Gender Gap Confirmed for TNF Inhibitor Response in Axial SpA Save

Men with axial spondyloarthritis (axSpA) were more likely than women to obtain substantial relief with tumor necrosis factor (TNF) inhibitors, a multinational study indicated.

After 6 months of treatment with these agents, 66% of men versus 53% of women had achieved "clinically important improvement," defined as a decrease of at least 1.1 in Axial Spondyloarthritis Disease Activity Score (ASDAS), according to Irene van der Horst-Bruinsma, MD, PhD, of Radboud UMC in Nijmegen, the Netherlands, and colleagues. That worked out to a relative risk of 0.81 for women to achieve meaningful relief (95% CI 0.77-0.84).

Women were also less likely to stay on the medications over time: 24 months after first starting a TNF inhibitor, 37% were still taking one, as opposed to 50% of male patients (P<0.001), the researchers reported in RMD Open.

The findings thus confirm numerous previous reports of a gender disparity in treatment response, based on small samples that often excluded patients without radiographic signs of inflammatory disease.

As a retrospective observational study, no firm conclusions could be drawn as to the reasons for the sex disparity. However, van der Horst-Bruinsma and colleagues listed a number of factors that likely play into it: "differences in body composition, distinct underlying molecular and cellular disease mechanisms (as suggested by variations in gene expression profiles), and differences in the manifestation and course of the disease." For example, women typically have more body fat; it's been suggested that this may lead to greater cytokine release that diminishes the effectiveness of TNF inhibitors.

Unlike most other rheumatic inflammatory diseases, axSpA prevalence is greater among men than women. About three-quarters of radiographic axSpA cases occur in men, while proportions are more equal for nonradiographic disease (i.e., no clear evidence of sacroiliitis on x-ray). Clinical presentations vary as well: women "tend to present with more peripheral complaints and higher prevalence of thoracic pain and widespread pain, and experience worse functional limitations and quality of life," van der Horst-Bruinsma's group observed, whereas men more often carry objective markers of inflammation and "radiographic damage."

But while the results suggest that female axSpA patients might do better with other types of targeted therapy, the researchers argued for a conservative approach. "To improve care for women with axSpA, we must better understand the pathophysiology of sex differences in treatment outcomes. Further research is needed to explore sex-tailored treatment strategies and their potential benefits," they wrote. Another factor to consider is that the new study did not assess potential sex differences with Janus kinase-associated (JAK) inhibitors or other alternatives to TNF blockers.

For their analysis, van der Horst-Bruinsma and colleagues drew on the EuroSpA Research Collaboration Network, a consortium of 15 national axSpA registries across Europe. Records for a total of nearly 28,000 patients were included in the analysis of treatment retention. The analysis of treatment response covered about 6,500 patients for whom ASDAS values had been obtained both at baseline and after 6 months of TNF inhibitor treatment. In that part of the study, about 40% of patients were women; 31% of female patients and 19% of men had nonradiographic disease.

No single TNF inhibitor drug dominated in the database: infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira) were each started by 20%-30% of patients; also used were golimumab (Simponi, 17%) and certolizumab pegol (Cimzia, 8%).

Treatment response at 6 months was the primary efficacy outcome, but the researchers also looked at responses through month 24. The sex difference remained evident, with little variation, throughout the entire study period: at 24 months the relative risk for clinically important improvement was 0.89 for women (95% CI 0.85-0.94). As well, the difference in response was also seen for both radiographic and nonradiographic disease.

Besides the exclusive focus on anti-TNF agents, limitations to the study included missing ASDAS data for most registry participants and losses to follow-up after 6 months. Van der Horst-Bruinsma and colleagues also noted that "it would have been valuable to examine whether specific factors, such as disease duration, CRP [C-reactive protein] levels, radiographic evidence of sacroiliitis on imaging, (extra)musculoskeletal manifestations, and comorbidities such as history of malignancy, fibromyalgia and depression, could account for the observed sex differences in treatment response."

Source Reference: Hellamand P, et al "Sex differences in the effectiveness of first-line tumour necrosis factor inhibitors in axial spondyloarthritis: results from the EuroSpA Research Collaboration Network" RMD Open 2023; DOI: 10.1136/rmdopen-2023-003325.