Tumor necrosis factor inhibitors as therapeutic agents for recurrent spontaneous abortion (Review)

Wu,Hong; You,Qingxia; Jiang,Yi; Mu,Fangxiang

doi:10.3892/mmr.2021.12487

Tumor necrosis factor inhibitors as therapeutic agents for recurrent spontaneous abortion (Review)

Authors:
- Hong Wu
- Qingxia You
- Yi Jiang
- Fangxiang Mu
View Affiliations

Affiliations: Department of Integrated TCM and Western Medicine, Southwest Hospital, Army Medical University, Chongqing 400038, P.R. China, Department of Reproductive Medicine, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
Published online on: October 11, 2021 https://doi.org/10.3892/mmr.2021.12487
Article Number: 847

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Recurrent spontaneous abortion (RSA) is a troublesome pregnancy disorder that manifests as sequential early pregnancy losses; its causes are diverse and complex. Among the known possible causes of RSA, the development of an immune disorder in response to the embryo appears to be the most pronounced. The imbalance between immune rejection and immune tolerance contributes to pregnancy loss in females with RSA, wherein the abnormal ratio of T helper (Th)1 cell‑related cytokines [predominantly tumor necrosis factor (TNF)‑α] and Th2 cell‑related cytokines is a strong risk factor for RSA. TNF‑α is a pro‑inflammatory cytokine and TNF inhibitors have been effective in the treatment of various autoimmune diseases, such as ankylosing spondylitis, and inflammatory diseases, such as ulcerative colitis. Based on their immunomodulatory properties, TNF inhibitors have been used in the treatment of RSA to reduce the immune rejection rate and improvement in pregnancy outcomes has been observed in females suffering from RSA who were treated with TNF inhibitors. The aim of the present review was to interpret the involvement of TNF‑α in the immunological disorder underlying RSA and summarize the clinical outcomes of TNF inhibitor treatment in patients with RSA.

View Figures

View References

1	Toth B, Vomstein K, Togawa R, Böttcher B, Hudalla H, Strowitzki T, Daniel V and Kuon RJ: The impact of previous live births on peripheral and uterine natural killer cells in patients with recurrent miscarriage. Reprod Biol Endocrinol. 17:722019. View Article : Google Scholar
2	Ozkan ZS, Deveci D, Simsek M, Ilhan F, Risvanli A and Sapmaz E: What is the impact of SOCS3, IL-35 and IL17 in immune pathogenesis of recurrent pregnancy loss? J Matern Fetal Neonatal Med. 28:324–328. 2015. View Article : Google Scholar
3	Pei CZ, Kim YJ and Baek KH: Pathogenetic factors involved in recurrent pregnancy loss from multiple aspects. Obstet Gynecol Sci. 62:212–223. 2019. View Article : Google Scholar
4	Ou H and Yu Q: Efficacy of aspirin, prednisone, and multivitamin triple therapy in treating unexplained recurrent spontaneous abortion: A cohort study. Int J Gynaecol Obstet. 148:21–26. 2020. View Article : Google Scholar
5	Alijotas-Reig J, Esteve-Valverde E, Ferrer-Oliveras R, Llurba E and Gris JM: Tumor Necrosis Factor-Alpha and pregnancy: Focus on biologics. An updated and comprehensive review. Clin Rev Allergy Immunol. 53:40–53. 2017. View Article : Google Scholar
6	Siwetz M, Blaschitz A, El-Heliebi A, Hiden U, Desoye G, Huppertz B and Gauster M: TNF-alpha alters the inflammatory secretion profile of human first trimester placenta. Lab Invest. 96:428–438. 2016. View Article : Google Scholar
7	Saito S, Nakashima A, Shima T and Ito M: Th1/Th2/Th17 and regulatory T-cell paradigm in pregnancy. Am J Reprod Immunol. 63:601–610. 2010. View Article : Google Scholar
8	Jerzak M, Ohams M, Gorski A and Baranowski W: Etanercept immunotherapy in women with a history of recurrent reproductive failure. Ginekol Pol. 83:260–264. 2012.
9	Fu J, Li L, Qi L and Zhao L: A randomized controlled trial of etanercept in the treatment of refractory recurrent spontaneous abortion with innate immune disorders. Taiwan J Obstet Gynecol. 58:621–625. 2019. View Article : Google Scholar
10	Winger EE and Reed JL: Treatment with tumor necrosis factor inhibitors and intravenous immunoglobulin improves live birth rates in women with recurrent spontaneous abortion. Am J Reprod Immunol. 60:8–16. 2008. View Article : Google Scholar
11	Sills ES, Walsh DJ, Shkrobot LV, Palermo GD and Walsh AP: Clinical experience with intravenous immunoglobulin and tnf-a inhibitor therapies for recurrent pregnancy loss. Ulster Med J. 78:57–58. 2009.
12	Sills ES, Perloe M, Tucker MJ, Kaplan CR and Palermo GD: Successful ovulation induction, conception, and normal delivery after chronic therapy with etanercept: A recombinant fusion anti-cytokine treatment for rheumatoid arthritis. Am J Reprod Immunol. 46:366–368. 2001. View Article : Google Scholar
13	Renaud SJ, Cotechini T, Quirt JS, Macdonald-Goodfellow SK, Othman M and Graham CH: Spontaneous pregnancy loss mediated by abnormal maternal inflammation in rats is linked to deficient uteroplacental perfusion. J Immunol. 186:1799–1808. 2011. View Article : Google Scholar
14	Gelber SE, Brent E, Redecha P, Perino G, Tomlinson S, Davisson RL and Salmon JE: Prevention of defective placentation and pregnancy loss by blocking innate immune pathways in a syngeneic model of placental insufficiency. J Immunol. 195:1129–1138. 2015. View Article : Google Scholar
15	Toth B, Wurfel W, Bohlmann M, Zschocke J, Rudnik-Schöneborn S, Nawroth F, Schleußner E, Rogenhofer N, Wischmann T, von Wolff M, et al: Recurrent Miscarriage: Diagnostic and Therapeutic Procedures. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry Number 015/050). Geburtshilfe Frauenheilkd. 78:364–381. 2018. View Article : Google Scholar
16	Winger EE, Reed JL, Ashoush S, Ahuja S, El-Toukhy T and Taranissi M: Treatment with adalimumab (Humira) and intravenous immunoglobulin improves pregnancy rates in women undergoing IVF. Am J Reprod Immunol. 61:113–120. 2009. View Article : Google Scholar
17	Baines MG, Duclos AJ, Antecka E and Haddad EK: Decidual infiltration and activation of macrophages leads to early embryo loss. Am J Reprod Immunol. 37:471–477. 1997. View Article : Google Scholar
18	Garrido-Gimenez C and Alijotas-Reig J: Recurrent miscarriage: Causes, evaluation and management. Postgrad Med J. 91:151–162. 2015. View Article : Google Scholar
19	Boomsma CM, Kavelaars A, Eijkemans MJ, Lentjes EG, Fauser BC, Heijnen CJ and Macklon NS: Endometrial secretion analysis identifies a cytokine profile predictive of pregnancy in IVF. Hum Reprod. 24:1427–1435. 2009. View Article : Google Scholar
20	Guo Z, Xu Y, Zheng Q, Liu Y and Liu X: Analysis of chromosomes and the T helper 17 and regulatory T cell balance in patients with recurrent spontaneous abortion. Exp Ther Med. 19:3159–3166. 2020.
21	Quenby S and Farquharson R: Uterine natural killer cells, implantation failure and recurrent miscarriage. Reprod Biomed Online. 13:24–28. 2006. View Article : Google Scholar
22	Lash GE and Bulmer JN: Do uterine natural killer (uNK) cells contribute to female reproductive disorders? J Reprod Immunol. 88:156–164. 2011. View Article : Google Scholar
23	Tuckerman E, Laird SM, Prakash A and Li TC: Prognostic value of the measurement of uterine natural killer cells in the endometrium of women with recurrent miscarriage. Hum Reprod. 22:2208–2213. 2007. View Article : Google Scholar
24	Tuckerman E, Mariee N, Prakash A, Li TC and Laird S: Uterine natural killer cells in peri-implantation endometrium from women with repeated implantation failure after IVF. J Reprod Immunol. 87:60–66. 2010. View Article : Google Scholar
25	Shimada S, Kato EH, Morikawa M, Iwabuchi K, Nishida R, Kishi R, Onoé K, Minakami H and Yamada H: No difference in natural killer or natural killer T-cell population, but aberrant T-helper cell population in the endometrium of women with repeated miscarriage. Hum Reprod. 19:1018–1024. 2004. View Article : Google Scholar
26	Manaster I and Mandelboim O: The unique properties of human NK cells in the uterine mucosa. Placenta. 29 (Suppl A):S60–S66. 2008. View Article : Google Scholar
27	Manaster I, Mizrahi S, Goldman-Wohl D, Sela HY, Stern-Ginossar N, Lankry D, Gruda R, Hurwitz A, Bdolah Y, Haimov-Kochman R, et al: Endometrial NK cells are special immature cells that await pregnancy. J Immunol. 181:1869–1876. 2008. View Article : Google Scholar
28	Kopcow HD, Allan DS, Chen X, Rybalov B, Andzelm MM, Ge B and Strominger JL: Human decidual NK cells form immature activating synapses and are not cytotoxic. Proc Natl Acad Sci USA. 102:15563–15568. 2005. View Article : Google Scholar
29	Guimond MJ, Wang B and Croy BA: Engraftment of bone marrow from severe combined immunodeficient (SCID) mice reverses the reproductive deficits in natural killer cell-deficient tg epsilon 26 mice. J Exp Med. 187:217–223. 1998. View Article : Google Scholar
30	Rai R, Sacks G and Trew G: Natural killer cells and reproductive failure-theory, practice and prejudice. Hum Reprod. 20:1123–1126. 2005. View Article : Google Scholar
31	Quenby S, Vince G, Farquharson R and Aplin J: Recurrent miscarriage: A defect in nature's quality control? Hum Reprod. 17:1959–1963. 2002. View Article : Google Scholar
32	Nakagawa K, Kwak-Kim J, Ota K, Kuroda K, Hisano M, Sugiyama R and Yamaguchi K: Immunosuppression with tacrolimus improved reproductive outcome of women with repeated implantation failure and elevated peripheral blood TH1/TH2 cell ratios. Am J Reprod Immunol. 73:353–361. 2015. View Article : Google Scholar
33	Raghupathy R, Makhseed M, Azizieh F, Hassan N, Al-Azemi M and Al-Shamali E: Maternal Th1- and Th2-type reactivity to placental antigens in normal human pregnancy and unexplained recurrent spontaneous abortions. Cell Immunol. 196:122–130. 1999. View Article : Google Scholar
34	Darmochwal-Kolarz D, Rolinski J, Leszczynska-Goarzelak B and Oleszczuk J: The expressions of intracellular cytokines in the lymphocytes of preeclamptic patients. Am J Reprod Immunol. 48:381–386. 2002. View Article : Google Scholar
35	Kwak-Kim JYH, Gilman-Sachs A and Kim CE: T helper 1 and 2 immune responses in relationship to pregnancy, nonpregnancy, recurrent spontaneous abortions and infertility of repeated implantation failures. Chem Immunol Allergy. 88:64–79. 2005.
36	Kwak-Kim JY, Chung-Bang HS, Ng SC, Ntrivalas EI, Mangubat CP, Beaman KD, Beer AE and Gilman-Sachs A: Increased T helper 1 cytokine responses by circulating T cells are present in women with recurrent pregnancy losses and in infertile women with multiple implantation failures after IVF. Hum Reprod. 18:767–773. 2003. View Article : Google Scholar
37	Wang WJ, Hao CF, Qu QL, Wang X, Qiu LH and Lin QD: The deregulation of regulatory T cells on interleukin-17-producing T helper cells in patients with unexplained early recurrent miscarriage. Hum Reprod. 25:2591–2596. 2010. View Article : Google Scholar
38	Zelenika D, Adams E, Humm S, Lin CY, Waldmann H and Cobbold SP: The role of CD4+ T-cell subsets in determining transplantation rejection or tolerance. Immunol Rev. 182:164–179. 2001. View Article : Google Scholar
39	Zenclussen AC, Gerlof K, Zenclussen ML, Sollwedel A, Bertoja AZ, Ritter T, Kotsch K, Leber J and Volk HD: Abnormal T-cell reactivity against paternal antigens in spontaneous abortion: Adoptive transfer of pregnancy-induced CD4+CD25+ T regulatory cells prevents fetal rejection in a murine abortion model. Am J Pathol. 166:811–822. 2005. View Article : Google Scholar
40	Yan L, Zheng D and Xu RH: Critical role of tumor necrosis factor signaling in mesenchymal stem cell-based therapy for autoimmune and inflammatory diseases. Front Immunol. 9:16582018. View Article : Google Scholar
41	Gabay C, Cakir N, Moral F, Roux-Lombard P, Meyer O, Dayer JM, Vischer T, Yazici H and Guerne PA: Circulating levels of tumor necrosis factor soluble receptors in systemic lupus erythematosus are significantly higher than in other rheumatic diseases and correlate with disease activity. J Rheumatol. 24:303–308. 1997.
42	Sharief MK and Hentges R: Association between tumor necrosis factor-alpha and disease progression in patients with multiple sclerosis. N Engl J Med. 325:467–472. 1991. View Article : Google Scholar
43	Belkhelfa M, Rafa H, Medjeber O, Arroul-Lammali A, Behairi N, Abada-Bendib M, Makrelouf M, Belarbi S, Masmoudi AN, Tazir M and Touil-Boukoffa C: IFN-ү and TNF-α are involved during Alzheimer disease progression and correlate with nitric oxide production: A study in Algerian patients. J Interferon Cytokine Res. 34:839–847. 2014. View Article : Google Scholar
44	Idriss HT and Naismith JH: TNF alpha and the TNF receptor superfamily: Structure-function relationship(s). Microsc Res Tech. 50:184–195. 2000. View Article : Google Scholar
45	Clark DA: Immunological factors in pregnancy wastage: Fact or fiction. Am J Reprod Immunol. 59:277–300. 2008. View Article : Google Scholar
46	Clark DA: Anti-TNFalpha therapy in immune-mediated subfertility: State of the art. J Reprod Immunol. 85:15–24. 2010. View Article : Google Scholar
47	Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y, El-Far M, Hill BJ, Noto A, Ancuta P, Peretz Y, et al: Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nat Med. 16:452–459. 2010. View Article : Google Scholar
48	Wedekind L and Belkacemi L: Altered cytokine network in gestational diabetes mellitus affects maternal insulin and placental-fetal development. J Diabetes Complications. 30:1393–1400. 2016. View Article : Google Scholar
49	Banerjee P, Jana SK, Pasricha P, Ghosh S, Chakravarty B and Chaudhury K: Proinflammatory cytokines induced altered expression of cyclooxygenase-2 gene results in unreceptive endometrium in women with idiopathic recurrent spontaneous miscarriage. Fertil Steril. 99:179–187 e2. 2013. View Article : Google Scholar
50	Tangri S and Raghupathy R: Expression of cytokines in placentas of mice undergoing immunologically mediated spontaneous fetal resorptions. Biol Reprod. 49:850–856. 1993. View Article : Google Scholar
51	Ito K, Karasawa M, Kawano T, Akasaka T, Koseki H, Akutsu Y, Kondo E, Sekiya S, Sekikawa K, Harada M, et al: Involvement of decidual Valpha14 NKT cells in abortion. Proc Natl Acad Sci USA. 97:740–744. 2000. View Article : Google Scholar
52	Alkhuriji AF, Alhimaidi AR, Babay ZA and Wary AS: The relationship between cytokine gene polymorphism and unexplained recurrent spontaneous abortion in Saudi females. Saudi Med J. 34:484–489. 2013.
53	Aboutorabi R, Behzadi E, Sadegh MJ, Fatehi SP, Semsarzadeh S, Zarrin Y, Kazemi M, Rafiee L and Mostafavi FS: The study of association between polymorphism of TNF-α gene's promoter region and recurrent pregnancy loss. J Reprod Infertil. 19:211–218. 2018.
54	Gerriets V, Bansal P, Goyal A and Khaddour K: Tumor Necrosis Factor Inhibitors. StatPearls [Internet]. StatPearls Publishing; Treasure Island, FL: 2021
55	Wang T and He C: TNF-α and IL-6: The link between immune and bone system. Curr Drug Targets. 21:213–227. 2020. View Article : Google Scholar
56	Zhang Y, Liu H, Tang W, Qiu Q and Peng J: Resveratrol prevents TNF-α-induced VCAM-1 and ICAM-1 upregulation in endothelial progenitor cells via reduction of NF-κB activation. J Int Med Res. 48:3000605209451312020.
57	Brunner C, Seiderer J, Schlamp A, Bidlingmaier M, Eigler A, Haimerl W, Lehr HA, Krieg AM, Hartmann G and Endres S: Enhanced dendritic cell maturation by TNF-alpha or cytidine-phosphate-guanosine DNA drives T cell activation in vitro and therapeutic anti-tumor immune responses in vivo. J Immunol. 165:6278–6286. 2000. View Article : Google Scholar
58	Psarras A, Antanaviciute A, Alase A, Carr I, Wittmann M, Emery P, Tsokos GC and Vital EM: TNF-α regulates human plasmacytoid dendritic cells by suppressing IFN-α production and enhancing T cell activation. J Immunol. 206:785–796. 2021. View Article : Google Scholar
59	Conrad C, Di Domizio J, Mylonas A, Belkhodja C, Demaria O, Navarini AA, Lapointe AK, French LE, Vernez M and Gilliet M: TNF blockade induces a dysregulated type I interferon response without autoimmunity in paradoxical psoriasis. Nat Commun. 9:252018. View Article : Google Scholar
60	Falcon BJ, Cotechini T, Macdonald-Goodfellow SK, Othman M and Graham CH: Abnormal inflammation leads to maternal coagulopathies associated with placental haemostatic alterations in a rat model of foetal loss. Thromb Haemost. 107:438–447. 2012. View Article : Google Scholar
61	Dignass AU, Hartmann F, Sturm A and Stein J: Management of inflammatory bowel diseases during pregnancy. Dig Dis. 27:341–346. 2009. View Article : Google Scholar
62	Pelechas E and Drosos AA: Etanercept biosimilar SB-4. Expert Opin Biol Ther. 19:173–179. 2019. View Article : Google Scholar
63	Spencer-Green G: Etanercept (Enbrel): Update on therapeutic use. Ann Rheum Dis. 59 (Suppl 1):i46–i49. 2000. View Article : Google Scholar
64	Elliot MJ, Maini RN, Feldmann M, Long-Fox A, Charles P, Katasikis P, Brennan FM, Bijl H, Ghrayeb J and Woody JN: Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum. 58 (2 Suppl):S92–S101. 2008. View Article : Google Scholar
65	Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, Rachmilewitz D, Wolf DC, Olson A, Bao W, et al: Maintenance infliximab for Crohn's disease: The ACCENT I randomised trial. Lancet. 359:1541–1549. 2002. View Article : Google Scholar
66	Yoo DH, Prodanovic N, Jaworski J, Miranda P, Ramiterre E, Lanzon A, Baranauskaite A, Wiland P, Abud-Mendoza C, Oparanov B, et al: Efficacy and safety of CT-P13 (biosimilar infliximab) in patients with rheumatoid arthritis: Comparison between switching from reference infliximab to CT-P13 and continuing CT-P13 in the PLANETRA extension study. Ann Rheum Dis. 76:355–363. 2017. View Article : Google Scholar
67	Zheng MK, Shih DQ and Chen GC: Insights on the use of biosimilars in the treatment of inflammatory bowel disease. World J Gastroenterol. 23:1932–1943. 2017. View Article : Google Scholar
68	Deeks ED: GP2015: An etanercept biosimilar. BioDrugs. 31:555–558. 2017. View Article : Google Scholar
69	Fiorino G, Gilardi D, Correale C, Furfaro F, Roda G, Loy L, Argollo M, Allocca M, Peyrin-Biroulet L and Danese S: Biosimilars of adalimumab: The upcoming challenge in IBD. Expert Opin Biol Ther. 19:1023–1030. 2019. View Article : Google Scholar
70	Nelson AL, Dhimolea E and Reichert JM: Development trends for human monoclonal antibody therapeutics. Nat Rev Drug Discov. 9:767–774. 2010. View Article : Google Scholar
71	Deeks ED: Certolizumab pegol: A review in inflammatory autoimmune diseases. BioDrugs. 30:607–617. 2016. View Article : Google Scholar
72	Maxwell LJ, Zochling J, Boonen A, Singh JA, Veras MM, Tanjong Ghogomu E, Benkhalti Jandu M, Tugwell P and Wells GA: TNF-alpha inhibitors for ankylosing spondylitis. Cochrane Database Syst Rev CD005468. 2015. View Article : Google Scholar
73	Steeland S, Libert C and Vandenbroucke RE: A new venue of TNF targeting. Int J Mol Sci. 19:14422018. View Article : Google Scholar
74	U.S. National Library of Medicine (NIH), . A Trial With Humanized TNFα Monoclonal Antibody Injection by Single Dose and Dose Escalation in Healthy Subjects. ClinicalTrials.gov Identifier: NCT02460393. NIH; Bethesda, MD: 2015, https://clinicaltrials.gov/ct2/show/NCT02460393June 2–2015