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  • Review Article
  • Published:

Treatment of systemic lupus erythematosus: new therapeutic avenues and blind alleys

Nature Reviews Rheumatology volume 10, pages 23–34 (2014)Cite this article

Subjects

Key Points

  • Despite the broad biological and clinical heterogeneity of systemic lupus erythematosus (SLE), specific pathways of immune dysregulation have been well characterized and are known to be relevant to significant subsets of patients

  • Selective targeting of key immune regulatory molecules seems to offer promise for effective disease management with lower toxicity than current therapies

  • Selection of patients that are likely to respond to a particular therapeutic agent could eventually be guided by biomarkers predictive and reflective of response to that treatment

  • Clinical trials of biologic agents in SLE are significantly confounded by aggressive use of background medications that decrease the ability to detect differences between the study and control groups

  • In patients with mild disease manifestations, withdrawal of background medications might allow the implementation of smaller, true placebo-controlled clinical trials

  • In patients with high baseline disease activity, withdrawal of background therapies might not be feasible, but these individuals tend to have less profound responses on background therapies, and therefore trials limited to these patients can succeed without withdrawal of these agents

Abstract

Despite rapid accumulation of knowledge about complex immune dysregulation in systemic lupus erythematosus (SLE) and major primary lupus syndromes, and a plethora of promising new treatments reaching preclinical and early clinical studies, advanced-phase trials of new biologic agents have repeatedly failed to achieve their clinical end points. It is possible that none of these agents work, but the accuracy of this suggestion is as unclear as the case for efficacy, owing to issues in the design of studies and the opacity of the data that have resulted. Disease heterogeneity and complexity might be a hurdle that is simply too high to overcome by existing methodological approaches, and the way forward to interpretable trial results remains unclear. Nonetheless, well-characterized patterns of immune pathology are shared by substantial subsets of patients, and selective targeting of one or more relevant immune system molecules seems to offer the promise of safer and more effective treatments. Evolution dictates a more personalized approach to therapy and trial design, but this option seems challenging in the current economic, regulatory and scientific environment. This Review addresses these concerns by considering the progress of some of the investigational treatments targeting key physiological abnormalities in lupus.

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Figure 1: Pathogenic mechanisms in SLE that can be therapeutically targeted.

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Authors and Affiliations

  1. Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, MS 22, Oklahoma City, 73104, OK, USA

    Aikaterini Thanou

  2. Clinical Pharmacology Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, MS 22, Oklahoma City, 73104, OK, USA

    Joan T. Merrill

Authors
  1. Aikaterini Thanou
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  2. Joan T. Merrill
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Contributions

A. Thanou researched data for the article and wrote the first draft of the manuscript. J. T. Merrill expanded the content of the article and reviewed/edited the manuscript before submission.

Corresponding author

Correspondence to Joan T. Merrill.

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Competing interests

A. Thanou declares that she has received a one-year research grant from RDRCC for funding of a clinical trial of dipyridamole in the treatment of lupus. J. T. Merrill declares that she has received speaking, consulting and/or training fees from Abbott/Abbvie, Amgen, Argos, Astellas, Baxter, Biogen Idec, Bristol Myers Squibb, Cephalon, DSMB, Dynavax, Eisai, EMD Serono, Genentech/Roche, HGS/GlaxoSmithKline, Idera, InCyte, Kirin, Lilly, Macrogenics, MedImmune/AstraZeneca, Neovacs, Novo Nordisk, Ono, Parexel, Pfizer, Questcor, RPS, Takeda and UCB, and has participated in clinical trial adjudication for DSMB.

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Thanou, A., Merrill, J. Treatment of systemic lupus erythematosus: new therapeutic avenues and blind alleys. Nat Rev Rheumatol 10, 23–34 (2014). https://doi.org/10.1038/nrrheum.2013.145

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