Sex and Gender Differences Among Patients With Axial Spondyloarthritis – An Interview With Katy Leung, MD

Research findings have demonstrated greater prevalence rates of axial spondyloarthritis (axSpA) among men compared with women, with a ratio of 10:1.¹ However, recent evidence indicates comparable rates since the classification of axSpA was broadened to include nonradiographic axSpA.²

Although greater structural damage on radiography and higher levels of inflammatory markers have been observed among men with axSpA, studies have consistently indicated that women with axSpA may experience a greater number and longer duration of symptoms, as well as higher levels of functional impairment.^3,4

In a 2019 cross-sectional cohort study of 313 patients with axSpA, radiographic axSpA was observed in 38.9% of women vs 63.7% of men; however, women vs men showed higher disease activity on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI; mean, 5.2±2.1 vs 4.6±2.2, respectively).² Similarly, in a 2020 study of 574 patients, BASDAI scores indicated that women vs men with axSpA experienced more spinal pain, peripheral symptoms, tenderness, fatigue, and morning stiffness.⁴

Research findings published in Clinical Rheumatology in 2021 indicated higher disease activity on the majority of BASDAI aspects, greater psychologic distress according to scores on the 12-Item General Health Questionnaire (GHQ-12), higher self-reported rates of diagnosed anxiety and depression, and greater functional limitations in men vs women with axSpA.¹

The lower occurrence of radiographic sacroiliitis, along with greater peripheral and extra-articular manifestations in women compared with men with axSpA, may lead to extended diagnostic and treatment delays vs the general axSpA population.⁵ A 2017 meta-analysis of 23,889 patients demonstrated diagnostic delays of 8.8 years in women vs 6.5 years in men with axSpA in comparison with results of a previous study that found a slightly wider gap in diagnostic delays (9.9 vs 6.3 years, respectively).⁶ The delays have been linked to lower odds of a positive response to biologic treatment.

Real-World Evidence of Gender Gap in axSpA

In light of the lack of evidence pertaining to axSpA in women, Mease et al compared the characteristics and burden of disease between women and men with axSpA in a real-world study.⁵ The study sample included 498 adult patients with axSpA (61.6% men) enrolled in the US-based Corrona Psoriatic Arthritis/Spondyloarthritis (PsA/SpA) Registry for whom sex information was available.

Analyses revealed the following observations in women vs men:

• Higher disease activity indicated by scores on the BASDAI, the Bath Ankylosing Spondylitis Functional Index (BADFI), and physician global assessment (P ≤.01)
• Higher tender and swollen joint counts (P ≤.01)
• Higher enthesitis scores (37.2% vs 20.2%, respectively; P <.01)
• Worse patient-reported outcome (PRO) measures including scores on visual analog scales for pain and fatigue, the Health Assessment Questionnaire for the Spondyloarthropathies (HAQ-S), and the EuroQol (all P <.05)
• Greater employment disruption, according to results of the Work Productivity and Activity Impairment questionnaire
• More frequent history of previous use of conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and current and previous prednisone use (both P <.05)
• Greater likelihood of diagnosed depression (25.7% vs 12.1%, respectively) and fibromyalgia (10.5% vs 1.0%, respectively; both P <.01)

The Influence of Sex and Gender in axSpA

Disparities are generally attributed to sex-related factors, including biological attributes, such as genetic and hormonal differences, as well as gender-related factors including the psychologic, social, and cultural influences that shape self-identity, explained Ying Ying “Katy” Leung, MD, a senior consultant in the department of rheumatology and immunology at Singapore General Hospital and associate professor at Duke-NUS Medical School, Singapore.³

“Genetic and hormonal differences may shape the immune response of the body, leading to disparity in the progression and damage of the spine,” she told us in an interview. The presence of the human leukocyte antigen (HLA)-B27 allele, which is associated with the male sex and greater magnetic resonance imaging (MRI) inflammation of the spine, has been cited as the most important genetic factor influencing disease expression in axSpA.⁶ Among the potentially relevant hormonal influences in axSpA, testosterone has been found to increase the pain threshold.⁶

In addition, women vs men were found to have more central pain sensitization, which aligns with previous findings of more widespread pain patterns along axial and peripheral articular areas in women vs men with axSpA.³ Women also have a greater number of pain receptors in the brain.⁶

However, a substantial “contributor to the differences between men and women with axSpA may be differences in the experience, perception, and communication of pain symptoms according to psychological and social influences,” Dr Leung stated. For example, the higher rates of depression in women with axSpA, as reported by Mease et al, may affect the ways in which these patients experience pain and other symptoms in axSpA.⁵

Dr Leung noted that psychologic comorbidities and gender norms may influence disease activity measurements that are based on PROs, and thus, it is ideal to incorporate objective measures of inflammation such as C-reactive protein (CRP).³ With regard to remaining research needs in this area, the identification of more objective inflammatory biomarkers warrant further attention.

“It is important for healthcare providers to take into account the different manifestations of axSpA between men and women,” especially the greater burden of peripheral disease in women, she said.³ “This helps to facilitate the diagnosis of axSpA in women while also recognizing the specific needs among men and women so as to tailor treatment to address the distinct healthcare needs of each patient.”

Disclosures: Dr Leung disclosed receipt of speaker fees from several pharmaceutical companies.

References

1. Garrido-Cumbrera M, Poddubnyy D, Gossec L, et al; EMAS Working Group. Gender differences in patient journey to diagnosis and disease outcomes: results from the European Map of Axial Spondyloarthritis (EMAS). Clin Rheumatol. 2021;40(7):2753-2761. doi:10.1007/s10067-020-05558-7
2.  de Jong H, Paramarta JE, de Winter J, Baeten D, van de Sande M. Differences between females and males in axial spondyloarthritis: data from a real-life cross-sectional cohort. Scand J Rheumatol. 2020;49(1):28-32. doi:10.1080/03009742.2019.1627410
3. Leung YY. Gender differences in disease activity and impact in axial spondyloarthritis. J Rheumatol. Published online July 1, 2021. doi:10.3899/jrheum.210564
4. Magrey M, de Vlam K, Bolce R, et al. Gender differences in baseline clinical characteristics among patients with ankylosing spondylitis and non-radiographic axial spondyloarthritis: data from 3 randomized ixekizumab controlled trials [abstract]. Arthritis Rheumatol. 2020;72(Suppl 10).
5. Mease PJ, McLean RR, Dube B, et al. Comparison of men and women with axial spondyloarthritis in the US-based Corrona Psoriatic Arthritis/Spondyloarthritis Registry. Published online April 15, 2021. J Rheumatol. doi:10.3899/jrheum.201549
6. Rusman T, van Bentum RE, van der Horst-Bruinsma IE. Sex and gender differences in axial spondyloarthritis: myths and truths. Rheumatology (Oxford). 2020;59(Suppl 4). doi:10.1093/rheumatology/keaa543