Alfred Kim, MD, on Circadian Function and Sleep Quality in Lupus

Dr Kim reviews the the impact of poor sleep and circadian dysfunction on patients with systemic lupus erythematosus.

Alfred Kim, MD, is an assistant professor of rheumatology at Washington University School of Medicine and director of the Lupus Center at Barnes Jewish Hospital in St. Louis, Missouri. 

TRANSCRIPT:

Hi there. My name's Al Kim. I'm an adult rheumatologist at Barnes Jewish Hospital in St. Louis, Missouri. I'm also on faculty at the Washington University School of Medicine, where I direct the Lupus Center. And today we're going to be talking about a lecture that I gave at the 2024 ACR Convergence meeting that just happened in Washington, DC, about the impact of sleep quality and circadian function issues in patients with lupus. This was part of a larger session called Catching Zs and Rheumatic Diseases. That was also done with Dr. Yvonne Lee at Northwestern and Patty Katz at UCSF who talked about both the therapies and also sleep issues in  RA. If you want to learn more about those two, I encourage you to go onto the convergence website where you can catch the session as is recorded.

But relevant to today, we'll talk about the impact of poor sleep and circadian dysfunction in patients with lupus. We got interested in this largely because, as most people who are rheumatologists know, we often run late and behind in our clinics. So for me, I usually run about 20 to 30 minutes late in my clinic, which means that patients are sitting in a pretty much environmentally sterile room. Basically, there's really little information on the walls that engages them. And so one of the most common things that happens when I walk in the room is that they're asleep. At first I just thought, well, it is just because I'm running late and there's nothing to do. But actually one of my fellows at the time, Dr. Alicia Hinze, who's now faculty at the Mayo Clinic, wondered if there's a pattern here because it's not just one or two patients that are asleep, it's all your patients that are asleep when you're coming in. And it made us think about whether or not we need to be taking a deeper dive into looking at sleep quality and then a result in circadian dysfunction in these patients.

But let me back up just a little bit because I just want to cover a couple topics here about what sleep is and what circadian rhythms are and what their relationship to one another is. So we all think, okay, well we sleep every day, and that's true to certain inequalities and we can talk about that in a second. But certainly over a 24 hour period, sleep is part of a larger program that is governed by your circadian rhythms. That's just really complex interplay that that integrates physiologic inputs, environmental inputs, but also then as outputs physical, mental and behavioral changes over a 24 hour cycle. So for example, we wake up in the morning, we have the highest energy level, we actually have the lowest body temperature to the time that body temperature starts to go up throughout the morning and then we start to peak in the afternoon.

But around that time, we kind of all have a little bit of a slump that's normal. And then as it darkens in the evening, we start getting sleepy and we start having other surges like melatonin, which then it helps trigger us to actually engage with sleep. And what really governs all this is that circadian rhythm and light isn't a major input for this. It actually is captured by the back of the eye with ferrin nerves that come from the pineal gland and the ssma nuclei that actually governs central circadian rhythm, which is going to be within the brain, but then that helps with the melatonin surge and programming peripheral circadian rhythm. So this is going to be outside of the brain, so like the lung, the liver muscles. Now what makes this tricky though too is that in peripheral circadian rhythms are also governed by two other things when we eat and our exercise load.

And so these can all alter and change what our circadian rhythm is doing. And so we'll talk about some of these and its impact in lupus in a second. The reason why we think this is important is because there is a strong relationship between circadian rhythms and immune responses. So for example, if you took healthy volunteers and changed their sleep cycle by shortening it even by a couple hours, you can see within a couple of days inflammatory cytokines like IL six TN, TNF alpha go up in these people compared to people that have maintained a normal sleep schedule. So even that short term sleep disturbance can create a pro-inflammatory environment. Now I'm going to cut to chase a little bit. Most of our patients with lupus have poor sleep quality that don't just last a few weeks. They last months if not years, sometimes up to 20 years.

We don't know the impact of that on the immune system. This is something that needs to be studied. We're going to be engaging in some of these studies in a little bit, but you have to wonder whether this persistent sleep, poor quality and the burden associated with that immunologically whether or not that could serve as a trigger for issues with the acquisition of autoimmunity or even flares. And this has been observed actually in some studies. Patty Katz has been running some sleep quality surveys and studies with patients with lupus through the California Lupus Epidemiology study or the Cole Study, and she's found that in lupus patients there's an enrichment of patients with poor sleep quality, obstructed sleep apnea, restless link syndrome in lupus patients and actually RA patients too compared to the controls or nonautoimmune patients. And we do know that in lupus patients, tiredness, sleeping problems ranked number 1 and 3 from patients as the highest unmet needs out of 74 needs that were surveyed even further. There's actually interesting data from Taiwan that show that in patients with poor sleep quality, so this is actually nonobstructive sleep apnea, but other reasons to have poor sleep quality that the acquisition of autoimmune diseases was higher in patients that slept poorly.

So there's a 1.8 hazard ratio increase in the acquisition of lupus and 1.6 increase in the hazard ratio for RA. So again, there's a lot of these arrows pointing to poor sleep quality, circadian dysfunction, and immune dysfunction that really suggests that this triad could be potential triggers for the acquisition and flaring of autoimmune issues. So when we took a look at this through our study, which we called SLEEPS or systemic lupus erythematosus and the evaluation of poor sleep, and again, Dr. Alicia Hinze came up with this super clever name, we wanted to look from 2 perspectives. We wanted to get the patient perspective, first of their sleep quality perception, and we can do this through what we call patient-reported outcomes. These are commonly implemented instruments that can give us information about patient perception of certain things. So there are various sleep quality measures that are out there.

And through this we found that patients with active lupus versus inactive lupus generally experienced higher or worse scores of sleep quality compared to those with inactive lupus. This is interesting, and I think it may be consistent with the current thinking that we have about the impact. There's kidney dysfunction, immune dysfunction, sleep quality. But I think what was more interesting was when we dissected out the timing of when we survey patients about their sleep quality and then looked into the future in their next visit—what was their lupus doing? Did it get worse? Did it get better? What we found was that patients with worse sleep quality at visit 1 versus patients that had better sleep quality at visit 1 had about a 3-fold increased risk of a flare at visit 2.

This is a bit striking and a little bit complicated because over time, this is usually over a 3-to-4 month period of interval time. A lot of things can happen, right? So may not be just sleep that is contributing to increased flare activity in the poor sleepers, but it is an interesting relationship and a hypothesis that needs to be tested moving forward, that sleep quality and then the resultant circadian function, whether it's going to be issues with it or maintenance of it, can potentially influence what's going on in terms of lupus clinical activity. Now there's another way to assess sleep quality that's a little bit more objective. And you can use instruments such as motion trackers on the wrist. There's one that's commonly used in the sleep world called Actigraphy. This is a noninvasive wearable typically worn on the wrist, like a watch that assesses activity and rest. And so you can actually determine 1314 circadian rhythm variables and 7 or 8 sleep quality variables just from what your right wrist activity is doing, which is quite remarkable.

But this is a validated instrument. It works just as well as polysomnogram, which is the gold standard for sleep quality assessment and circadian rhythm assessment. But polysomnogram is obviously much more invasive because you have to wear leads all around the body. So what we found using Actigraphy was that there is a 1-hour jet lag or what's called a kind of phase dependent circadian change in patients with active lupus versus inactive lupus. You may think 1 hour may not be that big of a difference, but whenever we have time changes like from standard to daylight or daylight to standard, we see a spike in cardiovascular events and motor vehicle accidents in the US. And there is an idea with some data behind it, especially with cardiovascular events, that if you end up altering having central circadian rhythms and peripheral circadian rhythms and kind of make them discordant instead of concordant, that's a risk factor for cardiovascular events in the general public.

So actually every time we go from standard to daylight or daylight to standard, we're actually creating this discordance which could explain the spike in the cardiovascular events that we see during these time points. But what we're seeing in active lupus is that having flaring lupus actually creates that 1-hour difference also compared to when they're not active. Remember that the leading cause of death in lupus patients is cardiovascular events. So this is kind of interesting as this entire story is starting to be weaved around. So I think there's a lot of things to extract out of this. Some of it we don't know the answers to yet. Why is sleep quality and circadian function poor in patients with lupus, particularly if they have active disease? We don't fully know the answer. Some of our analyses with our sleep group at Wash U suggest that chronic insomnia may be the major driving force of poor sleep in lupus patients a whole.

You may be surprised to hear that sleep is actually a learned behavior, which means you can unlearn it with children. You try to entrain them that the tiredness and fatigue at the end of the day, the darkening of the atmosphere. And so this gives you the melatonin surge and then the activity of sleep are all intertwined, but humans are the only species on the planet that deliberately delay sleep, which then means that we can actually start uncoupling the behavior of sleep with these kind of fatigue cues and biologic cues. And so this is a situation that this is exaggerated in patients with amplified pain syndrome or chronic pain syndrome, where at nighttime their pain sensitivity actually increases and their pain perception increases. So there you have worst case scenario where the behavior of sleep is actually antagonized because they have increased pain and so they actually unlearn completely the behavior of sleep and avoid it at nighttime in order to not have that amplified pain in patients with lupus.

It's unclear to me what that trigger is, but the majority of our lupus patients have the same phenomenon where they've colloquially 'forgotten how to sleep.' Much of the work that's done with our lupus patients in our sleep group is cognitive behavioral therapy for insomnia or CBTI. So either a sleep psychologist, which are not common, or an occupational therapist, which is much more common, typically engages patients with CBTI. We found this to be an effective therapy for patients with chronic insomnia. So it's something for you guys to consider. I think at the end of the day there's a lot of things that are interesting but remain phenomenology. Patients with lupus tend to sleep more poorly. Patients with lupus tend to have a history of poor sleep, which may be a trigger. Patients with lupus that are active have worse sleep variables and circadian dysfunction than patients that are inactive.

We have this now entire other story of the interface between sleep quality and circadian dysfunction and having increased proinflammatory cytokines just generally in our bloodstream. We're working on trying to link all of this together on top of trying to improve the patient experience of having poor sleep, whether or not it's through chronic insomnia or the hundreds of other sleep disorders that can be diagnosed. But at the end of the day, I think culture in the US, we don't really think about sleep quality and we don't necessarily ask our patients about this all the time. So I think the lesson learned here is, ask your patients about their sleep quality. Primary question, do you wake up refreshed? Duration of sleep is not necessarily important. It's more the quality of sleep. So if they wake up, refresh and have very little or no daytime somnolence, you can be confident that they have good sleep quality and you don't have to worry about it.

But the majority of lupus patients will have poor sleep quality. They will wake up refreshed normally, and they feel like they have some daytime somnolence issues in that situation. That's exactly when I bring in our sleep group to help with management. But during this, we're also trying to figure out the molecular mechanisms and other risk factors that can drive and promote poor sleep, which then may promote worse disease activity. So there's a lot out there that we kind of know and a lot that we don't know, but I think sleep quality in the lupus patients is something that needs to be better appreciated. And engagement with our sleep group and occupational therapist will be extraordinary helpful for our patients with lupus. So thanks for listening.