Reproduction, Fertility and Development Reproduction, Fertility and Development Society
Vertebrate reproductive science and technology
RESEARCH ARTICLE

The effects in vitro of TNF-α and its antagonist ‘etanercept’ on ejaculated human sperm

Nicola A. Pascarelli A C , Antonella Fioravanti A , Elena Moretti B , Giacomo M. Guidelli A , Lucia Mazzi B and Giulia Collodel B

A Rheumatology Unit, Azienda Ospedaliera Universitaria Senese, Policlinico Le Scotte, Viale Bracci, 14, 53100, Siena, Italy.

B Department of Molecular and Developmental Medicine, University of Siena, Policlinico Le Scotte, Viale Bracci, 14, 53100, Siena, Italy.

C Corresponding author. Email: pascarelli@unisi.it

Reproduction, Fertility and Development - https://doi.org/10.1071/RD16090
Submitted: 16 July 2015  Accepted: 16 March 2016   Published online: 17 May 2016

Abstract

Tumour necrosis factor (TNF)-α is primarily involved in the regulation of cell proliferation and apoptosis; in addition it possesses pro-inflammatory properties. Anti-TNF-α strategies involve either administration of anti-TNF-α antibody or soluble TNF receptor to mop up circulating TNF-α. Etanercept, a recombinant human TNF-α receptor, was found to be effective in the treatment of rheumatoid arthritis. The impact of TNF-α inhibitors on human fertility is of notable interest. This in vitro study investigated the effect of different concentrations of TNF-α and etanercept used alone or in combination on sperm viability, motility, mitochondrial function, percentage of apoptosis and chromatin integrity in swim-up selected human spermatozoa. A negative effect of TNF-α (300 and 500 ng mL–1) and etanercept (from 800 µg mL–1 to 2000 µg mL–1) individually on sperm viability, motility, mitochondrial function, percentage of apoptotic spermatozoa and sperm DNA integrity was demonstrated. However, at concentrations of 100 and 200 µg mL–1, etanercept can block, in a significant way, the toxic effects of TNF-α (500 ng mL–1) on studied sperm characteristics. Our results confirm that TNF-α has a detrimental effect on sperm function and suggest, for the first time, that etanercept may counteract the in vitro toxic action of TNF-α. This data appears to be quite promising, although further studies, both in vivo and in vitro, are needed to understand the exact mechanism of action of TNF-α and TNF-α antagonists on sperm function.

Additional keywords: apoptosis, mitochondrial function.


References

Agarwal, A., Saleh, R. A., and Bedaiwy, M. A. (2003). Role of reactive oxygen species in the pathophysiology of human reproduction. Fertil. Steril. 79, 829–843.
Role of reactive oxygen species in the pathophysiology of human reproduction.CrossRef | 12749418PubMed | open url image1

Bejarano, I., Lozano, G. M., Ortiz, A., García, J. F., Paredes, S. D., Rodríguez, A. B., and Pariente, J. A. (2008). Caspase 3 activation in human spermatozoa in response to hydrogen peroxide and progesterone. Fertil. Steril. 90, 1340–1347.
Caspase 3 activation in human spermatozoa in response to hydrogen peroxide and progesterone.CrossRef | 1:CAS:528:DC%2BD1cXhtlSrurbK&md5=0bf35ee00bfa0b8ee27a53f0ee560dd0CAS | 18155705PubMed | open url image1

Bian, J., Guo, X., Xiong, C., Li, J., Tian, Y., Ma, H., Zhang, Y., Nie, Y., Yu, L., and Xiao, L. (2004). Experimental study of the effect of rhTNF-alpha on human sperm mitochondrial function and motility in vitro. Zhonghua Nan Ke Xue 10, 415–419.
| 15267202PubMed | open url image1

Blandizzi, C., Gionchetti, P., Armuzzi, A., Caporali, R., Chimenti, S., Cimaz, R., Cimino, L., Lapadula, G., Lionetti, P., Marchesoni, A., Marcellusi, A., Mennini, F. S., Salvarani, C., and Girolomoni, G. (2014). The role of tumour necrosis factor in the pathogenesis of immune-mediated diseases. Int. J. Immunopathol. Pharmacol. 27, 1–10.
| 1:STN:280:DC%2BC2cnnsl2rsQ%3D%3D&md5=d897f7f86f6cab1d6b5e9923ca456725CAS | 24774503PubMed | open url image1

Buch, J. P., Kolon, T. F., Maulik, N., Kreutzer, D. L., and Das, D. K. (1994). Cytokines stimulate lipid membrane peroxidation of human spermatozoa. Fertil. Steril. 62, 186–188.
| 1:STN:280:DyaK2c3ntlyltQ%3D%3D&md5=1a6f5a1f955dbcf9f5e56ff911a707f6CAS | 8005288PubMed | open url image1

Carrasquel, G., Camejo, M. I., Michelangeli, F., and Ruiz, M. C. (2013). Effect of tumour necrosis factor-α on the intracellular Ca2+ homeostasis in human spermatozoa. Am. J. Reprod. Immunol. 70, 153–161.
Effect of tumour necrosis factor-α on the intracellular Ca2+ homeostasis in human spermatozoa.CrossRef | 1:CAS:528:DC%2BC3sXhsVCqt7bI&md5=24f08c51203768b8451dd7abf3e2ae67CAS | 23480259PubMed | open url image1

Castiglione, R., Salemi, M., Vicari, L. O., and Vicari, E. (2014). Relationship of semen hyperviscosity with IL-6, TNF-α, IL-10 and ROS production in seminal plasma of infertile patients with prostatitis and prostato-vesiculitis. Andrologia 46, 1148–1155.
Relationship of semen hyperviscosity with IL-6, TNF-α, IL-10 and ROS production in seminal plasma of infertile patients with prostatitis and prostato-vesiculitis.CrossRef | 1:CAS:528:DC%2BC2cXhvFShs7fK&md5=837929b2be79614dabb6dbe0598500e3CAS | 24329571PubMed | open url image1

Chopra, A., and Abdel-Nasser, A. (2008). Epidemiology of rheumatic musculoskeletal disorders in the developing world. Best Pract. Res. Clin. Rheumatol. 22, 583–604.
Epidemiology of rheumatic musculoskeletal disorders in the developing world.CrossRef | 18783739PubMed | open url image1

De, S. K., Chen, H. L., Pace, J. L., Hunt, J. S., Terranova, P. F., and Enders, G. C. (1993). Expression of tumour necrosis factor-alpha in mouse spermatogenic cells. Endocrinology 133, 389–396.
| 1:CAS:528:DyaK3sXltlOit7g%3D&md5=da10ab889c088adfc2c02acc3264255eCAS | 8319585PubMed | open url image1

Eisermann, J., Register, K. B., Strickler, R. C., and Collins, J. L. (1989). The effect of tumour necrosis factor on human sperm motility in vitro. J. Androl. 10, 270–274.
The effect of tumour necrosis factor on human sperm motility in vitro.CrossRef | 1:CAS:528:DyaL1MXlsFWktrc%3D&md5=9d26c3ecbd26bdbb81b427714a016b2aCAS | 2777718PubMed | open url image1

Estrada, L. S., Champion, H. C., Wang, R., Rajasekaran, M., Hellstrom, W. J., Aggarwal, B., and Sikka, S. C. (1997). Effect of tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) on human sperm motility, viability and motion parameters. Int. J. Androl. 20, 237–242.
Effect of tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) on human sperm motility, viability and motion parameters.CrossRef | 1:CAS:528:DyaK2sXnslWqsrs%3D&md5=1c56a8d7647e05631d9124120d0665ffCAS | 9401827PubMed | open url image1

Faber, B. M., Chegini, N., Mahony, M. C., and Coddington, C. C. (2001). Macrophage secretory products and sperm zona pellucida binding. Obstet. Gynecol. 98, 668–673.
| 1:CAS:528:DC%2BD3MXntVWqsb4%3D&md5=85331332179cd1121e069273ffb98f8bCAS | 11576586PubMed | open url image1

Gallon, F., Marchetti, C., Jouy, N., and Marchetti, P. (2006). The functionality of mitochondria differentiates human spermatozoa with high and low fertilising capability. Fertil. Steril. 86, 1526–1530.
The functionality of mitochondria differentiates human spermatozoa with high and low fertilising capability.CrossRef | 16996512PubMed | open url image1

Gillan, L., Evans, G., and Maxwell, W. M. (2005). Flow cytometric evaluation of sperm parameters in relation to fertility potential. Theriogenology 63, 445–457.
Flow cytometric evaluation of sperm parameters in relation to fertility potential.CrossRef | 15626410PubMed | open url image1

Goffe, B. (2004). Etanercept (Enbrel) – an update. Skin Therapy Lett. 9, 1–4, 9.
| 1:STN:280:DC%2BD2M%2Fjt1emtA%3D%3D&md5=a7e6385aaa4a9e558ac6871502f249b1CAS | 15657632PubMed | open url image1

Grattendick, K. J., Nakashima, J. M., Feng, L., Giri, S. N., and Margolin, S. B. (2008). Effects of three anti-TNF-α drugs: etanercept, infliximab and pirfenidone on release of TNF-α in medium and TNF-α associated with the cell in vitro. Int. Immunopharmacol. 8, 679–687.
Effects of three anti-TNF-α drugs: etanercept, infliximab and pirfenidone on release of TNF-α in medium and TNF-α associated with the cell in vitro.CrossRef | 1:CAS:528:DC%2BD1cXktlCqurs%3D&md5=c3ba8e3fceff1aec953cba27be7bdeb5CAS | 18387510PubMed | open url image1

Gruschwitz, M. S., Brezinschek, R., and Brezinschek, H. P. (1996). Cytokine levels in the seminal plasma of infertile males. J. Androl. 17, 158–163.
| 1:STN:280:DyaK28zgtlehug%3D%3D&md5=5f177e40fa06df04d8bab356e095baceCAS | 8723440PubMed | open url image1

Guazzone, V. A., Jacobo, P., Theas, M. S., and Lustig, L. (2009). Cytokines and chemokines in testicular inflammation: a brief review. Microsc. Res. Tech. 72, 620–628.
Cytokines and chemokines in testicular inflammation: a brief review.CrossRef | 1:CAS:528:DC%2BD1MXhtVOnurjJ&md5=05109a385a05f8c8868a8410183d3e1fCAS | 19263422PubMed | open url image1

Haidl, F., Haidl, G., Oltermann, I., and Allam, J. P. (2015). Seminal parameters of chronic male genital inflammation are associated with disturbed sperm DNA integrity. Andrologia 47, 464–469.
Seminal parameters of chronic male genital inflammation are associated with disturbed sperm DNA integrity.CrossRef | 1:CAS:528:DC%2BC2MXlvV2hurs%3D&md5=8477685bbc6ac3b0ab5d1492f493095aCAS | 25708510PubMed | open url image1

Havrylyuk, A., Chopyak, V., Boyko, Y., Kril, I., and Kurpisz, M. (2015). Cytokines in the blood and semen of infertile patients. Cent. Eur. J. Immunol. 40, 337–344.
Cytokines in the blood and semen of infertile patients.CrossRef | 26648778PubMed | open url image1

Hedger, M. P., and Meinhardt, A. (2003). Cytokines and the immune–testicular axis. J. Reprod. Immunol. 58, 1–26.
Cytokines and the immune–testicular axis.CrossRef | 1:CAS:528:DC%2BD3sXhsVCntLo%3D&md5=61261ab71d29845d50aeacf341e5ab0fCAS | 12609522PubMed | open url image1

Hong, C. Y., Park, J. H., Ahn, R. S., Im, S. Y., Choi, H. S., Soh, J., Mellon, S. H., and Lee, K. (2004). Molecular mechanism of suppression of testicular steroidogenesis by pro-inflammatory cytokine tumour necrosis factor alpha. Mol. Cell. Biol. 24, 2593–2604.
Molecular mechanism of suppression of testicular steroidogenesis by pro-inflammatory cytokine tumour necrosis factor alpha.CrossRef | 1:CAS:528:DC%2BD2cXis1ems7s%3D&md5=449a23a5f1b6356b4e7910dc0f10f5b3CAS | 15024051PubMed | open url image1

Idriss, H. T., and Naismith, J. H. (2000). TNF-alpha and the TNF receptor superfamily: structure–function relationship(s). Microsc. Res. Tech. 50, 184–195.
TNF-alpha and the TNF receptor superfamily: structure–function relationship(s).CrossRef | 1:CAS:528:DC%2BD3cXmtVeqtbk%3D&md5=06646af758f64fc92f206a2995043916CAS | 10891884PubMed | open url image1

Jain, A., and Singh, J. A. (2013). Harms of TNF inhibitors in rheumatic diseases: a focused review of the literature. Immunotherapy 5, 265–299.
Harms of TNF inhibitors in rheumatic diseases: a focused review of the literature.CrossRef | 1:CAS:528:DC%2BC3sXjtF2qsLc%3D&md5=0f1f303373390651191b9a722f70f5cfCAS | 23444956PubMed | open url image1

Koçak, I., Yenisey, C., Dündar, M., Okyay, P., and Serter, M. (2002). Relationship between seminal plasma interleukin-6 and tumour necrosis factor alpha levels with semen parameters in fertile and infertile men. Urol. Res. 30, 263–267.
Relationship between seminal plasma interleukin-6 and tumour necrosis factor alpha levels with semen parameters in fertile and infertile men.CrossRef | 12202945PubMed | open url image1

La Montagna, G., Malesci, D., Buono, R., and Valentini, G. (2005). Asthenoazoospermia in patients receiving anti tumour necrosis factor alpha agents. Ann. Rheum. Dis. 64, 1667.
Asthenoazoospermia in patients receiving anti tumour necrosis factor alpha agents.CrossRef | open url image1

Lampiao, F., and du Plessis, S. S. (2008). TNF-alpha and IL-6 affect human sperm function by elevating nitric oxide production. Reprod. Biomed. Online 17, 628–631.
TNF-alpha and IL-6 affect human sperm function by elevating nitric oxide production.CrossRef | 1:CAS:528:DC%2BD1cXhsFektbvO&md5=fce1d2ac9f32e7f93957eeb06e3a9825CAS | 18983746PubMed | open url image1

Marchetti, C., Jouy, N., Leroy-Martin, B., Defossez, A., Formstecher, P., and Marchetti, P. (2004). Comparison of four fluorochromes for the detection of the inner mitochondrial membrane potential in human spermatozoa and their correlation with sperm motility. Hum. Reprod. 19, 2267–2276.
Comparison of four fluorochromes for the detection of the inner mitochondrial membrane potential in human spermatozoa and their correlation with sperm motility.CrossRef | 15256505PubMed | open url image1

Markatseli, T. E., Papagoras, C., Kaltsonoudis, E., Voulgari, P. V., and Drosos, A. A. (2014). Reply to the comment “Effect of Infliximab on Male Fertility” by Younis et al. Joint Bone Spine 81, 103.
Reply to the comment “Effect of Infliximab on Male Fertility” by Younis et al.CrossRef | 24439962PubMed | open url image1

Maxwell, L. J., Zochling, J., Boonen, A., Singh, J. A., Veras, M. M., Tanjong Ghogomu, E., Benkhalti Jandu, M., Tugwell, P., and Wells, G. A. (2015). TNF-alpha inhibitors for ankylosing spondylitis. Cochrane Database Syst. Rev. 4, CD005468.
| 25887212PubMed | open url image1

Micu, M. C., Micu, R., Surd, S., Gîrlovanu, M., Bolboacă, S. D., and Ostensen, M. (2014). TNF-α inhibitors do not impair sperm quality in males with ankylosing spondylitis after short-term or long-term treatment. Rheumatology 53, 1250–1255.
TNF-α inhibitors do not impair sperm quality in males with ankylosing spondylitis after short-term or long-term treatment.CrossRef | 1:CAS:528:DC%2BC2cXhtVKhsLzJ&md5=c1838877e1e442b1ecdbbb3916a952f0CAS | 24599921PubMed | open url image1

Moretti, E., Cosci, I., Spreafico, A., Serchi, T., Cuppone, A. M., and Collodel, G. (2009). Semen characteristics and inflammatory mediators in infertile men with different clinical diagnoses. Int. J. Androl. 32, 637–646.
Semen characteristics and inflammatory mediators in infertile men with different clinical diagnoses.CrossRef | 1:CAS:528:DC%2BD1MXhsFOqt7vL&md5=ba856537d7118a665fecc1ee81b85f5cCAS | 18710409PubMed | open url image1

Murdaca, G., Spanò, F., Contatore, M., Guastalla, A., Magnani, O., and Puppo, F. (2014). Efficacy and safety of etanercept in chronic immune-mediated disease. Expert Opin. Drug Saf. 13, 649–661.
Efficacy and safety of etanercept in chronic immune-mediated disease.CrossRef | 1:CAS:528:DC%2BC2cXms1Wrtb4%3D&md5=4944b125b9417ab1736fe4439bbac59dCAS | 24654562PubMed | open url image1

Nadler, R. B., Koch, A. E., Calhoun, E. A., Campbell, P. L., Pruden, D. L., Bennett, C. L., Yarnold, P. R., and Schaeffer, A. J. (2000). IL-1 beta and TNF-alpha in prostatic secretions are indicators in the evaluation of men with chronic prostatitis. J. Urol. 164, 214–218.
IL-1 beta and TNF-alpha in prostatic secretions are indicators in the evaluation of men with chronic prostatitis.CrossRef | 1:CAS:528:DC%2BD3cXksVCku7w%3D&md5=5fc23db18bd44cc4578d0bd8d4803b5fCAS | 10840462PubMed | open url image1

Nestorov, I., Zitnik, R., DeVries, T., Nakanishi, A. M., Wang, A., and Banfield, C. (2006). Pharmacokinetics of subcutaneously administered etanercept in subjects with psoriasis. Br. J. Clin. Pharmacol. 62, 435–445.
Pharmacokinetics of subcutaneously administered etanercept in subjects with psoriasis.CrossRef | 1:CAS:528:DC%2BD28Xht1ehtbvF&md5=c2ad03832b86acc8d19b37b30bee7ca8CAS | 16995864PubMed | open url image1

Nickel, J. C. (2001). Special report on prostatitis: state of the art: highlights of the Third Annual International Prostatitis Collaborative Network Meeting October 23–25, Washington, DC. Rev. Urol. 3, 94–98.
| 1:STN:280:DC%2BD28rmtVOmtA%3D%3D&md5=afc2bdb4e38b922de980f67f7a723e3fCAS | 16985696PubMed | open url image1

Noriega, J., Bedaiwy, M., Sharma, R., and Falcone, T. (2004). Effect of tumour necrosis factor-alpha blocker (infliximab) on blastocyst development in vitro. Fertil. Steril. 81, 1704–1706.
Effect of tumour necrosis factor-alpha blocker (infliximab) on blastocyst development in vitro.CrossRef | 15193503PubMed | open url image1

Østensen, M., Khamashta, M., Lockshin, M., Parke, A., Brucato, A., Carp, H., Doria, A., Rai, R., Meroni, P., Cetin, I., et al. (2006). Anti-inflammatory and immunosuppressive drugs and reproduction. Arthritis Res. Ther. 8, 209.
Anti-inflammatory and immunosuppressive drugs and reproduction.CrossRef | 16712713PubMed | open url image1

Paasch, U., Grunewald, S., Fitzl, G., and Glander, H. J. (2003). Deterioration of plasma membrane is associated with activated caspases in human spermatozoa. J. Androl. 24, 246–252.
Deterioration of plasma membrane is associated with activated caspases in human spermatozoa.CrossRef | 1:CAS:528:DC%2BD3sXmsFCmsrY%3D&md5=077a0ae3f6c9f113ef245167382c7b8bCAS | 12634312PubMed | open url image1

Paoli, D., Gallo, M., Rizzo, F., Baldi, E., Francavilla, S., Lenzi, A., Lombardo, F., and Gandini, L. (2011). Mitochondrial membrane potential profile and its correlation with increasing sperm motility. Fertil. Steril. 95, 2315–2319.
Mitochondrial membrane potential profile and its correlation with increasing sperm motility.CrossRef | 1:CAS:528:DC%2BC3MXmsFWnsL4%3D&md5=91e984c52c40b3b3ea64832da7c12c19CAS | 21507394PubMed | open url image1

Paschou, S., Voulgari, P. V., Vrabie, I. G., Saougou, I. G., and Drosos, A. A. (2009). Fertility and reproduction in male patients with ankylosing spondylitis treated with infliximab. J. Rheumatol. 36, 351–354.
| 19040305PubMed | open url image1

Pentikäinen, V., Erkkilä, K., Suomalainen, L., Otala, M., Pentikäinen, M. O., Parvinen, M., and Dunkel, L. (2001). TNF-alpha downregulates the Fas ligand and inhibits germ-cell apoptosis in the human testis. J. Clin. Endocrinol. Metab. 86, 4480–4488.
| 11549697PubMed | open url image1

Perdichizzi, A., Nicoletti, F., La Vignera, S., Barone, N., D’Agata, R., Vicari, E., and Calogero, A. E. (2007). Effects of tumour necrosis factor-α on human sperm motility and apoptosis. J. Clin. Immunol. 27, 152–162.
Effects of tumour necrosis factor-α on human sperm motility and apoptosis.CrossRef | 1:CAS:528:DC%2BD2sXitlCrsLo%3D&md5=8c1312c785584585872a4b4b5d786d1bCAS | 17308869PubMed | open url image1

Politch, J. A., Tucker, L., Bowman, F. P., and Anderson, D. J. (2007). Concentrations and significance of cytokines and other immunologic factors in semen of healthy fertile men. Hum. Reprod. 22, 2928–2935.
Concentrations and significance of cytokines and other immunologic factors in semen of healthy fertile men.CrossRef | 1:CAS:528:DC%2BD2sXht1Shu7fK&md5=ff70eb7d0599341c74d0691644927143CAS | 17855405PubMed | open url image1

Pontari, M. A. (2002). Inflammation and anti-inflammatory therapy in chronic prostatitis. Urology 60, 29–33.
Inflammation and anti-inflammatory therapy in chronic prostatitis.CrossRef | open url image1

Puchner, R., Danninger, K., Puchner, A., and Pieringer, H. (2012). Impact of TNF-blocking agents on male sperm characteristics and pregnancy outcomes in fathers exposed to TNF-blocking agents at time of conception. Clin. Exp. Rheumatol. 30, 765–767.
| 22935608PubMed | open url image1

Ramonda, R., Foresta, C., Ortolan, A., Bertoldo, A., Oliviero, F., Lorenzin, M., Pizzol, D., Punzi, L., and Garolla, A. (2014). Influence of tumour necrosis factor-α inhibitors on testicular function and semen in spondyloarthritis patients. Fertil. Steril. 101, 359–365.
Influence of tumour necrosis factor-α inhibitors on testicular function and semen in spondyloarthritis patients.CrossRef | 1:CAS:528:DC%2BC3sXitVWju7zM&md5=0dd5fc67b533235cd4d990bc29b8798bCAS | 24332378PubMed | open url image1

Rezvani, A., and Ozaras, N. (2008). Infertility improved by etanercept in ankylosing spondylitis. Indian J. Pharmacol. 40, 276–277.
Infertility improved by etanercept in ankylosing spondylitis.CrossRef | 21279185PubMed | open url image1

Said, T. M., Agarwal, A., Falcone, T., Sharma, R. K., Bedaiwy, M. A., and Li, L. (2005). Infliximab may reverse the toxic effects induced by tumour necrosis factor alpha in human spermatozoa: an in vitro model. Fertil. Steril. 83, 1665–1673.
Infliximab may reverse the toxic effects induced by tumour necrosis factor alpha in human spermatozoa: an in vitro model.CrossRef | 1:CAS:528:DC%2BD2MXmt1Wlurs%3D&md5=05b5d3bfff3768dbee751aa60c7334b4CAS | 15950634PubMed | open url image1

Saougou, I., Markatseli, T. E., Papagoras, C., Kaltsonoudis, E., Voulgari, P. V., and Drosos, A. A. (2013). Fertility in male patients with sieronegative spondyloartropathies treated with infliximab. Joint Bone Spine 80, 34–37.
Fertility in male patients with sieronegative spondyloartropathies treated with infliximab.CrossRef | 1:CAS:528:DC%2BC38Xnt1Cht7c%3D&md5=8afe6df8ca14f44aca4b5f7d425e30cbCAS | 22575067PubMed | open url image1

Sarkar, O., Bahrainwala, J., Chandrasekaran, S., Kothari, S., Mathur, P. P., and Agarwal, A. (2011). Impact of inflammation on male fertility. Front. Biosci. 3, 89–95.
Impact of inflammation on male fertility.CrossRef | open url image1

Sfikakis, P. P. (2010). The first decade of biologic TNF antagonists in clinical practice: lessons learned, unresolved issues and future directions. Curr. Dir. Autoimmun. 11, 180–210.
The first decade of biologic TNF antagonists in clinical practice: lessons learned, unresolved issues and future directions.CrossRef | 1:CAS:528:DC%2BC3cXnvFWmsb8%3D&md5=1201d123adc2e87897b3340b95e22c6aCAS | 20173395PubMed | open url image1

Siebert, S., Tsoukas, A., Robertson, J., and McInnes, I. (2015). Cytokines as therapeutic targets in rheumatoid arthritis and other inflammatory diseases. Pharmacol. Rev. 67, 280–309.
Cytokines as therapeutic targets in rheumatoid arthritis and other inflammatory diseases.CrossRef | 1:CAS:528:DC%2BC2MXlsFSjtbg%3D&md5=bafa4d2ece7e51592e2d08af56800f36CAS | 25697599PubMed | open url image1

Suominen, J. S., Wang, Y., Kaipia, A., and Toppari, J. (2004). Tumour necrosis factor-alpha (TNF-alpha) promotes cell survival during spermatogenesis, and this effect can be blocked by infliximab, a TNF-alpha antagonist. Eur. J. Endocrinol. 151, 629–640.
Tumour necrosis factor-alpha (TNF-alpha) promotes cell survival during spermatogenesis, and this effect can be blocked by infliximab, a TNF-alpha antagonist.CrossRef | 1:CAS:528:DC%2BD2cXhtVGlurzN&md5=6cae101ee0d8b496eab69708614010d5CAS | 15538942PubMed | open url image1

Tejada, R. I., Mitchell, J. C., Norman, A., Marik, J. J., and Friedman, S. (1984). A test for the practical evaluation of male fertility by acridine orange (AO) fluorescence. Fertil. Steril. 42, 87–91.
| 1:STN:280:DyaL2c3gvV2quw%3D%3D&md5=0bbf7f7371c111bb9143413da88f4488CAS | 6724015PubMed | open url image1

Villiger, P. M., Caliezi, G., Cottin, V., Förger, F., Senn, A., and Østensen, M. (2010). Effects of TNF antagonists on sperm characteristics in patients with spondyloarthritis. Ann. Rheum. Dis. 69, 1842–1844.
Effects of TNF antagonists on sperm characteristics in patients with spondyloarthritis.CrossRef | 1:CAS:528:DC%2BC3cXhtlems7jM&md5=055766785b950e2ba3d2e82810e78612CAS | 20610443PubMed | open url image1

Wildi, L. M., and Haraoui, B. (2012). Reversible male infertility under treatment with an anti-TNF-α agent: a case report. Ann. Rheum. Dis. 71, 473–474.
Reversible male infertility under treatment with an anti-TNF-α agent: a case report.CrossRef | 1:CAS:528:DC%2BC38Xlt1Wlsb8%3D&md5=b70a504420215c7d947f16c6e93bed06CAS | 22138196PubMed | open url image1

World Health Organization (2010) ‘WHO Laboratory Manual for the Examination and Processing of Human Semen’. 5th edn. (WHO Press: Geneva.)

Xixi, M. A., and Shengoqian, X. U. (2013). TNF inhibitor therapy for rheumatoid arthritis. Biomed. Rep. 1, 177–184. open url image1

Younis, S., Rimar, D., Slobodin, G., Boulman, N., Rozenbaum, M., and Rosner, I. (2014). Effect of infliximab on male fertility: comment on the article “Fertility in male patients with seronegative spondyloarthropathies treated with infliximab” by Saougou et al., Joint Bone Spine 2013;80, 34–37. Joint Bone Spine 81, 102–103.
Effect of infliximab on male fertility: comment on the article “Fertility in male patients with seronegative spondyloarthropathies treated with infliximab” by Saougou et al., Joint Bone Spine 2013;80, 34–37.CrossRef | 1:CAS:528:DC%2BC3sXhvF2rsb%2FM&md5=d37d3f4e074dabdad2fd3fdaf806e2f8CAS | 24331412PubMed | open url image1



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