Nighttime Prednisone Could Address Morning Stiffness in RA

Rheumatologists have long struggled with a contradictory aspect of their work. During sleep, when patients appear most still, their inflammatory systems are most active.

Physicians who treat rheumatoid arthritis have long noted the morning stiffness that results. But, says Maurizio Cutolo, M.D., a professor of rheumatology at the University of Genoa, Italy, many physicians don’t take the next logical step: treating the inflammation with low-dose glucocorticoids administered at the night.

Dr. Cutolo reviewed the literature on this approach in a recent article for the journal RMD Open.  Not only does taking prednisone at bedtime work better, the newly available delayed-release formula (Rayos, Horizon Pharma) takes effect at 3 a.m., when it is needed the most, he says.

Studies as far back as 1964 have documented the advantages of treating inflammation at night. But physicians have often followed a more intuitive approach, recommending patients take prednisone at the time of day when symptoms are at their worst, he told Rheumatology Network.

“Usually the GP and the specialists give the low-dose in the morning,” he said. “This is not completely wrong, but it is not the optimum. It does not follow the concept that hormones must follow the circadian rhythm of endogenous production.”

In healthy patients, nighttime inflammation makes sense. The inflammatory system takes advantage of calories unavailable when muscles are in motion and digestion is active to attack pathogens or heal injuries.

The system follows a clock set by the suprachiasmatic nucleus, which responds to light and dark and sets the pace for such functions as sleep, heart rate, blood pressure and body temperature.

Acting on the endocrine system, it increases the production of melatonin and prolactin around 9 p.m, and these in turn activate cytokines, such as tumor necrosis factor (TNF) α and interleukin (L) 6, Dr. Cutolo says. Then around 3 a.m., it begins producing cortisol which will suppress these same cytokines over the next few hours.

In people with rheumatoid arthritis, this system is dysregulated, he explains. In particular, cortisol becomes less available in the wee hours of the morning. As a result, inflammation lingers as patients rise.

Exogenous glucocorticoids such as prednisone can take the place of the missing cortisol. Although prednisone plays a smaller role in the treatment of rheumatoid arthritis since the advent of drugs with fewer side effects, it can still be useful in low doses, Dr. Cutolo says.

He points out that the 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis endorsed the use of 5 low-dose glucocorticoids (less than 10 mg/day of prednisone or equivalent) in patients with moderate or high rheumatoid arthritis activity when starting traditional disease-modifying anti-rheumatic drugs (DMARDS) and biologics and in patients with DMARD failure or biologic failure.

But too often patients take prednisone between 6 a.m. and 8 a.m., says Dr. Cutolo, when it may come too late to curb the inflammation. “The best time, the optimal time, in chronic long-term treatment with low-dose glucocorticoids is availability at the time of maximum need, which is the middle of the night.”

In one study, administering 5 mg or 7.5 mg of prednisolone at 2:00 a.m. daily showed significant improvements in morning stiffness, joint pain, the Lansbury index, the Richie index, and morning serum concentrations of IL-6. Patients who took the same dose at 7:30 a.m. experienced an improvement in morning stiffness and IL-6 levels, but not in joint pain or either index.

The new delayed-release formulation of prednisone offers the advantage that patients don’t need to get up in the middle of the night to take it. And large-scale trials have shown that it has greater efficacy for long-term low-dose glucocorticoid treatment in patients with RA than the standard formula, with a similar safety profile, Dr. Cutolo reports.

The delayed release formula costs more, he acknowledged. In a British study, the cost was £649.70 ($918.06) per year versus £46.54 ($65.76) for the standard formula. But the delayed release formula was so much more effective in improving patients’ quality of life, that the authors judged it to be cost effective. If factors such as the patient’s productivity were taken into consideration, it might be even more cost effective, they wrote.

If low-dose glucocorticoids work better late at night, what about anti-proliferative drugs, such as methotrexate, leflunomide and cyclophosphamide? Studies so far suggest that methotrexate, too, is more effective when taken at bedtime than according to standard dosing protocols, Dr. Cutolo reports.

Likewise, research suggests that non-steroidal anti-inflammatory drugs (NSAIDs) are more effective when the regimen includes an evening dose than when it doesn’t, he says. And delayed-release forms of these drugs have recently been developed.

Not only does the circadian principle apply to other drugs, it may apply to other diseases by rheumatoid arthritis, including polymyalgia rheumatic (PMR) and ankylosing spondylitis, says Dr. Cutolo.

“Think about gout,” he says. “You never get gout attacks during the day, but only during the night.”

References:

Maurizio Cutolo. "Glucocorticoids and chronotherapy in rheumatoid arthritis," RMD Open 2016;2:e000203 doi:10.1136/rmdopen-2015-000203. Review.

JASVINDER A. SINGH, KENNETH G. SAAG, et al. "2015 American College of Rheumatology: Guideline for the Treatment of Rheumatoid Arthritis." Arthritis Care & Research DOI 10.1002/acr.22783

Nils Gunnar Arvidsona, Björn Gudbjörnssona, et al. "The timing of glucocorticoid administration in rheumatoid arthritis," Ann Rheum Dis 1997;56:27-31 doi:10.1136/ard.56.1.27

William Dunlop, Itrat Iqbal, et al. "Cost-effectiveness of modified-release prednisone in the treatment of moderate to severe rheumatoid arthritis with morning stiffness based on directly elicited public preference values," Clinicoecon Outcomes Res. 2013; 5: 555–564. Published online 2013 Oct 30. doi:  10.2147/CEOR.S47867. PMCID: PMC3816994