Abstract
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease involving most immune cells. Studies in both experimental animal models of lupus and patients with SLE have revealed a number of cytokine pathways that are important in the disease process. Among these are B-cell activating factor, which promotes B-cell survival and autoantibody production, interferon-α, which acts as an immune adjuvant, and tumor necrosis factor, which contributes to organ inflammation. This knowledge, in combination with the successful use of anti-TNF treatment in rheumatoid arthritis, has spurred the development of several biologic agents targeting different cytokines or their receptors in SLE. Consequently, many trials of anticytokine therapies for SLE are underway. Although most of these trials are small or in early phases, the results of some large studies have also been reported. In this Review, we discuss the rationale for anticytokine therapies in SLE and review agents currently in use, and those being developed and tested experimentally. We present the results from published trials and discuss the tentative conclusions that can be drawn regarding the efficacy of the new agents. Finally, we provide suggestions for the future of treatment for SLE, including new therapeutic strategies.
Key Points
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Many cytokine pathways of importance in the pathogenesis of systemic lupus erythematosus (SLE) have been identified and clinical trials of biologic agents targeting a number of these are underway
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The clinical efficacy of belimumab, a human monoclonal antibody that binds B lymphocyte stimulator, has been demonstrated in two phase III studies
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Monoclonal antibodies against tumor necrosis factor, interferon-α, interleukin-6 and interferon-γ are in early-phase trials, and there are several other potential cytokine targets for SLE therapy
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Owing to the heterogeneous nature of SLE, the precise cytokine target will probably differ between individual patients and could also vary according to disease stage
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New and improved biomarkers are needed in order to optimize anticytokine therapy for established disease and also to prevent disease exacerbation
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Acknowledgements
This work was supported by The Alliance for Lupus Research, the Swedish Research Council, the Dana Foundation, the Swedish Rheumatism Association, the King Gustaf V 80th Birthday Foundation, the Söderbergs Foundation, COMBINE, the Leap for Lupus Foundation and the NIH. The authors thank Jeffrey Ledbetter and Gunnar Alm for helpful discussions.
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L. Ronnblom has acted as a consultant for Active Biotech Research Inc., Medimmune Inc., Neovacs and Novo Nordisk A/S, and has and has participated in a clinical trial sponsored by Active Biotech. K. B. Elkon has received research grants from Hoffman La Roche, Merck Serono International S.A. (an affiliate of Merck KGaA, Darmstadt, Germany) and Zymogenetics.
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Rönnblom, L., Elkon, K. Cytokines as therapeutic targets in SLE. Nat Rev Rheumatol 6, 339–347 (2010). https://doi.org/10.1038/nrrheum.2010.64
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DOI: https://doi.org/10.1038/nrrheum.2010.64
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