Biologics Less Effective for Ankylosing Spondylitis in Women

Ingrid Hein

October 06, 2018

GHENT, Belgium — Women with ankylosing spondylitis do not respond to biologic treatment as well as men, and are less likely to follow-up and complete treatment, a new study reveals.

"At the moment, no distinction is being made between male and female treatment response in trials," Sophie Hoekstra, a student at VU University in Amsterdam, said here at the International Congress on Spondyloarthritides 2018.

"It may be that rheumatologists need to focus on a more gender-specific treatment," she told Medscape Medical News after her oral presentation.

TNF inhibitors are much less effective in women than men. "We don't know if it's due to biology or various gender differences, but we do know that women are often delayed in treatment," said Hoekstra.

Rheumatologists often perceive ankylosing spondylitis to be a male disease, and might not be "as quick to offer female patients TNF inhibitors," she explained. This is a problem because earlier diagnosis is known to improve patient outcomes.

It may be that rheumatologists need to focus on a more gender-specific treatment.

Hoekstra and her colleagues assessed 359 patients with ankylosing spondylitis — 120 (33.4%) female and 239 (66.6%) male — over a 5-year period. The researchers looked at demographic characteristics, lifestyle factors, and inflammatory markers, and scored patients at baseline, 3 months after their first assessment, and every 6 months thereafter.

Although there were no significant differences in smoking, alcohol consumption, or other lifestyle factors between men and women, women saw less improvement in disease activity parameters with TNF inhibitors than men.

However, adherence to the medication was worse for women, and their duration of follow-up on TNF inhibitor therapy was shorter than that for men (4.5 vs 5.4 years).

And women had significantly higher scores — which means worse symptoms — on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), which looks at fatigue, spinal pain, peripheral joint pain, local tenderness, and intensity and duration of morning stiffness, than men (= .010).

Table. Scores on the BASDAI at 1 Year
Domain Women Men P Value
Fatigue 5.64 4.52 .141
Spinal pain 4.24 3.7 .171
Peripheral joint pain 2.89 2.22 .072

Scores on the Ankylosing Spondylitis Disease Activity Score (ASDAS) were also much worse for women than men at 1 year.

Further study is needed. "We think that the drugs are less effective in women than men, but we don't know why," said lead investigator Irene van der Horst-Bruinsma, MD, PhD, from Amsterdam University and the VU University Medical Centre. "This has also been confirmed by other studies, including the DANBIO cohort."

It is really important to find the reasons for the discrepancy, she added. "We have to look at the immunologic and biological details. We know that there are more TH1 cells in males than in females, and more TH2 cells in females, but we don't know how this affects efficacy."

We think that the drugs are less effective in women than men, but we don't know why.

The lack of adherence and the level of efficacy of biologics in women in clinical trials was the topic of a presentation by Lianne Gensler, MD, from the UCSF Medical Center in San Francisco.

She explained that infection as an adverse reaction and adverse events overall are more often seen in women than men.

The mass variation in the male and female anatomy and biology could play a role in these differences.

Ankylosing spondylitis is extremely difficult to diagnose, and women are diagnosed, on average, 7 months later than men, according to one study (J Rheumatol. 2017;44:174-183).

Gensler noted that, when looking at patient-reported outcomes, the fact that women experience pain differently than men should be taken into account.

Women have higher nerve cell fiber density than men and undergo hormonal changes that could contribute to greater pain. "In pain studies, we see that women generally perceive and report more pain," she explained.

However, women are prescribed less pain medication for ankylosing spondylitis, "which could indicate a bias," she added.

Biology, Time of Diagnosis Important

Several presentations at the conference focused on attempts to understand differences in adherence to biologic treatment between men and women.

"The efficacy of TNF inhibitors seems to be lower in female patients," said Eric Gracey, PhD, from Ghent University.

"We don't know if that's biological or if there are various gender differences," he told Medscape Medical News after his presentation on the underlying biology of ankylosing spondylitis.

The effectiveness of a TNF inhibitor is highly dependent of when you give the drug to the patient. "If you get in there late, it's not as effective," Gracey explained.

And there is also an intrinsic biologic factor. "Men naturally have higher levels of TNF in their blood, and we see that male patients have a higher inflammatory profile than women in ankylosing spondylitis," he said, noting that this could be a clue.

In addition, ankylosing spondylitis affects people when they are 30 to 40 years of age, which is when a lot of women are trying to get pregnant. This could be one of the reasons they drop out of drug trials or stop taking the drugs, but there are "not adequate data" to determine this, he said.

But that theory is not shared by everyone.

"I don't think that's a primary reason," said Tamara Rusman, a PhD candidate at VU University Medical Center.

Many women "stop for a short interval" when pregnant "and while breast-feeding, but start treatment again with the biologic," she told Medscape Medical News.

It is also unlikely that chronic pain differences in women play a role. In fact, pointing to different pain experiences is a cop-out, said Rusman.

"It's too easy to say that. We see immunologic, genetic, and hormonal differences that more likely explain why female patients don't respond well," she added.

There is increasing evidence that potential gender differences have not been addressed sufficiently, or at all, during in drug development, as Rusman and colleagues pointed out in a recent study (Curr Rheumatol Rep. 2018;20:35).

Although there is increasing recognition of gender differences in axial spondyloarthritis, there is a lack of information about disease manifestations in female patients, said Rusman. More investigation is needed.

Hoekstra, Gracey, and Rusman have disclosed no relevant financial relationships. van der Horst-Bruinsma reports financial relationships with UCB, MSD, Pfizer, BMS, and AbbVie. Gensler reports financial relationships with AbbVie, Amgen, Janssen, Novartis, UCB, Galapagos, Eli Lilly, and Pfizer.

International Congress on Spondyloarthritides (SPA) 2018: Abstract 06. Presented October 6, 2018.

Follow Medscape Rheumatology on Twitter @MedscapeRheum and Ingrid Hein @ingridhein


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