The effect of anti-tumor necrosis factor agents on sexual dysfunction in male patients with ankylosing spondylitis: a pilot study

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Abstract

Sexual dysfunction is a common problem among patients with ankylosing spondylitis (AS). This study was an open-label study without placebo to assess sexual dysfunction in male patients with AS, and to determine whether sexual function might improve with the use of tumor necrosis factor (TNF)-α blockers. Twenty-two males with AS (age, 29–48 years) were treated for 3 months with TNF-α blockers. Before and after treatment, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was measured, and all patients completed the International Index of Erectile Function (IIEF) questionnaire, a self-administered measure of sexual dysfunction with five domains: erectile function (EF), intercourse satisfaction (IS), orgasmic function (OF), sexual desire (SD) and overall satisfaction (OS). There were significant improvements in BASDAI after treatment with TNF-α blockers (P<0.001). Anti-TNF-α treated patients showed significant improvements in four out of the five IIEF domains (EF, P<0.001; IS, P<0.001; SD, P=0.006; OS, P=0.033). Among patients with erectile dysfunction, there were significant improvements in three IIEF domains (EF, P=0.006; IS, P=0.007; SD, P=0.018). Only IS domain of IIEF showed a significant correlation with BASDAI (partial correlation coefficient = −0.484, P=0.026). This study showed that anti-TNF-α therapy may improve sexual dysfunction in male AS patients, in addition to reducing disease activity.

Introduction

Ankylosing spondylitis (AS) is a chronic inflammatory disease of the axial skeleton manifested by back pain and progressive stiffness of the spine. AS affects mostly young adults, with a peak age of onset between 20 and 30 years.1 Pain and stiffness in the back and joints and limitation of spinal mobility reduce the ability of patients to carry out daily activities and negatively affect quality of life. AS is also associated with an increased absence from work and a higher level of work disability compared with the general population.2 The most prevalent concerns of patients with AS are stiffness, pain and fatigue,3 and these make up the core components of the Bath AS Disease Activity Index (BASDAI).4

Sexual dysfunction is another important issue in patients with AS. Male patients with AS have been found to have significantly decreased sexual function, as assessed by the International Index of Erectile Function (IIEF) questionnaire and the Brief Male Sexual Function Inventory, compared with healthy controls.5, 6

Conventional management for AS has included exercise and treatment with non-steroidal anti-inflammatory drugs. In addition, traditional disease-modifying anti-rheumatic drugs, such as methotrexate and sulfasalazine, are of benefit for peripheral arthritis in AS patients. Inhibitors of tumor necrosis factor (TNF)-α have recently been shown to significantly reduce disease activity, including pain and stiffness, as well as to improve health-related quality of life.7 However, it is not known whether anti-TNF-α therapy also improves sexual dysfunction in AS patients. We therefore evaluated the effect of anti-TNF-α therapy on sexual dysfunction, as well as health-related quality of life and disease activity, in male patients with AS.

Materials and methods

Twenty-two married male patients 29–48 years old, who met the modified New York criteria for the diagnosis of AS,8 were enrolled consecutively at the commencement of treatment with TNF-α blocking agents. Patients with other known medical conditions that could affect sexual function, health-related quality of life and/or disease activity, were excluded. No patient had a history of treatment for erectile dysfunction (ED) or a history of previous treatment with TNF-α blockers. All patients had received non-steroidal anti-inflammatory drugs and sulfasalazine for at least 3 months before the treatment with TNF-α blockers and were enrolled at the start of TNF-α blocker therapy. AS disease activity was measured using BASDAI before and after 3 months of treatment.4

Before and after 3 months of treatment, all patients completed the Korean language version of the IIEF questionnaire,9, 10 a self-administered measure of erectile function (EF) comprising five domains: EF ( six questions with a maximum score of 30), intercourse satisfaction (IS, three questions with a maximum score of 15), orgasmic function, sexual desire and overall satisfaction (two questions each with a maximum score of 10). The IIEF is a highly sensitive and specific instrument for detecting changes in EF in response to treatment.9 Patients with a score of 25 or less in the EF domain were considered to have ED.5, 9

Before and after treatment, each patient also completed the RAND 36 item Health Survey 1.0, a measure of health-related quality of life, containing 36 items on the following eight scales: physical functioning, role limitations because of physical health problems, role limitations because of personal emotional problems, energy/fatigue, emotional well-being, social functioning, pain and general health. Each scale generates a score from 0 to 100, with a higher score indicating better health.11 We used a Korean language version of the questionnaire.12

The study protocol was approved by the institutional review board of the Asan Medical Center and all participants provided informed consent.

Statistical analyses were carried out using SPSS 14.0 software. The Wilcoxon signed rank test was used to analyze paired data in each individual before and after treatment. Linear regression analyses and bivariate correlation analyses (partial correlation coefficients adjusted by age) were used to assess correlations between changes in BASDAI and each domain of the IIEF.

Results

The 22 patients had a mean age of 37.8±5.8 years (range, 29–48 years), and a mean BASDAI at baseline of 7.2±1.5 (range, 4.75–10). Mean disease duration was 6.3±4.1 years (range, 0.6–14.2 years). Among these patients, 10 were treated with etanercept, 8 with infliximab and 4 with adalimumab. Overall, 14 of the 22 patients (63.6%) had ED at baseline, as determined by scores (25) in the EF domain of the IIEF.

After 3 months of treatment, the mean BASDAI decreased significantly to 2.3±1.5 (P<0.001). All variables of the RAND 36 item Health Survey 1.0 improved significantly after TNF-α blocker treatment. There were significant improvements in four out of the five IIEF domains (EF, P<0.001; IS, P<0.001; sexual desire, P=0.070; overall satisfaction, P=0.033) (Table 1). The proportion of patients with ED decreased to 45.5% after 3 months of TNF-α blocker treatment (Figure 1). Among 14 patients with ED, there were significant improvements in three IIEF domains (EF, P=0.006; IS, P=0.007; sexual desire, P=0.018) (Table 2). Four of them (28.6%) achieved normal EF.

Table 1 Comparison of clinical variables at baseline and after 3 months of anti-TNF therapy (n=22)
Figure 1
figure1

Effect of anti-tumor necrosis factor (TNF) therapy on erectile function in male patients with ankylosing spondylitis.

Table 2 Changes in IIEF domain score after 3 months of anti-TNF therapy in patients with erectile dysfunction (n=14)

Using linear regression, we assessed whether improvement in any IIEF domain was correlated with improvement in the BASDAI. Among the five domains of IIEF, changes in IS domain were significantly associated with the changes in the BASDAI after 3 months of treatment (r2=0.306, P=0.008). When adjusted by age, the change in IS domain of IIEF was significantly correlated with changes in the BASDAI (partial correlation coefficient=−0.484, P=0.026) (Table 3).

Table 3 Correlations between the changes in BASDAI and the changes in each domain of the IIEF after 3 months of anti-TNF therapy (n=22)

Discussion

Sexual dysfunction is an age-related problem that has a negative effect on quality of life.13 As AS mainly affects patients of sexually active age, sexual dysfunction in such patients is an important negative component of quality of life. Consistent with previous findings, we found that the majority of our male patients with AS had decreased sexual function and quality of life, despite being of socially and sexually active age.5, 6

To our knowledge, no previous study has evaluated treatment-related improvements in sexual dysfunction in AS patients. Thus, our study is the first to show that anti-TNF-α therapy could improve sexual dysfunction in male AS patients. We found that 3 months of anti-TNF-α therapy significantly improved disease activity, quality of life and sexual dysfunction (including EF) in male patients with active AS. The analysis of the correlation between BASDAI and sexual function indicated that treatment-associated changes in the BASDAI may partly explain the improvements in the sexual function.

Ankylosing spondylitis is a chronic inflammatory disease, in which TNF-α acts as an important inflammatory mediator.7 TNF-α may also have an important role in ED. For example, in patients with chronic obstructive pulmonary disease, serum TNF-α concentration, a marker of systemic inflammatory status, was significantly higher in patients with moderate-to-severe ED than in those with mild to moderate ED.14 In addition, expression of phosphodiesterase type 5, which hydrolyzes cGMP, was shown to be upregulated by nicotine and TNF-α, with the latter normalized by sildenafil, a phosphodiesterase type 5 inhibitor, suggesting that TNF-α and nicotine may blunt the pro-erectile action of nitric oxide.15

This observational study had several limitations, including the small number of patients and the short treatment duration. As this study was designed as a pilot study to evaluate reversibility of sexual dysfunction as an important component of health-related quality of life and the effectiveness of anti-TNF-α agents on sexual dysfunction, we enrolled consecutive patients who were being treated with our routine treatment protocol for AS indicated by the National Health Insurance program of Korea. In this protocol, 3 months of treatment with sulfasalzine and non-steroidal anti-inflammatory drugs was required before the trial of an anti-TNF-α agent. Most studies investigating treatments for ED had shown some improvements in placebo arm. It is possible that placebo response affected results in this study. Absence of placebo arm was another limitation of this study. However, there were some major difference between this study and most ED trials. First, we enrolled patients with AS, regardless of their sexual function, in whom anti-TNF therapy was indicated because their disease activity was not controlled by conventional treatments. Second, patients in this study received anti-TNF agents for their AS, not for their ED. There was no known effect of anti-TNF agents on sexual function, and they were not informed about any association of their treatment (or disease) and sexual function. Thus, it is unlikely that patients expected that anti-TNF therapy for AS may improve their sexual function. We also have results that 8 male patients with AS treated with sulfasalazine and non-steroidal anti-inflammatory drugs showed no significant improvement in all IIEF domain scores although significant improvement in their disease activity after 3 months of treatments (unpublished data). These results also suggest that placebo response might not be significant in this study.

Our results also suggest that sexual dysfunction in male patients with AS may be reversed with appropriate treatment, as can other indicators of quality of life. It is not clear, however, whether the improvements in sexual function were because of improvements in disease activity and quality of life or arose from direct therapeutic effects of anti-TNF agents, which block the adverse effects of TNF-α on sexual function.

In conclusion, we have shown here that anti-TNF-α therapy significantly improved sexual dysfunction as well as disease activity (measured by BASDAI) and health-related quality of life (RAND 36 item Health Survey 1.0) in male patients with active AS. Improvements in IS domain of the IIEF was significantly correlated with improvements in BASDAI. Studies in larger numbers of patients with longer-term follow up are needed to confirm these results and to evaluate whether these responses will be maintained both during and after treatment.

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1

    van der Linden SM, Valkenburg HA, de Jongh BM, Cats A . The risk of developing ankylosing spondylitis in HLA-B27 positive individuals. A comparison of relatives of spondylitis patients with the general population. Arthritis Rheum 1984; 27: 241–249.

  2. 2

    Boonen A, Chorus A, Miedema H, van der Heijde D, van der Tempel H, van der Linden S . Employment, work disability, and work days lost in patients with ankylosing spondylitis: a cross sectional study of Dutch patients. Ann Rheum Dis 2001; 60: 353–358.

  3. 3

    Ward MM . Health-related quality of life in ankylosing spondylitis: a survey of 175 patients. Arthritis Care Res 1999; 12: 247–255.

  4. 4

    Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, Calin A . A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J Rheumatol 1994; 21: 2286–2291.

  5. 5

    Pirildar T, Muezzinoglu T, Pirildar S . Sexual function in ankylosing spondylitis: a study of 65 men. J Urol 2004; 171: 1598–1600.

  6. 6

    Dincer U, Cakar E, Kiralp MZ, Dursun H . Assessment of sexual dysfunction in male patients with ankylosing spondylitis. Rheumatol Int 2007; 27: 561–566.

  7. 7

    Gorman JD, Sack KE, Davis Jr JC . Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor alpha. N Engl J Med 2002; 346: 1349–1356.

  8. 8

    van der Linden S, Valkenburg HA, Cats A . Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum 1984; 27: 361–368.

  9. 9

    Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A . The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 1997; 49: 822–830.

  10. 10

    Chung TG, Lee TK, Chung S, Lee MS, Kim YS, Ahn TY . The Korean version of the international index of erectile function(IIEF): Reliability and Validation Study. Korean J Urol 1999; 40: 1334–1343.

  11. 11

    Hays RD, Morales LS . The RAND-36 measure of health-related quality of life. Ann Med 2001; 33: 350–357.

  12. 12

    Han CW, Lee EJ, Iwaya T, Kataoka H, Kohzuki M . Development of the Korean version of Short-Form 36-Item Health Survey: health related QOL of healthy elderly people and elderly patients in Korea. Tohoku J Exp Med 2004; 203: 189–194.

  13. 13

    Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB . Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994; 151: 54–61.

  14. 14

    Karadag F, Ozcan H, Karul AB, Ceylan E, Cildag O . Correlates of erectile dysfunction in moderate-to-severe chronic obstructive pulmonary disease patients. Respirology (Carlton, Vic) 2007; 12: 248–253.

  15. 15

    Hotston MR, Jeremy JY, Bloor J, Koupparis A, Persad R, Shukla N . Sildenafil inhibits the up-regulation of phosphodiesterase type 5 elicited with nicotine and tumour necrosis factor-alpha in cavernosal vascular smooth muscle cells: mediation by superoxide. BJU Int 2007; 99: 612–618.

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Correspondence to B Yoo.

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Keywords

  • ankylosing spondylitis
  • sexual dysfunction
  • tumor necrosis factor-α

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