Should We Manage Men & Women Differently?

Sex Differences in PsA

WASHINGTON, D.C.—You don’t have to be a doctor or a scientist to understand that men and women are different. But when you are, you can prove it. Evidence shows that biological differences, such as genetics, hormones and pain processing, as well as social-cultural differences (i.e., gender roles, support systems and health seeking behavior) contribute to sex differences. These sex differences impact the clinical presentation, diagnosis, response to therapy and patient experience of illness.

At ACR Convergence, two incredible clinician-scientists shared data that speak to the effect of sex difference in psoriatic arthritis (PsA).

Clinical Features & Disease Course

Dr. Coates

Laura Coates, MBChB, PhD, associate professor, University of Oxford, U.K., kicked off the session describing sex differences in the presentation and disease course of PsA.

When it comes to diagnosis, women go to the doctor with musculoskeletal complaints about two years before PsA is confirmed. On the other hand, men tend to wait, presenting when symptoms are more severe.

Dr. Coates said, “Women present frequently before diagnosis, and this [fact] is a massive opportunity to identify early disease. They often aren’t being recognized as PsA or developing PsA. Conversely, men aren’t presenting as much, and that’s also a problem. We need to educate our male patients about seeking help in psoriasis clinics and/or the [primary care provider’s] office.”

Regarding disease domains, women are more likely to have polyarthritis and enthesitis. In contrast, men are more likely to have mono- or oligoarthritis, axial disease, more severe psoriasis, higher C-reactive protein levels and dactylitis.² A meta-analysis by Dr. Coates and colleagues showed that these patterns tend to persist through disease.³

“Global data is similar, with studies from China and Turkey showing the same pattern—more axial disease in men and more peripheral arthritis in women,” she said.

As for patient-reported outcomes, women generally report higher impact across almost all measures.^3,4 Dr. Coates said, “Perhaps unsurprisingly, we see this [aspect] reflected in mental health impact as well. You can see higher rates of anxiety, depression and a combination of the two in cohorts of people with PsA, and if you look at the gender split, it’s higher for women compared with men.”⁴

Should We Manage Men & Women Differently?

“For many years now, we’ve had clear recommendations that we should be doing treat to target in our patients with PsA,” said Dr. Coates. “But there are differences in how men and women perceive remission, and over 50% of our patients have quite a different opinion about disease activity compared with their clinician’s assessment.”^5,6

If men and women with PsA are so different, should our treatment strategies differ as well? Dr. Coates said, “I personally don’t have different targets for my patients, but I think this is something we should be aware of. Women seem to accept worse targets as an ‘acceptable symptom state’.”⁷

Dr. Eder

Treatment Response

Lihi Eder, MD, PhD, associate professor of medicine, University of Toronto, Ontario, Canada, continued the session with more data and insight into how sex differences affect treatment response in PsA.

 “Our approach to treatment is currently gender blinded,” said Dr. Eder. “We assume that what works for men automatically works for women, and this [belief] may not be true. We should be thinking about moving toward a more gender-specific approach.”

Example: Most drugs recommend the same dose for men and women. Zolpidem, a sedative-hypnotic, is one of few drugs that has a different FDA-approved dose for men and women due to safety concerns. But overall, Dr. Eder noted that “sex-specific dosing remains unusual.”

When you examine differences in efficacy across biologics with different mechanisms of action in PsA, results are striking. Dr. Eder said, “For all biologic therapies, all of them show preferential response in male patients compared with female patients, except for the Janus kinase (JAK) inhibitors and tyrosine kinase 2 (TYK2) inhibitors. Is there something different about these?”⁸

Men and women also discontinue drugs for different reasons, and Dr. Eder noted that “most of the studies looking at persistence [i.e., the time from initiation to discontinuation of therapy] aren’t looking at the reasons for discontinuation.”

Research from Dr. Eder and colleagues shows that most women discontinue therapy because their joints aren’t doing well, or they’re experiencing medication side effects. On the other hand, men will more often discontinued treatments because of concern about potential adverse effects, improvement in symptoms or a dislike of taking medications.⁹

Experience of Pain

So what causes these differences?

Men and women experience pain differently. Pain mechanisms differ qualitatively between men and women, and sex hormones also affect pain processing.¹⁰ Dr. Eder said, “It has been shown in multiple musculoskeletal conditions that female patients tend to report higher scores of pain, as well as lower thresholds for pain. And there are differences in the patterns of pain. Women are more likely to report more diffuse pain, which we may call fibromyalgia. We need to be aware of this [difference] and not automatically consider fibromyalgia in this situation. It may reflect true inflammatory pain.”¹¹

Of note, because pain is subjective, it can be affected by gender-related factors, such as gender roles.“There are differences in the way society expects boys and girls to respond to or report pain,” said Dr. Eder. Boys are expected to endure pain and be strong, so they may minimize pain reporting later. For women, it may not be perceived as weakness to report pain, so they’re more likely to report it early and see their physicians.”

Practical Applications of Knowledge

The data show that sex differences exist. So how can we adjust practice patterns to take these into account? Dr. Eder suggested:

• Closer monitoring of female patients because there’s data to show lower treatment efficacy with biologic therapies in women;
• More frequent use of sensitive imaging modalities, such as ultrasound or MRI, in women to detect active inflammation because they have a higher burden of pain and dysfunction;
• Asking men direct questions to assess symptom burden because they may downplay symptoms; and
• Managing pain regardless of the cause.

Future Directions

Last but not least, Dr. Eder urged, “People who do research need to report sex disaggregated data. Even if the study is underpowered to report sex differences, it can help later in meta-analyses.”

Samantha C. Shapiro, MD, is a clinician educator who is passionate about the care and education of rheumatology patients. She writes for both medical and lay audiences and practices telerheumatology.

References

1. Tarannum S, Widdifield J, Wu CF, et al. Understanding sex-related differences in healthcare utilisation among patients with inflammatory arthritis: A population-based study. Ann Rheum Dis. 2022 Feb;82(2):283–291.
2. Theander E, Husmark T, Alenius GM, et al. Early psoriatic arthritis: Short symptom duration, male gender and preserved physical functioning at presentation predict favourable outcome at 5-year follow-up. Results from the Swedish Early Psoriatic Arthritis Register (SwePsA). Ann Rheum Dis. 2014;73(2):407–413.
3. Coates LC, van der Horst-Bruinsma IE, Lubrano E, et al. Sex-specific differences in patients with psoriatic arthritis: A systematic review. J Rheumatol. 2023 Apr;50(4):488–496.
4. Orbai AM, Perin J, Gorlier C, et al. Determinants of patient-reported psoriatic arthritis impact of disease: An analysis of the association with sex in 458 patients from fourteen countries. Arthritis Care Res (Hoboken). 2020 Dec;72(12):1772–1779.
5. Egholm CL, Krogh NS, Pincus T, et al. Discordance of global assessments by patient and physician is higher in female than in male patients regardless of the physician’s sex: Data on patients with rheumatoid arthritis, axial spondyloarthritis, and psoriatic arthritis from the DANBIO registry. J Rheumatol. 2015 Oct;42(10):1781–1785.
6. Coates LC, Robinson DE, Orbai AM, et al. What influences patients’ opinion of remission and low disease activity in psoriatic arthritis? Principal component analysis of an international study. Rheumatology (Oxford). 2021 Nov 3;60(11):5292–5299.
7. Scriffignano S, Perrotta FM, Fatica M, et al. Patient acceptable symptoms state in psoriatic arthritis: does it differ between sexes? (AB1131). Ann Rheum Dis. 2023;82:1796.
8. Eder L, Mylvaganam S, Pardo J, et al. Sex-related differences in patient characteristics, and efficacy and safety of advanced therapies in randomised clinical trials in psoriatic arthritis: A systematic literature review and meta-analysis. Lancet Rheumatol. 2023 Dec;5(12):e716–e727.
9. Eder L, Richette P, Coates LC, et al. Gender differences in perceptions of psoriatic arthritis disease impact, management, and physician interactions: Results from a global patient survey. Rheumatol Ther. 2024 Oct;11(5):1115–1134.
10. Dance A. Why the sexes don’t feel pain the same way. Nature. 2019 Mar;567(7749):448–450.
11. Tarannum S, Leung YY, Johnson SR, et al. Sex- and gender-related differences in psoriatic arthritis. Nat Rev Rheumatol. 2022 Sep;18(9):513–526.