Why Sex and Gender Are Important Biomarkers in PsA

NEW YORK — Rheumatologists, dermatologists, drug manufacturers, and researchers do not pay enough attention to the role sex and gender play in the pathogenesis and presentation of psoriatic arthritis (PsA), Lihi Eder, MD, PhD, said at the Tenth Annual NYU Langone Advanced Seminar in Psoriasis and Psoriatic Arthritis. Being mindful that the disease and treatments affect men and women differently makes patient management more personalized and effective, she noted.

“We tend to ignore sex and gender when we manage our patients in our approach to psoriatic arthritis as well as other rheumatic diseases,” Eder said. “We have to start thinking about sex of the patient as a biomarker that can potentially help us personalize care and move from a gender-blinded to a gender-specific approach.”

Eder, the Canada Research Chair in Inflammatory Rheumatic Diseases at the Women’s College Hospital of the University of Toronto, Toronto, Ontario, Canada, said much of the obfuscation of the role gender plays in PsA begins with research. “There’s very little research into sex differences in PsA,” she said. A meta-analysis published last year by her group found that while 51% of participants in 54 PsA trials were women, only nine (17%) reported baseline characteristics by sex, 18 (33%) reported efficacy by sex, and two (4%) reported safety endpoints by sex.

Eder said sex is a biological factor, whereas gender is a “more complex” factor based on social and cultural aspects of men and women.

PsA Differences in Women vs Men

Although the prevalence of PsA in men and women is similar, sex affects the risk of developing rheumatic disease. For example, Eder cited a host of studies that showed Sjögren’s syndrome and systemic lupus erythematosus have a 9:1 and 7:1 prevalence in women vs men, whereas gout has a 1:4 prevalence.

Her group’s 2013 study, along with a 2023 study from Italy, found significant differences in how PsA disease activity and quality of life differ between the two sexes.

“Females tend to have a higher tender joint count and more clinical entheses,” Eder said. “They also have worse patient-reported outcomes when it comes to pain, fatigue, and physical dysfunction, and these are things that would influence quality of life.

“On the other hand, when we look at male patients, they tend to have higher CRP [C-reactive protein] levels, they tend to have more severe restriction in the spine, and they also tend to have more severe psoriasis.”

She added that women are less likely than men to develop joint damage that’s picked up on X-rays.

Questioning Drug Development 

A gender gap exists across four phases of drug development, Eder said. Preclinical studies tend to rely on single-sex models, phase 1 clinical trials target a standard 70-kg healthy male, and phase 2 and 3 trials as well as postmarketing surveillance do not consider gender in study design and have limited reporting of sex-specific endpoints, she said.

“So, it’s very hard to pick up these signals, and this may explain why most of the drugs that are withdrawn from the market pose a greater risk for women than for men,” she said, citing a 2001 Government Accountability Office report that found that 80% of prescription drugs withdrawn from the market pose a greater risk for women.

That gender bias also carries over to drug commercialization, she said. The sleeping pill zolpidem remains one of the few drugs for which the Food and Drug Administration has approved sex-specific dosing, Eder noted.

Her group’s 2023 meta-analysis showed that men and women respond differently to approved biological disease-modifying antirheumatic drugs. That research, which included a subanalysis of 18 trials and 6821 patients, found that men had a better American College of Rheumatology 20 response to tumor necrosis factor (TNF), interleukin-17 (IL-17), and IL-23 inhibitors, but there was no difference between the sexes in response to Janus-activated kinase (JAK) and tyrosine kinase 2 inhibitors. The same subanalysis also found no difference in the placebo response between men and women in those trials.

“So this raises the question: Should we consider the sex of the patient when we select treatments?” Eder said.

A French study last year reported that men had higher rates of persistence after 1 year: 62% vs 52% for women for TNF inhibitor, IL-17 inhibitor, and IL-23 inhibitor agents, but persistence rates for JAK inhibitors were similar between sexes.

“People ask me should we start favoring JAK inhibitors for females,” Eder said. “I think it’s premature. We need to do more research, but it does raise the question.”

A study published this year by Eder and her group reported that women were more likely than men to discontinue their medications because their symptoms did not improve or the side effects were intolerable.

Another sex-differentiating factor of PsA that clinicians should take into account, Eder said, is the way men and women experience pain. “Women tend to report higher levels of pain across different rheumatic conditions,” she said, citing her own group’s 2022 study and a 2020 Dutch study. Cultural differences in how the sexes approach pain may also come into play, with men expected to be more tolerant and women more susceptible to it, Eder added. 

Evidence Is Mounting, but More Is Needed

The evidence that explains why these apparent differences exist between men and women with PsA is still lacking, Eder said in an interview with Medscape Medical News. “It’s very hard now because we don’t know the differences,” she said. “It’s very hard to know the solutions when you don’t know why things are happening.”

Nonetheless, she said, in her own practice she tries to be attuned to pain in women and is trying to stay unbiased when her patients talk about pain.

“I’ve also started asking females as they go into menopause or around the age of the mid-40s — those that complain about pain — about other menopausal-related symptoms, which I didn’t do before,” Eder said. She said she counsels patients whose pain might be driven by potentially menopausal transition, especially if they’re taking hormone-replacement therapy. She added that she is also using objective measures to differentiate PsA-related pain from other causes, such as fibromyalgia or depression.

Asked to comment on this topic, Iannis Adamopoulos, PhD, associate professor of medicine and director of the Arthritis Program and Head of the Osteoimmunology Laboratory at Beth Israel Deaconess Medical Center, Boston, told Medscape Medical News, “the science is now building” to better understand how sex and gender influence PsA. He noted that the National Institutes of Health already mandates sex-specific mouse studies in any research it funds.

Human studies, however, must take into account a host of variables, Adamopoulos said. “You have more variation within the groups because you don’t control 100% of people; you don’t put them in cages,” he said.

In her presentation, Eder noted that her group’s research into sex dimorphisms in the proteomic profile in PsA found that men have 20 times more sex-specific differentially expressed proteins than women. But Adamopoulos said that “there are no male and female proteins at all. There could be different levels, but not different proteins.”

The research into sex differences in PsA is nascent, he said, adding, “There’s still a lot to uncover.” 

Eder disclosed financial relationships with AbbVie, Eli Lilly, Pfizer, Novartis, Johnson & Johnson, Bristol Myers Squibb, UCB, Fresenius Kabi, and Sandoz. Adamopoulos has no relevant financial disclosures.

Richard Mark Kirkner is a medical journalist based in the Philadelphia area.