systemic Lupus Erythematosus (SLE)" }]