Oxford Inflammatory Bowel Disease MasterClass

Environmental exposure: can we reduce

risk?

Dr Peter Lakatos, Budapest, Hungary

Oxford Inflammatory Bowel Disease MasterClass

Environmental exposure: can

we reduce risk?

Peter Laszlo Lakatos

1st Department of Medicine

Semmelweis University Budapest

Hungary

Objective

to discuss the role of environmental

factors in IBD

•in disease susceptibility

•in predicting disease phenotype

•During the course of the disease

•short-long term prognosis and risk for

complications?

Reducing risk of WHAT?

•disease susceptibility?

•disease phenotype?

•disease course progression?

•AND if we decrease certain risks will we

have to other complications?

IBD… a complex phenotype

Environmental factors in IBD

IBD drugs

(OC, NSAID)

flora

appendectomy diet (refined sugar, fat, fast food,

corn flakes, chocolate, coca-

cola, toothpaste)

hygiene

stress smoking

infections (measles, mycobacterium,

pharyngitis, tonsillitis,)

Disease susceptibility

Leone V J Gastroenterol 2013

Developed hygiene?

Developed hygiene? Urban environment and risk of CD (and UC)

Soon BMC Gastroenterology 2012

IRRCD: 1.42,

95%CI: 1.26-1.60

IRRUC: 1.17,

95%CI: 1.03-1.32

Developed hygiene?

Bernstein CN Am J GE 2006

Developed hygiene?

Bernstein CN Am J GE 2006

Vaccination?

Davis RL Arch Ped Adolesc Med 2001

Villumsen Inflamm Bowel Dis 2013

Diet?

Riordan AM Eur J Clin Nutr 1998;52:229-38.

„Studies are inconsistent and subject to important

methodological limitations. „

Diet: but how to measure?

Hou AJG 2011, Ng Gut 2013

Diet-fat: CD+ UC-

Hou AJG 2011, Ng Gut 2013

Fat intake and UC -

Ananthakrishnan Gut 2013 july

NHS study 30-55 yrs

at inclusion!

Diet: fat and the EPIC

Tjonneland GUT 2009, de Silva GE 2010

IBD in the elderly!

Diet- fruit, vegetable, fiber -?

Hou AJG 2011, g Gut 2013

Fiber intake and CD?!

Ananthakrishnan Gastro 2013 aug

NHS study 30-55 yrs

at inclusion!

„For each food item, a commonly used portion size was specified and

participants were asked how often they consumed the food on an

average over the past year.”??

Vitamin D

Ananthakrishnan Gastroenterology 2012

Data are increasing on the immunologic role of

vitamin D, particularly on the innate immune system

??

… and there is a seasonal

variation in vitamin D levels?

Bours PH Osteoporosis Int 2011

Is it the then sunlight? or vitamin D?

Nerich V Aliment Pharm Ther 2011

CD risk

Season of Birth and risk of IBD?

Shaw SY CGH 2013 aug

NSAID use?

Chan SS Aliment Pharm Ther 2011

An EPIC

IBD in the elderly?

BUT: age at inclusion and capture of Aspirin use?

NSAID dose and duration?

Anathakrishnan Ann Intern Med 2012

NHS study 30-55 yrs

at inclusion!

+ dose

+duration

of use

Oral contraceptive use

Godet PG Gut 1995, Cornish JA Am J GE 2008, Khalili GUT 2013

ORCD: 1.44, ORCD: 1.51, (14 studies)

95%CI: 1.12-1.86 95%CI: 1.17-1.96

ORUC: 1.29,

95%CI: 0.94-1.77 NHS study in CD HR:

2.82 (95% CI 1.65 to 4.82)

among current users

1.39 (95% CI 1.05 to 1.85)

among past users

Hormone replacement therapy

and risk of postmenopausal IBD

Khalili Gastroenterology 2012

NHS study 30-55 yrs

at inclusion!

Appendectomy and risk of UC

Rutgeerts NEJM 1994

Koutrobakis IBD 2002

Rate of appendectomy in UC: 1/174 (0.6%)

Rate of appendecytomy in controls: 41/161 (25.4%)

OR: 59.1 (95% CI, 18-189)

Appendicits? and risk of UC

Frisch M BMJ 2009

Life events

Lerebours E IBD 2007

Smoking

Mahid SS Mayo Clin Proc 2006

1.76

95%CI: 1.40-2.22

P<0.001

current

vs

never smoking

former

vs

never smoking

1.30

95%CI: 0.97-1.76

P=0.08

Mahid SS Mayo Clin Proc 2006

current

vs

never smoking

former

vs

never smoking

0.58

95%CI: 0.45-0.75

P<0.001

1.79

95%CI: 1.37-2.34

P<0.001

Smoking;

is the risk age-dependent?

Lakatos IBD 2013

Air pollution?

Kaplan GG Am J GE 2010

Is it infectious? Virus, bacteria or

worms?

CD: Infections? Antibiotics? Cause or indicator?

Halfvarson Inflamm Bowel Dis 2006

Antibiotics and CD? Indicator or bystander?

Hviid A Gut 2011 Virta E Am J Epidemiol 2012

Finland

Denmark (n=577627)

And, of course there is interaction...

Biederman PLOS One 2013

Smoking cessation

and composition

of intestinal

microflora

cessation non-smoker smoker

Predicting disease phenotype/disease

course?

Is diet predicting the relapse rate in UC?

Jowett SL Gut 2004

Can we modify the disease?

Vitamin D In DSS mouse maybe, in human?

In vitro, 1,25(OH)2D3 increased TEER, TJ proteins and mRNA expressions,

decreased the FITC-D permeability, and preserved structural integrity of the TJ in Caco-2 cells

Zhao H BMC Gastroenterology 2012

Vitamin D level is associated with

activity and QoL

Ulitsky JPEN J Parenter Enteral Nutr 2011

Vitamin D level and hospitlization/surgery predictor or indicator only?

Ananthakrishnan IBD 2013

Is stress associated with disease course in IBD?

Is stress associated with disease course in IBD?

Bitton Gut 2008

Psychiatric co-morbidity and risk of

hospitalization, drug use and surgery?

Ananthakrishnan Aliment Pharm Ther 2013

Smoking is associated with

probability of flares in CD

Cosnes J Gastroenterology 2001

Smoking and disease phenotype in CD

Aldhous M. Am J GE 2007

% w

ith

ou

t st

rict

ure

% w

ith

ou

t co

mp

lica

ted

dis

ease

Association between smoking, azathioprine/biological use

and need for surgery in patients with Crohn`s disease

follow-up (months)

300,00250,00200,00150,00100,0050,000,00

Su

rviv

al w

ith

ou

t su

rgery

1,0

0,8

0,6

0,4

0,2

0,0

censored

censored

censored

censored

IM / smoking

no IM / smoking

IM / no smoking

no IM / no smoking

pLogRank<0.001, pBreslow<0.001

Szamosi T EJGH2010

Association between smoking and colectomy in UC

Cosnes J Best Pract Res Clin GE 2004

OR: 0.57 (95%CI: 0.38-0.85)

Association between smoking and colectomy in UC

pLogRank=0.042, pBreslow=0.08

follow-up (months)

400,00300,00200,00100,000,00

Su

rviv

al w

ith

ou

t co

lecto

my

1,0

0,8

0,6

0,4

0,2

0,0censored

censored

smoking

no-smoking

Szamosi T EJGH2010

Air pollution and hospitalization? Probably not specific for IBD

Ananthakrishnan IBD 2011

Summary: Environmental factors

Molodecky NA, IBD 2011

Modifying evironmental factors?

Ananthakrishnan Curr Gastro Rep 2013

Environmental factors in IBD

• There are many methodological limitations

Molodecky NA, IBD 2011

So, how can we modify the environmental

exposure predisposing to IBD?

•Protective: breastfeeding, vitamin D,

fruit/vegetable, fiber, sunshine

•Avoid: developed hygiene but also early life

gastrointestinal infections/antibiotics, air polution,

NSAID, sugar?/fat?/red meat, stress-life events,

psychiatric co-morbidity, in females: contraceptives-

HRT, in males-do not born April-June (if you are

Canadian?)

•Conflictive: Smoke or not? depending whether you

are afraid of CD or UC?, have an appendectomy,

but only before the age of 20 yrs and only for

appendicits! Ideal place to live!