B Cell Depletion in Lupus and Sjogren's Syndrome: An Update
B Cell Depletion in Lupus and Sjogren's Syndrome: An Update
Purpose of review: The critical role of B cells in the pathogenesis of systemic lupus erythematosus and Sjogren's syndrome has provided a strong rationale to specifically target B cells. This review summarizes recent advances in the field of B cell depletion in systemic lupus erythematosus and Sjögren's syndrome.
Recent findings: Reports of successful B cell depletion therapy in refractory SLE have continued to surface over the last year. The accumulation of positive results therefore stands in stark contrast to the recent reports that two phase III randomized placebo controlled trials employing B cell depletion with rituximab in nonlupus and lupus nephritis (Explorer and Lunar, respectively) did not achieve. Multiple reasons, including trial design, limitations of outcome instruments and sort follow-up have been invoked to explain these disconcerting results. In the representative studies addressing B cell depletion in lupus in the last year, complete and partial remission in lupus nephritis has been achieved in 60–89% of cases. Improvements in the British Isles Lupus Assessment Group (BILAG) and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores were associated with decrease in anti-dsDNA and increase in complement levels. B cell depletion seemed quite efficacious also in pediatric SLE. While more definitive studies are still lacking for primary Sjogren's syndrome, incidental reports indicating potential efficacy have also been recently published.
Summary: Despite the disappointing results of Explorer and Lunar trials, other evidence continues to be published in support of the notion that B cell depletion could be useful for patients with refractory disease, including lupus nephritis, and antibody-mediated cytopenias, possibly in combination with other immunosuppressant medication.
The last several years have witnessed an explosion of interest in the potential of B cell depletion (BCD) as a promising therapeutic modality for the treatment of autoimmune diseases including systemic lupus erythematosus (SLE) and Sjögren's syndrome. These diseases are natural candidates for BCD since they both are characterized by florid B cell abnormalities and autoantibody production. In addition, B cells are also likely to play critical pathogenic roles through antibody-independent functions, including cytokine secretion and therefore, their elimination may also provide additional therapeutic benefit. Multiple observational studies as well as the cumulative experience of clinicians around the world created great expectations regarding the outcome of two large phase III trials of rituximab-induced BCD in extrarenal and renal SLE (Explorer and Lunar, respectively). Accordingly, the announcement that both these studies failed to meet their clinical endpoints has created disappointment and consternation in the field. Whereas the results of these trials are not yet fully available for review, any new studies published during the last year need be discussed within this reference framework. Given that both Explorer and Lunar assessed the benefit of rituximab when added to conventional therapies that are highly successful, at least for short-term outcomes, it becomes important to consider that one of the main uses of BCD, and perhaps the most beneficial, might be for the treatment of refractory disease. Similarly, it is imperative to understand whether the use of BCD may improve the long-term outcome of SLE (both in terms of prolonged responses as well as in terms of safety) or preferentially improve specific disease subsets. Conveniently, these considerations informed the majority of publications about BCD in SLE in the last year and therefore constitute the focus of this review.
Abstract and Introduction
Abstract
Purpose of review: The critical role of B cells in the pathogenesis of systemic lupus erythematosus and Sjogren's syndrome has provided a strong rationale to specifically target B cells. This review summarizes recent advances in the field of B cell depletion in systemic lupus erythematosus and Sjögren's syndrome.
Recent findings: Reports of successful B cell depletion therapy in refractory SLE have continued to surface over the last year. The accumulation of positive results therefore stands in stark contrast to the recent reports that two phase III randomized placebo controlled trials employing B cell depletion with rituximab in nonlupus and lupus nephritis (Explorer and Lunar, respectively) did not achieve. Multiple reasons, including trial design, limitations of outcome instruments and sort follow-up have been invoked to explain these disconcerting results. In the representative studies addressing B cell depletion in lupus in the last year, complete and partial remission in lupus nephritis has been achieved in 60–89% of cases. Improvements in the British Isles Lupus Assessment Group (BILAG) and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores were associated with decrease in anti-dsDNA and increase in complement levels. B cell depletion seemed quite efficacious also in pediatric SLE. While more definitive studies are still lacking for primary Sjogren's syndrome, incidental reports indicating potential efficacy have also been recently published.
Summary: Despite the disappointing results of Explorer and Lunar trials, other evidence continues to be published in support of the notion that B cell depletion could be useful for patients with refractory disease, including lupus nephritis, and antibody-mediated cytopenias, possibly in combination with other immunosuppressant medication.
Introduction
The last several years have witnessed an explosion of interest in the potential of B cell depletion (BCD) as a promising therapeutic modality for the treatment of autoimmune diseases including systemic lupus erythematosus (SLE) and Sjögren's syndrome. These diseases are natural candidates for BCD since they both are characterized by florid B cell abnormalities and autoantibody production. In addition, B cells are also likely to play critical pathogenic roles through antibody-independent functions, including cytokine secretion and therefore, their elimination may also provide additional therapeutic benefit. Multiple observational studies as well as the cumulative experience of clinicians around the world created great expectations regarding the outcome of two large phase III trials of rituximab-induced BCD in extrarenal and renal SLE (Explorer and Lunar, respectively). Accordingly, the announcement that both these studies failed to meet their clinical endpoints has created disappointment and consternation in the field. Whereas the results of these trials are not yet fully available for review, any new studies published during the last year need be discussed within this reference framework. Given that both Explorer and Lunar assessed the benefit of rituximab when added to conventional therapies that are highly successful, at least for short-term outcomes, it becomes important to consider that one of the main uses of BCD, and perhaps the most beneficial, might be for the treatment of refractory disease. Similarly, it is imperative to understand whether the use of BCD may improve the long-term outcome of SLE (both in terms of prolonged responses as well as in terms of safety) or preferentially improve specific disease subsets. Conveniently, these considerations informed the majority of publications about BCD in SLE in the last year and therefore constitute the focus of this review.
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