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Fertility in male patients with seronegative spondyloarthropathies treated with infliximab
Joint Bone Spine 80 (2013) 34–37
Available online at
www.sciencedirect.com
Original article
Fertility in male patients with seronegative spondyloarthropathies treated with infliximab Ioanna Saougou , Theodora E. Markatseli , Charalampos Papagoras , Evripidis Kaltsonoudis , Paraskevi V. Voulgari , Alexandros A. Drosos ∗,1 Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, 45110 Ioannina, Greece
a r t i c l e
i n f o
Article history: Accepted 12 March 2012 Available online 9 May 2012 Keywords: Spondyloarthropathies Ankylosing spondylitis Psoriatic arthritis Infliximab Male fertility
a b s t r a c t Objectives: The majority of patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are affected during their peak reproductive years. Tumor necrosis factor (TNF)␣ plays a pivotal role in the pathogenesis of both diseases. Today, anti-TNF␣ blockers are an essential treatment for these patients. To identify male patients who achieved pregnancy development during their management with anti-TNF␣ blockers (infliximab). Methods: We reviewed the data of 65 patients with AS and 30 patients with PsA who were followed-up in our rheumatology outpatients clinic and they were on infliximab therapy between January 2001 and December 2010. Results: We identified overall seven male patients with AS and three male patients with PsA who had fathered 14 healthy infants. Moreover, we recognized one man with PsA who was on infliximab and on concomitant therapy with MTX at the time of conception, whose wife had to proceed to therapeutic abortion due to congenital abnormalities of the fetus (hydrocephalia), while she was on the first trimester of pregnancy. Conclusions: We described male patients with AS and PsA who demonstrated no fertility problems while they were on infliximab treatment. The data designated in this report provide some supportive evidence for the safe use of infliximab in male patients who are affected of those inflammatory diseases during their peak reproductive years. © 2012 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction The majority of patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are affected during their peak reproductive years [1–7]. The fertility status and sexual function of patients with AS have been explored in several studies and controversial results have been obtained [8–10]. In testis, tumor necrosis factor (TNF)␣ is produced by germ cells and it has a role in the regulation of spermatogenesis [11]. TNF␣ levels are usually low in seminal plasma, but they tend to increase in inflammatory and infectious diseases. Spermatozoa exposed to pathological concentrations of TNF␣ can result in significant loss of their functional and genomic integrity [12]. TNF␣ blockers are indicated for the treatment of rheumatoid arthritis, Crohn’s disease, AS, PsA, psoriasis and ulcerative colitis [13–15]. Infliximab, a chimeric IgG1 monoclonal antibody against TNF␣ is pregnancy category B according to the US Food and Drug
Administration Classification. A growing body of evidence supports the notion that infliximab is low risk in pregnancy [16,17]. However, more recently data on anti-TNF␣ use in pregnancy from 1999 to date have been published [18]. According to these data, congenital abnormalities were observed in 7 to 10% of children born to mothers taking anti-TNF␣ antagonists whilst pregnant. Increasingly, men with spondyloarthropathies (SpAs) are concerned about fertility and other issues of reproductive health. Limited data have been published concerning the effects of infliximab on semen quality [19] and, thus, fertility and the reproductive ability. We have previously reported four cases of male patients with AS who were treated with infliximab and had fathered healthy infants while they were on therapy with infliximab [20]. In this report, we describe seven additional patients who achieved pregnancy development during their disease management with infliximab.
2. Methods ∗ Corresponding author. Tel.: +30 265 100 7503; fax: +30 265 100 7054. E-mail address: [email protected] (A.A. Drosos). 1 www.rheumatology.gr.
We reviewed the data of 65 male patients with AS according to the modified New York criteria [21] and 30 male patients with
1297-319X/$ – see front matter © 2012 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2012.03.004
I. Saougou et al. / Joint Bone Spine 80 (2013) 34–37
PsA according to the European Spondylarthropathy Study Group criteria [22] who were on infliximab therapy between January 2001 and December 2010. They were given infliximab (5 mg/kg body weight) intravenously at weeks 0, 2, 6 and every 8 weeks thereafter. If the clinical response was insufficient, the interval between the infusions was shortened to 6 weeks. We contacted all patients to ask for pregnancies, the conceptions of which had been made while on infliximab. As regards patients who were still on infliximab therapy at the time of the present study, we interviewed them at their visit for the scheduled infusion of infliximab therapy. We contacted with patients who had discontinued infliximab by phone. In case of a report of pregnancy of the partner, data concerning concomitant therapy at conception as well as details of pregnancy outcome including live births, spontaneous abortions or pregnancy terminations were collected. Furthermore, all our patients were asked about the time interval between initiation of attempts to father a child and conception. The questions were addressed only to the patients and not to the female partner. The study was approved by the Institutional Ethics Committee and informed consent was obtained from each participant. 3. Results From a total of 95 patients with SpAs we identified overall seven men with AS and three men with PsA who had fathered 14 healthy newborns (Table 1). In particular, four patients with AS became fathers of two children each during infliximab therapy, while six more patients became fathers of one child each. Moreover, we recognized one man with PsA who was on infliximab and on concomitant therapy with methotrexate (MTX) whose wife had to proceed to therapeutic abortion due to congenital abnormalities of the fetus (hydrocephalia), while she was on the first trimester of pregnancy. It is noteworthy that our patient did not withdraw MTX during the time of conception. The mean age of these 11 patients at the time of conception was 34.1 ± 4.2 years, with mean disease duration 7.1 ± 3.6 years. All our patients were on regular follow-up and all patients were in clinical remission (mean BASDAI = 1.58).
35
Infliximab was given every 8 weeks to all our patients and the number of infusions ranged between 7 and 46 at the time of conception. Regarding fertility issues, 51 of the 95 patients (53.7%) were already parents and did not have the desire to father another child. Different types of contraception were used by them or their partners. However, among the remaining 44 patients, we did not identify anyone who had the desire to father a child but who reported inability of the couple to conceive. Of note, all 11 pregnancies, which were recorded in our group of patients, occurred in a time period no longer than 12 months from the beginning of couples’ attempts to conceive. 4. Discussion In our study, favorable pregnancy outcomes were recorded after paternal exposure to infliximab therapy. However, in male, data concerning the effects of TNF␣ blockers on spermatogenesis are scarce. In vitro studies have shown that exposing spermatozoa to pathological concentrations of TNF␣ can result in significant loss of their functional and genomic integrity, which can be reversed by infliximab [12]. Furthermore, several studies have pointed out that increased production of Th1 cytokines such as TNF␣ plus interferon is linked to infertility. This has been noticed in inflammatory conditions [23] and in urogenital infections [24] where male fertility is reduced. Another study expressed the view that anti-TNF␣ drugs may offer a new safe and effective approach to treating patients with Th1-cytokine-dependent infertility and recurrent miscarriages [25]. Moreover, animal studies suggest that sperm count and motility, fertility and reproduction remain unaffected in mice administered with analogous monoclonal antibody that selectively inhibits TNF␣ [26]. It has also been demonstrated in vitro that TNF␣ effectively and dose dependently inhibits germ cell apoptosis in human seminiferous tubules [11]. Furthermore, in rat seminiferous epithelium, this prosurvival effect can be blocked by infliximab [27]. Mahadevan et al. [19] prospectively evaluated the changes in semen quality in men receiving infliximab for inflammatory
Table 1 Characteristics of patients with SpAs who had fathered healthy children during infliximab treatment. Patient
1
Disease
Age (yr)
Disease duration, (yr)
Number of infusions during conception
Concomitant therapy at conception
BASDAI at conception
Outcome
AS
38
14
1st child: 10th
1.8
Healthy boy
40
16
2nd child: 22nd
1.2
Healthy girl
30
2
1st child: 14th
1.6
Healthy boy
32
4
2nd child: 24th
1.1
Healthy boy
0.8 1.3
Healthy boy Healthy girl
3
AS
30 34
1 5
1st child: 7th 2nd child: 24th
Methylprednizone (4 mg/day) Cyclosporine A (100 mg/d) Methylprednizone (2 mg/day) MTX (15 mg/week) MTX (15 mg/week) None None
4
AS
30 32
7 9
1st child: 27th 2nd child: 39th
None None
0.9 1.5
Healthy girl Healthy girl
5
AS
33
6
1st child: 37th
None
1.7
Healthy girl
6
AS
32
4
1st child: 14th
None
1.5
Healthy girl
7
AS
41
8
1st child: 46th
None
1.1
Healthy girl
8
PsA
36
8
1st child: 32nd
None
0.7
Healthy boy
2
AS
9
PsA
37
11
1st child: 35th
None
0.9
Healthy girl
10
PsA
29
2
1st child: 9th
None
0.8
Healthy boy
11
PsA
39
4
1st child: 12th
MTX (15 mg/week)
0.5
Therapeutic abortion
36
I. Saougou et al. / Joint Bone Spine 80 (2013) 34–37
bowel disease (IBD). A significant increase in semen volume after infliximab infusion was noted, as well as a trend towards a reduction in sperm motility. This study concluded that infliximab may affect sperm morphology as well as sperm motility and that the effect on morphology is more profound with increased exposure to infliximab. In another small study of five male patients with AS treated with anti-TNF␣, the results showed that three patients had asthenozoospermia and four patients had teratozoospermia without alterations in follicle stimulating hormone, luteinizing hormone, prolactin and testosterone levels [28]. In addition, findings from a cross-sectional study described a negative effect of anti-TNF␣ therapy on seminal parameters (volume count, oligospermia, asthenospermia, sperm morphology) with an improvement in sperm motility [29]. On the other hand, it has been reported recently that although sperm abnormalities are more common in patients with active SpA compared to healthy controls, the sperm quality of patients with inactive disease receiving long-term therapy with anti-TNF␣ agents is comparable to that in healthy controls [30]. As far as anti-TNF␣ use in pregnancy is concerned, to date there are no available data from controlled clinical trials investigating the use of infliximab during pregnancy. Data derived from several registries support the fact that rates of live births, miscarriages and therapeutic terminations do not appear to be significantly different in women exposed to the drug [16,31]. However, according to the results derived from British registry (BSRBR), an increased rate of spontaneous abortions was observed among women patients with rheumatoid arthritis exposed to anti-TNF␣ at the time of conception compared to control group [32]. Furthermore, the fact that in the 32 patients with rheumatic diseases directly exposed to anti-TNF␣ therapies during or immediately prior to pregnancy – in one study – no major congenital malformations or evidence of maternal harm was noticed, deserves a comment [33]. The fertility status and sexual function of patients with SpAs have been explored in several studies and controversial results have been obtained [8,9]. Gordon et al. [8] reported that there was no evidence of increased rate of infertility, while Onose et al. reported that patients with SpAs have a certain degree of hypogonadism [34]. As regards the pregnancy outcome after paternal exposure to infliximab, limited data have been published concerning patients with SpAs. Of note, in a recent study, infliximab therapy was more favorable at conception than other immunomodulators in male patients with inflammatory bowel disease [35]. Nevertheless, information about the effects of infliximab on male fertility is scarce as we pointed out above. In our small cohort of male patients (seven with AS and four with PsA) who were on infliximab treatment, we noticed that all pregnancies that occurred except for one had a favorable outcome. One of our patients’ wife with PsA who was on infliximab and MTX treatment at the time of conception had to proceed to therapeutic abortion due to congenital abnormalities. To our knowledge, little information is available in the literature about paternal conception under MTX and pregnancy outcomes. In several case reports as well as in the largest so far prospective series of pregnancies that was recently published [36], no congenital malformation was observed in the offspring of fathers who had been exposed to MTX at the time of conception or within 3 months before conception. However, it is recommended that men should interrupt MTX at least 3 months before attempting conception (one spermatogenic cycle) [37]. In selected cases, another option could be the semen preservation before MTX treatment. In young male cancer patients, who will undergo therapy with antineoplastic drugs, sperm cryopreservation is a main strategy for fertility preservation due to the drugs’ teratogenic and genotoxic properties [38]. Although MTX is certainly less gonadotoxic than the other chemotherapeutic agents, the above strategy could also be applied in patients with SpA in whom the risk of
infertility is high, for example males with oligospermia or other related pathological conditions. One limitation of our study is the fact that our cohort of patients is small; however, the data designated in this report provide some supportive evidence for the safe use of infliximab in male patients who are affected of these inflammatory diseases during their peak reproductive years. Another limitation is that no data were available concerning the female partner such as age, body mass index and smoking status, which are well known factors impacting on fertility. Additionally, biological data are lacking. Neither patients’ hormonal status nor semen parameters before and during the treatment with infliximab were available. This evaluation could be informative about the impact of anti-TNF␣ blockers on sperm parameters and more generally, on spermatogenesis. Thus, our conclusions regarding fertility are rather indirect. In conclusion, we described male patients with AS and PsA who demonstrated no fertility problems while they were on infliximab treatment. Nevertheless, further prospective studies are necessary to decipher the complete effects of infliximab on male fertility.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
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I. Saougou et al. / Joint Bone Spine 80 (2013) 34–37 [20] Paschou S, Voulgari PV, Vrabie IG, et al. Fertility and reproduction in male patients with ankylosing spondylitis treated with infliximab. J Rheumatol 2009;36:351–4. [21] 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;27:361–8. [22] Dougados M, van der Linden S, Juhlin R, et al. The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum 1991;34:1218–27. [23] Estrada LS, Champion HC, Wang R, et al. Effect of tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) on human sperm motility, viability and motion parameters. Int J Androl 1997;20:237–42. [24] Perdichizzi A, Nicoletti F, La Vignera S, et al. Effects of tumour necrosis factoralpha on human sperm motility and apoptosis. J Clin Immunol 2007;27: 152–62. [25] Clark DA. Anti-TNFalpha therapy in immune-mediated subfertility: state of the art. J Reprod Immunol 2010;85:15–24. [26] Treacy G. Using an analogous monoclonal antibody to evaluate the reproductive and chronic toxicity potential for a humanized anti-TNFalpha monoclonal antibody. Hum Exp Toxicol 2000;19:226–8. [27] Suominen JS, Wang Y, Kaipia A, et al. Tumor necrosis factor-alpha (TNFalpha) promotes cell survival during spermatogenesis, and this effect can be blocked by infliximab, a TNF-alpha antagonist. Eur J Endocrinol 2004;151: 629–40. [28] La Montagna G, Malesci D, Buono R, et al. Does infliximab cause spermatogenesis alterations? Arthritis Rheum 2005;52:S216. [29] Ponchietti A, Erre GL, Fenu P, et al. Effect of TNF-alpha blockers on sperm count and motility in patients with rheumatic diseases: a cross-sectional study. Ann Rheum Dis 2009;68:229.
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[30] Villiger PM, Caliezi G, Cottin V, et al. Effects of TNF antagonists on sperm characteristics in patients with spondyloarthritis. Ann Rheum Dis 2010;69:1842–4. [31] Lichtenstein GR, Feagan BG, Cohen RD, et al. Serious infections and mortality in association with therapies for Crohn’s disease: TREAT registry. Clin Gastroenterol Hepatol 2006;4:621–30. [32] Verstappen SMM, King Y, Watson KD, et al. Anti-TNF therapies and pregnancy: outcome of 130 pregnancies in the British Society for Rheumatology Biologics Register. Ann Rheum Dis 2011;70:823–6. [33] Hyrich KL, Symmons DP, Watson KD, et al. British Society, for Rheumatology Biologics Register. Pregnancy outcome in women who were exposed to anti-tumor necrosis factor agents: results from a national population register. Arthritis Rheum 2006;54:2701–2. [34] Onose G, Peret¸ianu D, Zaharescu J, et al. Correlations between spondylarthropathic inflammatory troubles and gonadal (androgenic) troubles in men. Study on 30 cases with a new methodological analysis Rom J Intern Med 1995;33:93–111. [35] Sato A, Naganuma M, Asakura K, et al. Conception outcomes and opinions about pregnancy for men with inflammatory bowel disease. J Crohns Colitis 2010;4:183–8. [36] Beghin D, Cournot MP, Vauzelle C, et al. Paternal exposure to methotrexate and pregnancy outcomes. J Rheumatol 2011;38:628–32. [37] Visser K, Katchamart W, Loza E, et al. Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative. Ann Rheum Dis 2009;68:1086–93. [38] Ajala T, Rafi J, Larsen-Disney P, et al. Fertility preservation for cancer patients: a review. Obstet Gynecol Int 2010;2010:160386.
Available online at
www.sciencedirect.com
Original article
Fertility in male patients with seronegative spondyloarthropathies treated with infliximab Ioanna Saougou , Theodora E. Markatseli , Charalampos Papagoras , Evripidis Kaltsonoudis , Paraskevi V. Voulgari , Alexandros A. Drosos ∗,1 Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, 45110 Ioannina, Greece
a r t i c l e
i n f o
Article history: Accepted 12 March 2012 Available online 9 May 2012 Keywords: Spondyloarthropathies Ankylosing spondylitis Psoriatic arthritis Infliximab Male fertility
a b s t r a c t Objectives: The majority of patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are affected during their peak reproductive years. Tumor necrosis factor (TNF)␣ plays a pivotal role in the pathogenesis of both diseases. Today, anti-TNF␣ blockers are an essential treatment for these patients. To identify male patients who achieved pregnancy development during their management with anti-TNF␣ blockers (infliximab). Methods: We reviewed the data of 65 patients with AS and 30 patients with PsA who were followed-up in our rheumatology outpatients clinic and they were on infliximab therapy between January 2001 and December 2010. Results: We identified overall seven male patients with AS and three male patients with PsA who had fathered 14 healthy infants. Moreover, we recognized one man with PsA who was on infliximab and on concomitant therapy with MTX at the time of conception, whose wife had to proceed to therapeutic abortion due to congenital abnormalities of the fetus (hydrocephalia), while she was on the first trimester of pregnancy. Conclusions: We described male patients with AS and PsA who demonstrated no fertility problems while they were on infliximab treatment. The data designated in this report provide some supportive evidence for the safe use of infliximab in male patients who are affected of those inflammatory diseases during their peak reproductive years. © 2012 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction The majority of patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are affected during their peak reproductive years [1–7]. The fertility status and sexual function of patients with AS have been explored in several studies and controversial results have been obtained [8–10]. In testis, tumor necrosis factor (TNF)␣ is produced by germ cells and it has a role in the regulation of spermatogenesis [11]. TNF␣ levels are usually low in seminal plasma, but they tend to increase in inflammatory and infectious diseases. Spermatozoa exposed to pathological concentrations of TNF␣ can result in significant loss of their functional and genomic integrity [12]. TNF␣ blockers are indicated for the treatment of rheumatoid arthritis, Crohn’s disease, AS, PsA, psoriasis and ulcerative colitis [13–15]. Infliximab, a chimeric IgG1 monoclonal antibody against TNF␣ is pregnancy category B according to the US Food and Drug
Administration Classification. A growing body of evidence supports the notion that infliximab is low risk in pregnancy [16,17]. However, more recently data on anti-TNF␣ use in pregnancy from 1999 to date have been published [18]. According to these data, congenital abnormalities were observed in 7 to 10% of children born to mothers taking anti-TNF␣ antagonists whilst pregnant. Increasingly, men with spondyloarthropathies (SpAs) are concerned about fertility and other issues of reproductive health. Limited data have been published concerning the effects of infliximab on semen quality [19] and, thus, fertility and the reproductive ability. We have previously reported four cases of male patients with AS who were treated with infliximab and had fathered healthy infants while they were on therapy with infliximab [20]. In this report, we describe seven additional patients who achieved pregnancy development during their disease management with infliximab.
2. Methods ∗ Corresponding author. Tel.: +30 265 100 7503; fax: +30 265 100 7054. E-mail address: [email protected] (A.A. Drosos). 1 www.rheumatology.gr.
We reviewed the data of 65 male patients with AS according to the modified New York criteria [21] and 30 male patients with
1297-319X/$ – see front matter © 2012 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2012.03.004
I. Saougou et al. / Joint Bone Spine 80 (2013) 34–37
PsA according to the European Spondylarthropathy Study Group criteria [22] who were on infliximab therapy between January 2001 and December 2010. They were given infliximab (5 mg/kg body weight) intravenously at weeks 0, 2, 6 and every 8 weeks thereafter. If the clinical response was insufficient, the interval between the infusions was shortened to 6 weeks. We contacted all patients to ask for pregnancies, the conceptions of which had been made while on infliximab. As regards patients who were still on infliximab therapy at the time of the present study, we interviewed them at their visit for the scheduled infusion of infliximab therapy. We contacted with patients who had discontinued infliximab by phone. In case of a report of pregnancy of the partner, data concerning concomitant therapy at conception as well as details of pregnancy outcome including live births, spontaneous abortions or pregnancy terminations were collected. Furthermore, all our patients were asked about the time interval between initiation of attempts to father a child and conception. The questions were addressed only to the patients and not to the female partner. The study was approved by the Institutional Ethics Committee and informed consent was obtained from each participant. 3. Results From a total of 95 patients with SpAs we identified overall seven men with AS and three men with PsA who had fathered 14 healthy newborns (Table 1). In particular, four patients with AS became fathers of two children each during infliximab therapy, while six more patients became fathers of one child each. Moreover, we recognized one man with PsA who was on infliximab and on concomitant therapy with methotrexate (MTX) whose wife had to proceed to therapeutic abortion due to congenital abnormalities of the fetus (hydrocephalia), while she was on the first trimester of pregnancy. It is noteworthy that our patient did not withdraw MTX during the time of conception. The mean age of these 11 patients at the time of conception was 34.1 ± 4.2 years, with mean disease duration 7.1 ± 3.6 years. All our patients were on regular follow-up and all patients were in clinical remission (mean BASDAI = 1.58).
35
Infliximab was given every 8 weeks to all our patients and the number of infusions ranged between 7 and 46 at the time of conception. Regarding fertility issues, 51 of the 95 patients (53.7%) were already parents and did not have the desire to father another child. Different types of contraception were used by them or their partners. However, among the remaining 44 patients, we did not identify anyone who had the desire to father a child but who reported inability of the couple to conceive. Of note, all 11 pregnancies, which were recorded in our group of patients, occurred in a time period no longer than 12 months from the beginning of couples’ attempts to conceive. 4. Discussion In our study, favorable pregnancy outcomes were recorded after paternal exposure to infliximab therapy. However, in male, data concerning the effects of TNF␣ blockers on spermatogenesis are scarce. In vitro studies have shown that exposing spermatozoa to pathological concentrations of TNF␣ can result in significant loss of their functional and genomic integrity, which can be reversed by infliximab [12]. Furthermore, several studies have pointed out that increased production of Th1 cytokines such as TNF␣ plus interferon is linked to infertility. This has been noticed in inflammatory conditions [23] and in urogenital infections [24] where male fertility is reduced. Another study expressed the view that anti-TNF␣ drugs may offer a new safe and effective approach to treating patients with Th1-cytokine-dependent infertility and recurrent miscarriages [25]. Moreover, animal studies suggest that sperm count and motility, fertility and reproduction remain unaffected in mice administered with analogous monoclonal antibody that selectively inhibits TNF␣ [26]. It has also been demonstrated in vitro that TNF␣ effectively and dose dependently inhibits germ cell apoptosis in human seminiferous tubules [11]. Furthermore, in rat seminiferous epithelium, this prosurvival effect can be blocked by infliximab [27]. Mahadevan et al. [19] prospectively evaluated the changes in semen quality in men receiving infliximab for inflammatory
Table 1 Characteristics of patients with SpAs who had fathered healthy children during infliximab treatment. Patient
1
Disease
Age (yr)
Disease duration, (yr)
Number of infusions during conception
Concomitant therapy at conception
BASDAI at conception
Outcome
AS
38
14
1st child: 10th
1.8
Healthy boy
40
16
2nd child: 22nd
1.2
Healthy girl
30
2
1st child: 14th
1.6
Healthy boy
32
4
2nd child: 24th
1.1
Healthy boy
0.8 1.3
Healthy boy Healthy girl
3
AS
30 34
1 5
1st child: 7th 2nd child: 24th
Methylprednizone (4 mg/day) Cyclosporine A (100 mg/d) Methylprednizone (2 mg/day) MTX (15 mg/week) MTX (15 mg/week) None None
4
AS
30 32
7 9
1st child: 27th 2nd child: 39th
None None
0.9 1.5
Healthy girl Healthy girl
5
AS
33
6
1st child: 37th
None
1.7
Healthy girl
6
AS
32
4
1st child: 14th
None
1.5
Healthy girl
7
AS
41
8
1st child: 46th
None
1.1
Healthy girl
8
PsA
36
8
1st child: 32nd
None
0.7
Healthy boy
2
AS
9
PsA
37
11
1st child: 35th
None
0.9
Healthy girl
10
PsA
29
2
1st child: 9th
None
0.8
Healthy boy
11
PsA
39
4
1st child: 12th
MTX (15 mg/week)
0.5
Therapeutic abortion
36
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bowel disease (IBD). A significant increase in semen volume after infliximab infusion was noted, as well as a trend towards a reduction in sperm motility. This study concluded that infliximab may affect sperm morphology as well as sperm motility and that the effect on morphology is more profound with increased exposure to infliximab. In another small study of five male patients with AS treated with anti-TNF␣, the results showed that three patients had asthenozoospermia and four patients had teratozoospermia without alterations in follicle stimulating hormone, luteinizing hormone, prolactin and testosterone levels [28]. In addition, findings from a cross-sectional study described a negative effect of anti-TNF␣ therapy on seminal parameters (volume count, oligospermia, asthenospermia, sperm morphology) with an improvement in sperm motility [29]. On the other hand, it has been reported recently that although sperm abnormalities are more common in patients with active SpA compared to healthy controls, the sperm quality of patients with inactive disease receiving long-term therapy with anti-TNF␣ agents is comparable to that in healthy controls [30]. As far as anti-TNF␣ use in pregnancy is concerned, to date there are no available data from controlled clinical trials investigating the use of infliximab during pregnancy. Data derived from several registries support the fact that rates of live births, miscarriages and therapeutic terminations do not appear to be significantly different in women exposed to the drug [16,31]. However, according to the results derived from British registry (BSRBR), an increased rate of spontaneous abortions was observed among women patients with rheumatoid arthritis exposed to anti-TNF␣ at the time of conception compared to control group [32]. Furthermore, the fact that in the 32 patients with rheumatic diseases directly exposed to anti-TNF␣ therapies during or immediately prior to pregnancy – in one study – no major congenital malformations or evidence of maternal harm was noticed, deserves a comment [33]. The fertility status and sexual function of patients with SpAs have been explored in several studies and controversial results have been obtained [8,9]. Gordon et al. [8] reported that there was no evidence of increased rate of infertility, while Onose et al. reported that patients with SpAs have a certain degree of hypogonadism [34]. As regards the pregnancy outcome after paternal exposure to infliximab, limited data have been published concerning patients with SpAs. Of note, in a recent study, infliximab therapy was more favorable at conception than other immunomodulators in male patients with inflammatory bowel disease [35]. Nevertheless, information about the effects of infliximab on male fertility is scarce as we pointed out above. In our small cohort of male patients (seven with AS and four with PsA) who were on infliximab treatment, we noticed that all pregnancies that occurred except for one had a favorable outcome. One of our patients’ wife with PsA who was on infliximab and MTX treatment at the time of conception had to proceed to therapeutic abortion due to congenital abnormalities. To our knowledge, little information is available in the literature about paternal conception under MTX and pregnancy outcomes. In several case reports as well as in the largest so far prospective series of pregnancies that was recently published [36], no congenital malformation was observed in the offspring of fathers who had been exposed to MTX at the time of conception or within 3 months before conception. However, it is recommended that men should interrupt MTX at least 3 months before attempting conception (one spermatogenic cycle) [37]. In selected cases, another option could be the semen preservation before MTX treatment. In young male cancer patients, who will undergo therapy with antineoplastic drugs, sperm cryopreservation is a main strategy for fertility preservation due to the drugs’ teratogenic and genotoxic properties [38]. Although MTX is certainly less gonadotoxic than the other chemotherapeutic agents, the above strategy could also be applied in patients with SpA in whom the risk of
infertility is high, for example males with oligospermia or other related pathological conditions. One limitation of our study is the fact that our cohort of patients is small; however, the data designated in this report provide some supportive evidence for the safe use of infliximab in male patients who are affected of these inflammatory diseases during their peak reproductive years. Another limitation is that no data were available concerning the female partner such as age, body mass index and smoking status, which are well known factors impacting on fertility. Additionally, biological data are lacking. Neither patients’ hormonal status nor semen parameters before and during the treatment with infliximab were available. This evaluation could be informative about the impact of anti-TNF␣ blockers on sperm parameters and more generally, on spermatogenesis. Thus, our conclusions regarding fertility are rather indirect. In conclusion, we described male patients with AS and PsA who demonstrated no fertility problems while they were on infliximab treatment. Nevertheless, further prospective studies are necessary to decipher the complete effects of infliximab on male fertility.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
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