Rheumatoid Arthritis Chronotherapy

Maurizio Cutolo
European Musculoskeletal Review, 2012;7(1):29-32
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Abstract

In rheumatoid arthritis (RA) patients, joint stiffness and functional disability are especially recognised in the early morning hours, as a result of the nocturnal adrenal cortisol production being insufficient to inhibit the ongoing inflammatory/immune reactivity. Therefore, RA glucocorticoid treatment, by considering the existence of cellular circadian rhythms, may better downregulate the nocturnal upregulation of immune cell activity (and associated flare of pro-inflammatory cytokine synthesis) when available at night (chronotherapy). Accordingly, low-dose prednisone chronotherapy with modified-release prednisone (released at 03:00 hours) is currently available. The same approach has been found successful in patients with adrenal insufficiency. A chronotherapeutic approach in RA seems also to be useful with the management of disease-modifying drugs such as methotrexate. Regarding vitamin D, a circannual rhythm of low levels in winter and peaks in summertime showed a significant negative correlation with clinical RA status, as assessed using the 28-joint disease activity score. Since vitamin D exerts immunomodulatory activities, chronotherapy with seasonal (winter, spring) administration of vitamin D analogues might represent a further approach to optimise the treatment of RA patients.

Acknowledgement: The author wishes to acknowledge colleagues Rainer H Straub, Frank Buttgereit, Cornelia Spes, Rieke Alten, Alfonse Masi, Johannes WJ Bijlsma for their continuous co-operation and support.
Keywords
Chronobiology, circadian rhythms, rheumatoid arthritis, glucocorticoids, chronotherapy
Disclosure The author has no conflicts of interest to declare.
Received: December 20, 2011 Accepted January 23, 2012
Correspondence: Maurizio Cutolo, Full Professor of Rheumatology; Director, Research Laboratories and Academic Unit of Clinical Rheumatology, Department of Internal Medicine, University of Genova, Viale Benedetto XV, 6, 16132 Genova, Italy. E: mcutolo@unige.it

Rheumatoid arthritis (RA) is a chronic, multifactorial, immune-mediated inflammatory syndrome mainly characterised by the recruitment and activation of immune/inflammatory cells, synovial tissue hyperplasia and joint integrity destruction.1 In RA, the initial activation of the immune system also involves neuroendocrine mechanisms and leads to an inflammatory cascade followed by perpetuation and diffusion of the inflammatory reaction, resulting in articular but also extra-articular organ damage.2

In RA patients, joint stiffness and functional disability is evident in the early morning hours since adrenal cortisol production (night synthesis), under the chronic stress of the disease, becomes insufficient to inhibit the ongoing inflammatory/immune reactivity.3

Pro-inflammatory cytokines exhibit a peculiar rhythmicity according to the clinical symptoms of RA; in particular, serum tumour necrosis factor (TNF) and interleukin-6 (IL-6), together with other relevant immunological mediators, display an elevation in the early morning hours.

The basis on which to understand these rhythms is related to the alternation of sunlight and darkness that regulates the cyclical 24-hour period of human biological activity, generally reported as ‘circadian rhythms’ or referred as ‘chronobiology’. The central nervous biological CLOCK system (highly conserved and sophisticated molecular ‘clock’), ‘creates’ the internal circadian rhythms under the influence of light/dark alternations, and synchronises physical and functional activities including sleep, energy metabolism and immune functions.4,5

Interestingly, biological signalling and circadian/circannual rhythms occur in a complex network with interaction and involvement of the central nervous system (CNS).6

In particular, several immunological functions are dependent on the influence of sleep on circadian rhythms and loss of sleep, in turn, prevents these immunosupportive actions, which mainly alters the night production of glucocorticoids.7,8

Therefore, in both healthy and pathological conditions, neuroendocrine immune circadian reactivity is driven by nocturnal hormones such as melatonin (and prolactin) that, by increasing in the late evening, activate the night-time immune response and then, via a successive rise in cortisol levels, downregulate ongoing immune reactivity very early in the morning9,10 (see Figure 1).

Consequently, since the circadian rhythmicity of neuroendocrine pathways is closely coupled to immune/inflammatory reactions and related clinical symptoms, new chronotherapeutic approaches have been started in RA.10

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