title: Optimizing Anti-TNF-α Therapy: Serum Levels of Infliximab and Adalimumab Are Associated With Mucosal Healing in Patients With Inflammatory Bowel Diseases.
abstract: OBJECTIVE
  It is not clear what serum levels of anti-tumor necrosis factor are associated with reduced intestinal inflammation in patients with inflammatory bowel disease (IBD). We aimed to identify serum levels of infliximab and adalimumab associated with mucosal healing in patients with IBD and to evaluate the putative gain in control of inflammation by incremental increases in drug levels.
  
  
  METHODS
  We performed a retrospective cross-sectional study of 145 patients with IBD treated with infliximab (n = 78) or adalimumab (n = 67) at a medical center in Israel from 2009 through 2014. We collected data from colonoscopy examinations; mucosal healing was defined as simple endoscopic score of <3 or a Mayo score ≤1. These data were compared with serum levels of anti-tumor necrosis factor agents, clinical scores, and levels of C-reactive protein.
  
  
  RESULTS
  Median serum levels of infliximab and adalimumab were significantly higher in patients with mucosal healing than patients with active disease (based on endoscopy) (for infliximab, 4.3 vs 1.7 μg/mL, P = .0002; for adalimumab, 6.2 vs 3.1 μg/mL, P = .01). Levels of infliximab above 5 μg/mL (area under the curve = 0.75; P < .0001) and levels of adalimumab above 7.1 μg/mL (area under the curve = 0.7; P = .004) identified patients with mucosal healing with 85% specificity. Increasing levels of infliximab beyond 8 μg/mL produced only minimal increases in the rate of mucosal healing, whereas the association between higher level of adalimumab and increased rate of mucosal healing reached a plateau at 12 μg/mL. In patients with measurable levels of infliximab >3 μg/mL, the presence of antibodies to infliximab was associated with a lower rate of mucosal healing compared with patients with similar drug level without antibodies (16% vs 50%, respectively; P = .003).
  
  
  CONCLUSIONS
  In a retrospective study, we found significant association between serum levels of anti-tumor necrosis factor agents and level of mucosal healing. We propose that serum levels of 6-10 μg/mL for infliximab and 8-12 μg/mL for adalimumab are required to achieve mucosal healing in 80%-90% of patients with IBD, and that this could be considered as a "therapeutic window." Exceeding these levels produces only a negligible gain in proportion of patients with mucosal healing.
authors.affiliation: Department of Gastroenterology, Sheba Medical Center Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: bellageyshis@gmail.com.
authors.forename: Bella
authors.initials: B
authors.lastname: Ungar
authors.affiliation: Department of Gastroenterology, Sheba Medical Center Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Idan
authors.initials: I
authors.lastname: Levy
authors.affiliation: Department of Gastroenterology, Sheba Medical Center Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Yarden
authors.initials: Y
authors.lastname: Yavne
authors.affiliation: Department of Gastroenterology, Sheba Medical Center Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Miri
authors.initials: M
authors.lastname: Yavzori
authors.affiliation: Department of Gastroenterology, Sheba Medical Center Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Orit
authors.initials: O
authors.lastname: Picard
authors.affiliation: Department of Gastroenterology, Sheba Medical Center Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ella
authors.initials: E
authors.lastname: Fudim
authors.affiliation: Institute of Clinical Pharmacology, Sheba Medical Center Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ronen
authors.initials: R
authors.lastname: Loebstein
authors.affiliation: Israel Rambam Health Care Campus and Bruce Rappaport School of Medicine, Technion Institute of Technology, Haifa, Israel.
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Chowers
authors.affiliation: Department of Gastroenterology, Sheba Medical Center Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Rami
authors.initials: R
authors.lastname: Eliakim
authors.affiliation: Department of Gastroenterology, Sheba Medical Center Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Uri
authors.initials: U
authors.lastname: Kopylov
authors.affiliation: Department of Gastroenterology, Sheba Medical Center Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Shomron
authors.initials: S
authors.lastname: Ben-Horin
mesh_terms: D000068879:Adalimumab / Q000008:administration & dosage / Q000097:blood*; D000328:Adult; D002097:C-Reactive Protein / Q000032:analysis; D003113:Colonoscopy; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D056747:Immunomodulation; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D000069285:Infliximab / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D007413:Intestinal Mucosa / Q000473:pathology*; D007557:Israel; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D044967:Serum / Q000737:chemistry*; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; D000069285:Infliximab; D000068879:Adalimumab
keywords: Crohn’s Disease; Pharmacokinetics; Response to Therapy; Ulcerative Colitis