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This article is part of the supplement: Proceedings of Osteorheumatology 2011: International Congress on Bone Involvement in Arthritis

Meeting abstract

Why and how to optimize glucocorticoid treatment in rheumatoid arthritis

Maurizio Cutolo

Author Affiliations

Research Laboratory and Academic Unit of Clinical Rheumatology, Department of Internal Medicine, University of Genova, Genova, Italy

Arthritis Research & Therapy 2012, 14(Suppl 2):A19  doi:10.1186/ar3726

The electronic version of this article is the complete one and can be found online at: http://arthritis-research.com/content/14/S2/A19


Published:8 March 2012

© 2012 Cutolo; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Meeting abstract

Glucocorticoids (GC) are the most potent anti-inflammatory and immunosuppressive hormones mainly produced by the adrenal glands in humans.

The central nervous clock system, under the influence of light/dark alternation, "creates" the internal circadian rhythms and the organisms by "feeling" these rhythmic external changes, synchronize their physical activities, including sleep, related nocturnal hormone synthesis and immune function [1].

As a matter of fact, GC rise during the night around 3 am and start to exert anti-inflammatory and immunosuppressive activities. On the other hand, the nocturnal pineal hormone melatonin, that rises earlier in the night with darkness, has been linked to chronic inflammation since at normal to slightly elevated concentrations stimulate many aspects of the immune/inflammatory response, especially at the level of macrophages [2].

The immune-supportive role of melatonin and the reduced immune suppression linked to decreased endogenous GC (due to the chronic stress of the disease) have been delineated in the context of the circadian rhythms of immune/inflammatory reaction and related clinical (morning) symptoms, at least in RA [3].

Therefore, the most advanced approach to optimize the risk-benefit ratio of long-term low-dose GC treatment is the GC-chronotherapy, using a modified release (MR) prednisone (release during the night) and following the circadian rhythms.

In fact in RA, the circadian rhythms of clinical symptoms are more evident in the early morning hours, since preceded by nocturnal elevated levels of pro-inflammatory cytokines (i.e.IL-6). Therefore, since prevention of nocturnal rise of pro-inflammatory cytokines by GC therapy would be more effective than treating established symptoms in the morning and might reduce doses and side effects, a MR prednisone was developed, which releases prednisone approximately four hours after ingestion (i.e., at approximately 2-3 am when taken at bedtime) [4]. In addition to all recognized therapeutic effects obtained with conventional prednisone, MR prednisone was shown to have similar profile of adverse effects but without additional suppression of hypothalamic-pituitary-adrenal (HPA) axis [5].

In conclusion, night-time low dose long-term GC therapy in chronic rheumatic diseases such as RA, is today considered as an "hormonal replacement therapy" that optimally implement the peripheral insufficiency of endogenous GC in modulating the immune/inflammatory reaction.

References

  1. Cutolo M: Rheumatoid arthritis: circadian and circannual rhythms in RA.

    Nat Rev Rheumatol 2011, 7:500-502. PubMed Abstract | Publisher Full Text OpenURL

  2. Cutolo M, Maestroni GJ: The melatonin-cytokine connection in rheumatoid arthritis.

    Ann Rheum Dis 2005, 64:1109-1111. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  3. Cutolo M, Straub RH, Buttgereit F: Circadian rhythms of nocturnal hormones in rheumatoid arthritis: translation from bench to bedside.

    Ann Rheum Dis 2008, 6:905-908. OpenURL

  4. Buttgereit F, Doering G, Schaeffler A, et al.: Efficacy of modified-release versus standard prednisone to reduce duration of morning stiffness of the joints in rheumatoid arthritis (CAPRA-1): a double-blind, randomised controlled trial.

    Lancet 2008, 371:205-214. PubMed Abstract | Publisher Full Text OpenURL

  5. Alten R, Doring G, Cutolo M, et al.: Hypothalamus-pituitary-adrenal axis function in patients with rheumatoid arthritis treated with nighttime-release prednisone.

    J Rheumatol 2010, 37:2025-2031. PubMed Abstract | Publisher Full Text OpenURL