Gender Differences in Axial Spondyloarthritis: Comparing Disease Burden and Treatment

Although axial spondyloarthritis (axSpA) affects both men and women, atypical disease progression has been particularly recognized among women.¹ The reported statistical distribution of men to women has varied over the decade, decreasing from a ratio of 10:1 in early studies reported before 1975, to a ratio closer to 3:1 in more recent studies in the United States,² although a ratio of 1.03:1 has been reported in Switzerland.³ The uneven distribution of axSpA, particularly in earlier studies, may in part be explained by the low representation of women in pivotal clinical trials that are often not powered to detect gender differences or are analyzed for gender differences during postmarketing surveillance.⁴ Irrespective of the low clinical trial participation by women, differences in axSpA disease presentation, diagnosis, and response to treatment have been documented,^3,5-7 yet there are a paucity of studies focused on identifying the underlying factors contributing to axSpA gender differences. An improved understanding of the gender differences in axSpA disease can improve disease treatment and reduce disease burden.

Extraarticular manifestations of axSpA include enthesitis, psoriasis, inflammatory bowel disease, and acute anterior uveitis.⁸ Although the studies are limited and some are inconclusive, the general trend shows gender differences in pain distribution; among women, back, neck, knee, and hip pain appear to be more common, whereas foot and joint pain are more common among men.^6,7 Differences in extraarticular manifestations have also been reported; enthesitis and inflammatory bowel disease appear to be more prevalent in women and acute anterior uveitis is more prevalent in men. Furthermore, compared with men, disease burden is higher in women and quality of life is significantly lower. However, radiographic progression appears to be more severe in men compared with women, perhaps explained by the higher progression in the lumbar spine in men compared with the cervical spine in women. In early axSpA, women are reported to have greater disease activity and worse functional decline, despite fewer radiologic abnormalities compared with men.^6,7  

The underlying physiology to explain axSpA gender differences is largely unknown. The speculation, however, is that genetic, environmental, cultural, and societal factors that influence behavior and approach to health care play a role.⁹ A recent review by Rusman and colleagues provides new insight that may help to explain the gender differences and the potential clinical consequences.³ For example, significantly elevated levels of the inflammatory cytokines tumor necrosis factor (TNF) alpha, interleukin-17A, and C-reactive protein have been reported in male patients compared with their female counterparts. Differences in the expression of genes associated with axSpA have been reported and estrogen may have an anti-inflammatory effect on SpA manifestations³ The clinical effect of these gender differences is reflected in axSpA disease diagnosis, its treatment, and patient outcomes.

Although the onset of ankylosing spondylitis is comparable between men and women, a 3-year delay in diagnosis has been reported in women compared with men.¹⁰ A recent meta-analysis of 42 studies involving 23,883 patients showed a significantly wider diagnostic delay, 8.8 years for women compared with 6.5 years for men.¹¹ Differences in disease presentation and perception may contribute to the diagnostic delay; women are more likely to be misdiagnosed with fibromyalgia, particularly at the early stages of axSpA when the presenting symptom may be nonspecific back pain.³ Given the progressive and irreversible deformity that can occur in the absence of prompt effective treatment, the consequences of the longer diagnostic delay or misdiagnosis in women can have serious consequences. 

Differences in treatment response between men and women can also have serious consequences. TNF inhibitors have significantly improved outcomes for patients with axSpA; however, the efficacy of TNF has been reported to be significantly lower in women compared to men.³ Predictors of TNF inhibitor treatment response, including the presence of HLA-B27, the absence of enthesitis, short disease duration, and being naive to TNF inhibitors are negatively associated with female gender. The higher percentage of body fat in females and the influences of female hormones have also been thought to influence response to TNF inhibitors. Furthermore, compared with men, adherence to TNF treatment is lower and switching of TNF inhibitors is higher among women.³ Despite the higher burden of axSpA in women, these differences may help to explain the reduced treatment response and poorer outcomes of women with axSpA.

Despite the demonstrated gender differences in axSpA that have resulted in delayed diagnosis and poorer treatment outcomes in women, there are a paucity of large-scale studies focused on providing clarity and understanding of these differences to enable gender-specific approaches to axSpA and disease management. Until further studies are conducted, it is important that physicians be cognizant of these gender differences when treating female patients with axSpA to reduce disease burden and improve outcomes.

follow @RheumAdvisor

References

1. Strand V, Singh JA. Patient burden of axial spondyloarthritis.J Clin Rheumatol. 2017;23(7):383-391.
2. Will R, Edmunds L, Elswood J, Calin A. Is there sexual inequality in ankylosing spondylitis? A study of 498 women and 1202 men. J Rheumatol. 1990;17(12):1649-1652.
3. Rusman T, van Vollenhoven RF, van der Horst-Bruinsma IE. Gender differences in axial spondyloarthritis: women are not so lucky.Curr Rheumatol Rep. 2018;20(6):35.
4. Tannenbaum C, Day D; Matera Alliance. Age and sex in drug development and testing for adults.Pharmacol Res. 2017;121:83-93.
5. Lee W, Reveille JD, Weisman MH. Women with ankylosing spondylitis: a review.Arthritis Rheum. 2008;59(3):449-454.
6. Tournadre A, Pereira B, Lhoste A, et al. Differences between women and men with recent-onset axial spondyloarthritis: results from a prospective multicenter French cohort.Arthritis Care Res (Hoboken). 2013;65(9):1482-1489.
7. Roussou E, Sultana S. Spondyloarthritis in women: differences in disease onset, clinical presentation, and Bath Ankylosing Spondylitis Disease Activity and Functional indices (BASDAI and BASFI) between men and women with spondyloarthritides. Clin Rheumatol. 2011;30(1):121-127.
8. de Winter JJ, van Mens LJ, van der Heijde D, Landewé R, Baeten DL. Prevalence of peripheral and extra-articular disease in ankylosing spondylitis versus non-radiographic axial spondyloarthritis: a meta-analysis.Arthritis Res Ther. 2016;18:196.
9. Regitz-Zagrosek V. Sex and gender differences in health. Science & Society Series on Sex and Science.EMBO Rep. 2012;13(7):596-603.
10. Jones A, Harrison N, Jones T, Rees JD, Bennett AN. Time to diagnosis of axial spondyloarthritis in clinical practice: signs of improving awareness?Rheumatology (Oxford). 2014;53(11):2126-2127.
11. Jovaní V, Blasco-Blasco M, Ruiz-Cantero MT, Pascual E. Understanding how the diagnostic delay of spondyloarthritis differs between women and men: a systematic review and meta-analysis.J Rheumatol. 2017;44(2):174-183.