Advertisement

Predictive models assessing the response to ustekinumab highlight the value of therapeutic drug monitoring in Crohn's disease

Published:August 14, 2022DOI:https://doi.org/10.1016/j.dld.2022.07.015

      Abstract

      Background

      Despite the therapeutic efficacy of Ustekinumab (UST) in Crohn's disease (CD), loss of response (LOR) is observed over time. This study aims to evaluate the impact of the UST pharmacokinetics (PK) at induction on clinical and endoscopic outcomes, as well as to find predictive markers of UST response.

      Methods

      This retrospective study included 80 CD patients. Pharmacokinetics data (trough levels (TLs)) combined with clinical and biological parameters were fed into tailored logistic regression and tree-based ensemble techniques to predict clinical and endoscopic outcomes at one year of follow-up.

      Results

      TLs at week 16 were significantly lower among patients with moderate to severe endoscopic activity during the follow-up (p = 0.04). The best model to predict endoscopic outcome was obtained at week 16 by Random Forest with an area under the receiver operating characteristic curve of 0.92 ± 0.08, sensitivity 91% and specificity 75%, with key inputs such as lymphocyte and monocyte counts at week 8, and UST TLs and CRP at week 16.

      Conclusions

      This real-world study confirms the relationship between early UST TLs and both clinical and endoscopic outcomes. Models were developed for the task of predicting clinical and endoscopic remission in CD patients treated with UST, highlighting the clinical relevance of UST TLs at week 16.

      Keywords

      Abbreviations:

      ATU (Antibodies to ustekinumab), CD (Crohn’s disease), CRP (C-reactive protein), IMM (Immunosuppressor), LOR (Loss of response), PK (Pharmacokinetics), RCT (Randomized control trial), ROC (Receiver operating characteristic curve), UST (Ustekinumab), TDM (Therapeutic drug monitoring), TL (Trough level)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Digestive and Liver Disease
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Teng M.W.
        • Bowman E.P.
        • McElwee J.J.
        • Smyth M.J.
        • Casanova J.L.
        • Cooper A.M.
        • et al.
        IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases.
        Nat Med. 2015; 21: 719-729
        • Benson J.M.
        • Sachs C.W.
        • Treacy G.
        • Zhou H.
        • Pendley C.E.
        • Brodmerkel C.M.
        • et al.
        Therapeutic targeting of the IL-12/23 pathways: generation and characterization of ustekinumab.
        Nat Biotechnol. 2011; 29: 615-624
        • Sandborn W.J.
        • Gasink C.
        • Gao L.L.
        • Blank M.A.
        • Johanns J.
        • Guzzo C.
        • et al.
        Ustekinumab induction and maintenance therapy in refractory Crohn's disease.
        N Engl J Med. 2012; 367: 1519-1528
        • Sandborn W.J.
        • Feagan B.G.
        • Fedorak R.N.
        • Scherl E.
        • Fleisher M.R.
        • Katz S.
        • et al.
        A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn's disease.
        Gastroenterology. 2008; 135: 1130-1141
        • Liefferinckx C.
        • Verstockt B.
        • Gils A.
        • Noman M.
        • Van Kemseke C.
        • Macken E.
        • et al.
        Long-term clinical effectiveness of ustekinumab in patients with Crohn's disease who failed biologic therapies: a National Cohort Study.
        J Crohns Colitis. 2019; 13: 1401-1409
        • Biemans V.B.C.
        • van der Meulen-de Jong A.E.
        • van der Woude C.J.
        • Lowenberg M.
        • Dijkstra G.
        • Oldenburg B.
        • et al.
        Ustekinumab for Crohn's Disease: results of the ICC registry, a Nationwide Prospective Observational Cohort Study.
        J Crohns Colitis. 2020; 14: 33-45
        • Hanauer S.B.
        • Sandborn W.J.
        • Feagan B.G.
        • Gasink C.
        • Jacobstein D.
        • Zou B.
        • et al.
        IM-UNITI: three-year efficacy, safety, and immunogenicity of ustekinumab treatment of Crohn's disease.
        J Crohns Colitis. 2020; 14: 23-32
        • Gutierrez A.
        • Rodriguez-Lago I.
        How to optimize treatment with ustekinumab in inflammatory bowel disease: lessons learned from clinical trials and real-world data.
        Front Med (Lausanne). 2021; 8640813
        • Adedokun O.J.
        • Xu Z.
        • Gasink C.
        • Jacobstein D.
        • Szapary P.
        • Johanns J.
        • et al.
        Pharmacokinetics and exposure response relationships of ustekinumab in patients with Crohn's disease.
        Gastroenterology. 2018; 154: 1660-1671
        • Verstockt B.
        • Dreesen E.
        • Noman M.
        • Outtier A.
        • Van den Berghe N.
        • Aerden I.
        • et al.
        Ustekinumab exposure-outcome analysis in Crohn's disease only in part explains limited endoscopic remission rates.
        J Crohns Colitis. 2019; 13: 864-872
        • Battat R.
        • Kopylov U.
        • Bessissow T.
        • Bitton A.
        • Cohen A.
        • Jain A.
        • et al.
        Association between ustekinumab trough concentrations and clinical, biomarker, and endoscopic outcomes in patients with Crohn's disease.
        Clin Gastroenterol Hepatol. 2017; 15 (e2): 1427-1434
        • Soufflet N.
        • Boschetti G.
        • Roblin X.
        • Cuercq C.
        • Williet N.
        • Charlois A.L.
        • et al.
        Concentrations of ustekinumab during induction therapy associate with remission in patients with Crohn's disease.
        Clin Gastroenterol Hepatol. 2019; 17: 2610-2612
        • Painchart C.
        • Brabant S.
        • Duveau N.
        • Nachury M.
        • Desreumaux P.
        • Branche J.
        • et al.
        Ustekinumab serum trough levels may identify suboptimal responders to ustekinumab in Crohn's disease.
        Dig Dis Sci. 2020; 65: 1445-1452
        • Van den Berghe N.
        • Verstockt B.
        • Vermeire S.
        • Thomas D.
        • Declerck P.
        Higher drug exposure during the first 24 weeks of ustekinumab treatment is associated with endoscopic remission in Crohn’s disease.
        Clin Gastroenterol Hepatol. 2021; (pp. S1542-3565(21)01344-6)
        • Gisbert J.P.
        • Chaparro M.
        Predictors of primary response to biologic treatment [Anti-TNF, vedolizumab, and ustekinumab] in patients with inflammatory bowel disease: from basic science to clinical practice.
        J Crohns Colitis. 2020; 14: 694-709
        • Liefferinckx C.
        • Minsart C.
        • Cremer A.
        • Amininejad L.
        • Tafciu V.
        • Quertinmont E.
        • et al.
        Early vedolizumab trough levels at induction in inflammatory bowel disease patients with treatment failure during maintenance.
        Eur J Gastroenterol Hepatol. 2019; 31: 478-485
        • Liefferinckx C.
        • Minsart C.
        • Toubeau J.F.
        • Cremer A.
        • Amininejad L.
        • Quertinmont E.
        • et al.
        Infliximab trough levels at induction to predict treatment failure during maintenance.
        Inflamm Bowel Dis. 2017; 23: 1371-1381
        • Schoepfer A.M.
        • Beglinger C.
        • Straumann A.
        • Trummler M.
        • Vavricka S.R.
        • Bruegger L.E.
        • et al.
        Fecal calprotectin correlates more closely with the simple endoscopic score for Crohn's disease (SES-CD) than CRP, blood leukocytes, and the CDAI.
        Am J Gastroenterol. 2010; 105: 162-169
        • Toubeau J.F.
        • Bottieau J.
        • Vallée F.
        • De Grève Z.
        Deep learning-based multivariate probabilistic forecasting for short-term scheduling in power markets.
        IEEE Trans Power Syst. 2019; 34: 1203-1215
        • Hosmer D.W.
        • et al.
        Applied logistic regression.
        2nd ed. John Wiley and Sons, New York, NY2000: 160-164 (Chapter 5)
        • Liefferinckx C.
        • Bottieau J.
        • Toubeau J.F.
        • Thomas D.
        • Rahier J.F.
        • Louis E.
        • et al.
        Collecting new peak and intermediate infliximab levels to predict remission in inflammatory bowel diseases.
        Inflamm Bowel Dis. 2022; 28: 208-217
        • Yzet C.
        • Diouf M.
        • Singh S.
        • Brazier F.
        • Turpin J.
        • Nguyen-Khac E.
        • et al.
        No benefit of concomitant immunomodulator therapy on efficacy of biologics that are not tumor necrosis factor antagonists in patients with inflammatory bowel diseases: a meta-analysis.
        Clin Gastroenterol Hepatol. 2021; 19 (e8): 668-679
        • Sandborn W.J.
        • Rebuck R.
        • Wang Y.
        • Zou B.
        • Adedokun O.J.
        • Gasink C.
        • et al.
        Five-year efficacy and safety of ustekinumab treatment in Crohn’s disease: the IM-UNITI trial.
        Clin Gastroenterol Hepatol. 2022; 20: 578-590
        • Vermeire S.
        • Gils A.
        • Accossato P.
        • Lula S.
        • Marren A.
        Immunogenicity of biologics in inflammatory bowel disease.
        Therap Adv Gastroenterol. 2018; 11: 1756283-17750355
        • Costable N.J.
        • Borman Z.A.
        • Ji J.
        • Dubinsky M.C.
        • Ungaro R.C
        Prior immunogenicity to anti-TNF biologics is not associated with increased anti-drug antibodies to vedolizumab or ustekinumab.
        Dig Dis Sci. 2022; 67: 2480-2484
        • Vande Casteele N.
        • Jairath V.
        • Jeyarajah J.
        • Dulai P.S.
        • Singh S.
        • Shackelton L.M.
        • et al.
        Development and validation of a clinical decision support tool that incorporates pharmacokinetic data to predict endoscopic healing in patients treated with infliximab.
        Clin Gastroenterol Hepatol. 2021; 19 (e2): 1209-1217
        • Waljee A.K.
        • Wallace B.I.
        • Cohen-Mekelburg S.
        • Liu Y.
        • Liu B.
        • Sauder K.
        • et al.
        Development and validation of machine learning models in prediction of remission in patients with moderate to severe Crohn disease.
        JAMA Netw Open. 2019; 2e193721
        • Asahina A.
        • Kubo N.
        • Umezawa Y.
        • Honda H.
        • Yanaba K.
        • Nakagawa H.
        Neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and mean platelet volume in Japanese patients with psoriasis and psoriatic arthritis: response to therapy with biologics.
        J Dermatol. 2017; 44: 1112-1121