Possible Sex Differences Found in Early RA Drug Responses

Thomas R. Collins

September 13, 2022

Men with early rheumatoid arthritis who had previously never been treated with disease-modifying antirheumatic drugs (DMARDs) achieved remission significantly more often than women when given the interleukin (IL)-6 inhibitor tocilizumab (Actemra), according to new findings published in The Lancet Rheumatology.

Researchers also found that men had higher rates of remission than women when treated with certolizumab pegol (Cimzia), abatacept (Orencia), or conventional synthetic DMARDs, but the differences were not statistically significant.

Kristina Lend

The findings are based on a post-hoc analysis of data from the randomized, controlled, phase 4 NORD-STAR trial performed across Scandinavia, Iceland, and the Netherlands that is believed to be the first study on treatment-naive patients to specifically analyze the interaction between sex and treatment using interaction terms. In the study, outcomes for men versus women were compared within each treatment group and also to the conventional treatment arm used as the reference group.

"Our findings could provide guidance about the optimal treatment choice for DMARD-naive men and women with early RA," said first author Kristina Lend, MSc, research assistant at the Karolinska Institute, Stockholm, and PhD student at Amsterdam University Medical Center.

Researchers enrolled 812 patients between 2012 and 2018 and randomly assigned them to receive:

  • Conventional treatment involving methotrexate plus prednisolone tapered from 20 mg per day to 5 mg per day within 9 weeks or methotrexate plus sulfasalazine (2 g per day), hydroxychloroquine (35 mg/kg per week or 200 mg per day), and intra-articular glucocorticoids in the swollen joint (maximally four joints and 80 mg per visit);

  • the tumor necrosis factor (TNF) inhibitor certolizumab pegol with methotrexate;

  • the T-cell co-stimulation modulator abatacept with methotrexate; or

  • tocilizumab with methotrexate.

All of the patients were newly diagnosed, with symptoms for less than 24 months, and they had never taken a DMARD. Researchers used the Clinical Disease Activity Index (CDAI) as the primary tool for assessing remission. Patients started oral methotrexate initially at 10-15 mg per week and escalated within 4 weeks to a target dose of 25 mg per week.

In all groups, men achieved remission after 24 weeks at higher rates than women: 55% compared with 50% in the conventional arm; 57% vs. 52% with certolizumab pegol; 65% vs. 51% with abatacept; and 61% vs. 40% with tocilizumab. But in most cases, the 95% confidence intervals overlapped for men and women, meaning the differences didn't reach statistical significance.

However, in the tocilizumab group, the difference was significant.

Lend said it was interesting to see this difference with tocilizumab. The drug is known to reduce acute-phase reactants, such as C-reactive protein (CRP). But the CDAI doesn't take CRP or other acute phase reactants into account. Both men and women taking tocilizumab had significant reductions in CRP, and yet men ultimately did much better on the drug according to the CDAI, as well as other scales, such as the Disease Activity Score in 28 joints and Simplified Disease Activity Index.

Women in the conventional treatment arm actually achieved remission more often, at least in absolute numbers, than did women taking tocilizumab.

"It was surprising to see that men on tocilizumab treatment achieved higher remission rates than men in conventional treatment while women in tocilizumab treatment achieved lower remission rates than women in conventional treatment," she said.

Several factors could account for the differences in remission, she said. Subjective components when assessing remission — such as tender joint counts and a patient's own assessment of their disease activity — tend to be higher for women. Underlying biological mechanisms can play a role as well, with evidence suggesting that gonadal hormone concentrations modulate the immune system and affect pain signaling, influencing how the disease is experienced, she said.

Findings such as these could lead to a redrafting of treatment recommendations, Lend suggested.

"Conventional treatment is currently recommended over tocilizumab and other biologics for DMARD-naive men and women with early RA," she said. "We do feel that the overall results of the NORD-STAR trial could lead to a reassessment of these recommendations, and that more personalized treatment decisions will become the standard."

In an accompanying editorial, Alexandre Sepriano, MD, PhD, a rheumatologist at Hospital Egaz Moniz in Lisbon, and Elena Nikiphorou, MD, consultant rheumatologist at King's College London, said the analysis was generally well-designed, although perhaps too small.

"The NORD-STAR trial, compared to other studies, comes the closest to answering the question at hand," they wrote. "A fair conclusion is that (with the exception of tocilizumab) men and women respond similarly to biological DMARDs compared with conventional therapy. If true, this is reassuring news both to patients and clinicians."

They cautioned that the study was "probably underpowered" to answer the question authoritatively.

"Despite this, the study provides useful insights into sex-driven responses to treatment," they said. "Differences in methodological and analytical approaches will need to be considered in studies with similar intentions when interpreting the findings."

Ruth Fritsch-Stork, MD, PhD, professor of rheumatology at Sigmund Freud University in Vienna, who has studied sex and RA treatment in the Austrian BIOREG registry, said the findings are an important contribution to the literature.

"I think it is a very interesting paper, as little literature has been published about sex differences in RA patients regarding therapy," she said. "And the little that is known is ambiguous. So this paper is a badly needed piece in the puzzle of treatment response in RA."

Dr Ruth Fritsch-Stork

She said she wondered how much these findings will be applicable to typical clinical scenarios, in which tocilizumab is usually at least a second-line therapy, after use of conventional synthetic DMARDs — and often after anti-TNF therapy as well. But this study population was DMARD naive.

"Also, the literature usually describes a better outcome in men for anti-TNF, which was not seen here," she added.

"As the effect of tocilizumab seems to be greater in men not only in remission rates, but also in infection rates, I do believe an effect on the IL-6 signaling and immunological sequelae to be the underlying factor," Fritsch-Stork said. "However, I agree with the authors that unknown, noninflammatory, sex-dependent effects on pain sensation might play a role."

Even though the applicability of the study isn't clear, she said, "it is important information for future investigations."

Lend and Fritsch-Stork reported no relevant financial disclosures. Sepriano reported financial relationships with UCB, Novartis, and Lilly. Nikiphorou reported financial relationships with Pfizer, Gilead, Galapagos, Lilly, and Fresenius.

This story originally appeared on MDedge.com, part of the Medscape Professional Network.

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