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Journal ArticleDOI

Association Between Ustekinumab Trough Concentrations and Clinical, Biomarker, and Endoscopic Outcomes in Patients With Crohn's Disease

TL;DR: Ustekinumab therapy was effective in patients with CD who had not responded to or were intolerant to treatment with a TNF antagonist and was associated with biomarker reduction and endoscopic response.
About: This article is published in Clinical Gastroenterology and Hepatology.The article was published on 2017-09-01. It has received 171 citations till now. The article focuses on the topics: Ustekinumab & Trough Concentration.
Citations
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Journal ArticleDOI
TL;DR: An evidence-supported update of the ECCO-ESPGHAN guideline on the medical management of paediatric Crohn's disease is provided, establishing that it was key to identify patients at high risk of a complicated disease course at the earliest opportunity to reduce bowel damage.

237 citations

Journal ArticleDOI
TL;DR: Reactive TDM was appropriate for all agents both for primary non-response and secondary loss of response, and appropriate drug and anti-drug antibody concentration thresholds for biologics in specific clinical scenarios.

189 citations


Cites background from "Association Between Ustekinumab Tro..."

  • ...The current evidence supporting the role of TDM regarding ustekinumab is based on 2 exposure-response relationship studies showing that higher ustekinumab concentrations correlate to better therapeutic outcomes (Table 2).(49,89) At this time, there are still no studies comparing either proactive or reactive TDM with empiric ustekinumab optimization....

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Journal ArticleDOI
TL;DR: Serum concentrations of ustekinumab found to be proportional to dose and associate with treatment efficacy, and correlated inversely with level of C-reactive protein, and did not associate with use of immunomodulators.

156 citations

Journal ArticleDOI
TL;DR: Patients with PNR to anti-T NF agents are less likely to respond to second-line non-TNF biologics, as compared with patients who discontinued therapy due to secondary LOR or intolerance.
Abstract: Background and aims We sought to analyze whether response to a second-line biologic varies depending on the reason for discontinuation of the primary anti-TNF agent (primary non-response [PNR], secondary loss of response [LOR] after initial response, or intolerance), through a systematic review and meta-analysis. Methods Through a systematic search through May 31, 2017, we identified eight randomized controlled trials [RCTs] of biologics in patients with IBD with prior exposure to anti-TNF agents, that stratified response to second-line therapy by reason for discontinuing primary anti-TNF therapy [PNR vs. LOR vs. intolerance]. We estimated relative risk [RR] (and 95% confidence interval [CI]) of achieving clinical remission in patients with PNR as compared with patients with LOR, and intolerance, through random effects meta-analysis. Results As compared with patients who discontinued prior anti-TNF due to intolerance, patients with prior PNR were 24% less likely to achieve remission with second-line biologics (RR,0.76 [0.61-0.96]). As compared with patients who discontinued prior anti-TNF due to LOR, patients with prior PNR were 27% less likely to achieve remission with induction therapy with second-line biologics (RR,0.73 [0.56-0.97]), particularly to ustekinumab (RR,0.64 [0.52-0.80]). There was no difference in response to vedolizumab in patients with prior PNR or LOR to anti-TNF agents (RR,1.16 [0.85-1.58]). Conclusion Patients with PNR to anti-TNF agents are less likely to respond to second-line non-TNF biologics, as compared with patients who discontinued therapy due to secondary LOR or intolerance. This may be attributed to underlying pharmacokinetics and pharmacodynamics of anti-TNF agents in patients with PNR.

126 citations

Journal ArticleDOI
TL;DR: The quest for new treatment options for IBD is very active and justified by the high medical need and unresolved problems patients are facing, and oral agents inhibiting cell signaling have been explored successfully in IBD.
Abstract: The advent of anti-TNF agents has dramatically changed the treatment algorithms for IBD in the last 15 years, but primarily and more importantly secondary loss of response is often observed. Fortunately , new treatment options have been actively explored and some have already entered our clinical practice. In the class of anti-cytokine agents, the anti-IL12/IL23 monoclonal antibodies (mAbs) have entered clinical practice with the anti-p40 mAb ustekinumab in Crohn’s disease (CD). Also, more selective anti-IL23 agents (anti-p19) have shown efficacy and are being further developed, in contrast to agents inhibiting IL-17 downstream which have failed in clinical trials despite their clear efficacy in psoriasis (Verstockt et al. in Expert Opin Biol Ther 17(1):31–47, 2017; Verstockt et al. in Expert Opin Drug Saf 16(7):809–821, 2017). Following up on the efficacy of the anti-adhesion molecule vedolizumab, etrolizumab (anti-beta-7 integrin) and PF-00547659, an anti-MadCam mAb, are being developed (Lobaton et al. in Aliment Pharmacol Ther 39(6):579–594, 2014). Oral anti-trafficking agents, such as ozanimod, targeting the S1P receptor responsible for the efflux of T-cells from the lymph nodes, have also shown efficacy in patients with ulcerative colitis (UC) (Sandborn et al. in N Engl J Med 374(18):1754–1762, 2016). Oral agents inhibiting cell signaling have been explored successfully in IBD. Tofacitinib, a non-selective oral Janus kinase (JAK) inhibitor, is effective in patients with UC and several other more or less selective Jak1, 2 and 3 inhibitors are being developed for the treatment of CD and UC (Sandborn et al. in N Engl J Med 376(18):1723–1736, 2017; Vermeire et al. in Lancet 389(10066):266–275, 2017; De Vries et al. in J Crohns Colitis 11(7):885–93, 2017). Finally, despite initial disappointing results with systemic administration of mesenchymal stem cells, Alofisel, adipose tissue derived, allogeneic mesenchymal stem cells, locally injected in perianal fistula tracts, induce long-lasting beneficial effects and the drug has been approved in Europe (Panes et al. in Gastroenterology, 2017). In summary, the quest for new treatment options in IBD is very active and justified by the high medical need and unresolved problems patients are facing.

121 citations


Additional excerpts

  • ...The role of ustekinumab pharmacokinetics is unclear at this moment, but cohort data suggest that endoscopic healing is related to ustekinumab trough levels [13], which was also observed in a post hoc sub-analysis of the phase III program [14]....

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References
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Journal ArticleDOI
TL;DR: Patients with Crohn's disease who respond to an initial dose of infliximab are more likely to be in remission at weeks 30 and 54, to discontinue corticosteroids, and to maintain their response for a longer period of time, if inflIXimab treatment is maintained every 8 weeks.

3,870 citations

Journal ArticleDOI
01 Dec 2006-Science
TL;DR: A highly significant association is found between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23, which prioritize this signaling pathway as a therapeutic target in inflammatory bowel disease.
Abstract: The inflammatory bowel diseases Crohn's disease and ulcerative colitis are common, chronic disorders that cause abdominal pain, diarrhea, and gastrointestinal bleeding. To identify genetic factors that might contribute to these disorders, we performed a genome-wide association study. We found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23. An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) confers strong protection against Crohn's disease, and additional noncoding IL23R variants are independently associated. Replication studies confirmed IL23R associations in independent cohorts of patients with Crohn's disease or ulcerative colitis. These results and previous studies on the proinflammatory role of IL-23 prioritize this signaling pathway as a therapeutic target in inflammatory bowel disease.

2,937 citations

Journal ArticleDOI
TL;DR: Vedolizumab-treated patients with active Crohn's disease were more likely than patients receiving placebo to have a remission, but not a CDAI-100 response, at week 6; patients with a response to induction therapy who continued to receive vedolIZumab (rather than switching to placebo) were morelikely to be in remission at week 52.
Abstract: BackgroundUstekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn’s disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy. MethodsWe randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 w...

2,059 citations

Journal ArticleDOI
TL;DR: Adalimumab was well-tolerated, with a safety profile consistent with previous experience with the drug, and was significantly more effective than placebo in maintaining remission in moderate to severe CD through 56 weeks.

2,028 citations

Journal ArticleDOI
TL;DR: The epidemiology, immunobiology, amd natural history of Crohn's disease is discussed; new treatment goals and risk stratification of patients are described; and an evidence based rational approach to diagnosis is provided.

1,700 citations


"Association Between Ustekinumab Tro..." refers background in this paper

  • ...Crohn’s disease (CD) is a chronic debilitating inflammatory bowel disease.(1) In patients receiving anti–tumor necrosis factor (anti-TNF) medications, up to two-thirds have either primary nonresponse or secondary loss of response....

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