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Circadian rhythms in arthritis: Hormonal effects on the

immune/inflammatory reaction

Maurizio Cutolo a,, Rainer H. Straub b

aResearch Laboratory and Academic Unit of Clinical Rheumatology, Department of Internal Medicine,

University of Genova, Viale Benedetto XV, 6, IT-16132 Genova, Italyb Laboratory of Experimental Rheumatology and Neuroendocrino-Immunology, Department of Internal Medicine I,

University Hospital Regensburg, 93042 Regensburg, Germany

Available online 3 December 2007

Abstract

Biological signaling and rhythms occur in a complex network with participation and interaction of the central nervous

system, the autonomic nervous system, the endocrine glands, peripheral endocrine tissues and the immune system. It is a

clinical observation that patients affected by chronic immune/inflammatory conditions (i.e. rheumatoid arthritis/RA) exhibit

circadian, circamensual (females) and circannual rhythms of disease-related symptoms. Proinflammatory cytokines exhibit a

peculiar rhythmicity, in particular serum TNF and serum IL-6, and together with other relevant immunological parameters

display an elevation in the early morning hours in patients with RA. As a matter of fact, RA patients particularly experience

joint pain, morning stiffness, and functional disability in the early morning hours. Since circadian rhythmicity of

neuroendocrine pathways is closely coupled to immune/inflammatory reactions, new aspects at least concerning RAmanagement are suggested.

In particular, further investigations will indicate whether timed release of immunosuppressive/antiinflammatory drugs will

have increased efficacy and whether dosages can be reduced below critical levels above which adverse events appear.

2007 Elsevier B.V. All rights reserved.

Keywords: Rheumatoid arthritis; Circadian rhythms; Circannual rhythms; Hormones; Immune response; Cortisol

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

2. Circadian rhythms of hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

3. Circadian rhythms of the immune response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225

4. Links between rhythms of hormones and the immune response . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226

Available online at www.sciencedirect.com

Autoimmunity Reviews 7 (2008) 223228www.elsevier.com/locate/autrev

Corresponding author. Tel.: +39 010 353 7994; fax: +39 010 353 8885.

E-mail addresses: [email protected](M. Cutolo), [email protected] (R.H. Straub).

1568-9972/$ - see front matter 2007 Elsevier B.V. All rights reserved.doi:10.1016/j.autrev.2007.11.019
mailto:[email protected]:[email protected]://dx.doi.org/10.1016/j.autrev.2007.11.019http://dx.doi.org/10.1016/j.autrev.2007.11.019mailto:[email protected]:[email protected]


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5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226

Take home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227

1. Introduction

Biological processes and functions are well organized

in time, as evidenced by the expression of ultradian (high

frequency), circadian (approximately 24-h), circamensual

(approximately monthly), and circannual (approximately

yearly) rhythms and by the changes that occur with

menarche, reproduction, and menopause [1]. These

rhythms are mainly maintained on the basis of cyclical

changes depending on the light dark cycle [2]. Biologicalsignaling and rhythms occur in a complex network with

participation and interaction of the central nervous sys-

tem, the autonomic nervous system, the endocrine glands,

peripheral endocrine tissues and the immune system.

This network is responsible for the clinical observa-

tion that patients affected by chronic immune/inflamma-

tory conditions exhibit circadian, circamensual (females)

and circannual rhythms of disease-related symptoms.

The relationship has been studied also in patients with

rheumatoid arthritis (RA) [3,4]. Concerning the circa-

dian rhythms, it is the clinical experience of rheumatol-

ogists that RA patients particularly experience joint pain,morning stiffness, and functional disability in the early

morning hours. It is also remarkable that these diurnal

variations demonstrate large amplitudes, with the pa-

tient's condition being poor in the early morning and

disease activity being mild or moderate in the early

evening.

Since circadian rhythmicity of neuroendocrine path-

ways is tightly coupled to immune/inflammatory respon-

ses, an explanation of daily rhythms of arthritis-related

symptoms has been recently reported [5].

2. Circadian rhythms of hormones

The cycle of the hypothalamicpituitaryadrenal axis

(HPA axis) regulating cortisol synthesis shows a max-

imum in the early morning hours at 8:00 AM and a nadir

at midnight (Fig. 1A). Interestingly, in healthy subjects,

bone-resorbing activity is highest between 5:00 AM and

7:00 AM, which conforms to cortisol and tumor necrosis

factor (TNF)/interleukin-6 (IL-6) rhythms [6].

However, the cortisol rhythm in patients with RA

whose disease activity is relatively low to moderate does

not differ from that in healthy subjects (Fig. 1A). This is

the case with regard to the period, the amplitude, and the

time point of the minimum and peak of the cycle. On the

contrary, this rhythm can be highly disturbed in RA

patients when disease is in a very active stage, leading to

a flattening of the response curve, and two peaks appear,

in the morning and the afternoon [7].

Interestingly, RA patients with high disease activity

show elevated serum cortisol levels, which are, how-

ever, inadequately low in relation to their inflammatory

condition [7]. Since cortisol is the most potent endog-enous antiinflammatory substance, its up-regulation in

the early morning is most probably related to inhibition

of inflammation during the day, and its down-regulation

during the evening and night is linked to an increase of

inflammation during the early morning.

Besides cortisol, two other night hormones, melato-

nin and prolactin (Fig. 1B and C), show a clear 24-h

rhythm and have been linked to stimulation of the

immune system, which would lead to an increase in

proinflammatory conditions in RA, as recently showed

in RA patients treated at night with melatonin [810].

The typical circadian rhythm of melatonin exhibits amaximum at 3:00 AM, which is quite similar to that of

prolactin. When data from all available studies are com-

bined, the rhythms of these two hormones are not shown

to be markedly different in patients with RA as com-

pared with healthy controls (Fig. 1 B and C) [5]. How-

ever, one study demonstrated that serum levels of

melatonin reached a peak two hours earlier in RA pa-

tients than in controls [11].

In RA patients, melatonin levels exhibited a wide

plateau lasting 23 h, an effect not observed in healthy

controls [11]. After the peak was reached, melatoninlevels decreased similarly in RA patients and healthy

subjects. Furthermore, in a study of subjects from a

northern European country, serum levels of melatonin

appeared to be elevated in patients with RA as compared

with controls [12]. In addition, serum levels of prolactin

have been found during the night to be significantly

higher in RA patients compared with controls, and this

has been confirmed by others [13].

Both elevated melatonin and elevated prolactin will

probably establish a more proinflammatory environ-

ment exactly at the time point when cortisol levels are

lowest, and this is particularly true because the ratio of

224 M. Cutolo, R.H. Straub / Autoimmunity Reviews 7 (2008) 223228


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prolactin to cortisol peaks at 2:00 AM in RA patients

[13].

Both hormones, prolactin and melatonin, induce a

Th1 immune response and may thus lead to an unwanted

increase in related cellular immune phenomena in RA

patients during the night [14]. In healthy subjects, the

circadian rhythm of cortisol levels is similar in women

as compared to men, whereas a sex difference for

prolactin and melatonin has not been investigated [15].

Recently the pituitary gland has been suggested to

regulate prolactin rhythms as integration of photoper-iodic signals mediated by melatonin [16].

3. Circadian rhythms of the immune response

Proinflammatory cytokines exhibit a peculiar rhyth-

micity, in particular serum TNF and serum IL-6

(Fig. 1D). In healthy subjects, the peak value of TNF

is reached at 3:00 AM and that of IL-6 at 6:00 AM in

agreement with the sequence of TNF-induced IL-6

secretion that is observed in in vitro studies. Further-

more, a similar sequence of IL-6 and IL-6-dependent

secretion of fibrinogen has been documented, with

maximum fibrinogen levels at 10:00 AM [17]. In

patients with RA, the peak level of TNF has been

reported to appear at 6:00 AM and that of IL-6 at 7:00

AM, as a consequence both cytokines show a time shift

of the peak value towards the morning.

In healthy subjects, serum TNF and IL-6 levels are 25

pg/ml whereas in RA patients these levels are 2050 pg/ml.

Therefore, it becomes evident that the amplitude of the

curve is much higher and the curve necessarily must be

broadened for RA patients as compared with controls. In

healthy subjects, serum levels of TNF and IL-6 havealready begun to decrease around 6:00 AM and 9:00 AM,

respectively, whereas in RA patients these levels remain

elevated until 10:00 AM and 11:00 AM, respectively. The

observation that the amplitude is higher and the curve

broadened for these proinflammatory cytokines in RA

patients versus controls despite the similarity of the

circadian curves for serum cortisol, with similar amplitude

and shape, indicatesinadequate cortisol secretionin relation

to inflammation in RA [18].

It is interesting that serum levels of IL-2 and

interferon-gamma (IFN) demonstrate peak levels

between midnight and 2:00 AM in healthy subjects

Fig. 1. Circadian rhythms of serum cortisol (A), serum melatonin (B), serum prolactin (C), serum interleukin-6 (D), disease-related stiffness (E), and

disease-related pain (F). The data are given as % of the 24 h mean (modified according to [7]). The red lines and symbols give the data of RA patients,

and the black lines and symbols give the data of healthy subjects.

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(18). These two cytokines, similar to TNF, induce a Th1

immune response, as has also been reported for growth

hormone and prolactin. Thus, particularly during the

night, Th1 immune responses develop inducing a prepon-

derance of cellular immunity [4]. Cortisol and norepi-

nephrine (both mediators of the SNS), in contrast, supporta Th2 immune response and the levels of these factors are

particularly low between 11:00 PM and 5:00 AM [26].

Interestingly, a circadian rhythm exists for immunoglo-

bulins in RA, which has nicely been demonstrated for

IgA rheumatoid factor (peak at 8:00 AM) and IgM

rheumatoid factor (peak at 2:00 AM) [5]. Finally,

circulating immune complexes exhibit a circadian

rhythmicity in RA, with a peak between 6:00 AM and

9:00 AM [19].

In conclusion, several relevant immunological para-

meters display an elevation in the early morning hours inpatients with RA, which follows the rhythms of neuro-

endocrine mediators.

4. Links between rhythms of hormones and the

immune response

Recently, a lag time has been demonstrated between

increase in IL-6 levels and increase in cortisol levels

(plus 60120 min) or ACTH levels (plus 60 min) in

patients with RA [20]. Many independent studies

confirm the occurrence of this lag phase between IL-6

and cortisol in both healthy subjects and RA patients.Similarly, there is a lag time between increase in serum

cortisol levels and increase in serum TNF levels (5 h in

healthy subjects, 2 h in patients with RA).

Therefore, it is possible that increases in cytokine

levels during the early night drive the increase of cor-

tisol secretion and, most probably, also the activity of

the SNS [21]. In turn, these two systems may then

inhibit increased cytokines in the morning hours and

during the day. On the other hand, around midnight, the

decreases in levels of cortisol which inhibit secretion of

IL-6, TNF, and other cytokines together with the in-creases in levels of melatonin, growth hormone, and

prolactin, drive nocturnal increases of TNF, IFN, IL-2,

IL-12, and IL-6 [9,2123]. In summary, a strong con-

nection between changes in cytokines and hormones

levels, most probably, lead to up and down-regulation of

peripheral immune responses, permitting to RA-relevant

cytokines such as TNF, IFN, IL-2, and IL-6 to drive the

local proinflammatory process in joints and secondary

lymphoid organs in the early morning hours.

The clinical consequence is that the increased inflam-

matory conditions stimulate edema formation via bradyki-

nin/prostaglandins/substance P and also pain sensitization

[21]. These unwanted side effects (i.e. edema formation) of

elevated circulating proinflammatory cytokines ultimately

lead to symptoms of stiffness, pain, and functional

disability in the morning (Fig. 1E and F). In addition,

TNF and IL-6 play an important role in the worsening of

symptoms of several RA-related comorbidities, such ascardiovascular disease, osteoporosis, depression, and sleep

disturbances, all of which demonstrate maximum severity

during the night and in the early morning hours [21]. The

coupling of important neuroendocrine immunologic med-

iators (HPA axis together with SNS) and uncoupling of

other factors (HPA axis/SNS versus prolactin, melatonin,

growth hormone, TNF, IL-6, etc.) has the evolutionarily

conserved meaning to overcome infectious diseases, parti-

cularly during the night, with the final result to activate the

immune system [24].

In summary, an important finding in RA is increasedsecretion of prolactin/melatonin and inadequately low

secretion of cortisol; circadian curves of cortisol in fact

are very similar to those in healthy subjects. The ex-

pected increased cortisol secretion, in order to dampen

exaggerated proinflammatory cytokine secretion in RA,

is only visible in patients with very high disease activity

[6,7]. In any case, the somewhat higher cortisol levels

observed in patients with very active disease are not

sufficient to alleviate the disease process in RA. This

inadequacy of cortisol secretion support that treatment

with exogenous glucocorticoids at the beginning of RA,

during disease flares, or during smoldering inflamma-tion in mild-to-moderate RA can be viewed as a substi-

tution therapy for the functionally disturbed HPA axis.

Based on these neuroendocrine immune links, other

circamensual and circannual rhythms have been ob-

served in RA patients. For example, a relation of men-

strual (hormonal) cycle phase to clinical symptoms of

RA is well established [25].

On the other hands, significantly altered 25-(OH)D

serum levels were observed in RA patients with a cir-

cannual rhythm in winter and summer time and these

levels showed a significant correlation (negative) withRA clinical status [26]. This paper cannot cover all the

interesting details of this subject, and the interested

reader is referred to the literature [2740].

5. Conclusions

Since circadian rhythmicity of neuroendocrine

pathways is closely coupled to immune/inflammatory

reaction, the timed release of neuroendocrine factors and

modulation of the immune/inflammatory response accord-

ing to biological rhythms represents a new aspect at least of

RA management. Further investigations will indicate

226 M. Cutolo, R.H. Straub / Autoimmunity Reviews 7 (2008) 223228


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whether timed release of immunosuppressive/antiinflam-

matory drugs (i.e. corticosteroids) will lead to increased

efficacy and reduced dosages below critical levels above

which adverse events appear.

Take home messages

Biological signaling and rhythms occur in a complex

network with participation and interaction of the

central nervous system, the autonomic nervous sys-

tem, the endocrine glands, peripheral endocrine tissues

and the immune system

Proinflammatory cytokines exhibit a peculiar

rhythmicity, in particular serum TNF and serum

IL-6, and together with other relevant immunolo-

gical parameters display an elevation in the early

morning hours in patients with rheumatoid arthritis(RA) by following the rhythms of neuroendocrine

mediators.

RA patients particularly experience joint pain, morn-

ing stiffness, and functional disability in the early

morning hours since during the night, both elevated

melatonin and elevated prolactin seem to establish a

more proinflammatory environment closely at the

time point when cortisol (antiinflammatory steroid)

levels are lowest.

It might well be that timed release of immunosuppres-

sive/antiinflammatory drugs will display increased

efficacy and that dosages of these drugs might bereduced below critical levels above which adverse

events appear.

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