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• Impact of gender on outcomes in ankylosing spondylitis
  Ernst Feldtkeller
  Published on: 13 April 2016
• Response to Feldtkeller et al Letter
  Irene van der Horst-Bruinsma
  Published on: 13 April 2016

• Published on: 13 April 2016

  Impact of gender on outcomes in ankylosing spondylitis

  • Ernst Feldtkeller
  • Other Contributors:
    • Gudrun Lind-Albrecht

  Dear Editor,

  We read with interest the article on the impact of gender on outcomes in ankylosing spondylitis [1]. In their analysis of four controlled clinical trials, the authors found a higher burden of ankylosing spondylitis (AS) in female patients and less improvement in outcome measures compared with men, "despite women having a later disease onset and shorter disease duration". They conclude that the mechanism...

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  Dear Editor,

  We read with interest the article on the impact of gender on outcomes in ankylosing spondylitis [1]. In their analysis of four controlled clinical trials, the authors found a higher burden of ankylosing spondylitis (AS) in female patients and less improvement in outcome measures compared with men, "despite women having a later disease onset and shorter disease duration". They conclude that the mechanism behind this observation is unclear and additional research is necessary.
  Regrettably, the authors take the age at diagnosis as "disease onset" and ignore all the years in which the disease was not diagnosed correctly and did not get appropriate treatment. Because of the high prevalence of a long delay in diagnosis in the case of ankylosing spondylitis, the Assessment of SpondyloArthritis international Society (ASAS) concluded at their workshop in 2006 that the duration since diagnosis should never be called "disease duration" in the case of ankylosing spondylitis [2, 3]. As has been shown in [4, 5], the average age at disease onset (first symptoms of AS) does not differ significantly between male and female patients with AS, whereas the average delay in diagnosis is significantly larger in females (9,8 years compared to 8.4 years in males, p<0.01 [5]). A worse outcome in connection with a longer delay in diagnosis and a longer inappropriate treatment is not really surprising. It does not occur "despite a later disease onset" as stated in [1]. In contrast, the longer delay in diagnosis may well - besides other gender differences - contribute to the observed difference in disease outcome.
  In this connection it may be of interest that it has also been reported in the literature that the ankylosis progresses faster on average in male patients with AS than in females, connected with a higher prevalence of severe pain after a long disease duration in female patients, however not in males [5, 6]. This difference between genders might be the main contribution to the observation reported in [1].

  References

  1. van der Horst-Bruinsma IE, Zack DJ, Szumski A, et al. Female patients with ankylosing spondylitis: analysis of the impact of gender across treatment studies. Ann Rheum Dis 2013;72:1221-1224.

  2. Feldtkeller E, Erlendsson J. The definition of disease duration in ankylosing spondylitis: Comment on the article by Davis et al. Ann Rheum Dis eletter http://www.annrheumdis.com/cgi/eletters/65/11/1518#726, (12 Jul 2006)

  3. Feldtkeller E, Erlendsson J. Definition of disease duration in ankylosing spondylitis. Rheumatol Int 2008;28:693-696.

  4. van der Linden S.M., Valkenburg H.A., de Jongh B.M., et al. The risk of developing ankylosing spondylitis in HLA-B27 positive individuals. Arthritis Rheum 1984;27:241-249.

  5. Feldtkeller E, Bruckel J, Khan MA. Scientific contributions of ankylosing spondylitis patient advocacy groups, Curr Opin Rheumatol 2000;12: 239-247.

  6. Zink A, Braun J, Listing J, et al. Disability and handicap in rheumatoid arthritis and ankylosing spondylitis - results from the German rheumatological database. J Rheumatol 2000;27:613-622.

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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• Published on: 13 April 2016

  Response to Feldtkeller et al Letter

  • Irene van der Horst-Bruinsma, MD
  • Other Contributors:
    • Debra Zack, Annette Szumski, Andrew S. Koenig

  Dear Editor,

  We would like to thank you for your remarks regarding our manuscript van der Horst-Bruinsma et al Ann Rheum Dis 2013;72:1221- 1224.[1] We do agree that in ankylosing spondylitis, onset is more accurately described by onset of symptoms as opposed to age at diagnosis. Unfortunately, we did not collect the time-of-symptom-onset data in three of the four studies in this analysis. Thus, we used the age at d...

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  Dear Editor,

  We would like to thank you for your remarks regarding our manuscript van der Horst-Bruinsma et al Ann Rheum Dis 2013;72:1221- 1224.[1] We do agree that in ankylosing spondylitis, onset is more accurately described by onset of symptoms as opposed to age at diagnosis. Unfortunately, we did not collect the time-of-symptom-onset data in three of the four studies in this analysis. Thus, we used the age at diagnosis as proxy for disease onset. In the ASCEND study (females n=147; males n=419), we reviewed the onset of symptom data that was similar between females (mean 13.0 years) and males (mean 13.4 years), which supports Dr Feldtkeller's statement, "the average age of disease onset (first symptoms of AS) does not differ significantly between male and female patients with AS".[1, 3] In addition, the mean age of diagnosis in the ASCEND study was significantly higher for females versus males (36.3 years vs 32.2 years; p=0.0001) and mean delay of diagnosis was 1.5 years greater for females versus males (6.9 years vs 5.4 years; p=0.0481), both of which support Dr Feldtkeller's previous findings of a 1.5-year delay in diagnosis (females 9.8 years; males 8.4 years).[2, 3]
  The next question is whether a mean difference of 4 years in age at diagnosis between genders (females 35.0 years; males 31.2 years) would explain the gender differences in response to anti-TNF therapy? To address this, we analyzed if age at diagnosis (?40 years versus >40 years) contributed to gender differences in the ASCEND study. Our analysis demonstrated that almost all parameters had significantly less improvement and poorer week 12 outcomes in the >40 versus ?40 group regardless of gender. In addition, considering the mean age of the ?40 and >40 age groups is a 20 year difference (28.1 years vs 48.5 years, respectively), it is not expected for age at diagnosis to have as great of an impact on gender differences considering females were diagnosed on average only 4 years later compared to males.
  We further questioned if a longer delay in diagnosis was related to worse outcomes between genders and therefore, based on the median delay of 4 years in the ASCEND study, genders were analyzed based on their delay in diagnosis category (?4 years vs >4 years). In females, there were no noticeable differences in baseline characteristics or outcomes between the ?4 versus >4 year delay in diagnosis groups. Interestingly, males with a longer delay in diagnosis (>4 years) demonstrated worse baseline and post-treatment outcomes (ASDAS, BASFI, BASDAI, nocturnal back pain, and total back pain,) compared with the ?4 year group. However, these findings are confounded by multiple factors such as symptom duration, which is highly correlated with delay of diagnosis, making it difficult to determine if these results are due to delay in diagnosis, symptom duration, and/or other factors.
  Overall, the objective of our manuscript was to assess the impact of gender on clinical, functional and patient-reported outcomes within the limitations of the available studies due to the very limited data currently available on this topic. As Dr Feldtkeller has pointed out, there are multiple confounding factors (e.g. delay in diagnosis, symptom duration, and age at diagnosis) that may account for these observed gender differences in outcomes. So while "additional research is necessary to better understand female patients with AS," the gender analysis of 4 clinical trials in our original publication and additional analysis included herein may assist in understanding the female AS population until more conclusive data is available.[2]

  References

  1. Feldtkeller E, Lind-Albrecht G. Impact of gender on outcomes in ankylosing spondylitis. Ann Rheum Dis Published Online First: 14 August 2013

  2. Braun J, van der Horst-Bruinsma IE, Huang F, et al. Clinical efficacy and safety of etanercept versus sulfasalazine in patients with ankylosing spondylitis: a randomized, double-blind trial. Arthritis Rheum 2011;63:1543-51.

  3. Feldtkeller E, Bruckel J, Khan MA. Scientific contributions of ankylosing spondylitis patient advocacy groups. Curr Opin Rheumatol 2000;12:239-47.

  Conflict of Interest:

  IvdH-B is an investigator for clinical trials sponsored by Pfizer Inc. DZ is a former employee of Amgen. AS is an employee of Inventiv Health Inc who is a paid contractor to Pfizer Inc. AK is an employee of Pfizer. Editorial support was provided by Stephanie Eide of Engage Scientific Solutions and was funded by Pfizer Inc.

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  Conflict of Interest:
  None declared.

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