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Exclusive Preview: Dr Prather on the Role of Sleep in IMIDs
Dr Aric A. Prather, PhD, is the associate professor of Psychiatry and Behavioral Sciences at the University of California San Francisco, with a focus on the links between psychological stress and sleep and their effects on the immune system. He discussed with The Dermatologist the role of sleep and IMIDs prior to his session at IAS.
THE DERMATOLOGIST: Your research has noted associations between inflammation and sleep hygiene in addition to stress. How may sleep influence IMIDs, such as rheumatoid arthritis or psoriatic disease?
DR PRATHER: Anyone who treats patients with those conditions knows, across the board, that sleep disturbances are happening at a high rate, and that some of these are consequences of disease severity, discomfort, and pain.
In some cases, sleep influences these conditions directly by impacting the immune system. We've been really interested in what effects disturbed sleep and sleep loss have on the inflammatory system?
When you look at meta-analytic reviews of the literature1, thousands of participants who report more sleep disturbances also show elevations in proinflammatory mediators that underlie inflammation. These include key inflammatory proteins like interleukin-1 beta, IL-6, C-reactive protein, tumor necrosis factor-alpha, and so on. It is plausible that poor sleep leads to worsening IMID disease through its impact on inflammation.
The other way in which sleep impacts these conditions is by affecting one’s ability to cope with symptoms. Take the pain literature2 as a great example, we know that if we deprive someone of sleep, and then expose them to a pain task, their threshold for what they consider as painful is lessened. Anyone who's had a bad night's sleep can probably relate to this.
When people don't get the sleep they need, everything just feels worse. Little things feel like big things whether it’s stress, or any negative emotions. However, it also goes for symptoms of our disease where it becomes harder to manage.
Generally, women are more likely to have a number of IMIDs. Are there any links between sleep inflammation and sex? If so, could you explain the thought behind the link?
DR PRATHER: It’s true that there is some evidence that women report worse sleep quality than men3. It’s certainly one of the things that's interesting given the higher rates of IMIDs among women and the possibility that the influence of sleep on inflammation may help explain these difference4.
For example, we carried out a study5 several years ago in a large sample of almost 700 participants, where we followed them over five years. We measured their sleep quality at the beginning of the study and then measured their inflammation over the course of 5 years.
What we found was that individuals who reported poorer sleep at the beginning of the study showed a greater increase in their proinflammatory cytokines, interleukin-6 in this particular case, over that 5-year period, but that this was only true for women6.
This finding was consistent with several other research studies that have found a similar association, such that the link between sleep and inflammation is stronger among women7.
However, why this is happening is still an open question. It's possible that differences in reproductive hormones, which can play a regulatory role in inflammation, may help explain these observations. To date, however, this hasn’t been rigorously investigated.
How may systemic therapies or biologic agents influence sleep?
Sleep and the immune system are intimately tied, and they're bidirectional. Inflammatory proteins, as I mentioned, may change as a response to better or worse sleep. They also play a role in regulating sleep.
Sleep is categorized into two kinds of sleep: non-rapid eye movement (REM) sleep and REM sleep. REM sleep is most commonly associated with dreaming, while non-REM sleep cycles from light (N1) to deep (N3), and that deep part of non-REM sleep is critical for restoration.
Data suggest that low levels of inflammation can promote non-REM sleep, with proteins like TNF-alpha playing a central role.
Interestingly, there are dose-dependent effects, such that as inflammation increases, we see further promotion of non-REM sleep, but a blunting of REM sleep. What follows is, at really high levels, your sleep becomes very fragmented and disturbed.
There's been a lot of interest in whether inflammatory therapeutics, things like TNF-alpha receptor antagonists and blockades, may in fact have an impact on sleep in individuals who have conditions where those are used, such as IMIDs. Much of the work has been in the context of rheumatoid arthritis and the use of TNF-alpha inhibitors.
Several small studies support the idea that blocking inflammation may benefit sleep. For example, one study found that the first dose of infliximab led to an increase in sleep efficiency in RA patients8. Sleep efficiency reflects how consolidated your sleep is at a given time period where you try to sleep. In those patients, it was found to have increased.
There's been a couple of other studies where it's led to improvements in subjective quality, and a little bit of information around changes in sleep architecture9. Also, there is one study10 looking at an interleukin-6 inhibitor that found a reduction in sleep complaints over a 6-month period.
This means there does seem to be an inkling of data supporting the idea that these therapeutics can in fact impact sleep, but certainly, it hasn't been well investigated rigorously to this point.
My group is always interested in partnership with industry collaborators, including pharmaceutical companies, to get to the bottom of this because, again, sleep plays such an important role in how people cope with pain.
If we can find whether these drugs can improve sleep in these patients, where poor sleep is already a common complaint, I think that could be an added bonus along with the possibility of these drugs treating the diseases.
In your study, “Association of Atopic Dermatitis With Sleep Quality in Children”11, the results proved that atopic dermatitis is associated with impaired sleep quality throughout childhood. What interventions would you suggest to clinicians in order to improve this?
I was fortunate to work with some stellar dermatology collaborators, namely Dr. Katrina Abuabara, to examine sleep quality in children with of atopic dermatitis (AD) followed over more than 10 years. Not surprisingly, across the board, sleep quality was really impaired in these patients. Poorer sleep quality was more prevalent in those with active, more severe disease, and in those with comorbid asthma or allergic rhinitis. What was also interesting was that poorer sleep quality was observed in those with mild and inactive AD, compared to those without AD.
There are lots of possible explanations for why patients with AD have poor sleep, and future work identifying the mechanisms will help guide future interventions. There are certainly opportunities for interventions to improve the quality of sleep for children, adolescents, and adults who also experience atopic dermatitis in sleep quality.
The same is true for psoriasis as well, though this seems less researched compared to AD. In fact, very little is known about sleep and psoriasis, particularly when it comes to gold-standard measures of sleep, known as polysomnography (as opposed to self-report measures) to help close that gap in the literature.
We're launching a project led by Dr. Tina Bhutani, who directs the Dermatology Clinical Researcher Unit at UCSF, to bring healthy participants and those with moderate to severe psoriasis into the sleep lab to examine differences in sleep architecture, with the hope of identifying aspects of sleep physiology that may be between groups. Of course, we're also getting immune measures to better characterize that relationship, and I think there's a lot of opportunities there to help clarify the links between sleep and inflammation in this dermatologic condition.
Any pearls of wisdom regarding sleep and its effects on IMIDs that you'd like to share with specialists in those fields?
Obviously, there's a lot of science to be done. We really need to understand some of the underlying mechanisms and potential moderators of these associations regarding how sleep may influence the development and progression of these diseases. I also think there's a lot of opportunity for intervention.
For insomnia, as an example, cognitive behavioral therapy is the first-line treatment for treating insomnia in all groups.
I would urge clinicians to ask their patients about their sleep, and consider non-pharmacologic paths to improve sleep by reaching out to sleep medicine providers, and behavioral sleep medicine people like myself. Sleep complaints are highly prevalent in IMID patients. It is helpful in the clinical encounter to clarify when in the night is the patient having sleep trouble, how long has this been happening for, and then move towards, "Can we hook you up with the right people, so that we can treat your sleep alongside your current treatment for your condition?"
References:
1. Mullington JM, Simpson NS, Meier-Ewert HK, Haack M. Sleep loss and inflammation. Best Pract Res Clin Endocrinol Metab. 2010;24(5):775-784. doi:10.1016/j.beem.2010.08.014
2. Finan PH, Goodin BR, Smith MT. The association of sleep and pain: an update and a path forward. J Pain. 2013;14(12):1539-1552. doi:10.1016/j.jpain.2013.08.007
3. Krishnan V, Collop NA. Gender differences in sleep disorders. Curr Opin Pulm Med. 2006;12(6):383-389. doi:10.1097/01.mcp.0000245705.69440.6a
4. Dolsen MR, Crosswell AD, Prather AA. Links Between Stress, Sleep, and Inflammation: Are there Sex Differences?. Curr Psychiatry Rep. 2019;21(2):8. Published 2019 Feb 7. doi:10.1007/s11920-019-0993-4
5. Prather AA, Marsland AL, Hall M, Neumann SA, Muldoon MF, Manuck SB. Normative variation in self-reported sleep quality and sleep debt is associated with stimulated pro-inflammatory cytokine production. Biol Psychol. 2009;82(1):12-17. doi:10.1016/j.biopsycho.2009.04.008
6. Prather AA, Epel ES, Cohen BE, Neylan TC, Whooley MA. Gender differences in the prospective associations of self-reported sleep quality with biomarkers of systemic inflammation and coagulation: findings from the Heart and Soul Study. J Psychiatr Res. 2013;47(9):1228-1235.
7. Suarez EC. Self-reported symptoms of sleep disturbance and inflammation, coagulation, insulin resistance and psychosocial distress: evidence for gender disparity. Brain Behav Immun. 2008;22(6):960-968. doi:10.1016/j.bbi.2008.01.011
8. Zamarrón C, Maceiras F, Mera A, Gómez-Reino JJ. Effect of the first infliximab infusion on sleep and alertness in patients with active rheumatoid arthritis. Ann Rheum Dis. 2004;63(1):88-90. doi:10.1136/ard.2003.007831
9. Karatas G, Bal A, Yuceege M, et al. The evaluation of sleep quality and response to anti-tumor necrosis factor α therapy in rheumatoid arthritis patients. Clin Rheumatol. 2017;36(1):45-50. doi:10.1007/s10067-016-3387-6
10. Fragiadaki K, Tektonidou MG, Konsta M, Chrousos GP, Sfikakis PP. Sleep disturbances and interleukin 6 receptor inhibition in rheumatoid arthritis. J Rheumatol. 2012;39(1):60-62. doi:10.3899/jrheum.110617
11. Ramirez FD, Chen S, Langan SM, et al. Association of Atopic Dermatitis With Sleep Quality in Children. JAMA Pediatr. 2019;173(5):e190025. doi:10.1001/jamapediatrics.2019.0025
