title: Association Between Ustekinumab Trough Concentrations and Clinical, Biomarker, and Endoscopic Outcomes in Patients With Crohn's Disease.
abstract: OBJECTIVE
  Ustekinumab, an inhibitor of the p40 subunit of interleukins 12 and 23, is an effective treatment for patients with Crohn's disease (CD). Trough concentrations of tumor necrosis factor (TNF) antagonists and presence of anti-drug antibodies are associated with important clinical and endoscopic outcomes. We investigated associations between trough concentrations of ustekinumab and clinical, biomarker, and endoscopic outcomes of real-world patients with CD.
  
  
  METHODS
  We recruited 62 patients with CD who were either refractory or intolerant to TNF antagonists, treated with ustekinumab from April 2014 to September 2015. Patients received 90 mg of ustekinumab subcutaneously at weeks 0, 1, and 2 during induction and 90 mg every 4 or 8 weeks during maintenance. Clinical, biomarker, and endoscopic outcomes, trough concentrations of ustekinumab, and anti-drug antibodies were assessed at both week 10 postinduction therapy and at week 26 or later during maintenance therapy in a prospective longitudinal patient cohort or at week 26 or later during maintenance therapy in a cross-sectional patient cohort. Analysis was performed on data combined from both maintenance cohorts, which had similar outcomes at week 26 or later. A primary analysis determined if ustekinumab drug trough concentrations were associated with clinical response (reduction in Harvey Bradshaw Index score of 3 or greater), clinical remission (Harvey Bradshaw Index score <5), steroid-free clinical remission, biomarker (serum level of C-reactive protein [CRP] or level of fecal calprotectin) reduction, biomarker normalization (serum level of CRP below 5 mg/L or level of fecal calprotectin below 200 μg/g), endoscopic response (simple endoscopic score for CD reduced by 50% or more), or endoscopic remission (simple endoscopic score for CD of 2 or less).
  
  
  RESULTS
  At week 26 or beyond, 80.7% of patients had a clinical response, 66.1% were in clinical remission, 50.0% were in steroid-free clinical remission, 58.9% had an endoscopic response, and 19.6% were in endoscopic remission. The mean trough concentration of ustekinumab at this time point was higher in patients with an endoscopic response (4.7 μg/mL) than without (3.8 ug/mL; P = .03). An optimal ustekinumab threshold trough concentration at week 26 or later was found to be 4.5 μg/mL (area under the curve, 0.67). A greater proportion of patients with trough concentrations of ustekinumab above 4.5 μg/mL at week 26 or later had an endoscopic response (75.9%) than did patients with trough concentrations below this level (40.7%; P = .008). Patients with trough concentrations of ustekinumab above 4.5 μg/mL at week 26 or later also had a lower mean level of CRP (12.6 mg/L) than did patients with trough concentrations below this level (mean level of CRP, 23.9 mg/L; P = .04). We did not detect antibodies against ustekinumab in any patient.
  
  
  CONCLUSIONS
  Ustekinumab therapy was effective in patients with CD who had not responded to or were intolerant to treatment with a TNF antagonist. Maintenance trough concentrations of ustekinumab above 4.5 μg/mL at 26 weeks or later were associated with biomarker reduction and endoscopic response.
authors.affiliation: Division of Gastroenterology, Jewish General Hospital, Montreal, Canada; Division of Gastroenterology, McGill University Health Centre, Montreal, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Battat
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: Division of Gastroenterology, McGill University Health Centre, Montreal, Canada.
authors.forename: Talat
authors.initials: T
authors.lastname: Bessissow
authors.affiliation: Division of Gastroenterology, McGill University Health Centre, Montreal, Canada.
authors.forename: Alain
authors.initials: A
authors.lastname: Bitton
authors.affiliation: Division of Gastroenterology, Jewish General Hospital, Montreal, Canada.
authors.forename: Albert
authors.initials: A
authors.lastname: Cohen
authors.affiliation: Prometheus Laboratories Inc, San Diego, California.
authors.forename: Anjali
authors.initials: A
authors.lastname: Jain
authors.affiliation: Division of Gastroenterology, McGill University Health Centre, Montreal, Canada.
authors.forename: Myriam
authors.initials: M
authors.lastname: Martel
authors.affiliation: Division of Gastroenterology, McGill University Health Centre, Montreal, Canada.
authors.forename: Ernest
authors.initials: E
authors.lastname: Seidman
authors.affiliation: Division of Gastroenterology, McGill University Health Centre, Montreal, Canada. Electronic address: waqqas.afif@mcgill.ca.
authors.forename: Waqqas
authors.initials: W
authors.lastname: Afif
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000032:analysis; D002648:Child; D002675:Child, Preschool; D003113:Colonoscopy; D003424:Crohn Disease / Q000188:drug therapy* / Q000473:pathology*; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D016896:Treatment Outcome; D000069549:Ustekinumab / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D007155:Immunologic Factors; D000069549:Ustekinumab
keywords: Biologic; Inflammatory Bowel Disease; Therapeutic Drug Monitoring; UNITI