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Clocking in: chronobiology in rheumatoid arthritis

Nature Reviews Rheumatology volume 11, pages 349–356 (2015)Cite this article

Subjects

Key Points

  • Circadian rhythms of biological processes are genetically encoded and of crucial importance for cellular and physiological functions of the brain and body

  • Chronobiology has a prominent function in rheumatoid arthritis (RA), with major symptoms such as joint pain and stiffness usually being most pronounced in the morning

  • Therapy that recognizes the underlying chronobiology of RA might improve the benefit-to-risk balance

  • Timing the administration of NSAIDs or methotrexate according to biological rhythm determinants might help to optimize treatment outcomes in RA

  • New data on successful chronotherapy with glucocorticoids show that coordination of glucocorticoid administration with the nocturnal increase in IL-6 levels improves morning symptoms of RA

  • Chronotherapy might have the additional benefit of increasing sleep quality or quantity and relieving depressive and other affective symptoms that are comorbid with RA

Abstract

Circadian rhythms are of crucial importance for cellular and physiological functions of the brain and body. Chronobiology has a prominent role in rheumatoid arthritis (RA), with major symptoms such as joint pain and stiffness being most pronounced in the morning, possibly mediated by circadian rhythms of cytokine and hormone levels. Chronobiological principles imply that tailoring the timing of treatments to the circadian rhythm of individual patients (chronotherapy) could optimize results. Trials of NSAID or methotrexate chronotherapy for patients with RA suggest such an approach can improve outcomes and reduce adverse effects. The most compelling evidence for RA chronotherapy, however, is that coordinating the timing of glucocorticoid therapy to coincide with the nocturnal increase in blood IL-6 levels results in reduced morning stiffness and pain compared with the same glucocorticoid dose taken in the morning. Aside from optimizing relief of the core symptoms of RA, chronotherapy might also relieve important comorbid conditions such as depression and sleep disturbances. Surprisingly, chronobiology is not mentioned in official guidelines for conducting RA drug registration trials. Given the imperative to achieve the best value with approved drugs and health budgets, the time is ripe to translate the 'circadian concept' in rheumatology from bench to bedside.

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Figure 1: Internal circadian clocks and external Zeitgebers.
Figure 2: Molecular circadian clock mechanisms in a mammalian cell.
Figure 3: Responses to conventional prednisone versus chronotherapy for RA.
Figure 4: Effect of RA chronotherapy on associated depression.

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Authors and Affiliations

  1. Department of Rheumatology & Clinical Immunology, Charité University Medicine, Charitéplatz 1, Berlin, 10117, Germany

    Frank Buttgereit

  2. Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Waehringer Guertel 18–20, Vienna, A1090, Austria

    Josef S. Smolen

  3. Maynooth University Department of Psychology, National University of Ireland, Maynooth, County Kildare, Ireland

    Andrew N. Coogan

  4. Centre for Chronobiology, Psychiatric Hospital of the University of Basel, Wilhelm Klein-Strasse 27, Basel, CH4012, Switzerland

    Christian Cajochen

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All authors researched the data for the article, provided a substantial contribution to discussions of the content and contributed to writing the article and to review and/or editing of the manuscript before submission.

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F.B. declares that he has received consultancy fees, honoraria and travel expenses from Horizon Pharma (formerly Nitec Pharma) and Mundipharma International, and grant support from Horizon Pharma. C.C. declares that he has received honoraria for educational talks from Servier and Takeda and consultancy fees from Theva Pharma. J.S. and A.C. declare no competing interests.

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Buttgereit, F., Smolen, J., Coogan, A. et al. Clocking in: chronobiology in rheumatoid arthritis. Nat Rev Rheumatol 11, 349–356 (2015). https://doi.org/10.1038/nrrheum.2015.31

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