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Targeting Interferons in Systemic Lupus Erythematosus: Current and Future Prospects

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown aetiology that can be debilitating and life threatening. As new insights are gained into the underlying pathology of SLE, there have been an unprecedented number of new agents under development to treat the disease via a diverse range of targets. One such class of emerging agents target interferon (IFN) signalling. In this article, we review the preclinical evidence that the inhibition of the secretion and downstream effectors of both IFN-α and IFN-γ may be effective for the treatment of SLE. The primary agents that are currently in clinical development to treat SLE via the targeting of interferon pathways are monoclonal neutralising antibodies (Mab) that bind to and neutralise IFN-γ (AMG 811), IFN-α (sifalimumab, rontalizumab and AGS-009) or its receptor (anifrolumab), and IFN-α kinoid, which is a drug composed of inactivated IFN-α molecules coupled to the keyhole limpet haemocyanin protein. Phase I and II trials have demonstrated acceptable short-term safety with no increase in severe viral infections or reactivation, favourable pharmacokinetic profiles and an inhibition of IFN-associated gene overexpression; however, the impact of these drugs on disease activity must still be assessed in phase III clinical trials. This review concludes with a summary of the challenges that are inherent to this approach to managing SLE.

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Acknowledgments

This article was supported by the Assistance Publique-Hôpitaux de Paris, the Université Pierre et Marie Curie (UPMC Université Paris 6) and the Foundation Arthritis.

Conflict of interest

A. Mathian, M. Hie and F. Cohen-Aubart declare no commercial or financial conflict of interest. Z. Amoura has received honoraria from GSK, UCB, Amgen, Biogen Idec, Actelion, BMS, Teva, Roche, and Astra Zeneca.

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Correspondence to Zahir Amoura.

The SRI

The SRI

The SLE Responder Index (SRI) is an index based on improvement in disease activity that does not worsen the overall condition or cause the development of significant disease activity in new organ systems. The SRI was initially developed and used for clinical trials examining the use of belimumab in patients with SLE [100]. This composite index uses the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) [101], the British Isles Lupus Assessment Group (BILAG) SLE disease activity instruments [102] and the physician’s global assessment. It is defined as:

  1. 1.

    a ≥4-point reduction in SELENA-SLEDAI score,

  2. 2.

    no new BILAG A or no more than 1 new BILAG B domain score,

  3. 3.

    no deterioration from baseline in the physician’s global assessment by ≥0.3 points.

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Mathian, A., Hie, M., Cohen-Aubart, F. et al. Targeting Interferons in Systemic Lupus Erythematosus: Current and Future Prospects. Drugs 75, 835–846 (2015). https://doi.org/10.1007/s40265-015-0394-x

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Keywords

  • Systemic Lupus Erythematosus
  • Systemic Lupus Erythematosus Patient
  • Herpes Zoster
  • Active Systemic Lupus Erythematosus
  • Belimumab