Melanie Cole, MS (Host): Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole. And joining me today is Dr. Yvonne Lee. She's the Helen Myers McLoraine Professor of Rheumatology and an Associate Professor of Epidemiology at Northwestern. And she's here to tell us today about sex differences in pain and quantitative sensory testing in patients with rheumatoid arthritis.

Dr. Lee, thank you so much for being with us today. You conducted extensive research on pain mechanisms in rheumatoid arthritis. Give us an overview of the key factors that contribute to the unique pain experience in individuals with rheumatoid arthritis, some of the key sex-related differences in the experience of pain among patients and how these differences impact diagnosis and treatment approaches.

Dr Yvonne Lee: So first, thank you so much, Melanie, for having me here. It's great to be with you. And then, I think I just want to say that you really hit the nail on the head when you use the words unique and individuals. Pain is a very personal experience that is influenced really to varying degrees by different factors, such as biological factors, psychological factors, social factors. And in addition to all the factors that contribute to pain in your eye and in general population, patients with rheumatoid arthritis may also be affected by either acute pain from inflammation in their joints or chronic pain as a result of joint damage and/or chronic pain due to abnormalities in the way their central nervous system regulates the pain. So, I think it's very a unique experience and very multifactorial.

Melanie Cole, MS: Well, pain is somewhat subjective anyway. So, this is such an interesting topic. Now, your work involves advanced techniques like quantitative sensory testing and neuroimaging. How have these techniques enhanced our understanding of pain in rheumatoid arthritis? Explain the role of quantitative sensory testing in assessing that pain perception.

Dr Yvonne Lee: Right. As you mentioned, it is a very subjective experience, and there are many different pathways that really kind of work together and culminating in an individual's pain experience. So, quantitative sensory testing and neuroimaging are both tools that enable us to really just begin to dissect down to those pathways.

For example, they can indicate whether there are abnormalities in the way the brain and spinal cord processes pain. And if there are abnormalities, whether those pathways are related to more pain facilitation, so pathways that go up from the spinal cord into the brain or pathways related to descending pain inhibition or pathways that go from the brain down from the spinal cord, or a combination of both. So, they really help us to kind of get more at those specific pathways than say a numeric rating scale where you rate your pain on a scale of zero to ten.

Melanie Cole, MS: Yeah, that's so interesting. And you recently published findings in arthritis care and research regarding sex differences in pain and quantitative sensory testing in patients. I'd like you to tell us about this work, the methods you used and what you found out in the notable variations between male and female patients.

Dr Yvonne Lee: So, women are disproportionately affected by autoimmune conditions, such as rheumatoid arthritis, as well as chronic pain syndromes. So, compared to men with rheumatoid arthritis, women with RA are also more likely to suffer from more active disease. So, that was kind of the background for why we're studying this.

And the goal of our study was to really identify these sex differences in pain, assessed both by self report, because fundamentally that's how you have to assess pain, by self report; as well as by quantitative sensory testing to get down to more of those specific pathways that I mentioned earlier. And so, we use data from the Central Pain and Rheumatoid Arthritis Cohort, otherwise known as CPIRA. We had patients rate their pain intensity according to that 0 to 10 numeric rating scale that I mentioned earlier. But we also used other validated surveys from the Patient-Reported Outcomes Measurement Information System, otherwise known as PROMIS, to assess pain interference and other pain-related factors such as anxiety and depression and function.

And so, quantitative sensory testing included looking at pain thresholds at both articular and non-articular sites to get a sense for whether patients were more sensitive to pain and whether this was more a peripheral process or more of a central process. We also used quantitative sensory testing to assess temporal summation, to assess ascending pain facilitation and condition pain modulation to assess descending pain inhibition.

Melanie Cole, MS: Dr. Lee, I'd like you to speak a little bit about your findings and how they differ from what's currently available, the meaningful endpoints of your study. But before you do that, was there a difference in how they dealt with the pain? You're speaking of these quantitative sensory testing in their pain levels, but how about how they dealt with them? Women, we tend to see more doctors more easily. We are less hesitant to seek help for things that are causing us distress. Did you find any differences in how they actually dealt with the pain?

Dr Yvonne Lee: So, we didn't specifically look at the things that you just mentioned. However, we did assess pain interference, which is a measure of how much pain interferes with their functioning, so with their daily activities. And interestingly, while we did see a difference in pain intensity as well as some of the quantitative sensory testing measures. We did not see a difference in pain interference. So, this is interesting in that it seems like women are reporting at least higher pain intensity, but they're not letting it interfere with their lives as much, like for a given level of pain interference, their pain intensity, their pain interference seems to be similar to that of men's with lower pain intensity.

 Just to summarize again the main highlight findings were that women reported higher pain intensity and lower pressure pain thresholds at both joint and non-joint sites than men. However, as I mentioned earlier, pain interference did not differ between men and women and the other two quantitative sensory testing measures, temporal summation and condition pain modulation, also did not differ between men and women in the study.

So, with regards to what was unique about study, I think the unique part does lay in the quantitative sensory testing. And the value of lies in the information that they provide in aggregate on the underlying pathways that lead to each patient's individual pain experience.

So, the observation that women with rheumatoid arthritis reported lower pain thresholds at both articular and non-articular sites suggests that women and men differ in the way their peripheral and central nervous systems regulate pain. And this difference may predispose women to experiencing more intense pain than men. That said, we did not observe any difference in temporal summation or condition pain modulation, which are supposed to reflect the ascending pain facilitatory pathways and the descending inhibitory pain pathways, respectively. So, it's not clear still why exactly women with RA are more sensitive to pain than men. I think additional studies are still needed to probe at these causes, whether they may be due to sex-based neurobiological differences in pain perception or perhaps sex or gender differences in psychological factors, or societal influences, such as gender role expectations. I think a lot more needs to be done there to study that.

Melanie Cole, MS: Well then, in terms of clinical implications, Dr. Lee, how would you like other rheumatologists to approach pain management differently for female and male patients based on your work and your research for patients with RA based on your study findings?

Dr Yvonne Lee: I think the data regarding sex differences and quantitative sensory testing assessments still need to be validated before we make, great clinical changes based on those data. However, the observation that women with RA experience higher pain intensity than men with RA is well supported by several studies, including a meta-analysis by Dr. Cheryl Barnabe. And so, these results are impactful, I think, because rheumatologists frequently consider pain as an indicator of inflammation. And many of our composite disease activity measures include assessments, such as the tender joint count or patient Global assessment, which are heavily influenced by the pain experience. However, there are no modifications to disease activity thresholds based on sex or gender. And these assessments directly affect treatment decisions and outcomes. So, I think it's going to become increasingly important for healthcare providers to really consider the impact of sex and gender on pain, particularly as the field of rheumatology moves towards individualized treatment plans as a part of this precision medicine treatment approach.

Melanie Cole, MS: Before we wrap up, Dr. Lee, the field of rheumatology has seen so many advancements in the treatment options that are available for patients with rheumatoid arthritis. How do some of these new treatments affect that pain experience for patients? Speak about what challenges still remain in optimizing that pain relief because it can be quite a debilitating condition. And what's next for you when it comes in this area of study?

Dr Yvonne Lee: As you mentioned, rheumatology has experienced a great boon in treatments for rheumatoid arthritis and they are highly effective treatments, and these treatments can undoubtedly decrease pain by decreasing joint inflammation. However, when you mentioned challenges, you know, our previous studies have shown that despite treatment with some of these strong immunosuppressive medications, these biologic drugs that we have now, a significant subset of patients continue to have pain. And when you look at their measures of inflammation, the measures of inflammation look normal. And so, why is it that some of our patients continue to have pain even though they are on strong medications which appear to have suppressed their inflammation. And so, more research is definitely needed in that area to better understand the pathways that lead to kind of chronic pain that is resistant to those treatments.

And then in terms of what's next for us, we have really several interesting areas that we are moving forward. The first one that I want to mention is that we're examining the acute to chronic pain transition in patients with rheumatoid arthritis. We want to identify predictors of pain that, as I mentioned earlier, is unresponsive to your standard treatment with disease-modifying anti-rheumatic drugs for the RA. And it's really our hope that by identifying these factors, we may be able to prevent the development of chronic pain because once it is established, as you mentioned, it is very debilitating and sometimes challenging to treat. So, that's one area.

A second area we're looking at is examining the use of wearable technology, so things such as watches and patches to assess important health factors such as sleep, physical activity and heart rate variability and their relationships to pain. I think advances in wearable technology provide a really unique and valuable opportunity to assess patients in their real world environment, so outside of the snapshot that we see in a patient like at their clinic visit or at their research study visit, which may not be representative of their day-to-day activities and what's been going on for, say, the past three months or six months. And so, I think that's an area that we're very excited about.

And lastly, we've recently established collaborations with Dr. Debbie Winter and Dr. Carla Kuda, they're immunologists. Dr. Winter's a computational immunologist. And we're doing more translational studies to really examine the link between key drivers of rheumatoid arthritis pathogenesis and CNS regulation of pain. And if successful, I think these projects could deliver novel insights into the role of circulating peripheral blood mononuclear cells and altered pain regulation in patients with rheumatoid arthritis. And data from these studies would be used in future studies to look for like a biomarker for this chronic pain in patients with RA.

So, in summary, we're super excited about these studies. Recruitment is ongoing and we would really welcome the chance to discuss them with other healthcare providers. So, thank you for giving me this opportunity, Melanie.

Melanie Cole, MS: Thank you so much, Dr. Lee. This is such interesting work that you're doing. And I hope that you'll join us again and update us as things progress. And as you start those new fields of study, please come on and tell us all about it. Thank you again. To refer your patient or for more information, please visit our website at breakthroughsforphysicians.nm.org/rheumatology to get connected with one of our providers. And that concludes this episode of Better Edge, a Northwestern Medicine podcast for physicians. Please always remember to subscribe, rate and review this podcast and all the other Northwestern Medicine podcasts. I'm Melanie Cole. Thanks so much for joining us today.