Treatment of IBD in the elderly

Jean-Frédéric Colombel, MD Joannie Ruel, MD

Icahn School of Medicine at Mount Sinai, New York

Challenges in IBD

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 ageo 65% in their sixtieso 25% in their seventieso 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

EPIMAD Registry

1988-2006

6 909 CD 4 310 UC

689 (10%)

4 678 (68%)

1 175 (17%)367 (5%)

213 (5%)

2 434 (57%)

1 189 (27%)

474 (11%)

6 million inhabitants (9.3% of french population)3 Academic hospitals (CHU) (Lille, Rouen, Amiens)27 Regional hospitals250 adult gastroenterologists private and public12 pediatric gastroenterologists

Gower-Rousseau C et al. Gut 1994Gower-Rousseau C et al. DLD 2012

Natural history in elderly-onset IBD

0

10

20

30

40

50

60

70 %

14

26

60

At maximalFollow-up

Pediatric-onset

<17 y (N=213) 17-39 y

(N=2434) 40-59 y (N=1189) ≥ 60 (N=474)

0

10

20

30

40

50

60

70 Proctitis

Left-sided colitis

Extensive colitis

%

31

5048

29

4145

At maximal follow-up

0

10

20

30

40

50

60

70 %

17

49

34

Elderly-onset

Disease extension in 16%

6 years median follow-up

Disease extension in 49%

Charpentier C et al. Gut 2013, Gower-Rousseau C et al. Am J G 2009

UC: disease location and extension according to age

CD: Evolution of behavior from diagnosis to maximal follow-up

Inflammatory

Stricturing

Penetrating

78%

17%

5%

68%

22%

10%

Elderly-onset patients (>60 yrs at diagnosis)

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 depressiono 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

• Cancero Prior history of malignancyo 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

Nguyen GC, Sam J, Am J Gastroenterol 2008; 103: 2272-2280.

3% of elderly UC admissions hadvenous thromboembolism

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 prophylaxiso Incentive spirometryo Prompt removal of indwelling

catheterso Appropriate hand hygieneo Early initiation of physical and

occupational therapy

Nguyen GC et al. Am J Gastroenterol 2008Ananthakrishnan AN et al. J Crohns Colitis 2013Ananthakrishnan 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 2012Muller 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 1997Dignass 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 2010Ansari A et al. Aliment Pharmacol Ther 2010

Govani SM et al. J Crohns Colitis 2010Magro F et al. J Crohns Colitis 2013

Incidence rates of lymphoproliferative disorders according to thiopurine exposure grouped by age at entry in the cohort

Beaugerie L et al. Lancet 2009

CESAME

Specific therapeutic considerations

Anti-TNF therapy DATA ON SAFETY AND EFFICACY

Patients >65 years

with biologics(n=95)

Patients <65 years

with biologics(n=190)

Patients >65 years without biologics(n=190)

Serious infections

11% 2.6% 0.5%

Neoplasms

3% 0% 2%

Deaths 10% 1% 2%

Older age is an independent risk factor for serious infections and mortality in IBD patients on anti-TNFs

Cottone M et al. Clin Gastroenterol Hepatol 2011

Efficacy of Anti-TNF in the elderly

Reason for stopping the anti-TNF ≥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

ALL PATIENTS EXCLUDING PNR

Lobaton T et al. Leuven group.

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 -

Safety of anti-TNF in the elderly1

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 CDo 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

• Optimization of their nutritional status Kaplan GG et al. Arch Surg 2011Kaplan 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 2002Delaney CP et al. Ann Surg 2003Delaney CP et al. Dis Colon Rectum 2002

Therapeutic strategies in the elderly

Proposed step-up medical therapy in elderly-onset IBD

Biologic therapy is associated with a risk of severe infections in elderly patients with IBD.

A step-up approach of adding therapies may be preferred over a top-down approach in elderly-onset IBD.

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

Biologic

therapy

Methotrexate* >

Thiopurines

Antibiotics / Budesonide>

Corticosteroids

5-Aminosalicylates

* In patients with CD

RED FLAGS

• Importance of nutritional status

• Chemoprophylaxis for opportunistic infections

• Vaccination

• 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.