**Chronobiology of and Chronotherapy for Rheumatoid Arthritis**

Hideto To *University of Toyama Japan* 

#### **1. Introduction**

546 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

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Most humans have a relatively regular activity pattern (sleep, labor, and meal etc.). This activity can be roughly classified into the rest phase and active phase, and body temperature, heart rate, blood pressure, and the dominance of the sympathetic and parasympathetic nerves differ in each phase. These variations display daily rhythms, which are known as circadian rhythms.

Fig. 1. Circadian rhythm of mouse leukocyte count

For instance, ICR mice, which were housed under standardized light-dark cycle conditions (lights-on and lights-off at 7:00 and 19:00, respectively) at a room temperature of 24 ± 1oC (range) and a relative humidity of 60 ± 10% (range) and were allowed free access to food and water displayed a circadian rhythm in their leukocyte counts with a peak at noon and a trough at midnight (Fig. 1). Many organisms display rhythms in various factors (Table 1). In humans, heart rate and blood pressure decline at night. We spend much of our time in a standing position during the day and sleep in a recumbent position at night. It is thought that the wake-sleep transition and endogenous circadian rhythms are responsible for the circadian rhythms in heart rate and blood pressure. Circadian rhythms also exist for the

Chronobiology of and Chronotherapy for Rheumatoid Arthritis 549

are seldom observed in the daytime (Fig.2; Dethlefsen et al., 1985). In addition, the risks of spontaneous acute dissection and rupture of the thoracic aorta, myocardial ischemia, ischemic stroke, and subarachnoid hemorrhage are higher during the active phase than during the rest phase. The variations in heart rate, blood pressure, and blood flow, etc., induced by the wake-sleep transition are considered to affect the risk of such problems occurring. Interestingly, pain such as toothache, migraine, and rheumatoid arthritis pain is more acute in the early morning. Collectively, circadian rhythms are recognized in many diseases, and certain time periods are associated with a high risk or frequency of disease

Fig. 2. Circadian rhythm of asthmatic attacks in asthma patients (redrawn from the data of

Chronotherapy is defined as the administration of medications in accordance with biological rhythms in order to optimize therapeutic outcomes and/or control adverse effects, and it has been reported that many drugs such as antitumor drugs, antidepressants, and analgesic drugs show rhythm-dependent differences in their effects and pharmacokinetics (Tabuchi et al., 2005; Ushijima et al., 2005; Tampellini et al., 1998). These effects arise from the circadian rhythms found in elements of cellular physiology such as the cell cycle and the expression of receptors, hormones, and enzymes (Iurisci et al., 2006; Matsunaga et al., 2004; Koyanagi et al., 2006). Fig. 3 displays data for the dosing time-dependency of vomiting episodes in urogenital cancer patients treated with cisplatin (Kobayashi et al., 2001). Cisplatin (70 mg/m2) was given to the patients at 5:00 or 17:00. After the cisplatin administration, all episodes of vomiting during a 6-hour period were recorded. Vomiting was markedly

decreased in the patients treated at 17:00 compared with that at 5:00 (*P* = 0.061).

occurrence.

Dethlefsen et al., 1985)

levels of hormones such as cortisol and melatonin (MLT). The plasma level of cortisol peaks in the morning and that of MLT peaks at midnight. Bone marrow cells, intestinal mucosal cells, and hair matrix cells show relatively active cell division. In the day, there is also a period of time when the number of cells is actively increased by segmentation (DNA synthesis) as well as a period of dormancy. The circadian rhythm of bone marrow cell division involves a peak in the evening and a trough in the midnight, and that of rectal mucosal cell division is higher at 7:00 and lower at 19:00. Thus, various factors in the living body have their own circadian rhythms, and the phases of these cycles vary for each factor.


Table 1. Circadian rhythms of various factors in humans


Table 2. Circadian rhythms in the risk or frequency of disease occurrence

These circadian rhythms are also associated with the risk or frequency of disease occurrence (Table 2). For example, asthma attacks get worse between midnight and early morning and

levels of hormones such as cortisol and melatonin (MLT). The plasma level of cortisol peaks in the morning and that of MLT peaks at midnight. Bone marrow cells, intestinal mucosal cells, and hair matrix cells show relatively active cell division. In the day, there is also a period of time when the number of cells is actively increased by segmentation (DNA synthesis) as well as a period of dormancy. The circadian rhythm of bone marrow cell division involves a peak in the evening and a trough in the midnight, and that of rectal mucosal cell division is higher at 7:00 and lower at 19:00. Thus, various factors in the living body have their own circadian rhythms, and the phases of these cycles vary for each factor.

No. Factors Peak period Trough period Ref

8:00-13:00 8:00-13:00 8:00-14:00

No. Factors Peak period Trough period Ref

Table 2. Circadian rhythms in the risk or frequency of disease occurrence

2 Myocardial ischemia 8:00 0:00-4:00 Egstrup et al., 1991 3 Ischemic stroke 8:00 18:00-6:00 Argentino et al., 1990

5 Asthma 2:00-5:00 7:00-19:00 Dethlefsen et al., 1985 6 Temporal lobe epilepsy 15:00-21:00 0:00-5:00 Quigg et al., 1998 7 Pain sensitivity in teeth 4:00-7:00 11:00-17:00 Pöllmann et al., 1978 8 Migraine 4:00-10:00 21:00-1:00 Fox et al., 1998

These circadian rhythms are also associated with the risk or frequency of disease occurrence (Table 2). For example, asthma attacks get worse between midnight and early morning and

7

1

9

Cortisol Adiponectin Leptin-binding protein

Spontaneous acute dissection and rupture of the thoracic aorta

Stiffness, pain, and functional disability in rheumatoid arthritis

Table 1. Circadian rhythms of various factors in humans

<sup>9</sup>DNA synthesis in the

<sup>10</sup>DNA synthesis in the

<sup>4</sup>Subarachnoid

1 Body temperature 18:00-20:00 3:00-6:00 Lack et al., 2008 2 Heart rate 8:00-18:00 4:00-6:00 Clarke et al., 1976 3 Blood pressure 8:00-20:00 0:00-6:00 Degaute et al., 1991 4 Hepatic blood flow 8:00 14:00 Lemmer et al., 1991 5 Glomerular filtration 16:00 4:00 Koopman et al., 1989 6 Lymphocytes 12:00-17:00 7:00 Miyawaki et al., 1984

8 Melatonin 2:00-4:00 9:00-21:00 Kennaway et al., 1998

bone marrow 16:00 0:00 Smaaland et al., 1991

rectal mucosa 7:00 19:00 Buchi et al., 1991

hemorrhage 6:00-20:00 0:00-4:00 Vermeer et al., 1997

0:00-4:00 2:00-4:00 1:00-5:00

7:00-12:00 22:00-6:00 Gallerani et al., 1997

3:00-7:00 13:00-21:00 Straub et al., 2007

Gavrila et al., 2003

are seldom observed in the daytime (Fig.2; Dethlefsen et al., 1985). In addition, the risks of spontaneous acute dissection and rupture of the thoracic aorta, myocardial ischemia, ischemic stroke, and subarachnoid hemorrhage are higher during the active phase than during the rest phase. The variations in heart rate, blood pressure, and blood flow, etc., induced by the wake-sleep transition are considered to affect the risk of such problems occurring. Interestingly, pain such as toothache, migraine, and rheumatoid arthritis pain is more acute in the early morning. Collectively, circadian rhythms are recognized in many diseases, and certain time periods are associated with a high risk or frequency of disease occurrence.

Fig. 2. Circadian rhythm of asthmatic attacks in asthma patients (redrawn from the data of Dethlefsen et al., 1985)

Chronotherapy is defined as the administration of medications in accordance with biological rhythms in order to optimize therapeutic outcomes and/or control adverse effects, and it has been reported that many drugs such as antitumor drugs, antidepressants, and analgesic drugs show rhythm-dependent differences in their effects and pharmacokinetics (Tabuchi et al., 2005; Ushijima et al., 2005; Tampellini et al., 1998). These effects arise from the circadian rhythms found in elements of cellular physiology such as the cell cycle and the expression of receptors, hormones, and enzymes (Iurisci et al., 2006; Matsunaga et al., 2004; Koyanagi et al., 2006). Fig. 3 displays data for the dosing time-dependency of vomiting episodes in urogenital cancer patients treated with cisplatin (Kobayashi et al., 2001). Cisplatin (70 mg/m2) was given to the patients at 5:00 or 17:00. After the cisplatin administration, all episodes of vomiting during a 6-hour period were recorded. Vomiting was markedly decreased in the patients treated at 17:00 compared with that at 5:00 (*P* = 0.061).

Chronobiology of and Chronotherapy for Rheumatoid Arthritis 551

Hermida et al., 2010; Haus, 2007; Saito et al., 1991; Smolensky et al., 2007)**.** Hydroxymethyl glutaryl coenzyme A (HMGCoA) reductase participates in the biosynthesis of mevalonic acid and is the rate-limiting enzyme of cholesterol biosynthesis. The plasma mevalonic acid levels in healthy volunteers showed a clear circadian rhythm, with higher levels seen at night and lower levels observed at daytime (Fig. 4A). Simvastatin is an HMGCoA reductase inhibitor. When simvastatin was administered to hyperlipidemic patients once a day in the morning or evening, the evening group displayed a significantly decreased total cholesterol level compared with the morning group (Fig. 4B). Thus, cholesterol biosynthesis may be effectively inhibited when simvastatin is administered in the evening, when the activity of

Taken together, many organisms display circadian rhythms in various factors, and chronotherapy that takes into account circadian rhythms is thought to be a useful

Rheumatoid arthritis (RA) is an autoimmune disorder of unknown etiology and a chronic progressive disease that reduces the quality of life of individuals that suffer from the condition (Harris ED Jr., 1990; Gabriel SE., 2001). Although many requirements must be met to establish a diagnosis of RA, morning stiffness is a characteristic feature of RA (Arnett et al., 1988). Tumor necrosis factor- (TNF-), interleukin-1 (IL-1), and interleukin-6 (IL-6), which are inflammatory cytokines, show high concentrations in human blood and synovial fluid, and excess production of these cytokines plays a central role in the pathogenesis of RA (Feldmann et al., 1996; McInnes et al., 2005). Morning stiffness shows a circadian rhythm with a peak in the early morning in RA patients. The IL-6 concentration in blood also shows a circadian rhythm peaking from midnight to early morning, which mirrors the timing of

In this chapter, I would like to introduce the circadian rhythm of rheumatoid arthritis and

RA is an autoimmune disorder of unknown etiology, and morning stiffness is a characteristic of the condition (Arnett et al., 1988). Pain, functional disability, and stiffness show circadian rhythms with a peak in the early morning in many RA patients (Fig. 5) (Bellamy et al., 1991; Kowanko et al., 1982), and the circadian rhythms of pain and stiffness may play a role in local and systemic inflammatory responses. Herold and Günther (Herold et al., 1987) reported that plasma C-reactive protein (CRP) levels, an indicator of inflammatory responses, showed a circadian rhythm with a peak in the early morning and a trough in the evening in RA patients, which matches the rhythms of pain and stiffness. Proinflammatory cytokines, such as TNF- and IL-6, are secreted from activated monocytes, and macrophages increase CRP levels in hepatocytes. There are clear circadian rhythms in the blood concentrations of these cytokines, with higher levels seen in the early morning in RA patients (Crofford et al., 1997; Perry et al., 2009). Since the circadian rhythms of CRP and cytokines are similar, it is considered that cytokine rhythms contribute to the rhythm of CRP

HMGCoA reductase begins to increase.

morning stiffness (Crofford et al., 1997).

**2.1 Circadian rhythm of rheumatoid arthritis** 

**2. Chronobiology of rheumatoid arthritis** 

therapeutic method.

its mechanism.

levels.

Fig. 3. Number of vomiting episodes according to the time (5:00 vs 17:00) of cisplatin administration in patients with urogenital cancer (redrawn from the data of Kobayashi et al., 2001)

Fig. 4. Circadian rhythm of plasma mevalonic acid levels and the influence of simvastatin dosing time on total cholesterol levels (redrawn from the data of Jones et al., 1992, and Saito et al., 1991)

Moreover, it has been reported that circadian rhythms exist for asthma attacks and cholesterol synthesis, and medicinal treatment based on chronotherapy has been actively applied to the treatment of asthma, hypertension, and hyperlipidemia (D'Alonzo et al., 1995;

Fig. 3. Number of vomiting episodes according to the time (5:00 vs 17:00) of cisplatin

2001)

et al., 1991)

administration in patients with urogenital cancer (redrawn from the data of Kobayashi et al.,

Fig. 4. Circadian rhythm of plasma mevalonic acid levels and the influence of simvastatin dosing time on total cholesterol levels (redrawn from the data of Jones et al., 1992, and Saito

Moreover, it has been reported that circadian rhythms exist for asthma attacks and cholesterol synthesis, and medicinal treatment based on chronotherapy has been actively applied to the treatment of asthma, hypertension, and hyperlipidemia (D'Alonzo et al., 1995; Hermida et al., 2010; Haus, 2007; Saito et al., 1991; Smolensky et al., 2007)**.** Hydroxymethyl glutaryl coenzyme A (HMGCoA) reductase participates in the biosynthesis of mevalonic acid and is the rate-limiting enzyme of cholesterol biosynthesis. The plasma mevalonic acid levels in healthy volunteers showed a clear circadian rhythm, with higher levels seen at night and lower levels observed at daytime (Fig. 4A). Simvastatin is an HMGCoA reductase inhibitor. When simvastatin was administered to hyperlipidemic patients once a day in the morning or evening, the evening group displayed a significantly decreased total cholesterol level compared with the morning group (Fig. 4B). Thus, cholesterol biosynthesis may be effectively inhibited when simvastatin is administered in the evening, when the activity of HMGCoA reductase begins to increase.

Taken together, many organisms display circadian rhythms in various factors, and chronotherapy that takes into account circadian rhythms is thought to be a useful therapeutic method.
