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Clinical trials in systemic lupus erythematosus: the dilemma—Why have phase III trials failed to confirm the promising results of phase II trials?
  1. Ana Lorenzo-Vizcaya1,
  2. David Alan Isenberg2
  1. 1Department of Internal Medicine, Hospital del Barbanza, Ribeira, Spain
  2. 2Department of Rheumatology, University College London, London, UK
  1. Correspondence to Professor David Alan Isenberg, Department of Rheumatology, University College London, London WC1E 6BT, UK; d.isenberg{at}ucl.ac.uk

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease of unknown aetiology, characterised by the production of auto-antibodies and formation of immune complexes against self-antigens and complement activation. This inflammatory response can lead to tissue infiltration and eventually, to organ damage.

Patients with SLE invariably have periods of relapse and remission. Flares can occur even when the patient is on seemingly adequate treatment, which suggests that more effective therapies are necessary for the management of SLE. Thus, trials with many drugs against different targets, such as CD22, IL-12 and IL-23 or tyrosine kinases, have been carried out in recent years.

A frustrating feature of some of the biologic drugs used to treat SLE has been the reporting of successful phase II trials followed by failures of the phase III trials.

In this review, we will focus on phase II and III trials carried out with epratuzumab (anti CD22), baricitinib (Janus kinases inhibitor), rigerimod (P140 peptide) and ustekinumab (IL-12 and IL-23 inhibitor) and consider the reasons for their ultimate failure to ‘make the grade’. Likewise, we will try to explain the possible reasons that can influence why good results may be obtained in phase II trials and lead to undue optimism.

  • lupus nephritis
  • therapeutics
  • antirheumatic agents

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Footnotes

  • Handling editor Josef S Smolen

  • Contributors The authors have contributed equally to the writing of this review. AL-V did most of the initial background reading and the article 'emerged' from many detailed discussions and reiterations with DAI.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests DAI has acted as an advisor to Merck Serono, Astra Zeneca, Eli Lilly, Servier and Immupharma. The honoraria offered were passed onto a local arthritis charity.

  • Provenance and peer review Not commissioned; externally peer reviewed.