title: Levels of drug and antidrug antibodies are associated with outcome of interventions after loss of response to infliximab or adalimumab.
abstract: OBJECTIVE
  There is controversy about whether levels of anti-tumor necrosis factor (TNF) and antidrug antibodies (ADAs) are accurate determinants of loss of response to therapy. We analyzed the association between trough levels of anti-TNF agents or ADAs and outcomes of interventions for patients with loss of response to infliximab or adalimumab.
  
  
  METHODS
  We performed a retrospective study of pediatric and adult patients with inflammatory bowel disease and suspected loss of response to anti-TNF agents treated at medical centers throughout Israel from October 2009 through February 2013. We examined the correlation between outcomes of different interventions and trough levels of drug or ADAs during loss of response. An additional subanalysis was performed including only patients with a definite inflammatory loss of response (clinical worsening associated with increased levels of C-reactive protein or fecal calprotectin, or detection of inflammation by endoscopy, fistula discharge, or imaging studies).
  
  
  RESULTS
  Among 247 patients (42 with ulcerative colitis), there were 330 loss-of-response events (188 to infliximab and 142 to adalimumab). Trough levels of adalimumab greater than 4.5 mcg/mL and infliximab greater than 3.8 mcg/mL identified patients who failed to respond to an increase in drug dosage or a switch to another anti-TNF agent with 90% specificity; these were set as adequate trough levels. Adequate trough levels identified patients who responded to expectant management or out-of-class interventions with more than 75% specificity. Levels of antibodies against adalimumab >4 microgram per mL equivalent (mcg/mL-eq) or antibodies against infliximab >9 mcg/mL-eq identified patients who did not respond to an increased drug dosage with 90% specificity. Patients with high titers of ADAs had longer durations of response when anti-TNF agents were switched than when dosage was increased (P = .03; log-rank test), although dosage increases were more effective for patients with no or low titers of ADAs (P = .02). An analysis of definite inflammatory loss-of-response events (n = 244) produced similar results; patients with adequate trough levels had a longer duration of response when they switched to a different class of agent than when anti-TNF was optimized by either a dosage increase or by a switch within the anti-TNF class (P = .002; log-rank test).
  
  
  CONCLUSIONS
  The results of this retrospective analysis suggest that trough levels of drug or ADAs may guide therapeutic decisions for more than two-thirds of inflammatory bowel disease patients with either clinically suspected or definite inflammatory loss of response to therapy.
authors: Inflammatory Bowel Disease Center, Department of Gastroenterology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors: Henit
authors: H
authors: Yanai
authors: Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Rabin Medical Center, Petah Tiqva, Israel.
authors: Lev
authors: L
authors: Lichtenstein
authors: Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Institute for Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center, Petah Tiqva, Israel.
authors: Amit
authors: A
authors: Assa
authors: Rambam Health Care Campus and Bruce Rappaport School of Medicine, Technion Israel Institute of Technology, Haifa, Israel.
authors: Yoav
authors: Y
authors: Mazor
authors: Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Edmond and Lily Safra Children's Hospital, Tel-Hashomer, Israel.
authors: Batia
authors: B
authors: Weiss
authors: Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Pediatric Gastroenterology and Nutrition Unit, E Wolfson Medical Center, Holon, Israel.
authors: Arie
authors: A
authors: Levine
authors: Inflammatory Bowel Disease Center, Department of Gastroenterology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors: Yulia
authors: Y
authors: Ron
authors: Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Department of Gastroenterology, Sheba Medical Center, Tel-Aviv, Israel.
authors: Uri
authors: U
authors: Kopylov
authors: Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Edmond and Lily Safra Children's Hospital, Tel-Hashomer, Israel.
authors: Yoram
authors: Y
authors: Bujanover
authors: Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Institute for Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center, Petah Tiqva, Israel.
authors: Yoram
authors: Y
authors: Rosenbach
authors: Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Department of Gastroenterology, Sheba Medical Center, Tel-Aviv, Israel.
authors: Bella
authors: B
authors: Ungar
authors: Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Department of Gastroenterology, Sheba Medical Center, Tel-Aviv, Israel.
authors: Rami
authors: R
authors: Eliakim
authors: Rambam Health Care Campus and Bruce Rappaport School of Medicine, Technion Israel Institute of Technology, Haifa, Israel.
authors: Yehuda
authors: Y
authors: Chowers
authors: Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Institute for Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center, Petah Tiqva, Israel.
authors: Raanan
authors: R
authors: Shamir
authors: Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Rabin Medical Center, Petah Tiqva, Israel.
authors: Gerald
authors: G
authors: Fraser
authors: Inflammatory Bowel Disease Center, Department of Gastroenterology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors: Iris
authors: I
authors: Dotan
authors: Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Department of Gastroenterology, Sheba Medical Center, Tel-Aviv, Israel. Electronic address: shomron.benhorin@gmail.com.
authors: Shomron
authors: S
authors: Ben-Horin
mesh_terms: D000068879:Adalimumab; D000328:Adult; D000906:Antibodies / Q000097:blood*; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000493:pharmacokinetics / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D000069285:Infliximab; D007557:Israel; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D017211:Treatment Failure; D055815:Young Adult
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007155:Immunologic Factors; D000069285:Infliximab; D000068879:Adalimumab
keywords: Anti-TNF Antibodies; Crohn’s Disease; IBD; UC