Incidence and Paris Classification of Pediatric Inflammatory Bowel Disease

Re iew A icle Incidence and Pa is Classi ica ion o Pedia ic In lamma o y Bowel Disease Ka alin Esz e Mülle ,1Pe e Laszlo Laka os,2Ma ia Papp,3and Gabo Ve es1 11s Depa men o Pedia ics, Semmelweis Uni e si y, 53 B´ okay S ee , Budapes 1083, Hunga y 21s Depa men o Medicine, Semmelweis Uni e si y, Ko ´ anyi S. S ee 26A, Budapes 1083, Hunga y 32nd Depa men o Medicine, Uni e si y o Deb ecen, Nagye dei K¨ o ´ u 98, Deb ecen 4032, Hunga y Co espondence should be add essed o Gabo Ve es; e es.gab[email p o ec ed] .hu Recei ed 11 Decembe 2013; Accep ed 2 Feb ua y 2014; Published 20 Ma ch 2014 Academic Edi o : G aziella Gua iso Copy igh © 2014 Ka alin Esz e M¨ ulle e al. This is an open access a icle dis ibu ed unde he C ea i e Commons A ibu ion License, which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed. New epidemiological da a sugges ha he incidence o in lamma o y bowel disease (IBD) is inc easing. As a esul he bu den o disease accoun s o mo e s ains o he heal h ca e sys em. The clinical a iabili y que ies whe he disease cha ac e is ics a e ela ed o clinical ou come. Ou aim was o delinea e he la es esul s o incidence ends in pedia ic IBD and o compa e he i s expe iences wi h Pa is Classi ica ion. Incidence o pedia ic IBD has been inc easing in Wes e n Eu ope and in Eas e n Eu ope. To be e cha ac e ize IBD, Pa is Classi ica ion was in oduced and alida ed ecen ly. Ileocolonic in ol emen is he mos cha ac e is ic disease loca ion in C ohn’s disease (CD) based on applying Pa is Classi ica ion. The a e o pe ianal disease and complica ed beha iou in CD was simila . I is o in e es ha CD pa ien s wi h colonic in ol emen we e less likely o ha e s ic u ing disease compa ed wi h pa ien s wi h ileal in ol emen . In addi ion, pancoli is domina ed in ulce a i e coli is (UC). Howe e , mos coun ies lack p ospec i e, na ionwide epidemiological s udies o es ima e incidence ends. This e iew emphasizes he impo ance o na ionwide egis ies ha en oll all pedia ic IBD cases se ing eliable da a o “e e yday p ac ice.” These i s epo s ha e shown ha Pa is Classi ica ion is a use ul ool o de e mine he pedia ic IBD pheno ype. 1. In oduc ion The in lamma o y bowel diseases (IBD), C ohn’s disease (CD), and ulce a i e coli is (UC) a e ch onic in lamma o y diso de s o he gas oin es inal ac o unknown e iology. I is hypo hesized ha IBD is due o a dys egula ed mucosal immune esponse o commensal gu lo a in gene ically suscep ible indi iduals. Howe e , causes o he dys egula ed immune esponse a e no delinea ed. The luc ua ing disease cou se a ec s quali y o li e in IBD pa ien s signi ican ly. Fu he mo e, CD and UC accoun o subs an ial cos s o he heal h ca e sys em and socie y [1]. New epidemiological da a sugges ha he incidence and p e alence o IBD a e inc easing. In addi ion, medical he apy and disease man- agemen ha e changed signi ican ly in he las decade. IBD de elops du ing childhood o adolescence in up o 25% o IBD pa ien s. Acco ding o a ecen epo om he USA he o al hospi al cha ges o pedia ic CD inc eased signi ican ly om $81 million in 1997 o $194 million in 2009. Simila ly, o al hospi al cha ges o UC ose om $53 million in 1997 o $143 million in 2009 [2]. The clinical p esen a ion o CD and UC is highly a iable, wi h signi ican di e si y in pheno ypes o he diseases [11]. This di e si y in adul s is speci ied by di e ences in he loca ion, he na u al his o y, and he ou comes. The clinical he e ogenei y aised he ques ion whe he disease cha ac- e is ics (age, loca ion, and beha iou ) had been ela ed o clinical ou come. As a esul Vienna and Mon eal Classi- ica ions ha e been p ocessed o classi y IBD using clinical and epidemiological ea u es. Pa ien s a e classi ied based on pheno ypic cha ac e is ics (age, loca ion, and beha iou ). Oos enb ug e al. analyzed disease cha ac e is ics o 292 adul CD pa ien s acco ding o Vienna classi ica ion. The ope a ion a e was highe in pa ien s wi h ileocolonic localiza ion (𝑃< Hindawi Publishing Co po a ion Gas oen e ology Resea ch and P ac ice Volume 2014, A icle ID 904307, 10 pages h p://dx.doi.o g/10.1155/2014/904307 2Gas oen e ology Resea ch and P ac ice Table 1: Incidence a es o pedia ic- and adul -onse C ohn’s disease and ulce a i e coli is in di e en coun ies (/100,000). Pedia ic C ohn’s disease Adul C ohn’s disease Pedia ic ulce a i e coli is Adul ulce a i e coli is Hunga y (2007–2009/2002–2006) [3,4]4.8 8.9 2.1 11.9 No he n F ance (1988–1998/2006-2007) [5,6]2.3 6.7 0.8 3.4 Na ionwide/Mad id, Spain (2003–2007/2003–2005) [7,8]1.7 7.3 0.88 7.1 Copenhagen Coun y, Denma k (2002–2004/2003–2005) [9,10]3.1 8.6 2.7 13.4 0.05) and s ic u ing and pene a ing disease beha iou (𝑃< 0.001)[12], con i ming ha disease and epidemiological cha ac e is ics a e associa ed wi h ou come in CD. P e ious epidemiological s udies epo ed ma ked di - e ences in pedia ic- and adul -onse IBD. Ne e heless, p e ious classi ica ion sys ems (e.g., Mon eal Classi ica ion) we e no designed o alida ed o pedia ic pa ien s. The Pa is Classi ica ion is a new e idence-based consensus ec- ommenda ion o pedia ic modi ica ion o he Mon eal c i e ia [13]. So a , his new classi ica ion sys em has only been applied in a ew popula ion-based s udies. In his epo we summa ize he la es incidence ends o pedia ic IBD and he i s expe iences wi h Pa is Classi ica- ion. 2. Incidence o Adul -Onse In lamma o y Bowel Disease and Geog aphic Dis ibu ion C ohn e al. published a case se ies wi h ilei is e minalis in 1932 whe e he “ e minal” wo d, con a y o he popula belie , indica ed no he loca ion ( e minal ileum) bu he “deadly, e minal disease” [14]. The inc easing incidence o IBD was obse ed om he middle o he 20 h cen u y. Acco ding o he i s epidemiological s udies he incidence o IBD di e ed g ea ly in geog aphical a eas. The equency o IBD was highe in de eloped coun ies han in de eloping coun ies and highe in no he n a eas han in sou he n egions (Table 1)[15,16]. O no e, acco ding o he ecen s udies he adi ional geog aphical dis ibu ion o IBD has changed in he las 20 yea s. In mos Wes e n coun ies he incidence o adul UC and CD has s abilized, while incidence has been ising in egions wi h p e iously low incidence (Sou he n and Eas e n Eu opeandAsia).In hela es sys emic e iewabou he changes in he wo ldwide incidence o IBD he highes incidence o adul UC was 24.3/105pe son-yea s in Eu ope, 19.2/105in No h Ame ica, and 6.3/105in Asia and he Middle Eas . The highes incidence o adul CD was 20.2/105in No h Ame ica, 12.7/105in Eu ope, and 5.0/105in Asia and he Middle Eas . Fu he mo e, a s a is ically signi ican inc ease in incidence o IBD was obse ed in 75% o CD s udies and 60% o UC s udies [17]. Ex apola ion o he incidence igu es on he o al Eu opean popula ion indica es a ound 78.000 new cases o CD and 178.000 o UC yea ly [1]. The p e alence o CDmaybeup o1.6millionpeoplewi hCDand2.1million people wi h UC in Eu ope i epo ed p e alence a es a e ex apola ed o he o al Eu opean popula ion. Some s udies sugges ed ha he incidence o IBD dec eases om he no h o he sou h compa ing incidence wi hin some coun ies and be ween coun ies. The incidence o UC in Copenhagen, Denma k (8.1/105), was ou imes highe han in Bologna, I aly (1.9/105)[18]. Fo CD, he a e o 4.1/105in Copenhagen was i e imes highe han in Galicia, No h-Wes Spain (0–8/105). To es ablish he no h- sou h g adien in Eu ope a p ospec i e s udy (EC-IBD) was conduc ed in 20 cen e s ha ocused on equency o IBD ac oss he con inen . Acco ding o he EC-IBD s udy a es o UC in no he n cen e s we e 40% highe han hose in he sou h (11.4/105 e sus 8.9/105)[18]. I was concluded ha he excess is less han expec ed on he basis o p e ious s udies ha may sugges an inc ease in he incidence o IBD in Sou he n Eu ope whe eas hose in he no h may ha e eached a pla eau. Howe e , some ecen s udies s ill show signi ican di e ence in equency o IBD wi hin coun ies in child en and in adul s [6,7,19,20]. The e iology o he no h-sou h g adien is no delinea ed. The la es hypo hesis sugges s ha le el o i amin D is lowe in popula ions li ing in No he n Eu ope. Vi amin D is known o be an induce o NOD2 unc ion and he lack o i amin D may esul in he lowe ac i i y o NOD2 and his ac o may con ibu e o he highe incidence o CD in egions wi h low sun ise exposu e [21,22]. A ew popula ion-based coho da a ha e been epo ed om Eas e n Eu ope showing an inc ease in p e iously less indus ialized coun ies ecen ly [23]. The ele a ing a es o IBDin hesecoun iescouldbedue ome hodologicalbias ising awa eness o he disease and imp o ed a ailabili y o diagnos ic ools. Consequen ly, a p ospec i e, popula ion- based coho s udy (EpiCom s udy) was es ablished o in es iga e whe he he e is an eas -wes g adien in he incidence o IBD in Eu ope. Thi y-one cen e s pa icipa ed ac oss Eu ope and his coho o IBD pa ien s co e s a backg ound popula ion o 10.1 million people. The o e all annual incidence a es in all Wes e n Eu opean cen e s we e oughly wice as high as a es in all Eas e n Eu opean cen e s o CD (incidence a e a io (IRR = 1.9)) and UC (IRR = 2.1).Thediagnos icapp oach o CDandUCseemedsimila in Eas e n and Wes e n Eu ope. I is o in e es ha he incidences co ela ed wi h he GDP o each coun y [24]. Gas oen e ology Resea ch and P ac ice 3 The di e ence in incidence be ween Eas e n and Wes e n Eu opeand he apidinc easeinincidence a esinEas e n Eu ope suppo he ole o en i onmen al ac o s. In he pas wo decades he e has been a change in he li es yle in Eas e n Eu ope, including he die (wes e n li es yle). Due o wes e nized die (“junk ood,” ood addi i es) luminal an igen exposu e has been changed in his egion. This al e a ion may be an impo an igge in he pa hogenesis o IBD [23]. B ie ly, he incidence o IBD is ising wi h ime a ound he wo ld, indica ing i s eme gence as a global disease [17]. The he e ogenei y o IBD equency in di e en egions highligh s he oleo en i onmen al ac o s. 3. Incidence o Pedia ic-Onse IBD The majo i y o pedia ic popula ion-based epo s be o e 1990s showed ha he incidence o pedia ic IBD is ising and he equency o CD is highe han ha o UC (Figu e 1)[25– 27]. Some s udies mainly om No he n Eu ope desc ibed he dominance o UC [28,29]. Incidence o pedia ic IBD has been also ising acco ding o he egis y o Veszp em P o ince (Hunga y). In CD, incidence inc eased om 0 in 1977–1981 o 7.2/105in 2007–2011. The incidence o pedia ic UC inc eased om 0.7/105in 1977–1981 o 5.2/105in 2007– 2011 [30]. Tempo al ends in he incidence o pedia ic-onse IBD we e con o e sial un il ecen ly (Figu es 1and 2). A sys em- a ic e iew desc ibing he epidemiology o childhood-onse IBD was conduc ed o e alua e he al e a ion in incidence o e he las decades. A icles published du ing 1950–2009 we e sea ched and analyzed. S a is ical ends in incidence o pedia ic IBD we e es ed in nine publica ions; se en (77.8%) epo ed inc eased incidence o e ime. Twen y- i e s udies calcula ed empo al ends in CD incidence, and 15 (60.0%) desc ibed a signi ican inc ease. Twen y s udies analyzed empo al ends o incidence in UC. Fou (20.0%) o hem epo ed signi ican inc ease; howe e , 13 epo s (65.0%) showed no signi ican change. Rising a es o pedia ic IBD we e obse ed in bo h de eloped and de eloping na ions [31]. Recen ly a ew new epidemiological pedia ic coho s udies e ealed an inc easing end in incidence o pedia ic IBD. Hope e al. in es iga ed he incidence a e o pedia ic IBD be ween 2000 and 2010 in I eland. Incidence o IBD was 2.5/105in 2000 ha ele a ed o 5.6/105by 2010. The mean annual inc ease in CD incidence was 0.153 (𝑃= 0.04), and o UC i was 0.175 (𝑃 < 0.01) be ween 2000 and 2010 [32]. Geog aphically close o I eland a Sco ish epo ound a simila ising end. A na ional coho o p ospec i ely and e ospec i ely acqui ed inciden cases o pedia ic IBD diagnosed less han 16 yea s old in pedia ic se ices in Sco land was cap u ed o he pe iod 2003–2008. The incidence o CD was 4.75/105, and incidence a e o UC was 2.06/105. Signi ican inc ease in he incidence o IBD ( om 4.45/105,𝑃 < 0.0001), CD ( om 2.86/105,𝑃 < 0.0001), and UC ( om 1.59/105,𝑃 = 0.023)was oundcompa edwi h da a om 1990 o 1995 [33]. 0 1 2 3 4 5 6 7 8 9 10 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 No he n Cali o nia, USA No he n F ance I eland On a io, Canada No he n S ockholm Finland Cen al and Wes e n Slo enia Spain Texas, USA Figu e 1: Incidence ends in pedia ic C ohn’s disease om 1990 o 2010 [5,7,32,34–39]. 0 1 2 3 4 5 6 7 8 9 10 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 No he n Cali o nia, USA No he n F ance I eland On a io, Canada No he n S ockholm Finland Cen al and Wes e n Slo enia Spain Texas, USA Figu e 2: Incidence ends in pedia ic C ohn’s disease om 1990 o 2010 [5,7,32,34–39]. The sex- and age-s anda dized incidence o pedia ic IBD in No he n S ockholm du ing 2002–2007 was 12.8/105 o IBD, 9.2/105 o CD, and 2.8/105 o UC. An inc easing incidence a e o UC (58.4%, 𝑃 < 0.01)wasobse ed du ing he s udy pe iod. Howe e , empo al end o he incidence o IBD (3.2%, 𝑃 = 0.54)wasno ema kable. Meanwhile, he incidence a e o pedia ic IBD in No he n S ockholm was signi ican ly highe in 2002–2007 han ha published in ea lie s udy co e ing 1990–2001. The o me sha p inc ease in incidence o pedia ic CD seems o each a pla eau, al hough a a highe a e han epo ed om mos o he egions in he wo ld [34]. Ano he Scandina ian epo ound simila ends. In Eas e n Denma k he equencies o 4Gas oen e ology Resea ch and P ac ice UC and CD ha e adi ionally been simila [40]. The mean annual incidence a es in a p ospec i e coho du ing 2007– 2009 we e 6.4/105 o IBD, 3.2/105 o CD, and 3.1/105 o UC. The mean incidence a es o IBD o e he pas 12 yea s (1998– 2009) in Eas e n Denma k inc eased signi ican ly ( end es , 𝑃 = 0.02). The la es epo om Sou he n Eu ope was conduc ed in Spain. A e ospec i e su ey o pa ien s diagnosed below 18 yea s o age in he pe iod 1996–2009 was pe o med. Pa ien s’ da a we e ob ained om he hospi als’ da abases. Ma in- de-Ca pi e al. desc ibed also a ise in IBD om 0.97/105 o 2.8/105du ing 1996–2009. Al hough his inc ease is mo e e iden o CD ( om 0.53/105 o 1.7/105), UC has also isen ( om 0.39/105 o 0.88/105)[7]. An eas -wes g adien has been epo ed in adul s, as p e iously men ioned. A ecen s udy om Eas e n Eu ope has been published om he no h-eas e n pa o Slo enia. The mean annual incidence was 7.6/105 o IBD, 4.6/105 o CD, and 2.8/105 o UC. The incidence o o al IBD, CD, and UC inc eased om 5.7/105, 3.9/105,and1.8/10 5in he pe iod 2002–2004, espec i ely, o 8.9/105,5.0/10 5, and 3.4/105in he pe iod 2008–2010. Da a o ou p ospec i e Hunga ian Pedia ic IBD Regis y (HUPIR) a e compa able o he a e o Slo enia. The mean annual incidence a e o pedia ic IBD was 7.48/105, o CDi was4.72/10 5,and o UCi was 2.32/105du ing 2007–2009 in Hunga y [3]. The incidence o childhood IBD in Eas e n Eu ope seems o be high and compa able o ha in wes e n coun ies o Eu ope. In conclusion, incidence a e o pedia ic IBD has been inc easing in No he n and in Sou he n Eu ope as well as in Eas e n Eu ope. 4. Me hodological P oblems in Assessing Incidence o IBD in Di e en Regions Incidence a es epo ed in di e en s udies a e no always di ec ly compa able due o he e ogenei y in s udy design and diagnos ic c i e ia, and hese ac o s can d ama ically a ec he incidence a es. A key issue is ha some s udies use hospi al eco ds while o he s use su eys and adminis a i e da a. The age limi is an impo an inclusion c i e ion wi h g ea impac onincidence a e.Mos da aa e e ospec i e, only a ew p ospec i e popula ion-based s udies we e con- duc ed, especially epo s om Asia o Eas e n Eu ope [4,41]. Fu he mo e, he incidence a es a e o en an ex apola ion om one o mo e egions o a coun y; howe e , some s udies epo ed egional a ia ion in equency o IBD using consis en me hodologies, implying ha di e en egions wi hin a coun y may ha e di e en incidence a es [31]. In summa y, mos coun ies lack accu a e es ima es o incidence o pedia ic IBD. 5. Reasons o Rising Incidence The cause o inc easing incidence is no es ablished. Rising incidence seems o be ue bo h in child en and adul s, sugges ing ha he appa en inc eases in IBD incidence a e genuine [42]. Twin s udies ha e shown 16%–36% conco - dance a es in monozygo ic wins and 4% conco dance a es in dizygo ic wins sugges ing ha gene ic isk ac o s ha e some ole in he pa hogenesis o IBD [31]. As a esul , in he absence o la ge gene ic backg ound shi s, changing a es o IBD incidence highligh he impo ance o en i onmen al ac o s. The socioeconomic al e a ion in p e iously low-inciden a eas “ om de eloping o de eloped” may be ela ed o his ising occu ence. The sp ead o wes e n li es yle seems o be ela ed o heele a ioninincidenceo Eas e nEu opean coun ies and in Asian coun ies. In conco dance, emig an s o Sou h Asian o igin emig a ing o Canada and UK ha e been obse ed o ha e an inc eased isk o IBD, con i ming ha en i onmen al ac o s con ibu e o his highe isk [43]. The “cold chain hypo hesis” sugges ed ha e ige a ion may ha e al e ed he bac e ial con en o ou die , esul ing in he inc eased g ow h o disease- igge ing o ganisms [44]. The well-known “hygiene hypo hesis” sugges s ha a cleane en i onmen , smalle amilies, and lowe exposu e o a m animals ha e esul ed in inc eased isk o IBD in wes e nized na ions [45]. Fu he mo e, pe ina al and ea ly li e e en s may also play a signi ican ole in de eloping IBD [46]. 6. Incidence Ra es in Childhood in Di e en Age G oups The ising incidence could be he consequence o he shi owa ds onse a a younge age; howe e his inc ease is e iden in adul [17]andinpedia ic-onse IBD[31]aswell [47]. Incidence a e by age g oups in childhood could also b ing up u he ques ions. Only a ew s udies epo ed ends o incidence a e s a i ying he child en. Two s udies di ided pa ien s in o h ee age g oups (0–5 yea s, 6–10 yea s, and 11–15 yea s). Hende son e al. compa ed incidence a es o wo pe iods (1990–1995 and 2003–2008) and ound ha he e was a signi ican inc ease in incidence o pa ien s be ween 11 and 15 yea s ( om 7.8/105 o 11.8/105,𝑃 = 0.052)and pa ien s be ween 6 and 10 yea s ( om 4.3/105 o 7.4/105, 𝑃 = 0.039). F equency o IBD also inc eased in child en younge han 5 yea s, bu his end was no signi ican ( om 0.9/105 o 1.5/105,𝑃 = 0.292)[33]. This esul is simila o he epo om Texas [35]. Incidence o IBD (compa ed in pe iods o 1990–1996 and 1997–2002) inc eased signi ican ly in age g oups 10–14 yea s and 15–17 yea s. Howe e , in child en be ween 5 and 9 yea s he ise was no signi ican andincidencewass ableinchild enunde i e.Findingso a epo om Cali o nia a e compa able; he ising end o UC o e ime was signi ican o he age g oup 10 o 14 yea s (compa ing pe iods o 1996–1999, 2000–2002, and 2003–2006), bu he end in child en aged 15 o 17 yea s was no signi ican [36]. Chou aki e al. s a i ied pa ien s in o wo age g oups (0–9 yea s and 10–19 yea s) and also epo ed an ob ious inc ease o IBD in olde child en and a sligh inc ease in younge child en compa ing incidence a e o IBD in 1988–1990 and in 2006-2007 [6]. In con as wi h hese indings, Jakobsen e al. did no obse e di e ence in incidence a es o e a 12-yea pe iod (1998–2009) a e Gas oen e ology Resea ch and P ac ice 5 s a i ying he pa ien s in o h ee 5-yea age g oups (0–4 yea s, 5–9 yea s, and 10–14 yea s) [48]. The only epo desc ibing a signi ican ly ising incidence o IBD pa ien s younge han 5 yea s came om On a io, Canada [37]. Summa izing hese da a, only a ew s udies in es iga ed long e m changes o incidence in child en s a i ied by age. Acco ding o hese da a, incidence is clea ly inc easing in child en olde han 10 yea s. In con as , his end is no ob ious in child en younge han 5 yea s, sugges ing ha his subg oup o pa ien s is unique. One explana ion could be ha IBD in younge child en is mo e likely o be gene ically de e mined, and en i onmen al ac o s may con ibu e o lesse ex en o he pa hogenesis o in es inal in lamma ion. Howe e , in olde child en inc easing incidence by age highligh s he dominan ole o en i onmen al igge s. In conclusion, hese esul s sugges ha he ising incidence occu s mainly in child en olde han 10 yea s which could indica e he impo ance o en i onmen al ac o s. 7. Fi s Expe iences wi h Pa is Classi ica ion o Pa ien s wi h Pedia ic-Onse IBD IBD de elops du ing childhood o adolescence in up o 25% o pa ien s. Pedia ic IBD di e s in some clinical cha ac- e is ics om adul IBD. As p e iously men ioned, CD is mo e equen in child en han UC in con as o adul s. A male genome-wide associa ion dominance has been obse ed in child en wi h CD, while emales a e mo e equen ly a ec ed in adul hood. Despi e highe amilial occu ence o IBD in child en genomewide associa ion s udies showed ha mul iple genes con e ing suscep ibili y a e compa able [49,50]. A key ea u e o pedia ic-onse IBD is he po en ial impai ed g ow h e a da ion and delayed pube y. Acco ding o p e ious s udies compa ing IBD in child en and adul s [48,51,52], ileocecal loca ion is mo e common in adul s han in child en, while panen e ic disease is cha ac e is ic phenomenon in pedia ic-onse CD. I is o in e es ha he e is an associa ion be ween pedia ic CD pa ien s ca ying one o he h ee NOD2 mu a ions and ileocolonic in ol emen [53]. Howe e , younge child en wi h CD, simila o olde adul s and he elde ly, a e mo e likely o ha e colonic disease [54,55]. Fu he mo e, uppe gas oin es inal in ol emen is mo e common in pedia ic IBD (16–51%). This wide ange is due o wo me hodical app oaches. On one hand, he e is a di e ence in ou ine diagnos ic p ocedu e in adul s and child en, since wo kup o pedia ic IBD includes gas oscopy, ileocolonoscopy, and small bowel imaging [56]; meanwhile adul gas oen e ologis s pe o m usually ileocolonoscopy and adiology. This ou ine may lead o unde es ima ion o uppe gas oin es inal in ol emen in adul CD pa ien s. On he o he hand, disease in ol emen was de ined as ulce a ion o aph hous ulce s in Vienna Classi ica ion. Howe e , in se e al pedia ic epo s, mic oscopic in ol emen has been applied as a diagnos ic c i e ion. The e is no consensus a p esen abou wha abno mali ies should be ega ded as p oo o in ol emen in uppe gas oin es inal biopsies. Thus, many nonspeci ic indings on gas oduodenal biopsies may be in e p e ed as e idence o disease in ol emen in his Table 2: Compa ison o Mon eal and Pa is Classi ica ions o C ohn’s disease based on Le ine e al. [13]. Mon eal Classi ica ion Pa is Classi ica ion Age a diagnosis A1: below 17 yea s A2: 17–40 yea s A3: abo e 40 yea s A1a: 0–<10yea s A1b: 10–<17 yea s A2: 17–40 yea s A3: >40 yea s Loca ion L1: e minal ileal/ limi ed cecal disease L2: colonic L3: ileocolonic L4∗:isola eduppe disease L1: dis al 1/3 ileum / limi ed cecal disease L2: colonic L3: ileocolonic L4a: uppe disease p oximal o ligamen o T ei z∗ L4b: uppe disease dis al o ligamen o T ei z and p oximal o dis al 1/3 ileum∗ Beha iou B1: nons ic u ing nonpene a ing B2: s ic u ing B3: pene a ing p: pe ianal disease modi ie B1: nons ic u ing nonpene a ing B2: s ic u ing B3: pene a ing B2B3: bo h pene a ing and s ic u ing disease, ei he a he same o di e en imes p: pe ianal disease modi ie G ow h — G0: no e idence o g ow h delay G1: g ow h delay ∗In bo h he Mon eal and Pa is Classi ica ion sys ems L4 and L4a/L4b may coexis wi h L1, L2, and L3, espec i ely. egion [11]. In UC he e is also clea di e ence in disease loca ion be ween child en and adul s. Pedia ic-onse UC pa ien s a e mo e likely o ha e pancoli is (60–70%); howe e , 20–30% o adul s p esen wi h p oc i is. Due o weaknesses o Mon eal Classi ica ion wi h ega d o pedia ic IBD, a modi ied classi ica ion (Pa is) has been de ised [13]. The new Pa is Classi ica ion included classi ying age a diagnosis as A1a (0 o <10 yea s), A1b (10 o <17 yea s), A2(17 o40yea s),andA3(>40 yea s), dis inguishing disease abo e he dis al ileum as L4a (p oximal o ligamen o T ei z) and L4b (ligamen o T ei z o abo e dis al ileum), allowing bo h s enosing and pene a ing disease o be classi ied in he same pa ien (B2B3), deno ing he p esence o g ow h ailu e in he pa ien a any ime as G1 e sus G0 (ne e g ow h ailu e), adding E4 o deno e ex en o ulce a i e coli is ha is p oximal o he hepa ic lexu e, and deno ing e e se e e ulce a i e coli is du ing disease cou se by S1 (Tables 2and 3). 7.1. Newly Diagnosed Pedia ic IBD Pa ien s Acco ding o Pa is Classi ica ion. Recen ly a ew cen e - and popula ion-based s udies analyzed newly diagnosed pedia ic IBD pa ien s acco ding o Pa is Classi ica ion: (1) a s udy o p ospec i ely collec ed IBD pa ien s younge han 15 yea s diagnosed in No he n S ockholm (2002–2007) [34]; (2) a e ospec- i e s udy o IBD pa ien s younge han 16 yea s om 6Gas oen e ology Resea ch and P ac ice Table 3: Compa ison o Mon eal and Pa is Classi ica ions o ulce a i e coli is based on Le ine e al. [13]. Mon eal Classi ica ion Pa is Classi ica ion Ex en E1: ulce a i e p oc i is E2: le -sided UC (dis al o splenic lexu e) E3: ex ensi e (p oximal o splenic lexu e) E1: ulce a i e p oc i is E2: le -sided UC (dis al o splenic lexu e) E3: ex ensi e (hepa ic lexu e dis ally) E4: pancoli is (p oximal o hepa ic lexu e) Se e i y S0: clinical emission S1: mild UC S2: mode a e UC S3: se e e UC S0: ne e se e e∗ S1: e e se e e∗ ∗Se e e de ined by Pedia ic Ulce a i e Coli is Ac i i y Index (PUCAI). Table 4: Pa is Classi ica ion o pa ien s wi h C ohn’s disease in popula ion-based s udies in Eu ope [3,32,34,57,58]. No h- Eas e n Slo enia No he n S ockholm Eu okids Hunga y (HUPIR) I eland C ohn’s disease (𝑛)439658224731 Age, % (𝑛/𝑛) A1a 15 — 20% (244/1221) 11% (27/247) 26% (8/31) A1b — — 80% 78% (197/247) 74% (23/31) A2 — — 9% (23/247) Loca ion, % (𝑛/𝑛) L1∗20.9% (9/43) 8% (8/96) 16% 13.4% (33/247) 19% (6/31) L1 + L4a 2.3% — 3.6% (21) L1 + L4b 0 — 3.4% (20) 3% (7/247) 13% (4/31) L1 + L4ab 7% — 1.4% (8) ∗L2 4.6% (2/43) 71% (68/96) 28% (159/582) 27.5% (68/247) 45% (14/31) L2 + L4a 0 — 4.1% (24/582) L2 + L4b 0 — 3.8% (22/582) 6.8% (17/247) 3% (1/31) L2 + L4ab 0 — 1.2% (7/582) ∗L3 74.5% (32/43) 20% (19/96) 53% 58.7% (145/247) 32% (10/31) L3 + L4a 23.3% — 14.3% L3 + L4b 11.6% — 6.5% 49 16% (5/31) L3L4ab 16.3% — 4.3% L4 (Isola ed) 0 0 4% (18/582) 0.4% (1/247) 3% (1/31) All uppe gas oin es inal in ol emen 0.4% (1/247) L4a 48.9% (21/43) 17% (16/96) L4b 34.9% (15/43) 1% (1/96) Beha iou B1 86% (56/65) 95% (91/96) 82% (959/1177) 12.1% (216/256) 90% (28/31) B2 6% (4/65) 5% (5) 12% (144/1177) 2.3% (31/256) 6% (2/31) B3 8% (5/65) 0 5% (55/1177) 1.2% (6/256) 3% (1/31) B2B3 — 0 2% (19/1177) 0.6% (3/256) — Pe ianal disease — 8% (8/96) 9% (114/1207) 14.5% (37/247) 10% (3/31) G ow h (G1) G1 6.6% (16/244) 23% (4/31) ∗L1 + L4a, L1 + L4b, and L1 + L4ab pa ien s a e included in pa ien s wi h L1 loca ion. A1a: 0–<10 yea s, A1b: 10–<17 yea s, and A2: 17–<40 yea s. B1: nons ic u ing-nonpene a ing; B2: s ic u ing; B3: pene a ing; B2B3: bo h pene a ing and s ic u ing;G1:e idenceo g ow hdelay;L1:dis al1/3ilealdisease(limi ed cecal disease); L2: colonic disease; L3: ileocolonic disease; L4: uppe gas oin es inal ac disease; L4a: esophagogas oduodenal disease p oximal o ligamen o T ei z; L4b: dis al o ligamen o T ei z. Gas oen e ology Resea ch and P ac ice 7 Table 5: Pa is Classi ica ion o ulce a i e coli is pa ien s in popula ion-based s udies in Eu ope [3,32,34,57,58]. No h-Eas e n Slo enia No he n S ockholm Eu okids Hunga y (HUPIR) I eland Ulce a i e coli is (𝑛)39 29 578 121 14 E1 5.2% (2/39) 11% (3/29) 5% (27/578) 5% (6/121) 14% (2/14) E2 25.6% (10/39) 14% (4/29) 18% (104/578) 24.8% (30/121) 14% (2/14) E3 7.7% (3/39) 4% (1/29) 9% (50/578) 13.2% (16/121) 7% (1/14) E4 61.4% (24/39) 75% (21/29) 69% (397/578) 57% (69/121) 65% (9/14) Se e i y (S1) — — — 18.6% (13/121) 43% (6/31) E1: ulce a i e p oc i is; E2: le -sided ulce a i e coli is (dis al o splenic lexu e); E3: ex ensi e coli is (hepa ic lexu e dis ally); E4: pancoli is (p oximal o hepa ic lexu e); S1: se e e a some s age. I eland; (3) he Eu okids egis y, a p ospec i e, cen e - based egis y o newly diagnosed pedia ic IBD pa ien s in 44 IBD cen e s in 18 coun ies [57]; (4) a e ospec i e s udy on a coho o newly diagnosed child en aged 0–18 yea s om No h-Eas e n Slo enia (2002–2010) [58]; (5) ou p ospec i e, na ionwide, inciden coho o pedia ic IBD pa ien s younge han 18 yea s om Hunga y [3](Tables4 and 5). The main indings we e simila o ea lie epo s and we e compa able o each o he : (1) ileocolonic in ol emen was he cha ac e is ic disease loca ion in CD; (2) pancoli is domina edinUC;(3) a eo pe ianaldiseaseandcomplica ed beha iou was simila . Howe e , he epo s om No he n S ockholm and I elandshowedahighe a eo pu ecolonicCD han he o he s (71% and 45% e sus 27–28%), which is in con as wi h mos popula ion-based s udies om bo h Eu ope and No h Ame ica [40,59,60]. Among ea lie s udies wo epo s desc ibed simila igu es o isola ed colonic CD (Sco land 66% [51]) and Sweden 43% [61]). Fu he s udies a e needed o de e mine i hese con as s poin o possible disease-modi ying en i onmen al o o he ac o s. Howe e , all o hese s udies applied an age limi o 16 yea s, whe eas heagelimi o s udieswi hlowe a eo isola edcolonic in ol emen included pa ien s younge han 18 yea s. This di e ence in inclusion c i e ia may con ibu e o a shi o p opo ion o pa ien s wi h pu ely colonic CD. 7.2. Follow-Up and Pa is Classi ica ion. Hope e al. ollowed up I ish IBD pa ien s o 2 yea s and ound ha he p og es- sion o disease ex ension in CD du ing he i s 2 yea s o disease cou se was no equen [32]. This esul is in con as wi h he disease ex ension p esen ed by an Limbe gen e al. (39% a 2 yea s) [51]andbyVe nie -Massouillee al. (31% a median ollow-up o 84 mon hs) [60]. Analysis o he 196 childhood-onse CD pa ien s demons a ed ha 53 o 196 (27.0%) had panen e ic in ol emen (L3 + L4) a diagnosis [51]. Du ing 2 yea s ollow-up, 56 (39.1%) child en had p og ession in disease ex ension: changes we e mos ly due o ex ension om localized disease o mo e ex ensi e disease in ol ing he lowe gas oin es inal ac (41/56, 73.2%). Meanwhile, he p opo ions o disease loca ion in UChadno changedsigni ican ly[51]a las ollow-up.The con lic ing esul s may be due o me hodological di e ences (longe ec ui men and ollow-up pe iod in ea lie s udies). Howe e , he loca ion o disease changed o e ime in o he publica ions conduc ed in adul s as well [62]. This may que y he ela ionship o disease cou se and ini ial disease cha ac e is ics. In he epo om No h-Eas e n Slo enia p og ession o disease ex ension was also in es iga ed. A diagnosis, 16.3% had panen e ic disease (L3L4ab), while ex ensi e in ol emen was obse ed in 21.6% o pa ien s du ing he ollow-up pe iod [58]. In UC, p opo ion o pa ien s wi h pancoli is (E4) inc eased om 61.5% o 76.5%, espec i ely. A p esen a ion, only 6% o CD pa ien s had s ic u ing and 8% had pene a ing pheno ype, and hese complica ed pheno ypes doubled du ing he ollow-up. In ag eemen wi h hese igu es o he s udies also obse ed a simila 2- old ise in complica ed CD beha iou du ing he ollow-up [32,51, 60].InUC, a eo pa ien swi hpancoli is(E4)inc eased om 61.4% o 76.5%. 7.3. Pa is Classi ica ion and Clinical Cha ac e is ics. Associa- ion o epidemiological and disease cha ac e is ics, like amily his o y and ex ain es inal mani es a ions (EIM), wi h phe- no ype acco ding o Pa is Classi ica ion has been analyzed in wo ecen s udies. In ou s udy we did no ind any signi ican ela ionship be ween age and gende dis ibu ion o amily his o y, EIM, and disease loca ion in CD o in UC [3]. In con as , de Bie e al. desc ibed ha isola ed colonic disease was eco ded in 41% (47/114) o child en diagnosed be o e 10 yea s o age compa ed wi h 24% (111/467) o olde child en (𝑃 < 0.001)[57]. A simila end was ound in he Hunga ian coho , hough he di e ence was no signi - ican . The wo s udies concu ed ha uppe gas oin es inal in ol emen was no ela ed o age, gende , amily his o y o IBD, o p esence o EIM. Howe e , Laza e e al. desc ibed a signi ican ly g ea e isk o mul iple abdominal su ge ies in pa ien s wi h jejunal in ol emen han in pa ien s wi h uppe gas oin es inal in ol emen p oximal o he ligamen o T ei z [63]. Acco ding o Eu okids, a e o pe ianal disease occu ed mo e o en in pa ien s wi h B3 han in pa ien s wi h B1 (38% e sus 8%, 𝑃 < 0.001) and B2 (38% e sus 7%, 𝑃 < 0.001). In addi ion, pa ien s wi h L2 disease we e less likely o ha e s ic u ing disease complica ions compa ed wi h pa ien s wi h L1 o L3 disease (6% e sus 21% e sus 15%, 𝑃 = 0.005). These la e esul s we e no obse ed in ou s udy, which is may be due o he lowe numbe o included pa ien s (582 e sus 247). This disc epancy is p obably due o 8Gas oen e ology Resea ch and P ac ice he di e en popula ion o he wo s udies. Eu okids egis y is no a popula ion-based coho , bu a selec ion o cen e s wi h special in e es in IBD; meanwhile he HUPIR is a popula ion-based inciden coho in ol ing less se e e cases. This phenomenon emphasizes he impo ance o na ionwide egis ies ha en oll all pedia ic pa ien s wi h IBD including less se e e cases also. In conclusion, he i s epo s ha e shown ha Pa is Classi ica ion is a use ul ool o de e mine he cha ac e is ic pedia ic CD pheno ype. Loca ion o disease is compa able in s udies wi h Pa is Classi ica ion o s udies classi ying pa ien s acco ding o ea lie classi ica ion sys ems. 8. Conclusions The wo ldwide inc easing ends o IBD incidence seem o be e iden in adul s [17]aswellasinchild en[31]. Explo ing inc ease in incidence o IBD may p o ide use ul insigh s in o he pa hogenesis, especially wi h ega d o en i onmen al ac- o s ela ed o indus ializa ion, such as changes in hygiene, a mo e wes e nized die , economic g ow h, and he shi om u al o u ban en i onmen s [42]. Fu he mo e, clinical classi ica ion, like Pa is Classi ica ion, may con ibu e o de ine dis inc subg oup o pa ien s wi h di e en p ognosis wi h di e en he apeu ical app oach. Howe e , he e a e se e al me hodological clues ha complica e compa ing s udies om di e en egions. Con- sequen ly, mo e p ospec i e, popula ion-based s udies (da a should no only come om cen e specialized o IBD) a e needed o delinea e he equency o IBD and disease pheno ype. Con lic o In e es s The au ho s decla e ha he e is no con lic o in e es s ega ding he publica ion o his pape . Acknowledgmen s This wo k was suppo ed by he J´ anos Bolyai Resea ch and Schola ship o he Hunga ian Academy o Sciences (OTKA- K105530).Theau ho sa e hank ul o hepa icipan s o HUPIR G oup: And ´ as A a ´ o, D.S. and Ph.D., An al Dezs˝ o i, M.D. and Ph.D., ´ A on Cseh, M.D. and Ph.D., P´ e e V¨ o ¨ os, M.D., and Dol´ o esz Szab´ o, M.D., Is Depa men o Pedia ics, Semmelweis Uni e si y, Budapes ; Judi B. Ko ´ acs, M.D. and Ph.D., and Ma ianne Polg´ a , M.D. and Ph.D., Heim-Mada ´ asz Hospi al, Budapes ; M´ a a Balogh, M.D., Ma kuso szky Hospi al, Szomba hely; Pi oska B´ odi, M.D., P´ andy Hospi al, Gyula; Judi Czelecz and Ka alin Szige i, Be hesda Child en’s Hospi al, Budapes ; No´ emi Csosz´ anszki, M.D., and E ika Tomsi s, M.D. and Ph.D., 2nd Depa men o Pedia ics, Semmelweis Uni e si y, Budapes ; L´ aszl´ oG ´ a dos, M.D. and Ph.D., Zala Coun y Hospi al, Zalaege szeg; Ildik´ o Gu hy, M.D., and Gab iella Tomcsa, M.D., J´ osa Hospi al, Ny´ ı egyh´ aza; F. Ha angi, M.D. and Ph.D,, K´ a oly Schul z, M.D., and Ge gely T´ o h, M.D. and Ph.D., Balassa Hospi- al, Szeksz´ a d; ´ Agnes Ho ´ a h, M.D., Csolnoky Hospi al, Veszp ´ em; Ildik´ oKis,Sz .Bo b ´ ala Hospi al, Ta ab´ anya; M´ a a Ko ´ acs, M.D. and Ph.D., Pe z Coun y Hospi al, Gy˝ o ; ´ E a Micskey, M.D. and Ph.D., Budai Child en’s Hospi al, Budapes ; ´ E a Nemes, M.D. and Ph.D., Depa men o Pedia ics, Medical and Heal h Science Cen e , Uni e si y o Deb ecen, Deb ecen; ´ E a Poll´ ak, Magya Hospi al, Ajka; Ildik´ o Ros a, Schwei ze Hospi al, Ha an; E zs´ ebe Szakos, M.D. and Ph.D., BAZ Coun y Hospi al, Miskolc; Ka alin Szabados, He ´ enyiHospi al,Szolnok;E zs ´ ebe Sza hm´ a i, Ken´ ezy Hospi al, Deb ecen; Ka alin Tam´ as, Budapes ; And ´ as T´ a nok, M.D. and Ph.D., Depa men o Pedia ics, Uni e - si y o P´ ecs, P´ ecs; Is ´ an Tokodi, M.D., Sz . Gy¨ o gy Hospi al, Sz´ ekes eh´ e ´ a ; And ´ as T´ o h, Sz . L´ aszl´ oHospi al,Budapes ; ´ E a Vajdo ich, Bugyi Hospi al, Szen es; ´ Agnes V´ a konyi, M.D. and Ph.D., D´ aniel Sz˝ ucs, M.D., and No´ emi Vass, M.D., Depa men o Pedia ics, Szen -Gy¨ o gyi Albe Uni e si y, Szeged. Re e ences [1] J.Bu isch,T.Jess,M.Ma ina o,P.L.Laka os,andE.EpiCom, “The bu den o in lamma o y bowel disease in Eu ope,” Jou nal o C ohn’s and Coli is, ol.7,pp.322–337,2013. [2] J. C. Deb uyn, I. S. Soon, J. Hubba d, I. W obel, R. Panaccione, and G. G. Kaplan, “Na ionwide empo al ends in incidence o hospi aliza ion and su gical in es inal esec ion in pedia ic in lamma o y bowel diseases in he Uni ed S a es om 1997 o 2009,” In lamma o y Bowel Diseases, ol.19,pp.2423–2432, 2013. [3]K.E.Mulle ,P.L.Laka os,A.A a oe al.,“Incidence,Pa is classi ica ion, and ollow-up in a na ionwide inciden coho o pedia ic pa ien s wi h in lamma o y bowel disease,” Jou nal o Pedia ic Gas oen e ology and Nu i ion, ol.57,pp.576–582, 2013. [4] L.Laka os,L.S.Kiss,G.Da ide al.,“Incidence,diseasephe- no ype a diagnosis, and ea ly disease cou se in in lamma o y bowel diseases in Wes e n Hunga y, 2002–2006,” In lamma o y Bowel Diseases, ol.17,no.12,pp.2558–2565,2011. [5] S. Au in, F. Molini´ e, C. Gowe -Rousseau e al., “Incidence, clinical p esen a ion and loca ion a diagnosis o pedia ic in lamma o y bowel disease: a p ospec i e popula ion-based s udy in No he n F ance (1988–1999),” Jou nal o Pedia ic Gas oen e ology and Nu i ion, ol.41,no.1,pp.49–55,2005. [6] V. Chou aki, G. Sa oye, L. Dauche e al., “The changing pa e n o C ohn’s disease incidence in no he n F ance: a con inuing inc ease in he 10- o 19-yea -old age b acke (1988–2007),” Alimen a y Pha macology and The apeu ics, ol.33,no.10,pp. 1133–1142, 2011. [7] J. Ma in-de-Ca pi, A. Rod iguez, E. Ramos e al., “Inc easing incidence o pedia ic in lamma o y bowel disease in Spain (1996–2009): The SPIRIT Regis y,” In lamma o y Bowel Dis- eases, ol.19,no.1,pp.73–80,2013. [8] P. L´ opez-Se ano, J. L. P´ e ez-Calle,E.Ca e a-Alonsoe al., “Epidemiologic s udy on he cu en incidence o in lamma o y bowel disease in Mad id,” Re is a Espanola de En e medades Diges i as, ol.101,no.11,pp.768–772,2009. [9] I. Vind, L. Riis, T. Jess e al., “Inc easing incidences o in lam- ma o y bowel disease and dec easing su ge y a es in Copen- hagen Ci y and Coun y, 2003–2005: a popula ion-based s udy om he Danish C ohn coli is da abase,” Ame ican Jou nal o Gas oen e ology, ol. 101, no. 6, pp. 1274–1282, 2006. Gas oen e ology Resea ch and P ac ice 9 [10] C. Jakobsen, V. Wewe , F. U ne e al., “Incidence o ulce a i e coli is and C ohn’s disease in Danish child en: s ill ising o le elling ou ?” Jou nal o C ohn’s and Coli is, ol.2,no.2,pp. 152–157, 2008. [11] A. Le ine, “Pedia ic in lamma o y bowel disease: is i di e - en ?” Diges i e Diseases, ol.27,no.3,pp.212–214,2009. [12] L.E.Oos enb ug,H.M. anDullemen,G.J. eMee man,P.L. M. Jansen, and J. H. Kleibeuke , “Clinical ou come o C ohn’s disease acco ding o he Vienna classi ica ion: disease loca ion is a use ul p edic o o disease cou se,” Eu opean Jou nal o Gas oen e ology and Hepa ology, ol.18,no.3,pp.255–261, 2006. [13] A. Le ine, A. G i i hs, J. Ma kowi z e al., “Pedia ic modi i- ca ion o he Mon eal classi ica ion o in lamma o y bowel disease: he Pa is classi ica ion,” In lamma o y Bowel Diseases, ol. 17, no. 6, pp. 1314–1321, 2011. [14] B. B. C ohn, L. Ginzbu g, and G. D. Oppenheime , “Regional ilei is,” The Jou nal o he Ame ican Medical Associa ion, ol.99, pp. 1323–1329, 1932. [15] J. F. Maybe y, “Some aspec s o he epidemiology o ulce a i e coli is,” Gu , ol. 26, no. 9, pp. 968–974, 1985. [16] J. F. Maybe y and J. Rhodes, “Epidemiological aspec s o C ohn’s disease: a e iew o he li e a u e,” Gu , ol.25,no.8, pp.886–899,1984. [17] N. A. Molodecky, I. S. Soon, D. M. Rabi e al., “Inc easing incidence and p e alence o he in lamma o y bowel diseases wi h ime, based on sys ema ic e iew,” Gas oen e ology, ol. 142, no. 1, pp. 46.e42–54.e42, 2012. [18] S.Shi ananda,J.Lenna d-Jones,R.Logane al.,“Incidenceo in lamma o y bowel disease ac oss Eu ope: is he e a di e ence be ween no h and sou h? Resul s o he Eu opean collabo a i e s udy on in lamma o y bowel disease (EC-IBD),” Gu , ol.39, no. 5, pp. 690–697, 1996. [19] E. L. A mi age, M. C. Aldhous, N. Ande son e al., “Incidence o ju enile-onse C ohn’s disease in Sco land: associa ion wi h no he n la i ude and a luence,” Gas oen e ology, ol.127,no. 4, pp. 1051–1057, 2004. [20] A. Sonnenbe g and R. M. Gen a, “Geog aphic dis ibu ions o mic oscopic coli is and in lamma o y bowel disease in he Uni ed S a es,” In lamma o y Bowel Diseases, ol. 18, pp. 2288– 2293, 2012. [21] A. Jussila, L. J. Vi a, V. Salomaa, J. Maki, A. Jula, and M. A. Fa kkila, “High and inc easing p e alence o in lamma o y bowel disease in Finland wi h a clea No h-Sou h di e ence,” Jou nal o C ohn’s and Coli is, ol.7,pp.e256–e262,2013. [22] V. Ne ich, P. Jan chou, M.-C. Bou on-Ruaul e al., “Low exposu e o sunligh is a isk ac o o C ohn’s disease,” Alimen a y Pha macology and The apeu ics, ol.33,no.8,pp. 940–945, 2011. [23] L. Laka os and P. L. Laka os, “Is he incidence and p e alence o in lamma o y bowel diseases inc easing in Eas e n Eu ope?” Pos g adua e Medical Jou nal, ol.82,no.967,pp.332–337,2006. [24] J. Bu isch, N. Pede sen, S. Cuko ic-Ca ka e al., “Eas -Wes g adien in he incidence o in lamma o y bowel disease in Eu ope: he ECCO-EpiCom incep ion coho ,” Gu ,2013. [25] A. Ekbom, C. Helmick, M. Zack, and H.-O. Adami, “The epi- demiology o in lamma o y bowel disease: a la ge, popula ion- based s udy in Sweden,” Gas oen e ology, ol.100,no.2,pp. 350–358, 1991. [26] M. Cosg o e, R. F. Al-A ia, and H. R. Jenkins, “The epidemi- ology o paedia ic in lamma o y bowel disease,” A chi es o Disease in Childhood, ol.74,no.3,pp.460–461,1996. [27] E. A mi age, H. E. D ummond, D. C. Wilson, and S. Ghosh, “Inc easing incidence o bo h ju enile-onse C ohn’s disease and ulce a i e coli is in Sco land,” Eu opean Jou nal o Gas- oen e ology and Hepa ology, ol.13,no.12,pp.1439–1447,2001. [28] E. Langholz, P. Munkholm, P. A. K asilniko , and V. Binde , “In lamma o y bowel diseases wi h onse in childhood. Clinical ea u es, mo bidi y, and mo ali y in a egional coho ,” Scandi- na ian Jou nal o Gas oen e ology, ol.32,no.2,pp.139–147, 1997. [29]P.Tu unen,K.-L.Kolho,A.Au inen,S.Il anen,H.Huh ala, and M. Asho n, “Incidence o in lamma o y bowel disease in Finnish child en, 1987–2003,” In lamma o y Bowel Diseases, ol. 12, no. 8, pp. 677–683, 2006. [30] B.D.Lo asza,L.Laka osb,A.Ho a hce al.,“Incidence a es and disease cou se o pedia ic in lamma o y bowel diseases in Wes e nHunga ybe ween1977–2011,”Diges i e Li e Diseases, 2013. [31]E.I.Benchimol,K.J.Fo insky,P.Gozdy a,M.Vanden Heu el, J. Van Limbe gen, and A. M. G i i hs, “Epidemiology o pedia ic in lamma o y bowel disease: a sys ema ic e iew o in e na ional ends,” In lamma o y Bowel Diseases, ol.17,no. 1, pp. 423–439, 2011. [32]B.Hope,R.Shahdadpu i,C.Dunnee al.,“Rapid isein incidence o I ish paedia ic in lamma o y bowel disease,” A chi es o Disease in Childhood, ol.97,pp.590–594,2012. [33] P. Hende son, R. Hansen, F. L. Came on e al., “Rising incidence o pedia ic in lamma o y bowel disease in Sco land,” In lam- ma o y Bowel Diseases, ol.18,pp.999–1005,2012. [34] P.Malmbo g,L.G ahnquis ,J.Lindholm,S.Mon gome y,and H. Hildeb and, “Inc easing incidence o paedia ic in lamma- o y bowel disease in no he n S ockholm Coun y, 2002–2007,” Jou nal o Pedia ic Gas oen e ology and Nu i ion, ol.57,pp. 29–34, 2013. [35] H.M.Mala y,X.Fan,A.R.Opekun,C.Thibodeaux,andG.D. Fe y, “Rising incidence o in lamma o y bowel disease among child en: a 12-yea s udy,” Jou nal o Pedia ic Gas oen e ology and Nu i ion, ol.50,no.1,pp.27–31,2010. [36] O.Ab amson,M.Du an ,W.Mowe al.,“Incidence,p e alence, and ime ends o pedia ic in lamma o y bowel disease in No he n Cali o nia, 1996 o2006,” Jou nal o Pedia ics, ol.157, no. 2, pp. 233.e231–239.e231, 2010. [37] E. I. Benchimol, A. Gu mann, A. M. G i i hs e al., “Inc easing incidence o paedia ic in lamma o y bowel disease in On a io, Canada: e idence om heal h adminis a i e da a,” Gu , ol.58, no. 11, pp. 1490–1497, 2009. [38] P. Leh inen, M. Asho n, S. Il anen e al., “Incidence ends o pedia ic in lamma o y bowel disease in Finland, 1987–2003, a na ionwide s udy,” In lamma o y Bowel Diseases, ol.17,no.8, pp.1778–1783,2011. [39] R. O el, T. Kamhi, G. Vidma , and P. Mamula, “Epidemiology o pedia ic ch onic in lamma o y bowel disease in cen al and Wes e n Slo enia, 1994–2005,” Jou nal o Pedia ic Gas oen- e ology and Nu i ion, ol.48,no.5,pp.579–586,2009. [40] C. Jakobsen, A. Pae egaa d, P. Munkholm e al., “Pedia ic in lamma o y bowel disease: inc easing incidence, dec easing su ge y a e, and comp omised nu i ional s a us: a p ospec- i e popula ion-based coho s udy 2007–2009,” In lamma o y Bowel Diseases, ol.17,no.12,pp.2541–2550,2011. [41] L. P ideaux, M. A. Kamm, P. P. De C uz, F. K. Chan, and S. C. Ng, “In lamma o y bowel disease in Asia: a sys ema ic e iew,” Jou nal o Gas oen e ology and Hepa ology, ol.27,pp.1266– 1280, 2012.