Source: Ali T, et al. World J Gastroenterol. 2013;doi:10.3748/wjg.v19.i48.9231.

Cutolo M. Joint Bone Spine. 2019;doi: 10.1016/j.jbspin.2018.09.003.

Garland SN, et al. Explore (NY). 2015;doi:10.1016/j.explore.2015.08.004.

Ibarra-Coronado EG, et al. J Immunol Res. 2015;doi:10.1155/2015/678164.

Irwin MR, et al. Biol Psychiatry. 2016;doi: 10.1016/j.biopsych.2015.05.014.
Disclosures: Drerup, Irwin, Mehta, Prather and Wang report no relevant financial disclosures.
September 16, 2021
12 min read
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Losing sleep and the battle against rheumatic diseases

Source: Ali T, et al. World J Gastroenterol. 2013;doi:10.3748/wjg.v19.i48.9231.

Cutolo M. Joint Bone Spine. 2019;doi: 10.1016/j.jbspin.2018.09.003.

Garland SN, et al. Explore (NY). 2015;doi:10.1016/j.explore.2015.08.004.

Ibarra-Coronado EG, et al. J Immunol Res. 2015;doi:10.1155/2015/678164.

Irwin MR, et al. Biol Psychiatry. 2016;doi: 10.1016/j.biopsych.2015.05.014.
Disclosures: Drerup, Irwin, Mehta, Prather and Wang report no relevant financial disclosures.
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Jonas Salk said, “The mind, in addition to medicine, has powers to turn the immune system around.”

Salk might not have completely understood the importance of sleep for both the mind and the immune system, but rheumatologists do.

Considered only as a short-term fix, sleeping pills are unlikely to treat the underlying causes of many sleep problems experienced by patients with rheumatic diseases, Michelle Drerup, PsyD, DBSM, told Healio Rheumatology. Instead, she urged rheumatologists to utilize cognitive behavioral therapy for insomnia, “a multi-component, brief, structured intervention for insomnia that helps you identify and replace behaviors and thoughts that cause or worsen sleep problems with habits that promote sound sleep.”
Considered only as a short-term fix, sleeping pills are unlikely to treat the underlying causes of many sleep problems experienced by patients with rheumatic diseases, Michelle Drerup, PsyD, DBSM, told Healio Rheumatology. Instead, she urged rheumatologists to utilize cognitive behavioral therapy for insomnia, “a multi-component, brief, structured intervention for insomnia that helps you identify and replace behaviors and thoughts that cause or worsen sleep problems with habits that promote sound sleep.”

Source: Cleveland Clinic.

Every day in the clinic, rheumatologists see what happens to patients when they sleep, and when they do not sleep. It is often incumbent upon them to leverage both medicine and the mind to break the vicious cycle of poor sleep and a dysregulated immune system.

There is a long paper trail of data describing this cycle. Findings from Ali and colleagues in the World Journal of Gastroenterology succinctly described one aspect of the conundrum. “The inflammatory cytokines such as [tumor necrosis factor], [interleukin]-1, and IL-6 have been shown to be a significant contributor of sleep disturbances,” they wrote. “On the other hand, sleep disturbances such as sleep deprivation have been shown to upregulate these inflammatory cytokines.”

But there is also a physical manifestation of the cycle, according to Mala Mehta, MD, a rheumatologist with the Mid-Atlantic Permanente Medical Group at Kaiser Permanente in Falls Church, Virginia. “When a person suffers from pain and swelling, whether from a flare up of their rheumatic or autoimmune disease, or from active and uncontrolled disease, it is hard to get comfortable at night,” she told Healio Rheumatology.

Most patients would agree that the pain from poorly controlled disease can lead to a bad night’s sleep. But true to form for a discussion like this, Michael R. Irwin, MD, Cousins Professor of Psychiatry and Biobehavioral Sciences at the David Geffen School of Medicine at UCLA, sees it the other way. “It is really critical to understand that as patients lose sleep, their pain increases, not the other way around,” he said. “In longitudinal studies, sleep disturbance is preceding the hyperalgesia.”

Experts and patients are likely to debate these vicious cycles and feedback loops in panel discussions and in the pages of peer-reviewed journals far into the future. In the meantime, doctors have to treat patients who show increased disease activity and are unable to sleep, regardless of which came first. Understanding how this bidirectional relationship works could be the first clue to developing and following through with successful treatment paradigms in many rheumatology patients who would like nothing more than a solid night’s rest.

Cytokine Disturbance

“There is increasing evidence that poor sleep, characterized as short sleep duration — defined as less than 6 hours per night — along with poor sleep continuity and poor subjective sleep quality can impair different aspects of the immune system,” Aric A. Prather, PhD, associate professor of psychiatry and behavioral sciences at the University of California, San Francisco, said in an interview.

The studies investigating this hypothesis have largely focused on the infection prevention aspect of the immune system. In a paper published in the Journal of Immunological Research, Ibarra-Coronado and colleagues aimed to explain increased susceptibility to infections among individuals with poor or reduced sleep. Their findings showed that “impaired mitogenic proliferation of lymphocytes, decreased HLA-DR expression, the upregulation of CD14+, and variations in CD4+ and CD8+ T lymphocytes” all were potentially implicated. “Thus, we hypothesize that sleep and the immune-endocrine system have a bidirectional relationship in governing various physiological processes, including immunity to infections,” they wrote.

“It is thought that one of the essential functions of sleep is to restore homeostasis in every organ system in the body, including the immune system,” Andrew Wang, MD, PhD, rheumatologist at Yale Medicine and assistant professor of medicine and immunobiology at Yale School of Medicine, said in an interview. “It is essential to restore any tissues that may have been damaged during the activities of the waking hours.”

Prather explained why this basic understanding of the immune system is so important for the rheumatology patient. “Pro-inflammatory cytokines are key players when it comes to sleep, and not only does sleep appear to regulate cytokines, but cytokines — namely TNF and IL-1 beta — act on the brain to affect sleep,” he said. “In this way, the sleep-immune link reflects a feedforward loop, one of many as related to rheumatic/autoimmune conditions.”

Michael R. Irwin, MD
Michael R. Irwin

But the picture is not perfectly clear. In a 2016 study published in Biological Psychiatry, Irwin and colleagues conducted a review that included 72 studies evaluating associations between sleep disturbance and C-reactive protein, IL-6 and TNF-alpha.

A correlation was observed between sleep disturbance and higher levels of CRP (ES = .12; 95% CI, .05-.19) and IL-6 (ES = .20; 95% CI, .08-.31). In addition, shorter sleep duration, but not the extreme of short sleep, was associated with higher levels of CRP (ES = .09; 95% CI, .01-.17). However, this association was not comparable for IL-6 (ES = .03; 95% CI, -.09-14).

In short, the impact of poor sleep on cytokine activity is far from consistent and not yet completely understood. It is for this reason that Wang is practical about what to make of this information. “The causes of sleep disturbances are usually multifactorial, and so the approach to sleep disturbances should be multipronged,” he said.

There is much to be said about the type and nature of those multipronged interventions and how they may utilize both medicine and the mind. Simply identifying and categorizing patients is a good place to start.

First Steps

On a fundamental level, Michelle Drerup, PsyD, DBSM, of the Sleep Disorders Center, at the Cleveland Clinic, urged rheumatologists to encourage patients to prioritize sleep. “People with chronic or severe sleep difficulties should be evaluated for underlying causes and sleep disorders,” she said.

Wang underscored this point. “Identifying and treating a comorbid sleep disorder, like sleep apnea, should also happen early in the treatment cycle,” he said.

Mala Mehta, MD
Mala Mehta

For Mehta, a critical first step is simply recognizing that there is a sleep problem. “The next step is to discuss with the patient the importance of sleep as it relates to their immune system and their disease,” she said.

Mehta mentioned short sleep duration as a factor in poor immunity, but the issue is actually more nuanced. “Sleep has two dimensions that impact our overall health,” she said. “The first is duration or quantity, and the second is depth or quality.”

A patient may experience adverse outcomes if either the quantity or quality of the sleep is suboptimal. Thus, part of the conversation between the rheumatologist and patient should be to determine the extent to which quality and/or quantity are impacted.

In addition, understanding the difference between poor sleep and clinically significant poor sleep is also necessary, according to Irwin. To this end, he noted that there are diagnostic criteria for insomnia. “Insomnia is defined as difficulty sleeping three times a week, difficulty falling asleep or waking up too early for a duration of at least 3 months,” he said. “Also, if this sleep difficulty is producing daytime impairment, that is the formal diagnosis.”

Many rheumatology patients will fulfill some but not all of these criteria, according to Irwin. “They might only have this for a few weeks or a month, or they have disturbances in sleep but do not have daytime functioning issues,” he said.

But Irwin stressed that there is an important lesson to be learned from any individual who meets all of the criteria. “When you identify people who cross that threshold and have clinically significant insomnia, you see clinically significant inflammation,” he said.

Aric A. Prather, PhD
Aric A. Prather

Once a problem has been identified, it is important to get the patient to the right place, according to Prather. “Sleep medicine typically lives in departments like psychiatry, neurology and pulmonology,” he said.

For rheumatologists practicing in areas where a sleep medicine clinic is not easily accessible, Mehta offered some baseline-level tips. “Avoid caffeine after a certain time of day, leave the laptop and the cellphone out of the bedroom and avoid vigorous exercise shortly before bedtime,” she said. “Listening to calming music, doing gentle stretches, reading and using soft lighting can help a person as they get ready for bed. The importance of nutrition and exercise during the day should also be discussed to help break the cycle.”

Andrew Wang, MD, PhD
Andrew Wang

It is important to understand that while behavioral and pharmacotherapeutic interventions can be enormously effective, there are also factors that are simply beyond the control of any doctor, according to Wang.

“Modernity has greatly impacted our normal circadian alignment with the day-night cycle and greatly impacted day-to-day stresses,” he said. “Both light cues and stress levels play critical roles in initiating and maintaining sleep. These are ancient, evolutionarily conserved pathways that evolved to ensure we were awake and attentive when we needed to be for our survival. Every effort should be made to attempt to educate patients about the importance of abstaining from light-emitting devices prior to bed and in adopting activities that help them healthily cope with stress.”

At this point, when sleep disturbance has been identified, the average rheumatologist may be inclined to start targeting cytokines. But experts suggest otherwise. “It is not to say that sleep medicines should never be used, but that data are clear that behavioral interventions, namely cognitive behavioral therapy for insomnia, or CBT-I, are the correct first-line treatments,” Prather said.

Cognitive Coaching

Drerup laid out the basics. “CBT-I is a multi-component, brief, structured intervention for insomnia that helps you identify and replace behaviors and thoughts that cause or worsen sleep problems with habits that promote sound sleep,” she said. “Unlike sleeping pills, CBT-I helps you overcome the underlying causes of your sleep problem.”

The approach is based on a number of behavioral components, according to Mehta. “They are establishing a stable bedtime and wake time 7 days per week, reducing time in bed to approximate the total hours of estimated sleep or sleep restriction,” she said. “Encourage your patients to use the bed only for sleep and sex, to try to sleep only when sleepy and to get out of bed if anxiety occurs while unable to sleep.”

Other habits for good sleep hygiene include avoiding substances that interfere with sleep, foregoing naps and making the sleep environment comfortable.

Regarding the cognitive elements of CBT-I, Mehta said that anxious and catastrophic thoughts that are associated with sleeplessness should be addressed head on. In addition, expectations about the number of hours of sleep should be managed.

“CBT-I should also address misattributions regarding the effects of sleeplessness,” Mehta said. “Relaxation through progressive muscle relaxation, mindfulness and meditation also are essential.”

CBT-I is traditionally delivered in face-to-face individual or group settings, over four to eight sessions, according to Mehta. “Virtual therapy, either online or by telephone, can also be effective,” she said.

A silver lining of the pandemic is that, given the rise and ubiquity of telehealth, patients may be more open to online or virtual interventions of this kind. This could pay dividends as rheumatologists attempt to shepherd their patients into yoga, tai chi or other non-pharmacotherapeutic methods of improving sleep.

There’s an App for That

Like most other experts who deal with sleep, Irwin recognizes that not every rheumatologist is an expert in CBIT-I or has the time to guide patients through a dedicated CBT-I program. He understands that many areas of the country may have nothing even resembling a CBT-I center for hundreds of miles. This is why he is practical about such approaches, recommending that patients should be referred out to a sleep expert, join group activities or leverage technology to their advantage.

“We have a Mindful App from UCLA,” he said. “Anyone, anywhere can use it.”

The app, like other similar products, including the myStrength app from Kaiser Permanente, walks patients through a variety of mindfulness approaches and provides resources for a broad cross-section of patient groups.

“Online resources are often inferior to those that are delivered live, either as community-based programs or those that are physician-delivered,” Irwin said. “But they can still produce quantifiable improvements in insomnia and other sleep parameters.”

In fact, a growing body of evidence is showing that approaches ranging from mindfulness to tai chi may be comparable to CBT-I if executed correctly. In their 2015 study in Explore, Garland and colleagues tested strategies for combating insomnia in individuals with cancer. They assigned mindfulness-based cancer recovery to 32 patients and CBT-I to 40 patients. Results showed no significant differences between the two groups in terms of insomnia immediately following the intervention and through follow-up.

“We are starting to see some trials showing non-inferiority of other modalities compared with CBT-I,” Irwin said.

An additional factor for consideration is cost. “Many of these approaches are a fraction of the cost of CBT-I,” Irwin said, noting the proliferation of yoga and martial arts studios in all corners of the country.

That said, hurdles exist, namely that many insurance carriers refuse to cover non-medical interventions like tai chi, yoga or even gym memberships. It is for this reason that medications are an essential component to disease control and the ancillary benefits in sleep that may result.

Pharmacotherapeutic Approaches

“With our ever-expanding arsenal of tools that target specific inflammatory pathways, it is true that we have many more options to treat inflammatory diseases than we did even twenty years ago,” Wang said.

But the picture is still not so simple, according to Wang. “We still do not really know who is going to respond to which therapy because it is becoming increasingly clear that every patient may have their own flavor of a disease,” he said, noting that the research community continues to discover and categorize novel types and subtypes of the myriad rheumatologic and autoimmune conditions. A patient with one subtype of, say, rheumatoid arthritis may respond to one therapy, and gain the associated improvements in sleep parameters, while another patient with RA may not see those benefits.

“Rheumatologists need to educate patients that, until we have better methods to identify disease subtypes, the state-of-the-art now still requires trial and error to find a therapy that treats their version of the disease,” Wang said.

It is also important to understand that targeted therapies may not impact just immunity and inflammation, noted Wang. “They also impact a host of other physiologic processes, consistent with the ever-increasing recognition that the immune system is involved more broadly in homeostasis than in just protecting us from infections,” he said. “Thus, we are still discovering what direct roles these pathways have in, for example, sleep, independent of immunity/inflammation. Rheumatologists need to always listen with an open mind to their patients to figure out if a particular therapy is breaking the vicious cycle.”

Mehta offered another reason rheumatologists should be as careful as possible in their prescribing patterns for any given patient. “Many medications, such as opioids, steroids and diuretics, that are helpful for treating a disease can also negatively affect sleep for various reasons,” she said.

If there is a final consideration for the use of medications to treat sleep, it pertains to the synergy between medical and non-medical approaches. “When we are talking about behavioral interventions and targeted therapies, it is not either/or,” Irwin said. “Behavioral interventions should complement treatments.”

Across the Spectrum

“Poor sleep quality can be a problem across many rheumatology diseases, both autoimmune — such as RA and lupus — or non-autoimmune, such as fibromyalgia or osteoarthritis,” Mehta said.

Mehta highlighted the prevalence of fatigue in RA and lupus. “If a rheumatologist finds that the joints are not swollen, the labs are okay, yet fatigue is a persistent complaint, then the physician should discuss sleep issues with the patient,” she said. “Similarly, in osteoarthritis or fibromyalgia, lack of good quality of sleep can significantly impact pain.”

It can be challenging for a practitioner to address all these issues in an office visit, Mehta acknowledged. “Therefore, eliciting the help of a cognitive behavioral therapist and sometimes even a sleep specialist physician may be needed to help the patient get the necessary quantity and quality of sleep,” she said. “In the end, helping the patient sleep better will hopefully improve their overall autoimmune disease.”

Much of the research in this area has been done in RA, according to Prather.

In a paper published in Joint Bone Spine, Cutolo looked at parameters surrounding circadian rhythms in RA patients. “In chronic inflammatory conditions such as RA, the amplitude of the circadian rhythm of the anti-inflammatory endogenous cortisol availability is not increased as expected and requested, which indicate a reduced night cortisol secretion under the adrenal chronic stress induced by the disease,” he wrote. “Therefore, the prevention/treatment of the immune cell night hyperactivity, with related flare of cytokine synthesis and morning RA clinical symptoms, has been shown more effective when the availability of the exogenous glucocorticoids is obtained in the middle of the night (night release).”

A modified night-release dosing schedule of prednisone showed efficacy, according to Cutolo. He added that this may be applicable to NSAIDs and disease modifying anti-rheumatic drugs, as well. “The link between the circadian rhythms of the disease and the chronotherapy of RA is promising,” he wrote.

While such a treatment approach shows promise, like so many others in this arena, it will require validation and standardization. In the meantime, rheumatologists should continue to use available knowledge and the tools at hand to help patients get as much rest as possible. “In my experience as a behavioral sleep medicine provider, when you give someone their sleep back, so much of their experience improves,” Prather said.