C. Research agenda
1. Theme A: Optimizing biologic medications toward precision care in IBD
1) A pilot study to assess performance of point-of-care testing for infliximab and fecal calprotectin in IBD patients with secondary loss of response168
72 Therapeutic drug monitoring and fecal calprotectin testing in IBD patients with secondary loss of response to infliximab will help guide clinicians to the most appropriate intervention to recapture response, but TDM and FCP result reporting can be delayed, which slows treatment optimization.
Study design
In this study, we aimed to investigate the clinical utility of TDM, FCP and resultant early drug optimization, using rapid point-of-care (POC) testing. We prospectively included adult IBD patients of the IBD clinic of McGill University Health Center, from February 2017 to December 2019, who were assessed for a secondary clinical LOR to IFX (defined as worsening of symptoms based on a Harvey Bradshaw index [HBI] ≥ 5 for Crohn’s disease [CD] and partial Mayo score [pMS] ≥ 3 for ulcerative colitis [UC]). The study used ELISA tests performed by a central laboratory as reference standard, and measured the diagnostic performance of IFX through levels (TL) and FCP obtained with a POC device (BÜHLMANN device Quantum Blue®). Based on POC results, we implemented an algorithmic approach to TDM/FCP results.
The proportion of patients for whom immediate dose optimization was appropriate and clinical remission (HBI < 5, pMS < 2) at weeks 4 and 12 were also assessed as secondary outcomes in patients whose treatment was optimized early.
Preliminary results
Overall, we included 38 patients (60.5% female, mean age: 34.2 +/- 13.7 years); CD n= 21 (55.3%) with mean HBI 8+/- 5 and UC n=17 (44.7%) with mean partial Mayo 4.6+/- 1.9. Mean duration of prior biological treatment was 36.1 months +/- 36.7. With central laboratory analysis as reference, POC TL sensitivity was 88.4%, specificity was 87.5%, positive predictive value (PPV) was 95.8%, negative predictive value (NPV) was 70%, and accuracy was 88.2%. POC FC sensitivity was 100%, specificity 76.5%, PPV 81%, NPV 100%, and accuracy 88.2%. Pearson correlation between POC and reference tests were strong for TL (R= 0.77, p<0.0001) and FC (R=0.54, p=0.0001); 8/38 (21.1%) of patients had low TL and high FC; 14/38 (36.8%) patients had adequate TL and high FCP; 14/38 (36.8%) patients had adequate TL and low FCP; and, 2/38 (5.3%) patients had low TL and FCP. Of the 8 patients with low IFX trough and elevated FCP, treatment was modified (dose escalation/change therapy) in 7 (87.5%); all 6 (100%) patients with available follow-up data from this group were in clinical remission at Week 12. Immediate dose optimization in patients with adequate TL and low FCP would have resulted in an inappropriate management in 13/14 (92.9%) patients.
Using POC testing for IFX patients with a secondary LOR is clinically useful, correlates well with standardized testing, allows for immediate appropriate management of patients with low
73 IFX trough and high FCP, and results in a clinical remission at 12 weeks. In symptomatic patients with adequate trough concentration and inactive disease, immediate dose optimization without waiting for TDM results would not have been appropriate for most patients.
We know of no other published studies that assessed the utility of a rapid IFX optimization strategy based point-of-care devices for IFX, TDM, and fecal calprotectin measurements, in patients with secondary LOR. This work shows how POC testing can rapidly personalize treatment and prevent inappropriate escalation.
2) Optimizing early dose-based treatment with adalimumab in patients with Crohn's disease: an open-label randomized study
Adalimumab (ADAL) at standard doses led to a clinical remission in 36% of anti-TNF-α naive patients vs 12% of placebo patients (p=0.001).169 In patients who had been exposed to other anti-TNF-α medications, ADAL treatment led to clinical remission in 21% vs 7% of placebo patients at Week 12 (p=0.001).170 The etiology of partial or inadequate response (50%) during biologic treatment induction is likely related to a decrease in the bioavailability of the drug because the patient receives an inadequate dose (increased inflammatory load) or immunogenicity leads to increased clearance of drug. True primary non-response (20%) is likely related the implication of an alternate inflammatory pathway in disease activity (which is not targeted by the biologic that was initiated).124,147
The pharmacokinetics of ADAL can be influenced by multiple factors, including sex, body mass index, disease activity, albumin level, or concurrent immunomodulator use, any of which may alters drug clearance or immunogenicity.124 Therapy can be optimized through therapeutic drug monitoring (TDM). TDM is a vital component of personalized medicine; serum drug concentrations of biologic medications are pro-actively measured and used to guide clinical treatment decisions.147 The absence of anti-drug antibodies (ADA) and a therapeutic trough serum anti-TNF-α concentrations have been associated with significantly increased rates of clinical remission, steroid-free remission, mucosal healing, and decreased risk of colectomy.171-173 Recent guidelines support using TDM in a reactive setting for LOR, but there is not enough evidence to recommend TDM in a “proactive” setting; more prospective clinical data is needed to determine its usefulness for optimizing treatment with of biologic medications.145,174 Several studies have demonstrated an association between drug concentrations during induction treatment and improved outcomes for all anti-TNF-α medications. Recently, in a cohort of CD patients starting ADAL, low median concentrations at Week 4 were significantly associated with presence of ADA (8.4 µg/mL in ADA+ vs 12.8
74 µg/mL in ADA- patients, p = 0.006) at Week 12.175 ADAL serum levels at Week 4 were also significantly higher in patients who achieved biological remission (p=0.001) by Week 12.175 this indicates that trough concentrations greater than >15 µg/ml are likely associated with improved clinical outcomes.
In clinical trials with anti-TNF-α biologic therapy in CD (infliximab/adalimumab), clinical remission approaches only 30% after induction therapy (12 weeks post treatment initiation).169,170 There is a clear association between higher anti-TNF-α drug concentrations during induction and increased rates of complete remission (clinical and endoscopic) in patients with IBD.174 Using a personalized therapeutic drug monitoring (TDM) approach during induction therapy, where patients with lower drug concentrations are dose optimized, may improve remission rates.176
Study design
This is a Canadian multi-center randomized control trial that compares clinical and biochemical remission in CD patients who receive pro-active dose adjustment of anti-TNF-α (adalimumab) during induction therapy with those who receive standard-of-care dosing.
Hypothesis:
Early dose optimization of adalimumab during induction treatment in CD patients improves clinical and biochemical remission more than standard-of-care dosing.
Project Status
Recruitment is ongoing
3. Evaluating the association of residual concentrations of Vedolizumab (Entyvio) with endoscopic response in patients with chronic IBD.
The anti-integrin monoclonal antibody vedolizumab (VDZ) has demonstrated efficacy in treatment of Crohn's disease and ulcerative colitis. Therapeutically monitoring this drug may guide its use and improve clinical outcomes.
Our objective is to evaluate the correlation between VDZ exposure and outcome and to assess clinical predictors of VDZ response.
75 Study design
Two patient cohorts were included in this observational study. The prospective longitudinal cohort received standard VDZ induction with 300mg IV infusion at Weeks 0, 2 and 6, followed by every 8-weekly treatment. The treating clinician was blinded to TDM results;
VDZ dose escalation/interval adjustment was guided by clinical needs at clinician discretion.
Patients were assessed at Weeks 6, 10, 14, 30 and 54. A second cross-sectional cohort recruited patients already established on VDZ enrolled at any of the above timepoints onward. Some of these patients were also followed longitudinally. In our analysis, we combined data from these two cohorts at each of the protocolized timepoints and collected pre-defined patient demographic, clinical, laboratory and endoscopic data.
Project Status
We recruited 55 patients (24 UC and 31 CD). Our preliminary data from Weeks 14, showed that 18/38 patients (61.3%) achieved clinical remission, 16 (57.1%) of whom had steroid free clinical remission and 15 (53.6%) of whom had calprotectin of <250µg/g. Similar patient outcomes were observed at Week 52. The clinical remission, steroid free remission and calprotectin remission rates are 57%, 57% and 50% respectively. Of the 21 patients who were endoscopically assessed around Week 52, 12 (57%) achieved the pre-defined endoscopic response and 5 (23.8%) had endoscopic remission.
The median VDL trough was 34.7 µg/ml (22.5-41.9 µg/ml) at Week 6, 32.4 (23.7-40.3 µg/ml) at Week 10, 15.5 (8.7-23.5 µg/ml) at Week 14, 16.1 µg/ml (9.7-33.6 µg/ml) at Week 30, and18.2 µg/ml (8.9-32 µg/ml) at Week 54. There was no significant difference between UC and CD patients at any time point. No patient developed anti-VDL antibodies during the study. The Week 14 VDL trough level correlated strongly with the Week 54 endoscopic response (r=0.575, p=0.025) and endoscopic remission (r=0.759, p= 0.001). In those patients who achieved endoscopic remission at week 54, trough VDL level was significantly higher 18.2 µg/ml (8.9-32 µg/ml) than for those who failed did not (11.05 µg/ml, p= 0.008) (Graph 1). The area under the receiver-operating curve (AUROC) was 0.92 for VDL troughs of >27.6 µg/ml; sensitivity was 0.8 and specificity 0. Trough levels at Week 6, 10, and 54 did not significantly correlate with any clinical outcomes.
4. Evaluating the efficacy of ustekinumab (Stelara) re-induction in Crohn's disease patients who have lost treatment response.
Ustekinumab (Stelara), an inhibitor of IL-12 and IL-23, effectively induces and maintains remission in CD and UC patients. The drug is administered as an intravenous induction dose
76 of 6 mg/kg followed by subcutaneous maintenance therapy at an interval of up to 4-12 weeks, depending on the severity of the patient's disease. But many patients do not respond to therapy or lose secondary response to ustekinumab. We set out to determine if
ustekinumab re-induction, in which a new intravenous loading dose is re-administered to the patient, provokes a clinical and endoscopic response in patients with active Crohn's disease.
Study design
This retrospective observational study was carried out in several Canadian expert centers;
Swiss patients participating in the Swiss IBD cohort study will also be included. Preliminary results presented at ECCO 2019 revealed that ustekinumab re-induction safely induces a clinical and endoscopic response in these patients. A total of 28 patients (median age 35.5 years, 46% women) had been included and were reinduced by IV; 53.8% of patients had clinical remission with biochemical response. We therapeutically monitored drugs for UST in 10 patients prior to reinduction, and in 18 patients post-reinduction. Pre-reinduction UST concentrations were ≥ 1 μg/ml (mean 3.8 ± 3.5 μg/ml) in 80%, compared with 100% of reinduction UST concentrations (mean 6.4 ± 4.2 μg/ml). Mean UST concentration post-reinduction was significantly higher in patients who achieved the primary outcome (9.7 ± 4.1 μg/ml) than in those who did (4.8 ± 3.1 μg/ml, p = 0.01). No serious adverse events were reported after UST re-induction.
Project Status Analysis is ongoing.
Theme B: Setting up a pediatric transition program for precision care in IBD
1. Transition from pediatric to adult care in patients with chronic inflammatory bowel disease
Children and adolescents with IBD generally have more extensive and severe disease than adults, reducing their QoL. Adolescents may suffer greater psychological stress,
underscoring the need for adequate transitional care in this population. Transition comprises intentional and planned movement adolescents with IBD from pediatric to adult care
systems. It is process that involves patients, parents, and pediatric and adult health care providers. A patient’s care is not simply switched from one provider to another; rather, adolescents must acquire the knowledge and self-management skills to transition into adults capable of successfully managing their chronic disease. The process is lengthy and should be planned well in advance. Recent European and US guidelines propose establishing
77 specialized transitional clinics for adolescent IBD patients, since these are well-established in management of other chronic childhood diseases like diabetes and cystic fibrosis. No IBD study on this transition has drawn on evidence from multiple centers. IBD transition varies widely, and is often based on practical system-based approaches and individual health problems. In Switzerland, where there are no links between pediatric and adult practices, young IBD patients are often poorly prepared for the transition, which may have negative consequences for all concerned. The objective of this project is to accurately describe
current Swiss transition practices for IBD, identify barriers to pediatric transition, and create a transition program for IBD patients in collaboration with pediatric and adult health care providers.
Study design:
We implemented a pilot project at HUG to create a pediatric transition program that has had great success with patients. Our goal is to implement this transition program in Geneva and other hospitals in Switzerland and to compare clinical outcomes to a historical control group from the Swiss IBD cohort data.
Project Status:
When we submitted to the SIBDC, we proposed using cohort results for the comparison group, without intervention. The Swiss cohort supports this project and has asked for some modifications before it formally accepts our proposal. The transition program started in Geneva in 2018 and enrolled 19 children, of whom 11 have completed the process and 8 are still in the programs. Outcomes are encouraging; there has been no loss-to-follow-up after one year post-transfer, 100% of participants are adhering to treatment, and none of the adolescents in our program reported to the emergency department for an IBD-related problem.
78
VIII. References
1. Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet.
2018;390(10114):2769-2778.
2. Sykora J, Pomahacova R, Kreslova M, Cvalinova D, Stych P, Schwarz J. Current global trends in the incidence of pediatric-onset inflammatory bowel disease. World J Gastroenterol.
2018;24(25):2741-2763.
3. Aniwan S, Park SH, Loftus EV, Jr. Epidemiology, Natural History, and Risk Stratification of Crohn's Disease. Gastroenterol Clin North Am. 2017;46(3):463-480.
4. Bernstein CN, Wajda A, Svenson LW, et al. The epidemiology of inflammatory bowel disease in Canada: a population-based study. Am J Gastroenterol. 2006;101(7):1559-1568.
5. Braegger CP, Ballabeni P, Rogler D, et al. Epidemiology of inflammatory bowel disease: Is there a shift towards onset at a younger age? J Pediatr Gastroenterol Nutr. 2011;53(2):141-144.
6. Rogler G, Biedermann L, Scharl M. New insights into the pathophysiology of inflammatory bowel disease: microbiota, epigenetics and common signalling pathways. Swiss Med Wkly.
2018;148:w14599.
7. Ng SC. Epidemiology of inflammatory bowel disease: focus on Asia. Best Pract Res Clin Gastroenterol. 2014;28(3):363-372.
8. Collaborators GBDIBD. The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2020;5(1):17-30.
9. Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease.
Nature. 2007;448(7152):427-434.
10. Verstockt B, Smith KG, Lee JC. Genome-wide association studies in Crohn's disease: Past, present and future. Clin Transl Immunology. 2018;7(1):e1001.
11. Ananthakrishnan AN, Bernstein CN, Iliopoulos D, et al. Environmental triggers in IBD: a review of progress and evidence. Nat Rev Gastroenterol Hepatol. 2018;15(1):39-49.
12. McIlroy J, Ianiro G, Mukhopadhya I, Hansen R, Hold GL. Review article: the gut microbiome in inflammatory bowel disease-avenues for microbial management. Aliment Pharmacol Ther.
2018;47(1):26-42.
13. de Souza HS, Fiocchi C. Immunopathogenesis of IBD: current state of the art. Nat Rev Gastroenterol Hepatol. 2016;13(1):13-27.
14. Moller FT, Andersen V, Wohlfahrt J, Jess T. Familial risk of inflammatory bowel disease: a population-based cohort study 1977-2011. Am J Gastroenterol. 2015;110(4):564-571.
15. Orholm M, Munkholm P, Langholz E, Nielsen OH, Sorensen TI, Binder V. Familial occurrence of inflammatory bowel disease. N Engl J Med. 1991;324(2):84-88.
16. Bianco AM, Zanin V, Girardelli M, et al. A common genetic background could explain early-onset Crohn's disease. Med Hypotheses. 2012;78(4):520-522.
17. McGovern DP, Kugathasan S, Cho JH. Genetics of Inflammatory Bowel Diseases.
Gastroenterology. 2015;149(5):1163-1176 e1162.
18. Zhao M, Burisch J. Impact of Genes and the Environment on the Pathogenesis and Disease Course of Inflammatory Bowel Disease. Dig Dis Sci. 2019;64(7):1759-1769.
19. Hadizadeh F, Lees C.W, Labbé C. IBD Genomic Risk Loci and Overlap with Other Inflammatory Diseases. In. Molecular Genetics of Inflammatory Bowel Disease. Springer ed2019:91-115.
20. Jostins L, Ripke S, Weersma RK, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491(7422):119-124.
21. Liu JZ, van Sommeren S, Huang H, et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 2015;47(9):979-986.
22. Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease.
Nature. 2011;474(7351):307-317.
23. Ramos GP, Papadakis KA. Mechanisms of Disease: Inflammatory Bowel Diseases. Mayo Clin Proc. 2019;94(1):155-165.
24. Shaw MH, Kamada N, Warner N, Kim YG, Nunez G. The ever-expanding function of NOD2:
autophagy, viral recognition, and T cell activation. Trends Immunol. 2011;32(2):73-79.
79 25. Spehlmann ME, Begun AZ, Burghardt J, Lepage P, Raedler A, Schreiber S. Epidemiology of
inflammatory bowel disease in a German twin cohort: results of a nationwide study. Inflamm Bowel Dis. 2008;14(7):968-976.
26. Kaplan GG. The global burden of IBD: from 2015 to 2025. Nat Rev Gastroenterol Hepatol.
2015;12(12):720-727.
27. Shouval DS, Rufo PA. The Role of Environmental Factors in the Pathogenesis of Inflammatory Bowel Diseases: A Review. JAMA Pediatr. 2017;171(10):999-1005.
28. Chu KM, Watermeyer G, Shelly L, et al. Childhood helminth exposure is protective against inflammatory bowel disease: a case control study in South Africa. Inflamm Bowel Dis.
2013;19(3):614-620.
29. Allais L, Kerckhof FM, Verschuere S, et al. Chronic cigarette smoke exposure induces microbial and inflammatory shifts and mucin changes in the murine gut. Environ Microbiol.
2016;18(5):1352-1363.
30. Monick MM, Powers LS, Walters K, et al. Identification of an autophagy defect in smokers' alveolar macrophages. J Immunol. 2010;185(9):5425-5435.
31. Sher ME, Bank S, Greenberg R, et al. The influence of cigarette smoking on cytokine levels in patients with inflammatory bowel disease. Inflamm Bowel Dis. 1999;5(2):73-78.
32. Shaw SY, Blanchard JF, Bernstein CN. Association between the use of antibiotics in the first year of life and pediatric inflammatory bowel disease. Am J Gastroenterol.
2010;105(12):2687-2692.
33. Selby W, Pavli P, Crotty B, et al. Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn's disease. Gastroenterology. 2007;132(7):2313-2319.
34. Olszak T, An D, Zeissig S, et al. Microbial exposure during early life has persistent effects on natural killer T cell function. Science. 2012;336(6080):489-493.
35. Troelsen FS, Jick S. Antibiotic Use in Childhood and Adolescence and Risk of Inflammatory Bowel Disease: A Case-Control Study in the UK Clinical Practice Research Datalink. Inflamm Bowel Dis. 2020;26(3):440-447.
36. Kvasnovsky CL, Aujla U, Bjarnason I. Nonsteroidal anti-inflammatory drugs and
exacerbations of inflammatory bowel disease. Scand J Gastroenterol. 2015;50(3):255-263.
37. Khalili H, Higuchi LM, Ananthakrishnan AN, et al. Oral contraceptives, reproductive factors and risk of inflammatory bowel disease. Gut. 2013;62(8):1153-1159.
38. Ananthakrishnan AN, Khalili H, Konijeti GG, et al. Long-term intake of dietary fat and risk of ulcerative colitis and Crohn's disease. Gut. 2014;63(5):776-784.
39. Hou JK, Abraham B, El-Serag H. Dietary intake and risk of developing inflammatory bowel disease: a systematic review of the literature. Am J Gastroenterol. 2011;106(4):563-573.
40. Jowett SL, Seal CJ, Pearce MS, et al. Influence of dietary factors on the clinical course of ulcerative colitis: a prospective cohort study. Gut. 2004;53(10):1479-1484.
41. Vinolo MA, Rodrigues HG, Nachbar RT, Curi R. Regulation of inflammation by short chain fatty acids. Nutrients. 2011;3(10):858-876.
42. Sartor RB, Wu GD. Roles for Intestinal Bacteria, Viruses, and Fungi in Pathogenesis of Inflammatory Bowel Diseases and Therapeutic Approaches. Gastroenterology.
2017;152(2):327-339 e324.
43. Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci U S A. 2007;104(34):13780-13785.
44. Fujimoto T, Imaeda H, Takahashi K, et al. Decreased abundance of Faecalibacterium prausnitzii in the gut microbiota of Crohn's disease. J Gastroenterol Hepatol. 2013;28(4):613-619.
45. Varela E, Manichanh C, Gallart M, et al. Colonisation by Faecalibacterium prausnitzii and maintenance of clinical remission in patients with ulcerative colitis. Aliment Pharmacol Ther.
2013;38(2):151-161.
46. Ahmed I, Roy BC, Khan SA, Septer S, Umar S. Microbiome, Metabolome and Inflammatory Bowel Disease. Microorganisms. 2016;4(2).
47. van der Waaij LA, Harmsen HJ, Madjipour M, et al. Bacterial population analysis of human colon and terminal ileum biopsies with 16S rRNA-based fluorescent probes: commensal bacteria live in suspension and have no direct contact with epithelial cells. Inflamm Bowel Dis.
2005;11(10):865-871.
48. Png CW, Linden SK, Gilshenan KS, et al. Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria. Am J Gastroenterol.
2010;105(11):2420-2428.
80 49. Cader MZ, Kaser A. Recent advances in inflammatory bowel disease: mucosal immune cells
in intestinal inflammation. Gut. 2013;62(11):1653-1664.
50. Park JH, Peyrin-Biroulet L, Eisenhut M, Shin JI. IBD immunopathogenesis: A comprehensive review of inflammatory molecules. Autoimmun Rev. 2017;16(4):416-426.
51. Lloyd-Price J, Arze C, Ananthakrishnan AN, et al. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. Nature. 2019;569(7758):655-662.
52. Drossman DA, Patrick DL, Mitchell CM, Zagami EA, Appelbaum MI. Health-related quality of life in inflammatory bowel disease. Functional status and patient worries and concerns. Dig Dis Sci. 1989;34(9):1379-1386.
53. Clearfield HR. How does IBD affect quality of life? Inflamm Bowel Dis. 2008;14 Suppl 2:S45-46.
54. Duricova D, Pedersen N, Elkjaer M, Gamborg M, Munkholm P, Jess T. Overall and cause-specific mortality in Crohn's disease: a meta-analysis of population-based studies. Inflamm Bowel Dis. 2010;16(2):347-353.
55. Jess T, Gamborg M, Munkholm P, Sorensen TI. Overall and cause-specific mortality in
55. Jess T, Gamborg M, Munkholm P, Sorensen TI. Overall and cause-specific mortality in