Chronotherapy in RA Treatment: Tantalizing but Under-Studied

Morning stiffness is common for people with arthritis and that got researchers to thinking that if they could time drug therapy to match the body’s rhythms when pain receptors are most active, they could relieve that morning stiffness and potentially target flares.

That concept, known as chronotherapy or chronomedicine, aims to synchronize drug delivery to the body’s circadian rhythms. A few small clinical trials and observational studies have evaluated this concept, but most recently researchers in Japan completed a multicenter, nonrandomized, controlled study that found that almost twice as many patients who took baricitinib at night had a measurable improvement in symptoms than patients who took the Janus kinase (JAK) inhibitor in the morning.

“Chronotherapy refers to the strategic timing of medication, therapies, or other medical interventions to align with the body’s natural circadian rhythms,” Amanda Sammut, MD, chief of rheumatology at Harlem Hospital Center in New York City, told Medscape Medical News. “The goal of chronotherapy is to optimize therapeutic efficacy and minimize adverse events.”

Progress Slows After Nobel Prize

In 2017, Jeffrey Hall, Michael Rosbash, and Michael Young won the Nobel Prize in Medicine for their work isolating a gene that controls the normal daily biological rhythms. However, as researchers in Italy who have studied chronotherapy in inflammatory joint diseases have noted, transition of that knowledge to clinical practice has proceeded slowly.

“Growing knowledge of chronobiology applied to inflammatory joint diseases could stimulate the development of new drug strategies to treat patients in accordance with biological rhythms and minimize side effects,” the Italian researchers wrote.

“It should be evidence-based,” John Hogenesch, PhD, a neuroscientist at Cincinnati Children’s Hospital, Cincinnati, who has researched circadian rhythms, told Medscape Medical News. “Yet there are only about 140 studies in 50 years looking at drug timing.”

Sammut noted that chronotherapy is not yet incorporated into major rheumatoid arthritis (RA) treatment guidelines. “The temporal administration of anti-inflammatory agents to coincide with this cytokine surge presents a theoretically sound strategy to improve disease activity,” she said.

The most recent research in Japan, led by Akira Hashiramoto, MD, PhD, at Kobe University, Kobe, Japan, assigned 122 patients with RA to four open-label treatment groups: Either baricitinib 2 mg or 4 mg in the morning or evening. The primary endpoint was the percentage of patients with at least 20% improvement in the American College of Rheumatology response criteria (ACR20) at 12 weeks. Some of the secondary endpoints included ACR20, ACR50, and ACR70 response rates at other timepoints as well as changes in the Clinical Disease Activity Index (CDAI) at the same timepoints out to 1 year.

Hashiramoto told Medscape Medical News that the changes in swollen joint count (SJC) significantly improved in the evening vs the morning dosing group throughout the 52-week study period, and that changes in tender joint count, patient global assessment, and physician global assessment mostly occurred before 3 months.

“Therefore, we believe that the most important mechanism for achieving sustained CDAI remission at weeks 12, 24, and 52 is that chronotherapy maximized the effect of baricitinib by week 12 after initiation, when all components of CDAI have responded well,” he said. “The results demonstrate the crucial importance of the treat-to-target strategy.”

Earlier studies demonstrated the potential of chronotherapy. Researchers in Berlin, led by Frank Buttgereit, MD, at Charité-Universitätsmedizin Berlin, Berlin, Germany, reported in 2008 that modified-release prednisone reduced the duration of morning stiffness in RA. In 2013, Buttgereit’s group reported that low-dose prednisone chronotherapy when added to existing disease-modifying antirheumatic drugs produced significantly higher response rates than placebo for ACR20 — 48% vs 29% (P < .001), and more than double the rate for a 50% improvement (22% vs 10%; P < .006).

A 2011 study in Japan found that methotrexate chronotherapy can improve RA symptoms compared with traditional dosing methods, but Sammut cautioned that the results may not be entirely related to chronotherapy. The study switched patients from the standard methotrexate dose three times daily to once daily at bedtime, but with the same weekly dosing. “So even though the results showed improved disease activity scores and functional capacity, it may not be related to the actual chronotherapy portion alone,” Sammut said.

Role of the Circadian Clock

The body’s circadian clock is central to chronotherapy. A few studies have explored the role of the body’s internal clock in RA pathophysiology, including one by Buttgereit’s group in Berlin.

Buttgereit’s group reported in 2015 that circadian disruption altered circulating leukocyte rhythms in patients with RA. Specifically, they found the rhythms of effector CD8 + and CD4+ T cells, and interleukin (IL)–6R+ CD8+ T cells were abolished in patients with RA; and that IL-8R+ monocytes, CD20+ CD27+ memory B cells, and CD20+ human leukocyte antigen –DR+ activated B cells, which were not rhythmic in healthy individuals, had rhythmic circulation in the peripheral blood of patients with RA.

Researchers at Nova Southeastern University in Davie, Florida, conducted a literature review in 2023 in which they identified four common clock genes that were dysregulated in patients with RA: Circadian locomotor output cycles kaput; brain and muscle ARNT like-1; period; and cryptochrome.

Research has also been conducted on the diurnal variation of symptoms of polymyalgia rheumatica. In a 2016 observational study, Danish researchers reported that plasma concentrations of IL-6, IL-8, tumor necrosis factor–α, IL-1β, and IL-4 varied with time in both patients treated with prednisolone and untreated patients, peaking between 4:00 AM and 8:00 AM. With the exception of IL-1β, concentrations of these cytokines and of IL-10 were higher throughout the 24-hour observation period in treated patients, as were melatonin and cortisol levels, the latter peaking around 2:00 AM and 8:00 AM, respectively.

In his laboratory at Shriners Hospitals for Children — St. Louis — Farshid Guilak, PhD, has been researching circadian rhythms and timed-release therapy to minimize arthritic flares and prevent disease progression in people with RA or juvenile idiopathic arthritis.

“It turns out that not only does our brain have this region that cycles but virtually every other tissue in the body is on a 24-hour clock,” Guilak told Medscape Medical News. “Unlike the master clock, they’re called the peripheral clocks.”

These peripheral clocks in the joints dictate the ebb and flow of pain within them, he said. “The exact reason is not completely known, but my belief is that our tissues also have periods of activity and rest,” Guilak said.

“During the night we elevate a lot of the proteins and genes that are related to repair and regeneration, things that are related to cleaning out the cells, such as the process of autophagy. It’s very important in the brain and memory that if you don’t have these sleep periods, you don’t actually allow your tissues to reset and repair themselves.”

Inflammatory mediators peak between 3:00 AM and 5:00 AM, he said. “This is one reason why many people with arthritis wake up with morning stiffness,” he said.

“The clock regulates about 50% of drug transporters, targets, and metabolizing enzymes,” Hogenesch said. “About half of all small-molecule drugs have a short (less than 12-hour) half-life. This means as many as 25% of all drugs may be influenced by when they are taken.”

Guilak’s group reported that people who work night shift had a 25% higher risk for knee osteoarthritis and a 30% higher risk of having knee replacement than nonshift workers. “Disruption of sleep is a major risk factor for arthritis,” he said. “Doing shift work or getting < 6 hours of sleep a night significantly increases the risk of osteoarthritis.” 

Challenges in Adapting Chronotherapy in RA

Chronotherapy faces several barriers before it gains wider acceptance as a treatment approach in RA. One involves identifying specific circadian patterns in individual patients.

“The gold standard is the dim-light melatonin onset assay, which is only done in a tiny subset of patients in a tiny subset of academic medical centers,” Hogenesch said. More practical methods, he said, are using surveys, such as the Munich ChronoType Questionnaire, or actigraphy, which uses wearables, such as a Fitbit or Oura ring. “So [it will be] surveys and wearables for the near future,” he said.

The complexity of medical regimens for patients with RA poses another barrier to wider acceptance, Summat said. “The medication regimen for patients with RA, and for many other chronic diseases, usually includes multiple medications,” she said. “When you include timings of medications, it may make it more complicated and more difficult to adhere to the regimen.”

But other patients may be amenable to having a medication schedule, Sammut said. “Timing of medications is something that we should think about in our patients already,” she said. “For instance, if a patient is on a proton pump inhibitor, we would recommend taking it on an empty stomach half an hour before eating or drinking anything.” She suggested that physicians and pharmacists should collaborate on developing medication plans for patients. Individual patients’ sleep schedules are another factor to consider with chronotherapy, Sammut added.

Chronotherapy With Other Drugs

The JAK inhibitors tofacitinib and upadacitinib could potentially be used for chronotherapy in RA, Hashiramoto said. “The half-life, time after administration of the drug to reach maximum plasma concentration, or drug withdrawal of tofacitinib and upadacitinib are different from that of baricitinib, so the efficacy of bedtime dosing must be demonstrated in clinical trials,” he said.

“However, in our limited experience, tofacitinib tends to respond well in patients who start with only a single evening dose, with similar results to baricitinib 2 mg in the evening,” he said. “For upadacitinib, once daily in the evening is as effective as baricitinib.” 

Based on his group’s research, Hashiramoto said that chronotherapy does not increase adverse events with either tofacitinib or upadacitinib.

“We hope that follow-up studies of chronotherapy will be conducted in Europe and the United States, not only for baricitinib, but also for other JAK inhibitors,” he said.

Emerging Research: Unlocking Gene Circuits

Guilak’s research group has been investigating “chronogenetics,” circadian-based gene circuits that can be programmed into stem cells and that, once implanted in the body, match the patient’s circadian clock to deliver anti-inflammatory drugs daily at a specific time. The stem cells are administered in a drug-eluting implant — “like a spaghetti string rod full of cells injected under the skin,” he said — that is inserted into the joint. It’s designed to release drugs once a day. Guilak reported that these gene circuits produced effective amounts of IL-1 receptor antagonist in mice.

More recently, Guilak’s group reported on an implant that responds to both circadian and inflammatory signals to release therapeutic levels of IL-1 receptor antagonist not only at a specific time but also in response to activation of pain receptors. His group recently received a grant from the Advanced Research Project Agency for Health to develop the implant. “Our goal is to get this into patients in the next 3-5 years,” he said.

Hashiramoto reported receiving honoraria from AbbVie and honoraria and grants from Eli Lilly Japan. Guilak is an employee and shareholder of Cytex Therapeutics and has applied for patents on concepts on chronogenetics. Sammut and Hogenesch reported no relevant financial relationships.

Richard Mark Kirkner is a medical journalist based in Philadelphia.