title: Degree of TNF-α/IL-10 cytokine elevation correlates with IVF success rates in women undergoing treatment with Adalimumab (Humira) and IVIG.
abstract: OBJECTIVE
  In this retrospective observational study, we investigate whether the degree of preconception cytokine elevation predicts the risk of IVF failure.
  
  
  METHODS
  Seventy-six women undergoing fresh IVF/ICSI cycles (≤41 years, good responders with ≥5 embryos on day 3, each with ≥5 cells with a normal endometrium) and preconception tumor necrosis factor (TNF)-α/IL-10 cytokine elevation [PMA/ionomycin stimulated CD3(+) CD8(-) ; TNF-α/IL-10 ratio above 30.6 (normal range 13.2-30.6)] were retrospectively evaluated. This high cytokine population was divided into two subgroups. Group I included 39 women with severe preconception and pre-treatment TNF-α/IL-10 cytokine elevation >39.0 (mean 47.5 ± 7.5 pre-treatment, mean 31.5 ± 9.4 post-treatment) treated with preconception Adalimumab (Humira(®) ) and intravenous immunoglobulin (IVIG). Group II included 37 women with a moderate TNF-α/IL-10 ratio >30.6 and ≤39.0 (mean 35.2 ± 2.2 pre-treatment, mean 28.8 ± 8.5 post-treatment) treated with preconception Adalimumab and IVIG. Groups I and II were comparable in relation to baseline IVF characteristics and patient history.
  
  
  RESULTS
  The implantation rate (number of gestational sacs per embryo transfer, with an average of two embryos transferred per cycle) was 43% (36/83) for Group I and 56% (44/78) for Group II. The clinical pregnancy rate (fetal heart activity per IVF cycle started) was 67% (26/39) for Group I and 73% (27/37) for Group II. The delivery rate was 56% (22/39) for Group I and 68% (25/37) for Group II. The live birthrate per embryo transferred was 36% (30/83) for Group I and 45% (35/78) for Group II. Comparing Groups I and II, there was non-significant increase in implantation rate, clinical pregnancy rate, delivery rate, and live birthrate per embryo transferred (P = 0.1, 0.6, 0.4, and 0.3, respectively). However, when the subgroup with the least optimal cytokine conditions (Group I with inadequate cytokine suppression) was compared to the subgroup with the most optimal cytokine conditions (Group II with adequate cytokine suppression), the increase in implantation rate reached statistical significance [41% (19/46) to 64% (29/45); P = 0.04]. The reduction in TNF-α/IL-10 ratio following immunotherapy was highly significant (P < 0.0001).
  
  
  CONCLUSIONS
  The degree of preconception TNF/IL-10 elevation may correlate with an increased risk of IVF failure. Elevated TNF-α/IL-10 ratios can be corrected with therapy. It may be possible to improve IVF success rates by modulating high cytokine levels. Although our pilot database is small, the trends in the data are consistent and compelling. Larger studies are needed for confirmation.
authors.affiliation: Laboratory for Reproductive Medicine and Immunology, San Francisco, CA 94111, USA. ewinger@sbcglobal.net
authors.forename: Edward E
authors.initials: EE
authors.lastname: Winger
authors.forename: Jane L
authors.initials: JL
authors.lastname: Reed
authors.forename: Sherif
authors.initials: S
authors.lastname: Ashoush
authors.forename: Tarek
authors.initials: T
authors.lastname: El-Toukhy
authors.forename: Sapha
authors.initials: S
authors.lastname: Ahuja
authors.forename: Mohamed
authors.initials: M
authors.lastname: Taranissi
mesh_terms: D000068879:Adalimumab; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D005260:Female; D005307:Fertilization in Vitro / Q000187:drug effects*; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000494:pharmacology; D007247:Infertility, Female / Q000276:immunology* / Q000628:therapy; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012189:Retrospective Studies; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D058408:Th1-Th2 Balance / Q000187:drug effects; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016756:Immunoglobulins, Intravenous; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D000068879:Adalimumab