Perfect Timing: Circadian Rhythms, Your Health and Your Arthritis

By Linda Rath | July 7, 2023

Circadian rhythms are biological processes that steer the body through each day’s 24-hour cycle. They tell you when to eat, sleep and wake up in the morning. They evolved to help living things anticipate and adapt to the change from daylight to dark by shifting behavior and even the immune system over the course of a day. Nearly all forms of life, from the simplest microbes to humans, have circadian rhythms, and they’re all remarkably similar.

Think of these rhythms as the conductor of an orchestra, with the body’s organs, tissues and cells as instruments. All is harmonious when the instruments are in tune, but problems arise when they’re not. Some problems, like jet lag, are relatively minor; others, such as heart disease, cancer and rheumatoid arthritis (RA) can be serious.

Can’t Sleep? Your Circadian Rhythms Might Be To Blame

One of the clearest examples of circadian rhythms is the sleep-wake cycle. Most people with normal schedules are awake during the day when the hormone cortisol is higher and sleepy at night when levels of melatonin rise.

Circadian rhythms are controlled by molecular clocks — specific proteins and genes found in nearly every cell. Each cell has its own timetable for releasing hormones and chemicals that regulate blood pressure, weight, heart rate, blood sugar, breathing and mood.

The Big Ben of Circadian Clocks

The molecular, or peripheral, clocks are controlled by a master clock, a tiny knot of nerve cells in the brain called the suprachiasmatic nuclei (SCN), which synchronizes molecular clocks to the night-day cycle. Scientists once thought the SCN was activated by sleep-wake cycles, but they now know it’s triggered by light signals traveling from the retina to the brain.

The body’s internal clocks are exquisitely sensitive to environmental cues and can easily get out of sync when those cues are altered. Small changes in the time you eat or go to bed can realign the clocks. Major disruptions like shift work, which the National Toxicology Program and the International Agency for Research on Cancer agree likely causes cancer, are also associated with an increased risk of diabetes, cognitive problems, heart attack, stroke, and many autoimmune diseases, including RA.

Circadian Rhythms and the Immune System

Just about every cell in the body has circadian clocks that regulate their function, including immune cells. The clocks prime the cells to defend against viruses, bacteria and other bugs. But immune cells respond differently at different times of day. Inflammatory proteins like tumor necrosis factor (TNF) and interleukin (IL)-6 — both major sources of inflammation in RA — flare at night, while anti-inflammatory proteins subside.

These normal fluctuations are exaggerated in autoimmune disease. At 3 a.m., people with RA have 10 times more IL-6 in their blood than normal, which may explain why joint stiffness is worse in the morning.

Cortisol and melatonin are also out of sync in RA. Normally, cortisol peaks between 6 and 8 a.m., but it’s highest between 11 p.m. and 2 a.m. in RA patients — too early to counter the big nighttime peaks of inflammatory proteins.

And while some studies have reported that melatonin is anti-inflammatory, other research suggests it increases inflammation in RA, possibly because levels start to climb earlier and stay high longer than normal. Melatonin is also known to affect the expression of clock genes inside the joints.

Research points to a strong reciprocal relationship between the immune system and circadian rhythms. Severe alterations in internal timing can lead to the runaway inflammation responsible for RA and most other chronic diseases. At the same time, autoimmune conditions like RA disrupt natural circadian rhythms, making existing inflammation worse.

Elaine Husni, who directs the Arthritis and Musculoskeletal Center at Cleveland Clinic, says the immune system and circadian rhythms also interact in complicated ways through the microbiome — the vast communities of microbes that live in and on the body.

From birth, the precisely tuned microbiome trains the immune system to distinguish between harmful microbes and helpful ones, which prevents immune cells from attacking beneficial bacteria or the body’s own tissues. But when the microbiome is unbalanced, with fewer anti-inflammatory microbes, a weakened intestinal lining and an overall loss of diversity, inflammation can flare, leading directly to RA and other autoimmune diseases.

The microbiome has its own circadian rhythms, with some species of microbes more active at night and others during the day. There are also constant fluctuations in metabolites that are essential for health. Disruption of the microbiome’s circadian rhythms has been shown to lead to dysbiosis and a severe disordering of the microbiome, which increases the risk of heart attack, stroke, diabetes, cancer and neurodegenerative diseases like Alzheimer’s.

Losing Time

In many ways, the modern world conspires against healthy circadian rhythms:

• Electric lights and screens. Once-dark nights are now permanently lit up. Blue light from devices is especially disruptive. It interferes with melatonin production, which is why sleep experts advise turning off screens an hour or two before bed. In one small study comparing different types of light, a single hour of bright white light or blue light in the evening was found to raise cortisol levels and depress melatonin. To be clear: Blue light isn’t always bad. The biggest source of blue light is the sun, and it’s important to get plenty of natural light during the day. The problem is that most people get blue light at night, too.
• Irregular meals. Although light is the main driver of circadian rhythms, consistent mealtimes aren’t far behind. Skipped meals and round-the-clock snacking — especially right before bed — are known disrupters of circadian rhythms. Sweets are known to contribute to insomnia, and food manufacturers now are marketing melatonin-infused cookies, ice cream and candy bars to sleep-deprived consumers. Experts say, “Don’t buy it.”
• Shift work. About 16% of U.S. workers and up to 30% of people worldwide have late-night, early-morning or rotating shifts, with women generally working more irregular schedules than men. Unlike jet lag, which is a temporary mismatch between the body’s normal patterns and new food and sleep cues, shift work jumbles all the body’s clocks, and many people never fully adjust to it.

Getting Back in Sync

Most people don’t have anything intrinsically wrong with their circadian rhythms, and disruptions can often be fixed with simple lifestyle changes:

• Dim the lights and unplug devices at least an hour before bed. Try finding ways to relax before bed that don’t involve TV, a tablet or phone, like reading, yoga, meditation or relaxing in a warm bath. If you can’t give up nighttime screens, consider blue light-blocking glasses, which filter out varying degrees of blue light. A 2020 meta-analysis of 12 small studies found that blue light blockers improved sleep in people with insomnia or certain mental health challenges but were less effective in normal sleepers.  It’s hard to draw firm conclusions from this analysis because it’s small and the studies varied considerably. Still, for people who can’t give up their screens, experts say wearing blue light blockers for two to three hours before sleep is worth a try.
• Eat regular, healthy meals. You don’t necessarily need three meals a day, but when you do eat, make it around the same time. If you follow an intermittent fasting schedule, stick to the same eating window. Healthy food makes a big difference, too. Most foods in the Mediterranean diet – olive oil, salmon, avocados and walnuts, for example – are relatively high in melatonin or the nutrients needed to make it. Processed food and highly refined carbs have few nutrients and are associated with poor sleep.

Disruptions in circadian rhythms caused by shift work are much harder to correct. They’re affected by sleep disruption as well as light and have long-lasting health consequences. A few interventions have been tried with varying success, including:

• Light therapy
• Wearing sunglasses after a night shift
• Trying to coordinate shift work with a worker’s chronotype – that is, whether they’re naturally an early bird or night owl  

Matching Medication to Circadian Rhythms

A few decades ago, scientists realized that circadian rhythms might affect the effectiveness of medications and even the severity of side effects. This proved at least partially true in patients with RA who took modified-release (MR) prednisone, which is timed to release at night, when inflammation is highest. In studies, these patients had a 50% reduction in morning stiffness and a nearly 30% drop in IL-6 compared to those taking regular prednisone, though side effects were similar.  In comparisons with placebo, MR prednisone led to significantly less disease activity and fatigue, better physical function and even remission.

Because all forms of prednisone can have severe side effects, even after just a few doses, the American College of Rheumatology (ACR) recommends limiting its use or avoiding it entirely. So researchers decided to look at methotrexate — the first-line treatment for inflammatory and autoimmune forms of arthritis. Research showed that patients who received a daily dose of methotrexate at bedtime had lower disease activity scores and considerably improved function compared to those who took it with breakfast and dinner.

Time’s Up

The effects of circadian rhythms on life are so dramatic that some researchers have suggested instituting society-wide “circadian hygiene” practices. Meanwhile, it doesn’t take a lot of work to make sure your own circadian rhythms are in sync. And if you take medication for arthritis or anything else, you might want to talk to your doctor about syncing that, too.