edited_cutolo_Layout 1 03/12/2009 11:22 Page 41
Autoimmune Diseases Rheumatoid Arthritis
Night-time Glucocorticoid – A Paradigm Shift in
Glucocorticoid Therapy in Rheumatoid Arthritis?
Maurizio Cutolo
Director, Research Laboratories and Clinical Academic Unit of Rheumatology, Department of Internal Medicine, and
Director, Post-graduate School of Rheumatology, University of Genoa
Abstract
Altered circadian rhythms of nocturnal hormones in rheumatoid arthritis (RA) patients play a role in the disease’s symptoms, and increased
serum concentrations of melatonin (MLT) are observed in RA patients compared with healthy controls. The pro-inflammatory effects of MLT
are poorly contrasted by lower than expected early morning endogenous production (and serum levels) of cortisol in RA patients. The
adrenal hormone cortisol is the nocturnal endogenous steroid with anti-inflammatory actions. The circadin cycle of the hypothalamic–
pituitary–adrenal (HPA) axis has a peak in the early morning hours at 8am but a nadir at midnight. However, the rise of the inflammatory
cytokines (i.e. interleukin [IL]-6) and related inflammatory reactions start at around 1am to 2am, followed shortly after (around 2am to 3am)
by a cortisol peak. Therefore, treatment with exogenous glucocorticoids must respect the circadian rhythms of hormonal production in
order to optimise clinical efficacy and to reduce doses and adverse effects. A modified-release prednisone formulation that respects the
circadian rhythms of glucocorticoid production is now available.
Keywords
Rheumatoid arthritis, circadian rhythms, glucocorticoids, cortisol, melatonin, inflammatory cytokines, synovial tissue
Disclosure: The author has no conflicts of interest to declare.
Received: 2 August 2009 Accepted: 11 August 2009
Correspondence: Maurizio Cutolo, Director, Research Laboratories and Clinical Academic Unit of Rheumatology, Department of Internal Medicine, and Director,
Post-graduate School of Rheumatology, University of Genova, Viale Benedetto XV, 6, 16132 Genova, Italy. E:
mcutolo@unige.it
The Link Between Night-time Inflammation and In patients with RA and in healthy subjects, MLT levels increased
Morning Symptoms in Rheumatoid Arthritis progressively from 8pm to the early morning hours. However, they
Rheumatoid arthritis (RA) is a chronic inflammatory polyarthritis reached peak levels at midnight in patients with RA, which was at
characterised by inflammation and altered humoral and cellular least two hours earlier than in controls. Subsequently, MLT
immune responses, leading to destruction and subsequent loss of concentrations in RA reached a plateau that lasted for two to three
function of multiple joints. Genetic and environmental factors hours, which was not observed in controls. The study confirmed
also contribute to the disease.
1–3
The most evident diagnostic that the nocturnal rhythm of MLT also occurs in patients with RA,
clinical characteristic in RA is that disease symptoms follow but with an earlier peak and a broader plateau in the early morning
obvious circadian rhythms, with an increase of activity in the early (see Figure 1).
morning hours, abatement during the day and a smaller increase in
the early evening.
4,5
Accordingly, in human peripheral blood mononuclear cells, at
physiological concentrations MLT has been reported to stimulate
A number of papers have reported a temporal relationship between the production of interferon-γ (IFN-γ), IL-1, IL-2, IL-12 and,
elevated levels of pro-inflammatory cytokines (i.e. tumour necrosis particularly, IL-6, but not IL-4.
9,10
In addition, MLT was found to
factor [TNF], interleukin [IL]-1 and IL-6) and clinical symptoms of RA, enhance production of inflammatory cytokines from cultured
such as morning stiffness.
6,7
Several of these cytokines are highly human monocytes/macrophages, including IL-12, and turning the
elevated in patients with active RA in the early hours of the day, MLT/IL-2 connection towards the enhancement of T-cell immunity.
11
but after noon they are almost non-existent. Their release pattern MLT was found to be detectable at high concentrations in synovial
and serum concentrations, respectively, possibly triggered by fluids from patients who had RA, and binding sites for MLT were
pro-inflammatory hormones such as melatonin (MLT) or by a present in synovial macrophages.
12
superordinate neuroendocrine centre in the hypothalamus, follow a
strict 24-hour daily cycle. In particular, by evaluating MLT levels in Interestingly, IL-1, IL-12, TNF-α and particularly IL-6 production
patients with RA with a focus on analyses of circadian variations, (T helper-1 cytokines/promoting cytokines) reach their peak during
serum levels at 8pm and 8am were found to be significantly higher the night and early morning, shortly after MLT serum levels are
in patients with RA than in healthy controls (p<0.05)
8
(see Figure 1). highest and plasma cortisol is lowest (see Figure 1). Therefore, MLT
The differences were more evident in patients who were over 60 upregulates cytokine production and immune function during the
years of age. night.
13
Interestingly, the treatment of RA patients with MLT was found
© TOUCH BRIEFINGS 2009 41
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92 |
Page 93 |
Page 94 |
Page 95 |
Page 96 |
Page 97 |
Page 98 |
Page 99 |
Page 100 |
Page 101 |
Page 102 |
Page 103 |
Page 104 |
Page 105 |
Page 106 |
Page 107 |
Page 108 |
Page 109 |
Page 110 |
Page 111 |
Page 112 |
Page 113 |
Page 114 |
Page 115 |
Page 116