The key symptoms of polymyalgia rheumatica (PMR) show a diurnal variation, with pain and stiffness peaking in the morning, Danish researchers found.
The timing of the peak in symptoms correlates with the variation in concentrations of inflammatory cytokines, melatonin, and cortisol over the course of the day, according to Henrik Galbo, MD, and Lisbeth Kall of Copenhagen University Hospital.
"In untreated patients, pain and stiffness peak between 04:00 and 08:00 and then decline to a nadir at 16:00," the researchers wrote online in Arthritis Research & Therapy.
"In rheumatoid arthritis, key clinical symptoms and findings show a circadian variation, with more prominent joint swelling, stiffness, and pain occurring in the early morning."
This diurnal variation in symptoms of rheumatoid arthritis has been shown to correspond with a variation in plasma levels of inflammatory cytokines, but whether a similar pattern exists in PMR -- the most common chronic autoimmune disease of the elderly -- has not been established.
Therefore, the investigators monitored clinical symptoms and plasma concentrations of cytokines, melatonin, and cortisol for 24 hours in 10 consecutive patients with PMR and seven healthy subjects. Both groups were studied before and after 13 days of glucocorticoid treatment.
Symptoms of global pain and generalized muscle stiffness were assessed by patients and their physicians using a 0 to 10 visual analog scale (VAS) at 12:00, 16:00, 20:00, 04:00 and 08:00.
The cases enrolled had clinical remissions after 13 days of prednisolone treatment, as well as marked reductions in the levels of C-reactive protein (CRP) and erythrocyte sedimentation rate. After 13 days of prednisolone, "symptoms were negligible and showed no diurnal variation," the researchers reported.
The concentrations of interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, IL-4, and IL-1β varied significantly over the day in both groups -- again peaking in the early morning, between 04:00 and 08:00. Concentrations of each, except for IL-1β, were significantly higher throughout the 24-hour observation period in PMR patients than in controls.
Diurnal variations in both groups were also observed for cortisol and CRP concentrations, which were significantly higher in PMR patients than in controls. Cortisol concentrations peaked around 08:00, at which time CRP reached its lowest point.
On day 14 of prednisolone treatment, the IL-6, IL-8 and TNF-α concentrations were lower than before treatment in both patients and controls. The concentrations of CRP were also reduced, but the levels of IL-4 and IL-1β did not change significantly.
The concentrations of cortisol and IL-10 concentrations were also significantly increased between 10:00 and 14:00 with prednisolone treatment in both PMR patients and controls.
The finding that concentrations of the anti-inflammatory cytokines IL-4 and IL-10 were increased in PMR patients is a new one, Galbo and Kall said: "Furthermore, it is a new observation that the above-mentioned differences between patients and control subjects exist throughout the day."
There were significant diurnal variations in melatonin levels in both PMR patients and controls, regardless of prednisolone treatment, with peak concentrations occurring around 02:00 (about 4 hours earlier than the peak cytokine concentrations).
The time course of the increase in melatonin levels supports the contention that melatonin stimulates cytokine production, "which in turn accounts at least partly for the clinical symptoms," the researchers noted.
"The view is supported by the finding that, in PMR, prednisone diminishes the levels of both melatonin and proinflammatory cytokines while abolishing symptoms throughout the day."
The peak in TNF-α and 24-hour area under the curve (AUC) concentrations correlated with both the peak in patient-reported pain (r=0.6 and r=0.7, respectively) and the highest level of stiffness (r=0.6 and r=0.8, respectively).
In addition, IL-6 24-hour AUC correlated with the average patient-reported pain level during the hours of 04:00 to 08:00 (r=0.6).
As in rheumatoid arthritis, in which diurnal variation in cytokine concentrations has been proposed to partially explain the circadian rhythm of clinical symptoms, "it is an intriguing possibility that also in PMR the circadian variation in these symptoms is, to a great extent, caused by a parallel variation in cytokine levels," the investigators said.
The study was funded by the Capital Region of Denmark, the Foundation for Health Research, and the Copenhagen Muscle Research Center.
The authors reported no competing interests.
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