ECCO 2016: Professor Stefan Schreiber (Kiel, Germany) discusses some of the issues in managing Crohn’s disease.

In it for the long haul – managing the complexity of Crohn’s disease

by Maria Dalby

Michael Kamm (Melbourne, Australia), Remo Panaccione (Alberta, Canada) and Stefan Schreiber (Kiel, Germany).

When treating a condition like Crohn’s disease (CD) with its complex aetiology and pathogenesis, it is important to establish long-term treatment goals to not only achieve symptom resolution but also minimise the risk of long-term complications. Professor Michael Kamm from Melbourne, Australia chaired a symposium dedicated to optimising the use of biological therapies in CD. In his introduction he reminded the audience that CD is a condition that puts clinicians to the test both in the short and long term.

CD is a complex condition which manifests itself in and outside the gastrointestional tract. The underlying cause is thought to be a combination of genetic predisposition, environmental factors and a deficient host immune system.¹ Dr Remo Panaccione, from Calgary in Canada, predicted that, although this is in many ways a very exciting time for IBD specialists with several new therapeutic agents due to become available in the next few years, this will also increase the complexity of the decision-making in CD. Safety is paramount; the prospect of medical therapy for global suppression of the immune system is daunting for patients and it is important that the clinician respects these concerns in the discussion of benefit versus risk. Current anti-TNF biologics are highly effective as induction therapy in anti-TNF-naïve and anti-TNF failure patients, with response rates of 50-70% noted in clinical studies with infliximab^{2, 3} and adalimumab.^4-6 However, recent data from the TREAT registry shows that anti-TNF therapy is an independent predictor of serious infections in a population of 6,273 patients followed for more than 5 years.⁷ The increased risk of serious infection is particularly pronounced in patients aged over 65.⁸ The product labels of both infliximab and adalimumab contain lengthy warnings and precautions regarding the risk of not only infections but also malignancies, and some countries have also imposed ‘black box’ warnings over the risk of developing lymphoma on anti-TNF therapy. This information is available in the public domain and makes for challenging discussions with patients.

In contrast, the gut-selective anti-α4 integrin vedolizumab, which Professor Panaccione described as a “spectacular development” in IBD, is associated with favourable efficacy and safety profiles. A recently published analysis of integrated safety data from six clinical trials with vedolizumab comprising 2,830 patients with a total of 4,811 patient-years of exposure, showed no increased risk of any infection or serious infection associated with vedolizumab exposure.⁹ No cases of cases of progressive multifocal leukoencephalopathy (PML) were observed and only very few malignancies.⁹ Vedolizumab has been shown to maintain remission for up to 3 years¹⁰ which reflects the control of inflammation in the lamina propria. Results from an open-label extension of the GEMINI study programme indicate that CD and UC patients with a continued response to vedolizumab sustained long-term endoscopic healing.¹¹ Additional subgroup analyses from the GEMINI 2 study indicate that vedolizumab treatment is associated with shorter time to fistula closure¹² and resolution of extraintestinal manifestations^{13, 14} in CD, although these findings remain to be documented in prospective clinical trials.

The real-life clinical experience with vedolizumab that is emerging in the medical literature is largely consistent with its clinical trial profile and supports the finding that vedolizumab is highly effective for achieving a sustained clinical response and inducing remission in both biologic-naïve patients and those with previous exposure, with a favourable tolerability profile. Professor Stefan Schreiber, from Kiel in Germany, presented data from a number of cohorts that have been presented recently. In the Boston Massachusetts General Hospital (MGH) and Brigham and Women’s Hospital (BWH) multicentre cohort of 107 CD patients, most of them heavily pre-treated with active disease, response rates continued to increase beyond 6 weeks which suggests that some patients with previous exposure may take a bit longer to respond.¹⁵ Similar results were reported in the French early-access programme with 173 CD patients¹⁶ and the German Registry of 174 CD patients.¹⁷  The German Registry also highlighted a significant steroid-sparing effect of vedolizumab in both CD and UC.¹⁷ The safety profile in these cohorts is more complex than in controlled clinical trials as real-life patients will have more concomitant conditions and medications that would not be allowed in trials, but the overall trend is that vedolizumab is well tolerated. Smaller cohorts have also been published in Sweden¹⁸, Spain¹⁹ and the US^20-23 which confirm these findings. Real-world endoscopic data is as yet limited but indicates mucosal healing rates in the order of 20-30%.^{20, 21, 23-25} As more data becomes available on real-life use of vedolizumab, clinical practice is changing – up to 30% of patients in US centres are now receiving vedolizumab as their first biologic therapy.^26-30

 

References

1. Sartor RB. Mechanisms of disease: pathogenesis of Crohn’s disease and ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol 2006;3:390-407.
2. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002;359:1541-9.
3. Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med 1997;337:1029-35.
4. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology 2007;132:52-65.
5. Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology 2006;130:323-33; quiz 591.
6. Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med 2007;146:829-38.
7. Lichtenstein GR, Feagan BG, Cohen RD, et al. Serious infection and mortality in patients with Crohn’s disease: more than 5 years of follow-up in the TREAT registry. Am J Gastroenterol 2012;107:1409-22.
8. Cottone M, Kohn A, Daperno M, et al. Advanced age is an independent risk factor for severe infections and mortality in patients given anti-tumor necrosis factor therapy for inflammatory bowel disease. Clin Gastroenterol Hepatol 2011;9:30-5.
9. Colombel JF, Sands BE, Rutgeerts P, et al. The safety of vedolizumab for ulcerative colitis and Crohn’s disease. Gut 2016.
10. Vermeire S, Feagan BG, Mody R, et al. P603 Response and remission rates with up to 3 years of vedolizumab treatment in patients with Crohn’s disease. ECCO. Amsterdam, 2016.
11. Noman M, Ferrante M, Bisschops R, et al. OP024 Mucosal healing and dysplasia surveillance in a large referral Centre cohort of patients with Crohn’s disease and ulcerative colitis treated with vedolizumab ECCO, 2016.
12. Feagan B, Schwartz D, Danese S, et al. Vedolizumab for the Treatment of Fistulising Crohn’s Disease: An Exploratory Analysis of Data From GEMINI 2. J Crohns Colitis 2015;9:S333-S334.
13. Lakatos PL, Lakatos L, Kiss LS, et al. Treatment of extraintestinal manifestations in inflammatory bowel disease. Digestion 2012;86 Suppl 1:28-35.
14. Rubin D, Feagan B, Dryden G, et al. P-105 The Effect of Vedolizumab on Extraintestinal Manifestations in Patients with Crohn’s Disease in GEMINI 2. Inflammatory Bowel Diseases 2016;22:S42-S43.
15. Shelton E, Allegretti JR, Stevens B, et al. Efficacy of Vedolizumab as Induction Therapy in Refractory IBD Patients: A Multicenter Cohort. Inflamm Bowel Dis 2015;21:2879-85.
16. Amiot A, Grimaud JC, Peyrin-Biroulet L, et al. Effectiveness and Safety of Vedolizumab Induction Therapy for Patients With Inflammatory Bowel Disease. Clin Gastroenterol Hepatol 2016.
17. Baumgart DC, Bokemeyer B, Drabik A, et al. Vedolizumab induction therapy for inflammatory bowel disease in clinical practice – a nationwide consecutive German cohort study (VEDOibd). Aliment Pharmacol Ther 2016;in press.
18. Eriksson C, Almer S, Björk JA, et al. Tu1368 Vedolizumab in Inflammatory Bowel Disease, the First Experience From the Swedish IBD Registry (SWIBREG). Gastroenterology 2015;148:S-871.
19. Chaparro M, Sierra-Ausin M, Mesonero F, et al. ECCO, 2016.
20. Chaudrey K, Lightner A, Singh S, et al. P-033 YI Efficacy and Safety of Vedolizumab for Inflammatory Bowel Disease in Clinical Practice. Inflammatory Bowel Diseases 2016;22:S19-S20.
21. Dulai PS, Singh S, Narula N, et al. Vedolizumab for Moderate to Severely Active Inflammatory Bowel Disease: A Multicenter U.S. Consortium. Am J Gastroenterol 2015;110:S809.
22. Lucci MB, Collins E, Cao B, et al. Sa1198 Initial Vedolizumab Cohort: Patient Characteristics and Clinical Response. Gastroenterology 2015;148:S-255.
23. Christensen B, Goeppinger SR, Colman RJ, et al. Tu1350 Vedolizumab in the Treatment of IBD: The University of Chicago Experience. Gastroenterology 2015;148:S-866.
24. Vivio E, Kanuri ND, Dey N, et al. Tu1369 Vedolizumab Efficacy and Safety in a Tertiary Care IBD Clinical Practice. Gastroenterology 2015;148:S-871-S-872.
25. Shafran I, Laughlin R, Burgunder P. P-006 Evidence of Mucosal Healing in Patients with Crohn’s Disease Treated with Open-Label Vedolizumab: A Case Series. Inflammatory Bowel Diseases 2016;22:S11.
26. Khalid JM, Reynolds M, Alam Nl, et al. Characteristics of Patients With Crohn’s Disease Initiating Vedolizumab Therapy in Real-World Clinical Practice. Am J Gastroenterol 2015;110:S773-S774.
27. Liang H, Manne S, Shick J, et al. P682 Clinical characteristics of Crohn’s disease or ulcerative colitis patients who initiated vedolizumab or an anti-TNF-α as first biologic therapy. ECCO. Amsterdam, 2016.
28. Mody R, Chastek B, Patel H. Characteristics of Patients Treated With Vedolizumab for Infl ammatory Bowel Disease in the United States. Am J Gastroenterol 2015;110:S779-S780.
29. Raluy M, Fraeman K, Donaldson R, et al. P167 Real-world treatment persistence with vedolizumab in Crohn’s disease and ulcerative colitis patients ECCO. Amsterdam, 2016.
30. Reynolds M, Alam N, Raluy M, et al. P239 Hospitalisations and characteristics of patients with ulcerative colitis and Crohn’s disease treated with vedolizumab in real-world clinical practice: results from a multicentre study. ECCO. Amsterdam, 2016.