Circadian rhythms of inflammation

Circadian variation of symptoms caused by inflammation is common to conditions including rheumatoid arthritis, polymyalgia rheumatica, ankylosing spondylitis, asthma, depression and many more. The adrenal circadian rhythm is an important factor when serum cortisol is inadequate relative to inflammation. An excellent paper published in Arthritis Research & Therapy examines the dynamics and clinical significance of circadian variation in inflammation associated with glucocorticoid regulation, an important consideration for anti-inflammatory treatment.

Brain's central circadian oscillator connects with immune system

The suprachiasmatic nucleus of the hypothalamus that generates the circadian rhythm connects profusely to other brain centers and to the immune system through the HPA axis.

"The circadian activity of this particular nucleus is transferred to the immune system via the hypothalamic hypothalamic-pituitary-adrenal (HPA) axis, leading to the typical undulation of clinical symptoms in chronic inflammatory diseases with a maximum in the early morning hours. In this review we will describe circadian rhythms in rheumatoid arthritis (RA) and other rheumatic and chronic inflammatory diseases, dysfunction of the HPA axis in RA and other rheumatic and chronic inflammatory diseases, the problem of adrenal suppression by glucocorticoid (GC) therapy, and whether or not chronotherapy with prednisone is more effective and aggravates adrenal suppression."

This pertains to the classic aggravation of stiffness and pain in the morning as well as the oscillation of other symptoms caused by inflammation, including neuropsychiatric disorders.

Nocturnal inflammation, melatonin and cortisol

As melatonin goes up at night cortisol, which 'keeps a lid on' inflammation, goes down and inflammatory biomarkers are seen to increase.

"Classical symptoms of RA, such as morning stiffness and swelling, show a clear temporal relationship with nocturnally elevated levels of proinflammatory cytokines, as a consequence of a cascade of increased nocturnal inflammation. Several of these cytokines, such as tumor necrosis factor (TNF) alpha and interleukin (IL)-6, are highly increased in patients with active RA in the early hours of the day, but are found at very low levels after noon."

This is characteristic of a healthy cortisol rhythm...

"Also, the cortisol rhythm - which is also present in healthy individuals, and therefore is primary, with low levels at night - may explain nocturnal inflammation. Since cortisol is the strongest endogenous anti-inflammatory substance, its downregulation during the evening and night is linked to an increase of inflammation during the early morning, and its upregulation in the early morning is most probably related to inhibition of inflammation during the day. The early morning inflammatory signs, typical for many inflammatory rheumatic conditions, can thus be explained."

Polymyalgia rheumatica, ankylosing spondylitis and asthma

These conditions too have cyclic undulations that correspond to the circadian rhythm of immune activity, with implications for treatment.

"Furthermore, in polymyalgia rheumatica (PMR), symptoms of pain and stiffness typically are most prominent during the early morning, similar to RA...Of note, in ankylosing spondylitis - another inflammatory arthritic condition - pain and stiffness also seem to be most prominent during the early morning hours. Finally, it is now also evident that symptoms of diseases such as RA, which is T helper 1 dependent, but also asthma, which is T helper 2 dependent, are influenced by diurnal rhythms and natural regulatory T cells. In particular, secretion of IL-2, interferon gamma and IL-10 by naïve CD4⁺ T cells follows a diurnal rhythm."

This ties together the nervous, immune and hormonal systems that interact in a rhythmic fashion:

"All of these processes are closely linked to regulatory interactions between the endocrine, nervous and immune systems, with distinct 24-hour daily rhythms (neuroendocrine immunology)."

HPA axis dysfunction in chronic inflammatory disorders

Normally the adrenocortical response should track the circadian oscillator or inflammation. The authors describe a fascinating study in which the cortisol response to infusions of the pro-inflammatory cytokine IL-6 were delineated:

"In a fairly heroic study in 18 healthy young men, either saline or low or high doses of recombinant human IL-6 were infused into one femoral artery for 3 hours. Subjects experienced clinical symptoms such as shivering and discomfort during high-dose IL-6 administration, but were asymptomatic during low-dose IL-6 administration. Plasma cortisol concentrations did not change during infusion of saline but markedly increased during both high and low doses of IL-6. While concentrations of plasma cortisol declined after 2 hours of infusion in low doses of IL-6, they remained elevated in high doses of IL-6 at 3 hours of infusion...The increase of cortisol levels in reaction to IL-6 infusion is provoked by activation of the HPA axis. Remarkably, the relation between IL-6 levels and the adrenocorticotropic hormone (ACTH)/cortisol levels is linear. In a study of 15 healthy young men in which recombinant IL-6 was applied subcutaneously, plasma ACTH concentrations and plasma cortisol levels increased dose dependently, and the ratio of hormone to IL-6 serum levels was constant."

By contrast however, in chronic inflammation levels of cortisol are insufficient to 'put out the fire.'

"In chronic inflammation, cortisol secretion appears to be inadequate in relation to inflammation. In a retrospective study with 34 patients with RA, 46 patients with reactive arthritis and 112 healthy subjects, the authors measured serum levels of IL-6, TNF and cortisol. The absolute levels of IL-6 were lower in healthy controls than in reactive arthritis and RA patients. However, the ratio of serum cortisol to serum cytokines was much higher in healthy controls than in reactive arthritis and RA patients, due to similar cortisol levels in all groups."

And in another RA study...

"...comparing the circadian course of ACTH and cortisol levels in patients with RA and in healthy subjects, despite 10 times higher serum levels of cytokines in patients with RA, serum level curves of ACTH and cortisol were identical. The ACTH/cortisol hormone secretion in patients with RA is thus inadequate in relation to inflammation."

And giant cell arteritis...

"In a study comparing serum values of ACTH, cortisol and CRP in patients with PMR/giant cell arteritis and controls, ACTH and cortisol levels were not different in patients with PMR/giant cell arteritis and controls, whereas the ratios of serum ACTH/serum CRP and serum cortisol/serum CRP were significantly lower in PMR/giant cell arteritis patients than in healthy controls. Thus, in PMR/giant cell arteritis there also appears to be an inadequate cortisol secretion in relation to inflammation in terms of relative adrenal insufficiency."

The liver-HPA-kidney axis in chronic inflammation

In important observations that call to mind principles of traditional Chinese medicine (TCM), the authors delineate the function of hepato-hypothalamic-pituitary-adrenal-renal axis:

"Recently, evidence has accumulated, been reviewed and presented as a concept that dysfunction of the HPA axis in chronic inflammation is not simply an adaptation to chronic stress, but may be due to increased negative feedback of active cortisol on the HPA axis. The HPA axis has been recognized to be extendable to a hepato-hypothalamic-pituitary-adrenal-renal axis by GC [glucocorticoid] metabolism."

The liver in chronic inflammation

The kidney inactivates cortisol to protect its receptor from over-stimulation and subsequent suppression, and the liver turns it back on:

"Active cortisol is converted to inactive cortisone mainly by the kidney, via 11β-hydroxysteroid dehydrogenase (11β-HSD) type 2, in order to protect the nonspecific mineralocorticoid receptor from activation by cortisol. On the other hand, the major organ for converting inactive cortisone to active cortisol is the liver, via 11β-HSD1."

Pro-inflammatory cytokines over-activate the liver 11β-HSD1 enzyme:

"Expression of 11β-HSD1 is markedly enhanced by TNF and proinflammatory cytokines. The liver therefore becomes an important player in systemic inflammation, even if the conversion also occurs in multiple other tissues including the brain, adipocytes, vascular cells, osteoblasts and fibroblasts. Given the role of the 11β-HSD1 in GC metabolism, its effect on the HPA axis and its interaction with inflammatory cytokines, it is hypothesized that in chronic inflammatory diseases, cytokine-induced increased expression of 11β-HSD1 induces a change in the HPA axis. Increased negative feedback of active cortisol on the HPA axis induced during inflammation may thus be the mechanism of dysfunction of the HPA axis in chronic inflammation."

Tertiary adrenal insufficiency

Synthetic glucocorticoids such as prednisone suppress adrenal function through the same negative feedback mechanism:

"During the physiological regulation of the HPA axis, cortisol release is terminated by negative feedback regulation of cortisol on the hypothalamus and anterior pituitary. Also, synthetic GCs - as applied in GC therapy - can cause negative feedback regulation, leading to adrenal suppression in terms of tertiary adrenal insufficiency."

Besides the clinical presentation, this can be confirmed by low cortisol and ACTH levels and lack of increase in plasma cortisol with the corticotropin-releasing hormone (CRH) or ACTH stimulation test. The magnitude of the dose matters:

"The frequency of adrenal suppression increases with increasing GC dosages. In arthritis and asthma patients treated with prednisone equivalent doses ranging from 5 to 20 mg, cortisol response in the ACTH test was normal (that is, cortisol rise ≥7 μg/dl) in all of the patients taking a single morning dose of 5 to 7.5 mg prednisone, was blunted (that is, cortisol rise <7 μg/dl) in 33% and 47% of the patients taking 10 to 12.5 mg and 15 mg prednisone, respectively, and was suppressed (no rise) in 44% of the patients taking 20 mg prednisone."

Duration also takes its toll:

"After 12 weeks of 7.5 mg prednisolone, the mean values for the 60-minute response to ACTH were reduced by 35%. Following treatment, 46% of patients taking 7.5 mg prednisolone failed to reach the normal maximum cortisol response to ACTH, even if the HPA axis response generally remained within the normal range."

Chronotherapy with prednisone

Primary concerns are maximizing effectiveness while minimizing adrenal suppression through negative feedback regulation. Several daily divided doses worsen the tendency to suppression:

"In the 1960s several studies confirmed that splitting the daily dose into several divided doses strongly increases the risk of adrenal suppression. For example, whereas endogenous cortisol secretion was not altered with a single dose of 8 mg triamcinolone given at 8:00 a.m., application of four divided 2 mg doses resulted in marked suppression of cortisol levels."

Timing of the single dose also matters:

"The time point of application of the single daily dose also plays a role for adrenal suppression. This can be explained easily: circadian GC secretion exhibits two peaks, one large peak in the morning around 8:00 a.m. and a smaller peak in the afternoon around 2:00 p.m. Of note, cortisol levels are high during the first peak in the morning, causing downregulation of ACTH levels via negative feedback regulation. In consequence, cortisol secretion is also downregulated. At a certain point, reduced cortisol levels cause upregulation of ACTH again, leading in turn also to upregulation of cortisol secretion during the second peak in the afternoon. If exogenous GCs were applied in the evening, the so-called quiet period for the adrenal gland, this would cause a negative signal on ACTH and therefore also cortisol secretion in the morning."

Note: With a healthy cortisol rhythm the afternoon "bump" in cortisol may be barely discernible. A single daily dose is easier to manage but many patients require two to control inflammation.Several studies evaluating nocturnal doses at 2:00 a.m. yielded better results for morning stiffness than conventional morning doses. But the impracticality of dosing at 2:00 am plus questions about HPA suppression led to the development of a modified-release (MR) prednisone tablet that releases the dose four hours after ingestion (2 a.m. if taken at 10 p.m.).

"MR prednisone produced a clinically relevant reduction of morning stiffness of the joints in addition to all known therapeutic effects of immediate-release prednisone...These results lead to the question of whether chronotherapy with MR prednisone affects adrenal suppression. The influence of long-term, low-dose chronotherapy with MR prednisone on the HPA axis was investigated by CRH tests in a subgroup of 28 patients in the CAPRA-1 study...There were no measurable differences in mean cortisol changes after CRH injection between baseline and the end of the study. Furthermore, there was no indication that changing treatments from immediate-release prednisone to MR prednisone increased the risk of HPA axis insufficiency, or resulted in deterioration of preexisting suppression.There was thus no difference between immediate-release prednisone and MR prednisone in numbers of normal/suppressed/no response reactions. In addition, no adverse events that could be attributed to HPA axis insufficiency were observed during treatment with low-dose MR prednisone for the entire treatment period of 12 months."

Dosing at 2:00 a.m. (by modified release) may even benefit HPA axis activity:

"A recent study showed an increase of endogenous cortisol after 2 weeks of MR prednisone therapy in patients with active RA who had received no GCs by any route in the preceding 3 months. MR prednisone released at 2:00 a.m. suppressed the pathological early morning rise in plasma IL-6 in RA. The nocturnal rise in plasma cortisol was not suppressed but was enhanced with a peak value increase from 14.1 to 19.3 μg/dl, consistent with a changing relationship between HPA axis and immune system activation. This observation may be an indication that the HPA axis is preserved and is activated even more during MR prednisone treatment compared with pre-MR prednisone treatment."

Clinical Note

Minimizing adrenal suppression while enhancing anti-inflammatory effectiveness by circadian dosing of prednisone also implies that effect of other anti-inflammatory agents can be enhanced by chronotherapeutic timing. Curcumin is one of the most extensively researched natural anti-inflammatory agents. A study published in the Nutrition Journal on the comparative absorption of curcumin formulations demonstrates that a newer preparation markedly extends the plasma concentrations of bioactive components including the key metabolite tetrahydrocurcumin.

"The potential health benefits of curcumin are limited by its poor solubility, low absorption from the gut, rapid metabolism and rapid systemic elimination. The purpose of this study was the comparative measurement of the increases in levels of curcuminoids (curcumin, demethoxycurcumin, bisdemethoxycurcumin) and the metabolite tetrahydrocurcumin after oral administration of three different curcumin formulations in comparison to unformulated standard."

A curcumin phytosome formulation (CP), a formulation with volatile oils of turmeric rhizome (CTR) and a formulation of curcumin with a combination of hydrophilic carrier, cellulosic derivatives and natural antioxidants (CHC) were compared to a standardized curcumin mixture (CS). There was a dramatic result in favor of the CHC preparation.

"Total curcuminoids appearance in the blood was 1.3-fold higher for CTR and 7.9-fold higher for CP in comparison to unformulated CS. CHC showed a 45.9-fold higher absorption over CS and significantly improved absorption over CP (5.8-fold) and CTR (34.9-fold, all p < 0.001)."

Tetrahydrocurcumin is particularly valuable...

"Tetrahydrocurcumin plays an important role in the antioxidant mechanism of curcumin and has been shown to be the most potent antioxidant of the curcuminoids measured in this study. In addition, tetrahydrocurcumin has been reported to have health promoting benefits. It has been shown to have greater anti-inflammatory potency than curcumin in carrageenan-induced paw edema."

The data shows that the CHC preparation yields high levels of curcuminoids that would sustain through the night into the morning if taken at bedtime to cover the critical inflammatory period when cortisol levels are naturally low. Adrenal suppression is, of course, not a concern with curcumin. This is advantageous not just for rheumatological disorders but all conditions involving chronic inflammation.The authors of the first study conclude:

"From a GC perspective, circadian rhythms of the HPA axis and connected subsystems, including the immune system, appear to be essential for understanding of pathophysiology and treatment in rheumatology. The circadian rhythm of the HPA axis in chronic inflammatory diseases may be defective in terms of not bringing the body into a position to overcome the signs and symptoms of the disease. GC therapy serves as a necessary aid to overcome the disease and perhaps restore the deranged circadian rhythm. In a number of patients (around 50%), GC therapy causes adrenal suppression, probably mainly due to as yet undefined individual factors (apart from dose, substance and duration of therapy). In order not to aggravate adrenal suppression, GC therapy should be applied in accordance with the circadian rhythm, to achieve greatest efficacy along with highest safety. It has been suggested that when the single morning dose is not effective enough to achieve sufficient disease control, especially in patients with strong night symptoms and morning stiffness, split doses in the morning and afternoon, or chronotherapy with MR prednisone, can to some extent avoid aggravation of adrenal suppression."