Geriatrics and Gerontology; Family Practice; Psychiatry and Mental Health; Health (social science)
Abstract :
[en] The therapeutic management of older patients with inflammatory bowel disease (IBD) is challenging, particularly because of the absence of evidence-based guidelines for these patients, who seem to frequently be excluded from clinical trials. In this systematic review we investigated the exclusion of older patients with IBD from phase 3 studies registered on PubMed and ClinicalTrials.gov, by assessing the upper limit of age exclusion criteria and the percentage of patients older than 65 years included in the trials. Exclusion criteria other than age were also recorded, and comorbidities were analysed separately. Our review of 222 phase 3 studies shows that older patients are frequently excluded from IBD clinical trials because of their age, which was used as an exclusion criterion in 129 (58%) of the 222 assessed trials. Of the 32 trials that detailed the percentage of included patients who were 65 years or older, only 763 (5·4%) patients of the 14 124 patients included were older than 65 years. In addition to age, patients were also excluded because of comorbidities (mainly renal, hepatic, and cardiovascular, and used as an exclusion criterion in 76% of trials), a history of dysplasia (45% of trials), and previous treatment for IBD (19% of trials). We propose a three-step process that should enable the inclusion of all older patients in IBD clinical trials, regardless of their age, comorbidities, and frailty.
Disciplines :
Gastroenterology & hepatology
Author, co-author :
VIEUJEAN, Sophie ; Centre Hospitalier Universitaire de Liège - CHU > > Service de gastroentérologie, hépatologie, onco. digestive
Caron, Bénédicte; Department of Gastroenterology and Inserm NGERE U1256, Nancy University Hospital, University of Lorraine, Vandoeuvre-lès-Nancy, France
Jairath, Vipul; Department of Medicine, Western University, London, Canada ; Department of Epidemiology and Biostatistics, Western University, London, Canada ; Alimentiv, London, Canada
Benetos, Athanase; Inserm, DCAC, University of Lorraine, Vandoeuvre-lès-Nancy, France ; CHRU-Nancy Brabois, Department of Clinical Geriatrics, University of Lorraine, Vandoeuvre-lès-Nancy, France
Danese, Silvio; Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milan, Italy
LOUIS, Edouard ; Centre Hospitalier Universitaire de Liège - CHU > > Service de gastroentérologie, hépatologie, onco. digestive
Peyrin-Biroulet, Laurent; Department of Gastroenterology and Inserm NGERE U1256, Nancy University Hospital, University of Lorraine, Vandoeuvre-lès-Nancy, France
Language :
English
Title :
Is it time to include older adults in inflammatory bowel disease trials? A call for action
SV was financially supported by the National Fund for Scientific Research (grant numbers 32729160 and 40001034).BC reports lecture fees from AbbVie, Amgen, Ferring Pharmaceuticals, Janssen Pharmaceuticals, and Takeda; and consulting fees from Celltrion and Janssen Pharmaceuticals. VJ has received consulting and advisory board fees from AbbVie, Alimentiv (formerly Robarts Clinical Trials), Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris Pharmaceuticals, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead Sciences, Janssen Pharmaceuticals, Merck, Mylan, Pandion, Pendopharm, Pfizer, Protagonist Therapeutics, Reistone Biopharma, Roche, Sandoz, Second Genome, Takeda, Teva Pharmaceuticals, and Topivert Pharma; and speaker's fees from AbbVie, Ferring Pharmaceuticals, Galapagos, Janssen Pharmaceuticals, Pfizer, Shire, and Takeda. SD has served as a consultant for Schering-Plough, AbbVie, Actelion, Alphawasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring Pharmaceuticals, Genentech, Grünenthal, Johnson & Johnson, Millennium Takeda, Merck Sharp & Dohme, Nikkiso Europe, Novo Nordisk, Nycomed, Pfizer, Pharmacosmos, UCB Pharma, and Vifor; and as a speaker for Pfizer, Takeda, AbbVie, and Janssen Pharmaceuticals. EL reports research grants from Janssen Pharmaceuticals, Pfizer, Ferring Pharmaceuticals, Dr Falk Pharma, AbbVie, and Takeda; educational grants from AbbVie, Janssen Pharmaceuticals, Fresenius Kabi, and Takeda; speaker's fees from AbbVie, Dr Falk Pharma, Ferring Pharmaceuticals, Janssen Pharmaceuticals, Pfizer, Galapagos, and Takeda; advisory board membership of AbbVie, Celgene, Ferring Pharmaceuticals, Janssen Pharmaceuticals, Bristol Myers Squibb, Pfizer, Takeda, Galapagos, Gilead Sciences, Arena Pharmaceuticals, and Eli Lilly; and has served as a consultant for AbbVie. LP-B reports personal fees from Galapagos, AbbVie, Janssen Pharmaceuticals, Genentech, Ferring Pharmaceuticals, Tillots Pharma, Pharmacosmos, Celltrion, Takeda, Boerhinger Ingelheim, Pfizer, Index Pharmaceuticals, Sandoz, Celgene, Biogen, Samsung Bioepis, Alma Bio Therapeutics, Sterna Biologicals, Nestlé, Inotrem, Enterome, Allergan, Merck Sharp & Dohme, Roche, Arena Pharmaceuticals, Gilead Sciences, Hikma Pharmaceuticals, Amgen, Bristol Myers Squibb, Vifor Pharma, Norgine, Mylan, Eli Lilly, Fresenius Kabi, Oppilan Pharma, Sublimity Therapeutics, Applied Molecular Transport, OSE Immunotherapeutics, Enthera, Theravance, and Pandion Therapeutics; grants from AbbVie, Merck Sharp & Dohme, Takeda, and Fresenius Kabi; and stock options for Clinical Trials Mobile Application. SV and AB declare no competing interests.
Rocchi, A, Benchimol, EI, Bernstein, CN, et al. Inflammatory bowel disease: a Canadian burden of illness review. Can J Gastroenterol 26 (2012), 811–817.
Cosnes, J, Gower-Rousseau, C, Seksik, P, Cortot, A, Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology 140 (2011), 1785–1794.
Jeuring, SF, van den Heuvel, TR, Zeegers, MP, et al. Epidemiology and long-term outcome of inflammatory bowel disease diagnosed at elderly age—an increasing distinct entity?. Inflamm Bowel Dis 22 (2016), 1425–1434.
Coward, S, Clement, F, Benchimol, EI, et al. Past and future burden of inflammatory bowel diseases based on modeling of population-based data. Gastroenterology 156 (2019), 1345–1353.
Charpentier, C, Salleron, J, Savoye, G, et al. Natural history of elderly-onset inflammatory bowel disease: a population-based cohort study. Gut 63 (2014), 423–432.
Nguyen, GC, Targownik, LE, Singh, H, et al. The impact of inflammatory bowel disease in Canada 2018: IBD in seniors. J Can Assoc Gastroenterol 2:suppl 1 (2019), S68–S72.
Burisch, J, Pedersen, N, Čuković-Čavka, S, et al. East–west gradient in the incidence of inflammatory bowel disease in Europe: the ECCO-EpiCom inception cohort. Gut 63 (2014), 588–597.
Kaplan, GG, Ng, SC, Globalisation of inflammatory bowel disease: perspectives from the evolution of inflammatory bowel disease in the UK and China. Lancet Gastroenterol Hepatol 1 (2016), 307–316.
Gower-Rousseau, C, Vasseur, F, Fumery, M, et al. Epidemiology of inflammatory bowel diseases: new insights from a French population-based registry (EPIMAD). Dig Liver Dis 45 (2013), 89–94.
Nguyen, GC, Sheng, L, Benchimol, EI, Health care utilization in elderly onset inflammatory bowel disease: a population-based study. Inflamm Bowel Dis 21 (2015), 777–782.
Molodecky, NA, Soon, IS, Rabi, DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 142 (2012), 46–54.
Travis, S, Is IBD different in the elderly?. Inflamm Bowel Dis 14:suppl 2 (2008), S12–S13.
Bernstein, CN, Wajda, A, Svenson, LW, et al. The epidemiology of inflammatory bowel disease in Canada: a population-based study. Am J Gastroenterol 101 (2006), 1559–1568.
Sturm, A, Maaser, C, Mendall, M, et al. European Crohn's and Colitis Organisation topical review on IBD in the elderly. J Crohn's Colitis 11 (2017), 263–273.
Lakatos, PL, David, G, Pandur, T, et al. IBD in the elderly population: results from a population-based study in western Hungary, 1977–2008. J Crohn's Colitis 5 (2011), 5–13.
Ha, CY, Katz, S, Clinical implications of ageing for the management of IBD. Nat Rev Gastroenterol Hepatol 11 (2014), 128–138.
Juneja, M, Baidoo, L, Schwartz, MB, et al. Geriatric inflammatory bowel disease: phenotypic presentation, treatment patterns, nutritional status, outcomes, and comorbidity. Dig Dis Sci 57 (2012), 2408–2415.
LeBlanc, JF, Wiseman, D, Lakatos, PL, Bessissow, T, Elderly patients with inflammatory bowel disease: updated review of the therapeutic landscape. World J Gastroenterol 25 (2019), 4158–4171.
Kochar, B, Long, MD, Galanko, J, Raffals, LE, Ananthakrishnan, A, Sandler, RS, Inflammatory bowel disease is similar in patients with older onset and younger onset. Inflamm Bowel Dis 23 (2017), 1187–1194.
Nguyen, GC, Bernstein, CN, Benchimol, EI, Risk of surgery and mortality in elderly-onset inflammatory bowel disease: a population-based cohort study. Inflamm Bowel Dis 23 (2017), 218–223.
Bollegala, N, Jackson, TD, Nguyen, GC, Increased postoperative mortality and complications among elderly patients with inflammatory bowel diseases: an analysis of the national surgical quality improvement program cohort. Clin Gastroenterol Hepatol 14 (2016), 1274–1281.
Nguyen, GC, Elnahas, A, Jackson, TD, The impact of preoperative steroid use on short-term outcomes following surgery for inflammatory bowel disease. J Crohn's Colitis 8 (2014), 1661–1667.
Everhov, ÅH, Halfvarson, J, Myrelid, P, et al. Incidence and treatment of patients diagnosed with inflammatory bowel diseases at 60 years or older in Sweden. Gastroenterology 154 (2018), 518–528.
Kariyawasam, VC, Kim, S, Mourad, FH, et al. Comorbidities rather than age are associated with the use of immunomodulators in elderly-onset inflammatory bowel disease. Inflamm Bowel Dis 25 (2019), 1390–1398.
Johnson, SL, Bartels, CM, Palta, M, Thorpe, CT, Weiss, JM, Smith, MA, Biological and steroid use in relationship to quality measures in older patients with inflammatory bowel disease: a US Medicare cohort study. BMJ Open, 5, 2015, e008597.
Kochar, B, Kalasapudi, L, Ufere, NN, Nipp, RD, Ananthakrishnan, AN, Ritchie, CS, Systematic review of inclusion and analysis of older adults in randomized controlled trials of medications used to treat inflammatory bowel diseases. Inflamm Bowel Dis 27 (2021), 1541–1543.
WHO. Men, ageing and health: achieving health across the lifespan. https://apps.who.int/iris/handle/10665/66941, 2001. (Accessed 9 August 2021)
The World Bank. Population ages 80 and above, male. https://data.worldbank.org/indicator/SP.POP.80UP.MA.5Y?end=2020&most_recent_value_desc=true&start=1960&view=chart, 2019. (Accessed 9 August 2021)
WHO. Life expectancy by age. https://www.worldlifeexpectancy.com/your-life-expectancy-by-age, 2018. (Accessed 9 August 2021)
Nimmons, D, Limdi, JK, Elderly patients and inflammatory bowel disease. World J Gastrointest Pharmacol Ther 7 (2016), 51–65.
Gorgoulis, V, Adams, PD, Alimonti, A, et al. Cellular senescence: defining a path forward. Cell 179 (2019), 813–827.
Frey, N, Venturelli, S, Zender, L, Bitzer, M, Cellular senescence in gastrointestinal diseases: from pathogenesis to therapeutics. Nat Rev Gastroenterol Hepatol 15 (2018), 81–95.
Prašnikar, E, Borišek, J, Perdih, A, Senescent cells as promising targets to tackle age-related diseases. Ageing Res Rev, 66, 2021, 101251.
Higgins, JPT, Green, S, (eds.) Cochrane handbook for systematic reviews of interventions, version 5.1.0, 2011, The Cochrane Collaboration, Chichester.
Hutton, B, Salanti, G, Caldwell, DM, et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med 162 (2015), 777–784.
Targan, SR, Hanauer, SB, van Deventer, SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor α for Crohn's disease. N Engl J Med 337 (1997), 1029–1035.
Present, DH, Rutgeerts, P, Targan, S, et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med 340 (1999), 1398–1405.
Rutgeerts, P, Sandborn, WJ, Feagan, BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 353 (2005), 2462–2476.
Reinisch, W, Angelberger, S, Petritsch, W, et al. Azathioprine versus mesalazine for prevention of postoperative clinical recurrence in patients with Crohn's disease with endoscopic recurrence: efficacy and safety results of a randomised, double-blind, double-dummy, multicentre trial. Gut 59 (2010), 752–759.
Feagan, BG, Sandborn, WJ, Mittmann, U, et al. Omega-3 free fatty acids for the maintenance of remission in Crohn disease: the EPIC randomized controlled trials. JAMA 299 (2008), 1690–1697.
Colombel, JF, Schwartz, DA, Sandborn, WJ, et al. Adalimumab for the treatment of fistulas in patients with Crohn's disease. Gut 58 (2009), 940–948.
Lichtenstein, GR, Kamm, MA, Boddu, P, et al. Effect of once- or twice-daily MMX mesalamine (SPD476) for the induction of remission of mild to moderately active ulcerative colitis. Clin Gastroenterol Hepatol 5 (2007), 95–102.
Leombruno, JP, Nguyen, GC, Grootendorst, P, Juurlink, D, Einarson, T, Hospitalization and surgical rates in patients with Crohn's disease treated with infliximab: a matched analysis. Pharmacoepidemiol Drug Saf 20 (2011), 838–848.
Grimaud, JC, Munoz-Bongrand, N, Siproudhis, L, et al. Fibrin glue is effective healing perianal fistulas in patients with Crohn's disease. Gastroenterology 138 (2010), 2275–2281.
Kamm, MA, Sandborn, WJ, Gassull, M, et al. Once-daily, high-concentration MMX mesalamine in active ulcerative colitis. Gastroenterology 132 (2007), 66–75.
Sands, BE, Feagan, BG, Rutgeerts, P, et al. Effects of vedolizumab induction therapy for patients with Crohn's disease in whom tumor necrosis factor antagonist treatment failed. Gastroenterology 147 (2014), 618–627.
Regueiro, M, Feagan, BG, Zou, B, et al. Infliximab reduces endoscopic, but not clinical, recurrence of Crohn's disease after ileocolonic resection. Gastroenterology 150 (2016), 1568–1578.
Feagan, BG, Sandborn, WJ, D'Haens, G, et al. Randomised clinical trial: vercirnon, an oral CCR9 antagonist, vs. placebo as induction therapy in active Crohn's disease. Aliment Pharmacol Ther 42 (2015), 1170–1181.
Colombel, JF, Panaccione, R, Bossuyt, P, et al. Effect of tight control management on Crohn's disease (CALM): a multicentre, randomised, controlled phase 3 trial. Lancet 390 (2017), 2779–2789.
Lang, A, Salomon, N, Wu, JC, et al. Curcumin in combination with mesalamine induces remission in patients with mild-to-moderate ulcerative colitis in a randomized controlled trial. Clin Gastroenterol Hepatol 13 (2015), 1444–1449.
Fedorak, RN, Feagan, BG, Hotte, N, et al. The probiotic VSL#3 has anti-inflammatory effects and could reduce endoscopic recurrence after surgery for Crohn's disease. Clin Gastroenterol Hepatol 13 (2015), 928–935.
Feagan, BG, Sandborn, WJ, Gasink, C, et al. Ustekinumab as induction and maintenance therapy for Crohn's disease. N Engl J Med 375 (2016), 1946–1960.
Gasche, C, Ahmad, T, Tulassay, Z, et al. Ferric maltol is effective in correcting iron deficiency anemia in patients with inflammatory bowel disease: results from a phase-3 clinical trial program. Inflamm Bowel Dis 21 (2015), 579–588.
Atreya, R, Reinisch, W, Peyrin-Biroulet, L, et al. Clinical efficacy of the Toll-like receptor 9 agonist cobitolimod using patient-reported-outcomes defined clinical endpoints in patients with ulcerative colitis. Dig Liver Dis 50 (2018), 1019–1029.
Therkelsen, SP, Hetland, G, Lyberg, T, Lygren, I, Johnson, E, Effect of a medicinal Agaricus blazei Murill-based mushroom extract, AndoSan™, on symptoms, fatigue and quality of life in patients with ulcerative colitis in a randomized single-blinded placebo controlled study. PLoS One, 11, 2016, e0150191.
Yokoyama, T, Ohta, A, Motoya, S, et al. Efficacy and safety of oral budesonide in patients with active Crohn's disease in Japan: a multicenter, double-blind, randomized, parallel-group phase 3 study. Inflamm Intest Dis 2 (2018), 154–162.
Rubin, DT, Cohen, RD, Sandborn, WJ, et al. Budesonide multimatrix is efficacious for mesalamine-refractory, mild to moderate ulcerative colitis: a randomised, placebo-controlled trial. J Crohn's Colitis 11 (2017), 785–791.
Bonaz, B, Sinniger, V, Pellissier, S, Vagus nerve stimulation: a new promising therapeutic tool in inflammatory bowel disease. J Intern Med 282 (2017), 46–63.
Sandborn, WJ, Su, C, Sands, BE, et al. Tofacitinib as induction and maintenance therapy for ulcerative colitiS. N Engl J Med 376 (2017), 1723–1736.
Travis, S, Feagan, BG, Peyrin-Biroulet, L, et al. Effect of adalimumab on clinical outcomes and health-related quality of life among patients with ulcerative colitis in a clinical practice setting: results from InspirADA. J Crohn's Colitis 11 (2017), 1317–1325.
López-Sanromán, A, Vera-Mendoza, I, Domènech, E, et al. Adalimumab vs azathioprine in the prevention of postoperative Crohn's disease recurrence. A GETECCU randomised trial. J Crohn's Colitis 11 (2017), 1293–1301.
Panés, J, García-Olmo, D, Van Assche, G, et al. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial. Lancet 388 (2016), 1281–1290.
Cross, RK, Langenberg, P, Regueiro, M, et al. A randomized controlled trial of telemedicine for patients with inflammatory bowel disease (TELE-IBD). Am J Gastroenterol 114 (2019), 472–482.
Hibi, T, Imai, Y, Senoo, A, Ohta, K, Ukyo, Y, Efficacy and safety of golimumab 52-week maintenance therapy in Japanese patients with moderate to severely active ulcerative colitis: a phase 3, double-blind, randomized, placebo-controlled study—(PURSUIT-J study). J Gastroenterol 52 (2017), 1101–1111.
Motoya, S, Watanabe, M, Wallace, K, et al. Efficacy and safety of dose escalation to adalimumab 80 mg every other week in Japanese patients with Crohn's disease who lost response to maintenance therapy. Inflamm Intest Dis 2 (2018), 228–235.
D'Haens, GR, Sandborn, WJ, Zou, G, et al. Randomised non-inferiority trial: 1600 mg versus 400 mg tablets of mesalazine for the treatment of mild-to-moderate ulcerative colitis. Aliment Pharmacol Ther 46 (2017), 292–302.
Watanabe, K, Motoya, S, Ogata, H, et al. Effects of vedolizumab in Japanese patients with Crohn's disease: a prospective, multicenter, randomized, placebo-controlled phase 3 trial with exploratory analyses. J Gastroenterol 55 (2020), 291–306.
Motoya, S, Watanabe, K, Ogata, H, et al. Vedolizumab in Japanese patients with ulcerative colitis: a phase 3, randomized, double-blind, placebo-controlled study. PLoS One, 14, 2019, e0212989.
Greener, T, Boland, K, Milgrom, R, et al. Higher adalimumab maintenance regimen is more effective than standard dose in anti-TNF experienced Crohn's disease patients. Eur J Gastroenterol Hepatol 33 (2021), 1274–1279.
Sandborn, WJ, Vermeire, S, Tyrrell, H, et al. Etrolizumab for the treatment of ulcerative colitis and Crohn's disease: an overview of the phase 3 clinical program. Adv Ther 37 (2020), 3417–3431.
Tromm, A, Bunganič, I, Tomsová, E, et al. Budesonide 9 mg is at least as effective as mesalamine 4.5 g in patients with mildly to moderately active Crohn's disease. Gastroenterology 140 (2011), 425–434.
Ye, BD, Pesegova, M, Alexeeva, O, et al. Efficacy and safety of biosimilar CT-P13 compared with originator infliximab in patients with active Crohn's disease: an international, randomised, double-blind, phase 3 non-inferiority study. Lancet 393 (2019), 1699–1707.
Hyun, SB, Kitazume, Y, Nagahori, M, et al. Magnetic resonance enterocolonography is useful for simultaneous evaluation of small and large intestinal lesions in Crohn's disease. Inflamm Bowel Dis 17 (2011), 1063–1072.
Reinisch, W, Mishkin, DS, Oh, YS, et al. Impact of various central endoscopy reading models on treatment outcome in Crohn's disease using data from the randomized, controlled, exploratory cohort arm of the BERGAMOT trial. Gastrointest Endosc 93 (2021), 174–182.
Danese, S, Sandborn, WJ, Colombel, JF, et al. Endoscopic, radiologic, and histologic healing with vedolizumab in patients with active Crohn's disease. Gastroenterology 157 (2019), 1007–1018.
Uygun, A, Ozturk, K, Demirci, H, et al. Fecal microbiota transplantation is a rescue treatment modality for refractory ulcerative colitis. Medicine, 96, 2017, e6479.
Sandborn, WJ, Feagan, BG, D'Haens, G, et al. Ozanimod as induction and maintenance therapy for ulcerative colitis. N Engl J Med 385 (2021), 1280–1291.
Sands, BE, Sandborn, WJ, Panaccione, R, et al. Ustekinumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 381 (2019), 1201–1214.
Chen, B, Gao, X, Zhong, J, et al. Efficacy and safety of adalimumab in Chinese patients with moderately to severely active Crohn's disease: results from a randomized trial. Therap Adv Gastroenterol, 13, 2020 1756284820938960.
Sands, BE, Peyrin-Biroulet, L, Loftus, EV Jr, et al. Vedolizumab versus adalimumab for moderate-to-severe ulcerative colitis. N Engl J Med 381 (2019), 1215–1226.
Sandborn, WJ, Rutgeerts, P, Enns, R, et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med 146 (2007), 829–838.
Sands, BE, Feagan, BG, Sandborn, WJ, et al. Mongersen (GED-0301) for active Crohn's disease: results of a phase 3 study. Am J Gastroenterol 115 (2020), 738–745.
Sandborn, WJ, Baert, F, Danese, S, et al. Efficacy and safety of vedolizumab subcutaneous formulation in a randomized trial of patients with ulcerative colitis. Gastroenterology 158 (2020), 562–572.
Howaldt, S, Domènech, E, Martinez, N, Schmidt, C, Bokemeyer, B, Long-term effectiveness of oral ferric maltol vs intravenous ferric carboxymaltose for the treatment of iron-deficiency anemia in patients with inflammatory bowel disease: a randomized controlled noninferiority trial. Inflamm Bowel Dis 28 (2022), 373–384.
Sandborn, WJ, Ghosh, S, Panes, J, et al. Efficacy of upadacitinib in a randomized trial of patients with active ulcerative colitis. Gastroenterology 158 (2020), 2139–2149.
Hanauer, S, Liedert, B, Balser, S, Brockstedt, E, Moschetti, V, Schreiber, S, Safety and efficacy of BI 695501 versus adalimumab reference product in patients with advanced Crohn's disease (VOLTAIRE-CD): a multicentre, randomised, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol 6 (2021), 816–825.
Feagan, BG, Danese, S, Loftus, EV Jr, et al. Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial. Lancet 397 (2021), 2372–2384.
Pompilus, F, Ciesluk, A, Strzok, S, et al. Development and psychometric evaluation of the assessment of self-injection questionnaire: an adaptation of the self-injection assessment questionnaire. Health Qual Life Outcomes, 18, 2020, 355.
Dehmer, C, Greinwald, R, Löffler, J, et al. No dose-dependent tubulotoxicity of 5-aminosalicylic acid: a prospective study in patients with inflammatory bowel diseases. Int J Colorectal Dis 18 (2003), 406–412.
Feagan, BG, Sandborn, WJ, Lichtenstein, G, Radford-Smith, G, Patel, J, Innes, A, CDP571, a humanized monoclonal antibody to tumour necrosis factor-α, for steroid-dependent Crohn's disease: a randomized, double-blind, placebo-controlled trial. Aliment Pharmacol Ther 23 (2006), 617–628.
Gibson, PR, Fixa, B, Pekárková, B, et al. Comparison of the efficacy and safety of Eudragit-L-coated mesalazine tablets with ethylcellulose-coated mesalazine tablets in patients with mild to moderately active ulcerative colitis. Aliment Pharmacol Ther 23 (2006), 1017–1026.
Lichtenstein, GR, Zakko, S, Gordon, GL, et al. Mesalazine granules 1.5 g once-daily maintain remission in patients with ulcerative colitis who switch from other 5-ASA formulations: a pooled analysis from two randomised controlled trials. Aliment Pharmacol Ther 36 (2012), 126–134.
Andus, T, Kocjan, A, Müser, M, et al. Clinical trial: a novel high-dose 1 g mesalamine suppository (Salofalk) once daily is as efficacious as a 500-mg suppository thrice daily in active ulcerative proctitis. Inflamm Bowel Dis 16 (2010), 1947–1956.
Hiwatashi, N, Suzuki, Y, Mitsuyama, K, Munakata, A, Hibi, T, Clinical trial: effects of an oral preparation of mesalazine at 4 g/day on moderately active ulcerative colitis. A phase III parallel-dosing study. J Gastroenterol 46 (2011), 46–56.
Reinisch, W, Travis, S, Hanauer, S, Wang, H, Shara, N, Harris, MS, AST-120 (spherical carbon adsorbent) in the treatment of perianal fistulae in mild-to-moderate Crohn's disease: FHAST-1, a phase 3, multicenter, placebo-controlled study. Inflamm Bowel Dis 20 (2014), 872–881.
Sandborn, WJ, Bosworth, B, Zakko, S, et al. Budesonide foam induces remission in patients with mild to moderate ulcerative proctitis and ulcerative proctosigmoiditis. Gastroenterology 148 (2015), 740–750.
Gardenbroek, TJ, Pinkney, TD, Sahami, S, et al. The ACCURE-trial: the effect of appendectomy on the clinical course of ulcerative colitis, a randomised international multicenter trial (NTR2883) and the ACCURE-UK trial: a randomised external pilot trial (ISRCTN56523019). BMC Surg, 15, 2015, 30.
Kobayashi, T, Suzuki, Y, Motoya, S, et al. First trough level of infliximab at week 2 predicts future outcomes of induction therapy in ulcerative colitis—results from a multicenter prospective randomized controlled trial and its post hoc analysis. J Gastroenterol 51 (2016), 241–251.
Launay, O, Abitbol, V, Krivine, A, et al. Immunogenicity and safety of influenza vaccine in inflammatory bowel disease patients treated or not with immunomodulators and/or biologics: a two-year prospective study. J Crohn's Colitis 9 (2015), 1096–1107.
Gordon, GL, Zakko, S, Murthy, U, et al. Once-daily mesalamine formulation for maintenance of remission in ulcerative colitis. J Clin Gastroenterol 50 (2016), 318–325.
Suzuki, Y, Iida, M, Ito, H, et al. 2.4 g mesalamine (Asacol 400 mg tablet) once daily is as effective as three times daily in maintenance of remission in ulcerative colitis: a randomized, noninferiority, multi-center trial. Inflamm Bowel Dis 23 (2017), 822–832.
Naganuma, M, Aoyama, N, Tada, T, et al. Complete mucosal healing of distal lesions induced by twice-daily budesonide 2-mg foam promoted clinical remission of mild-to-moderate ulcerative colitis with distal active inflammation: double-blind, randomized study. J Gastroenterol 53 (2018), 494–506.
Sands, BE, Katz, S, Wolf, DC, et al. A randomised, double-blind, sham-controlled study of granulocyte/monocyte apheresis for moderate to severe Crohn's disease. Gut 62 (2013), 1288–1294.
Neeb, L, Bayer, A, Bayer, KE, et al. Transcranial direct current stimulation in inflammatory bowel disease patients modifies resting-state functional connectivity: a RCT. Brain Stimul 12 (2019), 978–980.
Chaparro, M, Gordillo, J, Domènech, E, et al. Fendrix vs Engerix-B for primo-vaccination against hepatitis B infection in patients with inflammatory bowel disease: a randomized clinical trial. Am J Gastroenterol 115 (2020), 1802–1811.
Colombel, JF, Sandborn, WJ, Reinisch, W, et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med 362 (2010), 1383–1395.
Kruis, W, Jonaitis, L, Pokrotnieks, J, et al. Randomised clinical trial: a comparative dose-finding study of three arms of dual release mesalazine for maintaining remission in ulcerative colitis. Aliment Pharmacol Ther 33 (2011), 313–322.
Maeda, Y, Ng, SC, Durdey, P, et al. Randomized clinical trial of metronidazole ointment versus placebo in perianal Crohn's disease. Br J Surg 97 (2010), 1340–1347.
Kruis, W, Kiudelis, G, Rácz, I, et al. Once daily versus three times daily mesalazine granules in active ulcerative colitis: a double-blind, double-dummy, randomised, non-inferiority trial. Gut 58 (2009), 233–240.
Feagan, BG, McDonald, JW, Panaccione, R, et al. Methotrexate in combination with infliximab is no more effective than infliximab alone in patients with Crohn's disease. Gastroenterology 146 (2014), 681–688.
Louis, E, Mary, JY, Vernier-Massouille, G, et al. Maintenance of remission among patients with Crohn's disease on antimetabolite therapy after infliximab therapy is stopped. Gastroenterology 142 (2012), 63–70.
Hébuterne, X, Lémann, M, Bouhnik, Y, et al. Endoscopic improvement of mucosal lesions in patients with moderate to severe ileocolonic Crohn's disease following treatment with certolizumab pegol. Gut 62 (2013), 201–208.
Sandborn, WJ, Colombel, JF, Frankel, M, et al. Anti-CD3 antibody visilizumab is not effective in patients with intravenous corticosteroid-refractory ulcerative colitis. Gut 59 (2010), 1485–1492.
Sands, BE, Anderson, FH, Bernstein, CN, et al. Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med 350 (2004), 876–885.
Sandborn, WJ, Abreu, MT, D'Haens, G, et al. Certolizumab pegol in patients with moderate to severe Crohn's disease and secondary failure to infliximab. Clin Gastroenterol Hepatol 8 (2010), 688–695.
Lichtiger, S, Binion, DG, Wolf, DC, et al. The CHOICE trial: adalimumab demonstrates safety, fistula healing, improved quality of life and increased work productivity in patients with Crohn's disease who failed prior infliximab therapy. Aliment Pharmacol Ther 32 (2010), 1228–1239.
Hawkey, CJ, Allez, M, Clark, MM, et al. Autologous hematopoetic stem cell transplantation for refractory Crohn disease: a randomized clinical trial. JAMA 314 (2015), 2524–2534.
Colombel, JF, Rutgeerts, PJ, Sandborn, WJ, et al. Adalimumab induces deep remission in patients with Crohn's disease. Clin Gastroenterol Hepatol 12 (2014), 414–422.
Gillespie, D, Farewell, D, Barrett-Lee, P, et al. The use of randomisation-based efficacy estimators in non-inferiority trials. Trials, 18, 2017, 117.
Sands, BE, Blank, MA, Patel, K, van Deventer, SJ, Long-term treatment of rectovaginal fistulas in Crohn's disease: response to infliximab in the ACCENT II study. Clin Gastroenterol Hepatol 2 (2004), 912–920.
Sandborn, WJ, van Assche, G, Reinisch, W, et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 142 (2012), 257–265.
Sandborn, WJ, Colombel, JF, Sands, BE, et al. Abatacept for Crohn's disease and ulcerative colitis. Gastroenterology 143 (2012), 62–69.
Reinisch, W, Sandborn, WJ, Hommes, DW, et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut 60 (2011), 780–787.
Sandborn, WJ, Colombel, JF, D'Haens, G, et al. One-year maintenance outcomes among patients with moderately-to-severely active ulcerative colitis who responded to induction therapy with adalimumab: subgroup analyses from ULTRA 2. Aliment Pharmacol Ther 37 (2013), 204–213.
Louis, E, Löfberg, R, Reinisch, W, et al. Adalimumab improves patient-reported outcomes and reduces indirect costs in patients with moderate to severe Crohn's disease: results from the CARE trial. J Crohn's Colitis 7 (2013), 34–43.
Panaccione, R, Loftus, EV Jr, Binion, D, et al. Efficacy and safety of adalimumab in Canadian patients with moderate to severe Crohn's disease: results of the Adalimumab in Canadian SubjeCts with ModErate to Severe Crohn's DiseaSe (ACCESS) trial. Can J Gastroenterol 25 (2011), 419–425.
Watanabe, M, Hibi, T, Lomax, KG, et al. Adalimumab for the induction and maintenance of clinical remission in Japanese patients with Crohn's disease. J Crohn's Colitis 6 (2012), 160–173.
Loftus, EV Jr, Colombel, JF, Schreiber, S, et al. Safety of long-term treatment with certolizumab pegol in patients with Crohn's disease, based on a pooled analysis of data from clinical trials. Clin Gastroenterol Hepatol 14 (2016), 1753–1762.
Sandborn, WJ, Korzenik, J, Lashner, B, et al. Once-daily dosing of delayed-release oral mesalamine (400-mg tablet) is as effective as twice-daily dosing for maintenance of remission of ulcerative colitis. Gastroenterology 138 (2010), 1286–1296.
Hanauer, SB, Feagan, BG, Lichtenstein, GR, et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 359 (2002), 1541–1549.
Panaccione, R, Ghosh, S, Middleton, S, et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology 146 (2014), 392–400.
Rutgeerts, P, Feagan, BG, Marano, CW, et al. Randomised clinical trial: a placebo-controlled study of intravenous golimumab induction therapy for ulcerative colitis. Aliment Pharmacol Ther 42 (2015), 504–514.
Sandborn, WJ, Feagan, BG, Marano, C, et al. Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 146 (2014), 85–95.
Gross, V, Bunganic, I, Belousova, EA, et al. 3g mesalazine granules are superior to 9 mg budesonide for achieving remission in active ulcerative colitis: a double-blind, double-dummy, randomised trial. J Crohn's Colitis 5 (2011), 129–138.
Cross, RK, Arora, M, Finkelstein, J, Acceptance of telemanagement is high in patients with inflammatory bowel disease. J Clin Gastroenterol 40 (2006), 200–208.
Sandborn, WJ, Schreiber, S, Feagan, BG, et al. Certolizumab pegol for active Crohn's disease: a placebo-controlled, randomized trial. Clin Gastroenterol Hepatol 9 (2011), 670–678.
Travis, SP, Danese, S, Kupcinskas, L, et al. Once-daily budesonide MMX in active, mild-to-moderate ulcerative colitis: results from the randomised CORE II study. Gut 63 (2014), 433–441.
Sandborn, WJ, Travis, S, Moro, L, et al. Once-daily budesonide MMX® extended-release tablets induce remission in patients with mild to moderate ulcerative colitis: results from the CORE I study. Gastroenterology 143 (2012), 1218–1226.
Dewint, P, Hansen, BE, Verhey, E, et al. Adalimumab combined with ciprofloxacin is superior to adalimumab monotherapy in perianal fistula closure in Crohn's disease: a randomised, double-blind, placebo controlled trial (ADAFI). Gut 63 (2014), 292–299.
Flourié, B, Hagège, H, Tucat, G, et al. Randomised clinical trial: once- vs. twice-daily prolonged-release mesalazine for active ulcerative colitis. Aliment Pharmacol Ther 37 (2013), 767–775.
Lichtenstein, GR, Ramsey, D, Rubin, DT, Randomised clinical trial: delayed-release oral mesalazine 4·8 g/day vs. 2·4 g/day in endoscopic mucosal healing—ASCEND I and II combined analysis. Aliment Pharmacol Ther 33 (2011), 672–678.
Sandborn, WJ, Feagan, BG, Rutgeerts, P, et al. Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med 369 (2013), 711–721.
Feagan, BG, Rutgeerts, P, Sands, BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 369 (2013), 699–710.
De Cruz, P, Kamm, MA, Hamilton, AL, et al. Crohn's disease management after intestinal resection: a randomised trial. Lancet 385 (2015), 1406–1417.
Feagan, BG, Sandborn, WJ, D'Haens, G, et al. The role of centralized reading of endoscopy in a randomized controlled trial of mesalamine for ulcerative colitis. Gastroenterology 145 (2013), 149–157.
Dignass, A, Stoynov, S, Dorofeyev, AE, et al. Once versus three times daily dosing of oral budesonide for active Crohn's disease: a double-blind, double-dummy, randomised trial. J Crohn's Colitis 8 (2014), 970–980.
Sun, J, Yuan, Y, Mesalazine modified-release tablet in the treatment of ulcerative colitis in the active phase: a Chinese, multicenter, single-blind, randomized controlled study. Adv Ther 33 (2016), 400–409.
Sandborn, WJ, Colombel, JF, Enns, R, et al. Natalizumab induction and maintenance therapy for Crohn's disease. N Engl J Med 353 (2005), 1912–1925.
Sandborn, WJ, Baert, F, Danese, S, et al. Efficacy and safety of vedolizumab subcutaneous formulation in a randomized trial of patients with ulcerative colitis. Gastroenterology 158 (2020), 562–572.
Sun, J, Yuan, Y, Mesalazine modified-release tablet in the treatment of ulcerative colitis in the remission phase: a Chinese, multicenter, single-blind, randomized controlled study. Adv Ther 33 (2016), 410–422.
Argollo, M, Gilardi, D, Peyrin-Biroulet, C, Chabot, JF, Peyrin-Biroulet, L, Danese, S, Comorbidities in inflammatory bowel disease: a call for action. Lancet Gastroenterol Hepatol 4 (2019), 643–654.
Ananthakrishnan, AN, Frailty in patients with inflammatory bowel disease. Gastroenterol Hepatol 17 (2021), 263–268.
Clegg, A, Young, J, Iliffe, S, Rikkert, MO, Rockwood, K, Frailty in elderly people. Lancet 381 (2013), 752–762.
Fried, LP, Tangen, CM, Walston, J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 56 (2001), M146–M156.
Xue, QL, The frailty syndrome: definition and natural history. Clin Geriatr Med 27 (2011), 1–15.
Dent, E, Kowal, P, Hoogendijk, EO, Frailty measurement in research and clinical practice: a review. Eur J Intern Med 31 (2016), 3–10.
Benetos, A, Petrovic, M, Strandberg, T, Hypertension management in older and frail older patients. Circ Res 124 (2019), 1045–1060.
Fried, LP, Ferrucci, L, Darer, J, Williamson, JD, Anderson, G, Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care. J Gerontol A Biol Sci Med Sci 59 (2004), 255–263.
Faye, AS, Colombel, JF, Aging and IBD: a new challenge for clinicians and researchers. Inflamm Bowel Dis 28 (2022), 126–132.
Pawelec, G, Goldeck, D, Derhovanessian, E, Inflammation, ageing and chronic disease. Curr Opin Immunol 29 (2014), 23–28.
Ananthakrishnan, AN, Shi, HY, Tang, W, et al. Systematic review and meta-analysis: phenotype and clinical outcomes of older-onset inflammatory bowel disease. J Crohn's Colitis 10 (2016), 1224–1236.
Kochar, B, Cai, W, Cagan, A, Ananthakrishnan, AN, Pretreatment frailty is independently associated with increased risk of infections after immunosuppression in patients with inflammatory bowel diseases. Gastroenterology 158 (2020), 2104–2111.
Kochar, B, Cai, W, Cagan, A, Ananthakrishnan, AN, Frailty is independently associated with mortality in 11 001 patients with inflammatory bowel diseases. Aliment Pharmacol Ther 52 (2020), 311–318.
Qian, AS, Nguyen, NH, Elia, J, Ohno-Machado, L, Sandborn, WJ, Singh, S, Frailty is independently associated with mortality and readmission in hospitalized patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol 19 (2021), 2054–2063.
Faye, AS, Wen, T, Soroush, A, et al. Increasing prevalence of frailty and its association with readmission and mortality among hospitalized patients with IBD. Dig Dis Sci 66 (2021), 4178–4190.
Telemi, E, Trofymenko, O, Venkat, R, Pandit, V, Pandian, TK, Nfonsam, VN, Frailty predicts morbidity after colectomy for ulcerative colitis. Am Surg 84 (2018), 225–229.
Wolf, JH, Hassab, T, D'Adamo, CR, et al. Frailty is a stronger predictor than age for postoperative morbidity in Crohn's disease. Surgery 170 (2021), 1061–1065.
Faye, AS, Colombel, JF, Age is just a number—frailty associates with outcomes of patients with inflammatory bowel disease. Gastroenterology 158 (2020), 2041–2043.
Kochar, BD, Cai, W, Ananthakrishnan, AN, Inflammatory bowel disease patients who respond to treatment with anti-tumor necrosis factor agents demonstrate improvement in pre-treatment frailty. Dig Dis Sci 67 (2022), 622–628.
Dent, E, Martin, FC, Bergman, H, Woo, J, Romero-Ortuno, R, Walston, JD, Management of frailty: opportunities, challenges, and future directions. Lancet 394 (2019), 1376–1386.
Negm, AM, Kennedy, CC, Thabane, L, et al. Management of frailty: a systematic review and network meta-analysis of randomized controlled trials. J Am Med Dir Assoc 20 (2019), 1190–1198.
US Food & Drug Administration. Study of drugs likely to be used in the elderly. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072048.pdf, 1989. (Accessed 20 October 2021)
Bayer, A, Tadd, W, Unjustified exclusion of elderly people from studies submitted to research ethics committee for approval: descriptive study. BMJ 321 (2000), 992–993.
Pijpers, E, Ferreira, I, van de Laar, RJJ, Stehouwer, CD, Nieuwenhuijzen Kruseman, AC, Predicting mortality of psychogeriatric patients: a simple prognostic frailty risk score. Postgrad Med J 85 (2009), 464–469.
Subramaniam, S, Aalberg, JJ, Soriano, RP, Divino, CM, New 5-factor modified frailty index using American College of Surgeons NSQIP data. J Am Coll Surg 226 (2018), 173–181.
Gilbert, T, Neuburger, J, Kraindler, J, et al. Development and validation of a Hospital Frailty Risk Score focusing on older people in acute care settings using electronic hospital records: an observational study. Lancet 391 (2018), 1775–1782.
Asscher, VER, Waars, SN, van der Meulen-de Jong, AE, et al. Deficits in geriatric assessment associate with disease activity and burden in older patients with inflammatory bowel disease. Clin Gastroenterol Hepatol, 2021 published online June 19. https://doi.org/10.1016/j.cgh.2021.06.015.
Solomon, D, Brown, AS, Brummel-Smith, K, et al. Best paper of the 1980s: National Institutes of Health Consensus Development Conference statement: geriatric assessment methods for clinical decision-making. J Am Geriatr Soc 51 (2003), 1490–1494.
Rubenstein, LZ, Harker, JO, Salvà, A, Guigoz, Y, Vellas, B, Screening for undernutrition in geriatric practice: developing the short-form Mini-Nutritional Assessment (MNA-SF). J Gerontol A Biol Sci Med Sci 56 (2001), M366–M372.
Charlson, ME, Pompei, P, Ales, KL, MacKenzie, CR, A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 40 (1987), 373–383.
Khan, N, Vallarino, C, Lissoos, T, Darr, U, Luo, M, Risk of infection and types of infection among elderly patients with inflammatory bowel disease: a retrospective database analysis. Inflamm Bowel Dis 26 (2020), 462–468.
Bibbins-Domingo, K, Grossman, DC, Curry, SJ, et al. Screening for colorectal cancer: US Preventive Services Task Force recommendation statement. JAMA 315 (2016), 2564–2575.
Wang, J, Nakamura, TI, Tuskey, AG, Behm, BW, Polypharmacy is a risk factor for disease flare in adult patients with ulcerative colitis: a retrospective cohort study. Intest Res 17 (2019), 496–503.
Stallmach, A, Hagel, S, Gharbi, A, et al. Medical and surgical therapy of inflammatory bowel disease in the elderly—prospects and complications. J Crohn's Colitis 5 (2011), 177–188.
Tran, V, Limketkai, BN, Sauk, JS, IBD in the elderly: management challenges and therapeutic considerations. Curr Gastroenterol Rep, 21, 2019, 60.
Katz, S, Pardi, DS, Inflammatory bowel disease of the elderly: frequently asked questions (FAQs). Am J Gastroenterol 106 (2011), 1889–1897.
Katz, S, Ford, AB, Moskowitz, RW, Jackson, BA, Jaffe, MW, Studies of illness in the aged. The index ADL: a standardized measure of biological and psychological function. JAMA 185 (1963), 914–919.
Lawton, MP, Brody, EM, Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 9 (1969), 179–186.
Roberts, HC, Denison, HJ, Martin, HJ, et al. A review of the measurement of grip strength in clinical and epidemiological studies: towards a standardised approach. Age Ageing 40 (2011), 423–429.
Abellan van Kan, G, Rolland, Y, Andrieu, S, et al. Gait speed at usual pace as a predictor of adverse outcomes in community-dwelling older people an International Academy on Nutrition and Aging (IANA) Task Force. J Nutr Health Aging 13 (2009), 881–889.
Tuijl, JP, Scholte, EM, de Craen, AJ, van der Mast, RC, Screening for cognitive impairment in older general hospital patients: comparison of the Six-Item Cognitive Impairment Test with the Mini-Mental State Examination. Int J Geriatr Psychiatry 27 (2012), 755–762.
Wagtmans, MJ, Verspaget, HW, Lamers, CB, van Hogezand, RA, Crohn's disease in the elderly: a comparison with young adults. J Clin Gastroenterol 27 (1998), 129–133.
Tsang, P, Rotterdam, H, Biopsy diagnosis of colitis: possibilities and pitfalls. Am J Surg Pathol 23 (1999), 423–430.
Lichtenstein, GR, Feagan, BG, Cohen, RD, et al. Drug therapies and the risk of malignancy in Crohn's disease: results from the TREAT™ Registry. Am J Gastroenterol 109 (2014), 212–223.
Nyboe Andersen, N, Pasternak, B, Basit, S, et al. Association between tumor necrosis factor-α antagonists and risk of cancer in patients with inflammatory bowel disease. JAMA 311 (2014), 2406–2413.
Beaugerie, L, Svrcek, M, Seksik, P, et al. Risk of colorectal high-grade dysplasia and cancer in a prospective observational cohort of patients with inflammatory bowel disease. Gastroenterology 145 (2013), 166–175.
Bressler, B, Panaccione, R, Fedorak, RN, Seidman, EG, Clinicians' guide to the use of fecal calprotectin to identify and monitor disease activity in inflammatory bowel disease. Can J Gastroenterol Hepatol 29 (2015), 369–372.
Velissaris, D, Pantzaris, N, Koniari, I, et al. C-reactive protein and frailty in the elderly: a literature review. J Clin Med Res 9 (2017), 461–465.
LeBlanc, JF, Wiseman, D, Lakatos, PL, Bessissow, T, Elderly patients with inflammatory bowel disease: updated review of the therapeutic landscape. World J Gastroenterol 25 (2019), 4158–4171.
Lobatón, T, Ferrante, M, Rutgeerts, P, Ballet, V, Van Assche, G, Vermeire, S, Efficacy and safety of anti-TNF therapy in elderly patients with inflammatory bowel disease. Aliment Pharmacol Ther 42 (2015), 441–451.
Desai, A, Zator, ZA, de Silva, P, et al. Older age is associated with higher rate of discontinuation of anti-TNF therapy in patients with inflammatory bowel disease. Inflamm Bowel Dis 19 (2013), 309–315.
Colombel, JF, Loftus, EV Jr, Tremaine, WJ, et al. The safety profile of infliximab in patients with Crohn's disease: the Mayo clinic experience in 500 patients. Gastroenterology 126 (2004), 19–31.
Hempenius, L, Slaets, JP, Boelens, MA, et al. Inclusion of frail elderly patients in clinical trials: solutions to the problems. J Geriatr Oncol 4 (2013), 26–31.
