Challenges in IBD Treatment of IBD in the elderly Jean-Frédéric Colombel, MD Joannie Ruel, MD Icahn School of Medicine at Mount Sinai, New York Conflicts of interest disclosure J-F Colombel has served as consultant, advisory board member or speaker for or received research grants from Abbvie, Amgen, Bristol Meyers Squibb, Celltrion, Ferring, Genentech, Giuliani SPA, Given Imaging, Janssend and Janssen, Merck & Co., Millenium Pharmaceuticals Inc., Nutrition Science Partners Ltd., Pfizer Inc. Prometheus Laboratories, Sanofi, Schering Plough Corporation, Takeda, Teva Pharmaceuticals, UCB Pharma, Vertex, Dr. August Wolff GmbH & Co. Fit versus frail elderly Outline • Epidemiology • Special considerations • Medical and surgical therapies in the elderly • Therapeutic strategies in the elderly Epidemiology Aging of the population makes elderly-onset IBD and IBD in elderly patients with disease starting at a younger age a rising problem. Epidemiology • 10-15 % of IBD cases will receive their diagnosis > 60 years of age o 65% in their sixties o 25% in their seventies o 10% in their eighties • • 1/20 cases of CD & 1/8 of UC cases are diagnosed in patients > 60 years of age Elderly IBD population will increase as majority of IBD patients attain an older age Special considerations Differential diagnosis • Consider an appropriate differential diagnosis before making a definitive diagnosis • • • • • • • Ischemic colitis Infectious colitis Complicated diverticular disease and SCAD Drug-associated colitis Microscopic colitis Radiation colitis Neoplasia Natural history in elderly-onset IBD EPIMAD Registry 1988-2006 6 million inhabitants (9.3% of french population) 3 Academic hospitals (CHU) (Lille, Rouen, Amiens) 27 Regional hospitals 250 adult gastroenterologists private and public 12 pediatric gastroenterologists 6 909 CD 367 (5%) 1 175 (17%) 4 310 UC 474 (11%) 689 (10%) 213 (5%) 1 189 (27%) 4 678 (68%) 2 434 (57%) Gower-Rousseau C et al. Gut 1994 Gower-Rousseau C et al. DLD 2012 UC: disease location and extension according to age Proctitis % 70 60 48 41 50 40 Left-sided colitis 50 Extensive colitis 45 31 30 29 20 10 Elderly-onset 0 <17 y (N=213) Pediatric-onset 70 % 60 17-39 y (N=2434) 40-59 y (N=1189) % ≥ 60 (N=474) 70 6 years median follow-up 50 34 60 40 50 30 40 30 26 14 Disease extension in 16% 20 Disease extension in 49% 10 49 60 0 At maximal Follow-up Charpentier C et al. Gut 2013, Gower-Rousseau C et al. Am J G 2009 17 20 10 0 At maximal follow-up CD: Evolution of behavior from diagnosis to maximal follow-up Elderly-onset patients (>60 yrs at diagnosis) 5% 17% Penetrating Stricturing 10% 22% 78% Inflammatory 68% Pediatric-onset patients (<17 yrs at diagnosis) Natural history in elderly patients with younger age at-onset • In elderly patients with disease onset at a younger age, a more aggressive presentation may still occur. • Crohn's disease activity does not burn out with time, and roughly 25% of patients still have active disease 20 years after diagnosis. Etienney I et al. GCB 2004 Comorbidities • Heart failure o • Caution as worsening and new onset HF have been reported Diabetes mellitus o Increased risk of infections o Steroid use may disturb glycemic control • Cancer o Risk of reactivation of latent cancer • Anxiety and depression o May influence compliance & outcome of therapy in the elderly Polypharmacy • Cross-sectional study of 128 IBD patients aged >65 years, patients were taking an average of 9.5 routine medications. • Severe polypharmacy (>10 med) is associated with comorbidity index scores and steroid use, but not with disease activity or type. • 80% of patients had at least one medication interaction, with the majority involving IBD therapies (63%). • CHECK for interactions before prescribing any IBD therapy in order to prevent potential adverse effects Parian AM et al. DDW 2013 Increased risk … • • • • Denutrition Infections including C.difficile colitis DVT/Thromboembolism Cancer o Prior history of malignancy o Reactivation of latent cancer Major risk for cancer = past history of malignancy Beaugerie L et al. Gut 2013 Increased risk of C. difficile infection Increased risk of venous thromboembolism 3% of elderly UC admissions had venous thromboembolism Nguyen GC, Sam J, Am J Gastroenterol 2008; 103: 2272-2280. Increased risk of hospitalization • • • • • IBD hospitalizations < age 64 (n=105,423) IBD hospitalizations > age 65 (n=35,573) Elderly IBD accounted for one quarter of IBD hospitalizations in 2004 Elderly UC – 33.7% of total UC hospitalizations Elderly CD – 20.3% of total CD hospitalizations Ananthakrishnan AN et al. Inflamm Bowel Dis 2009 IBD hospitalization mortality by age • Significant in-hospital morbidity and mortality with increased rates of VTE, pneumonia, UTI, sepsis, and C.difficile infection. • Preventive measures: o VTE/DVT prophylaxis o Incentive spirometry o Prompt removal of indwelling catheters o Appropriate hand hygiene o Early initiation of physical and occupational therapy Nguyen GC et al. Am J Gastroenterol 2008 Ananthakrishnan AN et al. J Crohns Colitis 2013 Ananthakrishnan AN et al. Gut 2008 Ananthakrishnan AN, et al. Inflamm Bowel Dis 2009 Outline • Epidemiology • Special considerations • Medical and surgical therapies in the elderly • Therapeutic strategies in the elderly Specific concerns of medical therapy • • It is currently unknown if treatment goals in older patients should be different with regard to the need for clinical and endoscopic remission. There are no sweeping conclusions to be made from clinical trials since this aged population with comorbidities is excluded from almost all new drug development programs. Specific therapeutic considerations 5-ASAs • The wide use of 5-ASAs among patients with elderly- onset CD is suggestive of a possible role in patients with mild CD. • 5-ASAs are effective for inducing and maintaining remission in UC and appear comparable in efficacy in both younger and older patients. • Foam formulation of topical therapy and single daily dosing of oral 5-ASAs may improve compliance. • Creatinine clearance should be monitored in the elderly every 6-12 months during therapy, especially when long-term high-dose regimens are used. • Drug interactions with warfarin, 6-MP, AZA Solberg IC, et al. Clin Gastroenterol Hepatol 2007 Dignass A et al. J Crohns Colitis 2012 Muller AF, et al. Aliment Pharmacol Ther 2005 Specific therapeutic considerations Corticosteroids • The use of corticosteroids carries the risk of precipitating or exacerbating pre-existing diabetes mellitus, congestive heart failure, hypertension, altered mental status and osteoporosis. • Early bone densitometry, with repeated annual examinations, and vit D & calcium supplementation with > 12 weeks of steroids. • Treatment with budesonide may be considered as it interferes less with bone metabolism; budesonide in UC. • Drug interactions: phenytoin, phenobarbital, ephedrine, rifampin. Akerkar GA et al. Am J Gastroenterol 1997 Dignass A et al. J Crohns Colitis 2010 Specific therapeutic considerations Immunomodulators • Immunomodulators should be considered in patients with corticosteroid dependence to maintain remission. • In elderly patients with adequate kidney function, methotrexate should be considered as aging is a risk factor for lymphoma and skin cancer in patients exposed to thiopurines. • Allopurinol use could potentially have a benefit in reducing the thiopurine dose but its concomitant use with immunomodulators increases the incidence of infection in older patients with lower absolute lymphocyte counts. Dignass A et al. J Crohn’s Colitis 2010 Ansari A et al. Aliment Pharmacol Ther 2010 Govani SM et al. J Crohns Colitis 2010 Magro F et al. J Crohns Colitis 2013 CESAME Incidence rates of lymphoproliferative disorders according to thiopurine exposure grouped by age at entry in the cohort Beaugerie L et al. Lancet 2009 Specific therapeutic considerations Anti-TNF therapy DATA ON SAFETY AND EFFICACY Older age is an independent risk factor for serious infections and mortality in IBD patients on anti-TNFs Patients >65 Patients <65 years with years with biologics biologics (n=95) (n=190) Patients >65 years without biologics (n=190) Serious infections 11% 2.6% 0.5% Neoplasms 3% 0% 2% Deaths 10% 1% 2% Cottone M et al. Clin Gastroenterol Hepatol 2011 Efficacy of Anti-TNF in the elderly ALL PATIENTS Reason for stopping the anti-TNF EXCLUDING PNR ≥65 (n=63) <65 (n=118) Primary NR (%) 44 19 Loss of response (%) 6 37 Side effects (%) 19 29 Remission-other (%) 31 14 P < 0.001 Lobaton T et al. Leuven group. Safety of anti-TNF in the elderly1 Adverse events ≥ 65 anti-TNF (n=63) < 65 anti-TNF (n=118) ≥65 IS-CS (n=70) Infection (%) 21 12 20 Infection with hospitalization (%) 13 (p= 0.026) 3 16 Any SAE (%) 56 (p= 0.028) 39 10 Need for surgery (%) 19 10 14 Death (%) 6 1 Malignancy (%) 6 2 19 Acute reaction with antiTNF (%) 5 11 - Delayed hypersensitivity with antiTNF (%) 4 11 - Lobaton T et al. Leuven group Why surgery? • • • More aggressive disease presentation at diagnosis in UC in the elderly? Suboptimal response to conventional therapy? Physicians’ concerns about recommending immunosuppressive agents for older patients with comorbidities? o Disease recurrence tends to be lower postoperatively among elderly-onset CD o However, time to recurrence may be shorter for older patients Wagtmans MJ et al. J Clin Gastroenterol 1998 Surgery • • • • Approximately 25% of intestinal IBD surgeries are among pateints over the age of 55 years. Older age is associated with an eight-fold increased risk of in-hospital postoperative mortality, with bowel perforation and sepsis reported as leading causes of death. Older age is associated with an higher postoperative morbidity When considering surgical options: • • Consider pre-existing comorbidities – multidisciplinary care Kaplan GG et al. Arch Surg 2011 Optimization of their nutritional status Kaplan GG et al. Gastroenterology 2008 Juneja M et al. Dig Dis Sci 2012 IPAA – patient selection • For elderly UC patients requiring colectomy : IPAA vs functional ileostomy: • • Consider their overall functional status Evaluate the anorectal zone pre-operatively • Sphincter tone weakens with aging, which may impact functional outcomes following pouch creation • >40% of elderly pts experience FI and the majority have nocturnal seepage • Major postoperative complications in 24% • Pouch failure rate : 4% Delaney CP et al. Ann Surg 2002 Delaney CP et al. Ann Surg 2003 Delaney CP et al. Dis Colon Rectum 2002 Therapeutic strategies in the elderly Proposed step-up medical therapy in elderlyonset IBD Biologic therapy is associated with a risk of severe infections in elderly patients with IBD. Biologic therapy Methotrexate* A step-up approach of adding therapies may be preferred over a top-down approach in elderly-onset IBD. > Thiopurines Antibiotics / Budesonide Azathioprine should be avoided in patients >65 years In patients requiring anti-TNF therapy for induction, monotherapy for maintenance of remission or association with methotrexate should be preferred > Corticosteroids 5-Aminosalicylates * In patients with CD RED FLAGS • • Importance of nutritional status • • • Vaccination Chemoprophylaxis for opportunistic infections DVT prophylaxis for hospitalized patients Assess psychologic status & evaluate social support Conclusion • There are many uncertainties regarding therapeutic strategies in the elderly • Lack of efficacy and safety data from clinical trials in this population – often excluded • Risks of misdiagnosis • Increased risk of side-effects • High rate of comorbidities • Polypharmacy • Recent evidence has outlined that the disease course of elderly-onset IBD is less aggressive than that in the younger population. • This distinction should be considered when discussing therapeutic management in this complex population.