Possible undertreatment of women with Crohn disease in Poland

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1 ORIGINAL ARTICLE Possible undertretment of women with Crohn disese in Polnd A subgroup nlysis from prospective multicenter study of ptients on nti tumor necrosis fctor therpy Piotr Eder 1, Mri Kłopock 2, Mri Wiśniewsk Jrosińsk 3, Rent Tlr Wojnrowsk 4, Driusz Mj 5, Ig Detk Kowlsk 6, Jrosłw Kierkuś 7, Andrzej Śliwczyński 8,9, Ariel Liebert 2, Mrek Bugjski 10,11, Mciej Goncirz 12, Edyt Zgórowicz 10,11 1 Deprtment of Gstroenterology, Nutrition nd Internl Medicine, Poznn University of Medicl Sciences, Heliodor Święcicki Clinicl Hospitl, Poznń, Polnd 2 Deprtment of Vsculr Diseses nd Internl Medicine, Nicolus Copernicus University, Collegium Medicum, Bydgoszcz, Polnd 3 Deprtment of Gstroenterology, Medicl University of Lodz, Łódź, Polnd. 4 Deprtment of Digestive Trct Diseses, Medicl University of Lodz, Łódź, Polnd 5 Deprtment of Gstroenterology, Militry Institute of Medicine, Wrsw, Polnd 6 Deprtment of Gstroenterology, District Hospitl, Końskie, Polnd 7 Deprtment of Gstroenterology, Heptology nd Immunology, The Children s Memoril Helth Institute, Wrsw, Polnd 8 Deprtment of Qulity Benefits, Procedures nd Stndrds, Fculty of Helth Sciences, Medicl University of Lodz, Łódź, Polnd 9 Centrl Office of the Ntionl Helth Fund, Wrsw, Polnd 10 Deprtment of Gstroenterology, Heptology nd Clinicl Oncology, Medicl Center for Postgrdute Eduction, Wrsw, Polnd 11 The Mri Skłodowsk Curie Memoril Cncer Centre nd Institute of Oncology, Deprtment of Gstroenterology nd Heptology, Wrsw, Polnd 12 Deprtment of Gstroenterology, Min District Hospitl, Sosnowiec, Polnd KEY WORDS nti tumor necrosis fctor, biologicl tretment, Crohn disese, SATIMOS study, sex Correspondence to: Edyt Zgórowicz, MD, PhD, Klinik Gstroenterologii Onkologicznej, Centrum Onkologii Instytut im. Mrii Curie-Skłodowskiej, ul. Roentgen 5, Wrszw, Polnd, phone: , emil: ezgorowicz@wp.pl Received: July 7, Accepted: August 28, Published online: August 31, Conflict of interest: see t the end of the text. Pol Arch Intern Med. 2017; 127 (10): doi: /pmw.4095 Copyright by Medycyn Prktyczn, Krków ABSTRACT INTRODUCTION In Polnd, nti tumor necrosis fctor (TNF) therpy for Crohn disese (CD) is reimbursed in inflmmtory disese (CD ctivity index [CDAI] >300 points) or perinl disese, in cses where conventionl tretment hs filed. OBJECTIVES We ssessed ptients receiving TNF inhibitors to estblish how limited ccess to the therpy influences the selection of the popultion for tretment. PATIENTS AND METHODS Consecutive dult ptients with CD strting infliximb or dlimumb in the yers 2014 to 2015 were included in the study. Age t symptom onset nd dignosis of CD, disese loction nd behvior, previous tretment, CDAI, nd body mss index (BMI) were evluted. Subsequently, the ge nd sex of ll ptients with CD on nti TNF therpy reimbursed by the Polish Ntionl Helth Fund were nlyzed. RESULTS Among 256 ptients, there were 113 women (44.1%) nd 143 men (55.9%). The medin time from dignosis to enrollment ws longer in women thn in men (9 yers vs 5.5 yers; P = 0.02), nd the proportion of women receiving TNF inhibitors for 5 yers or less since dignosis ws lower thn tht of men (42.5% vs 57.7%; P = 0.017). Disese loctions, behvior, nd CDAI were similr between the groups, while the medin BMI ws lower in women thn in men (20.6 kg/m 2 vs 22.6 kg/m 2 ; P = 0.01). In Polnd in generl, in the yers 2010 to 2015, TNF inhibitors for CD were tken by fewer women thn men (2208 vs 4789; 46%; 95% confidence intervl, 45 48). The medin ge of treted women ws 29 yers nd tht of men 27 yers (P <0.001). CONCLUSIONS Compred with their mle counterprts, women with CD receive TNF inhibitors less frequently, t n older ge, nd following longer disese durtion. It is unknown whether this is regionl or more widespred phenomenon.

2 INTRODUCTION Anti tumor necrosis fctor (nti TNF) ntibodies improve the qulity of life in ptients with inflmmtory bowel disese (IBD) 1 nd likely modify the course of the disese vi mucosl heling nd reduced rte of surgeries. 2-7 With n cceptble dverse event profile, TNF inhibitors cn be considered the sfest nd most effective therpy for IBD. 8 The erlier in the course of the disese the nti TNF tretment is introduced, the higher the probbility of response nd long term remission. 9,10 For Crohn disese (CD), nti TNF tretment is recommended in ptients with moderte or severe flre up of luminl disese or perinl disese who re unresponsive or intolernt to conventionl therpy, s well s tretment of choice in extensive relpsing disese. 11 The ctul use of nti TNF drugs depends on country specific reimbursement regultions nd vries significntly even within the Europen Union, with the lowest use per estimted number of ptients with IBD reported in some Estern Europen countries, including Polnd. 12 Since 2010, the cost of infliximb or dlimumb therpy hs been reimbursed by the Polish Ntionl Helth Fund (Nrodowy Fundusz Zdrowi [NFZ]) in ptients with CD with CD ctivity index (CDAI) exceeding 300 points, or with perinl fistuls, if these ptients hve proved resistnt or intolernt to conventionl therpies. Until recently, the mximum reimbursement period hs been 12 months, but since 2017 the biosimilr infliximb hs been reimbursed for up to 24 months nd dlimumb for up to 12 months. Access to TNF inhibitors for ptients with ulcertive colitis (UC) is even more limited, s only the biosimilr infliximb is reimbursed for up to 12 months. The cost of the newest biologic drug pproved for IBD, the nti α4β7 subunit integrin ntibody vedolizumb, is not reimbursed in Polnd. The im of this pper ws to evlute the demogrphic chrcteristics of cohort of Polish ptients with CD who were strted on nti TNF therpy. By compring them with other cohorts reported in the literture, we imed to estblish how the limited ccess to TNF inhibitors in Polnd influences the chrcteristics of the popultion selected for tretment. PATIENTS AND METHODS Ptients Dt nlyzed in this pper come from the SATIMOS study (Sfety of Anti tumor Necrosis Fctor [TNF] Monoclonl Antibodies in Inflmmtory Bowel Disese, NCT ), which is prospective, multicenter, observtionl cohort study imed t chrcterizing the sfety of tretment using nti TNF monoclonl ntibodies in ptients with IBD in Polnd. This study ws initited by the Intestinl Section of the Polish Society of Gstroenterology. The study enrolled consecutive ptients who were strted on nti TNF tretment (infliximb or dlimumb) due to CD, UC, or indeterminte colitis between Jnury 1, 2014, nd December 31, The prticipting centers included gstroenterology units from both university nd non university hospitls: 14 units providing cre for dult ptients nd 10 units for peditric ptients. In ptients who gve informed consent, the following dt were collected in n electronic dtbse: medicl history, previous tretment (minoslicyltes, corticosteroids, budesonide, zthioprine, 6 mercptopurine, cyclosporine A, methotrexte, infliximb, dlimumb, nd certolizumb), previous surgery, CDAI, disese loction, indiction for biologicl tretment, nd extrintestinl mnifesttions. During the nti TNF tretment, dt on response to nd tolernce of the tretment were lso collected t ech visit. Additionlly, to vlidte the demogrphic dt collected in the prospective SATIMOS cohort, the nlysis ws extended to include the retrospective dt from the NFZ on the number, ge, nd sex of ll ptients with CD who were eligible for tretment with TNF inhibitors ccording to the reimbursement regultions in Polnd in the yers from 2010 to Dt nlysis The dtbse ws prepred by the Polish softwre compny Mednet, which is lso responsible for qulity ssurnce nd storge. Twice yer, the records were checked for completeness nd logics, with incomplete dtsets being reported to the respective dt entering persons, who were sked to complete missing dt. The present nlysis of the dt from the SATIMOS study is limited to dult ptients with CD. The nlysis of pst nd concomitnt therpy ws bsed on the mediction therpy dt sheet from the bseline visit. Sttisticl nlysis Vribles were described by reference to frequencies, medins, nd interqurtile rnges (IQRs). The χ 2 test nd Fisher exct test were used to compre ctegoricl vribles. Since continuous vribles did not follow norml distribution, the Mnn Whitney Wilcoxon test ws used for comprisons. A P vlue of less thn 0.05 ws considered significnt. The Bonferroni correction ws used for multiple comprisons. All nlyses were performed with the Stt softwre, version 13.1 (Stt Corportion, College Sttion, Texs, United Sttes). Ethicl considertions The Ethics Committee of the Mri Skłodowsk Curie Memoril Cncer Centre nd Institute of Oncology pproved the study (document no., 29/2013), nd the Polish Inspector Generl for Personl Dt Protection ws informed bout dt collection. RESULTS Demogrphic chrcteristics of ptients receiving nti TNF tretment in Polnd (SATIMOS study) Of the 285 ptients with CD registered in the dtbse, 29 were excluded from the nlysis due to incomplete records. The finl smple included 256 ptients (113 women [44.1%] ORIGINAL ARTICLE Possible undertretment of women with Crohn disese in Polnd 675

3 TABLE 1 Clinicl chrcteristics of ptients with Crohn disese in the SATIMOS study Vrible Women Men All P vlue n = 113 (44.1%) n = 143 (55.9%) n = 256 Age t symptom onset, y, medin (IQR) 22 (17 31) 22.5 (18 29) 22 (17 29) Age t dignosis, y, medin (IQR) 23 (19 34) 25 (19 31) 24 (19 32) Age t enrollment, y, medin (IQR) 31 (24 44) 31 (24 37) 31 (24 39) Time from symptom onset to enrollment, y, 9 (1 52) 5.5 (1 36) 7 (1 52) medin (IQR) Time from dignosis to enrollment, y, medin (IQR) 7 (3 10) 5 (2 10) 5 (2 10) Disese loction, % L L L Disese behvior, % B1 (inflmmtory) B2 (stricturing) B3 (penetrting) Perinl disese, % Yes No Smoking, % Pst Current Never Intestinl resection, % Yes No Perinl bscess dringe, % Yes No Intr-bdominl bscess Yes dringe, % No BMI, kg/m 2, medin (IQR) 20.6 ( ) 22.6 ( ) 21.6 ( ) A P vlue of less thn 0.05 denotes significnt differences. Percentges my not totl 100 becuse of rounding. Abbrevitions: BMI, body mss index; CD, Crohn disese; IQR; interqurtile rnge TABLE 2 Phrmcologicl tretment in ptients with Crohn disese in the SATIMOS study Vrible Women Men All P vlue n = 113 (44.1%) n = 143 (55.9%) n = 256 Anti TNF therpy strted within 5 yers of dignosis, 5 yers % >5 yers History of biologicl tretment, % Yes No Current immunosuppressive therpy, % Yes No Indiction for current nti TNF therpy, % Luminl disese Perinl disese CDAI t entry to the study in ptients ( ) with predominnt luminl disese, medin (IQR) ( ) ( ) Use of nti TNF therpy in the current study, % Adlimumb Infliximb Abbrevitions: CDAI, Crohn disese ctivity index; TNF, tumor necrosis fctor; others, see TABLE 1 nd 143 men [55.9%]). Clinicl chrcteristics of the study groups re presented in TABLES 1 nd 2. The medin ge of ptients t enrollment ws 31 yers; t development of symptoms, 22 yers; nd t dignosis, 24 yers. Immunosuppressive tretment t enrollment ws tken by 63.4% of the ptients, while 44.1% of the ptients hd received nti TNF tretment t some point in the pst. Comprison of women nd men on nti TNF tretment in Polnd (SATIMOS study) Given the pprent 676

4 FIGURE 1 Women nd men with Crohn disese receiving tumor necrosis fctor (TNF) inhibitors ccording to the decde of life. Dt re presented s percentge of the totl popultion treted. P vlue <0.006 Anti-TNF therpy by sex, % Women Men Age group, y numericl dominnce of men receiving TNF inhibitors for CD, we nlyzed sex differences in demogrphic nd tretment chrcteristics of the study popultion (TABLES 1 nd 2). The medin ge t inclusion into the study of women nd men ws the sme (31 yers), nd no significnt differences were observed between the sexes in terms of ge t disese presenttion or dignosis. However, the medin time from dignosis to ge t entry to the study ws significntly longer in women thn in men, nd the proportion of women receiving biologicl tretment within 5 yers of dignosis ws significntly lower thn tht of men. The rtes of biologicl nd immunosuppressive tretment in the pst were similr in men nd women. Moreover, there were no significnt differences in the current use of immunosuppressive drugs, lthough the rte observed mong men ws 7.8% higher thn tht in women. Disese loction nd behvior, s well s indictions for nti TNF tretment, were similr in both sexes. More women hd undergone intestinl resections nd more men were current or former smokers, but these differences did not rech significnce. The severity of CD s mesured by the CDAI ws similr in women nd men, but the medin BMI t the strt of tretment ws significntly lower in women thn in men. Dt from the Polish Ntionl Helth Fund for the yers 2010 to 2015 The number of women nd men in every decde of life treted with TNF inhibitors in the yers from 2010 to 2015 is presented in TABLE 3. Significntly more men (2581 of the totl 4789 ptients [54%]; 95% confidence intervl [CI], 52 55) thn women (2208 [46%]; 95% CI, 45 48) received nti TNF tretment for CD. Significntly more men in their second nd third decdes of life received TNF inhibitors compred with women. On the other hnd, in the first, fifth, sixth, nd seventh decdes of life, the number of women ws significntly higher thn tht of men. The medin ge of the treted women ws 29 yers (IQR, yers), while tht of men ws 27 yers (IQR, yers) (P <0.001). The proportions of women nd men with CD in ech decde of life who received TNF inhibitors, out of the totl popultion treted re shown in FIGURE 1. DISCUSSION Our study of ntionl cohort of ptients with CD treted with TNF inhibitors in Polnd reveled tht women receive nti-tnf therpy less often thn men, t n older ge, nd following longer disese course. The clinicl course of IBD is heterogeneous nd depends on genetic, environmentl, nd other poorly defined fctors. It is believed tht ll therpeutic interventions should be individulized nd dpted to disese behvior nd the ptient s needs. 11,13 Little is known bout the effect of sex on disese course nd tretment strtegies, especilly when biologicl therpy is considered. An extensive epidemiologicl review showed tht the dignosis of CD is not sex specific. 14 There hve been no popultion studies of the incidence nd prevlence of CD in Polnd, but ccording to study nlyzing ntionl trends s regrds hospitliztion rtes for IBD in the yers 1991 to 1996 nd 2003 to 2007, in 3 of the 11 yers women were considerbly more likely to be hospitlized for CD thn men, while no difference ws observed for the remining yers. 15 Therefore, it seems tht the smller number of ORIGINAL ARTICLE Possible undertretment of women with Crohn disese in Polnd 677

5 TABLE 3 Number of women nd men in ech decde of life receiving nti tumor necrosis fctor therpy in Polnd in the yers Age group, y Women, n Men, n P vlue < < < < < Becuse of the Bonferroni correction, P vlue of less thn denotes significnt differences. women treted with TNF inhibitors in our study cnnot be explined by lower prevlence of CD in this popultion. Another possible reson for the lower use of TNF inhibitors in women with CD could be milder course of the disese, but gin, the review of the literture does not seem to confirm this hypothesis. A recent study ssessing sex differences mong 5782 dolescents hospitlized for CD showed tht, s compred with men, women were slightly more likely to hve nemi, infection, nd mood disorders, s well s hd more blood product trnsfusions. Other therpeutic procedures were performed both in men nd women with similr frequency. 16 Such sex relted differences hve not been described mong dult ptients with IBD. Although sex hormones influence systemic nd mucosl immunity, s well s intestinl permebility, this is probbly only reflected in some vritions in the clinicl course of IBD during pregnncy nd the menstrul cycle. 17 However, it should be noted tht some differences in the occurrence of extrintestinl mnifesttions hve been described. Dt from Swiss IBD cohort study regrding disese phenotype nd its clinicl mnifesttions showed tht femle sex is risk fctor for developing xil or peripherl inflmmtory rticulr disese. 18 There lso seems to be higher prevlence of eye nd skin involvement in women. As regrds environmentl fctors, there is some evidence tht smoking is ssocited with higher risk of disbling CD mong women, while it hs lso been suggested tht the use of ntibiotics nd ppendectomy re more closely ssocited with the development of CD in women. 17 In summry, the course of CD would seem to be similr in women nd men, with the former mnifesting higher occurrence of severl extrintestinl mnifesttions. Therefore, there re no dt to justify less ggressive tretment in women with CD. We nlyzed the vilble cohort studies on dult ptients receiving TNF inhibitors to compre the demogrphic chrcteristics of our cohort with those of ptients from other countries. In Belgin cohort of 720 ptients with CD treted with dlimumb, 19 the medin ge t dignosis ws 24 yers nd the medin disese durtion ws 11 yers, while the rtes of previous nti TNF tretment nd surgery for CD were 64.7% nd 41%, respectively. Concomitnt immunosuppressive drugs were tken by 41% of ptients. Compred with these dlimumb treted ptients, the Polish infliximb- or dlimumb treted ptients were younger, hd shorter disese durtion, nd received previous nti TNF therpy less frequently, but were chrcterized by higher rte of concomitnt use of immunosuppressive drugs. Women comprised 61% of the Belgin cohort, which is 15% more thn in our popultion. In Swiss cohort of 146 ptients with CD treted with infliximb, the men ge t dignosis ws 27 yers nd the men disese durtion ws 9 yers, lso mking the Swiss cohort older thn the Polish one. 20 Immunosuppressive therpy ws dministered in 44% of the Swiss ptients. This cohort gin hd higher prevlence of women (55%). In n older single center cohort of 614 infliximb treted ptients from Leuven in Belgium, 21 the medin ge t dignosis ws 22.8 yers nd the medin disese durtion prior to the first use of infliximb ws 7.6 yers. In this cohort, women represented 61% of the totl popultion. None of the bove studies were subject to ny further sex specific nlyses. We my thus conclude tht Polish ptients with CD resemble their counterprts in Western countries in tht they re selected for nti TNF t similr stge of the disese, or even slightly erlier. A high CDAI (the cutoff level required for tretment dministrtion in Polnd) is most often seen in the erly phses of CD in young people, which my be the reson for the lower medin ge of the Polish cohort. Unfortuntely, Polish women hve lower chnces of receiving TNF inhibitors thn Polish men, nd lso lower thn their counterprts in other countries. Except for registry study from the Netherlnds reporting tht lmost 70% of the 131 ptients with IBD treted with biologicl drugs were men, 22 we did not identify studies showing lower rte of nti TNF use in women thn in men. A recent cross sectionl study from the United Sttes, which included 5782 hospitlized dolescent ptients with CD, showed tht the rtes of using biologics were lmost identicl in women nd men (16% vs 15%, respectively). 16 Similrly, there is some evidence suggesting sex differences in the use of thiopurines, methotrexte, nd clcineurin inhibitors for CD or UC. In lrge cohort of Germn ptients with CD or UC prticipting in multicenter, prospective, internet bsed study, immunosuppressive drugs were prescribed significntly more often mong men. 23 The uthors lso showed tht, in generl, women with CD received IBD specific medictions less frequently, with the phenomenon of no tretment in IBD lso being noted more often mong femle ptients. 23 Furthermore, in retrospective Asin cohort study, Lw et l 24 reported delyed use of immunosuppressive therpy 678

6 in women, prticulrly those younger thn 40 yers. Our study lso reveled tht immunosuppressive drugs re currently prescribed more often in men thn in women, lthough the difference ws not significnt. Interestingly, in their cross sectionl nlysis of 1409 peditric ptients with IBD, Lee et l 25 found no significnt differences in medicl therpy, including infliximb, between girls nd boys. According to the Polish dt from the NFZ, women receiving TNF inhibitors for CD were significntly older thn men (29 yers vs 27 yers). This is in line with the nlysis of the SATIMOS cohort, which showed tht significntly smller proportion of women received the tretment within 5 yers of CD dignosis, s compred with men. One possible explntion for the observed differences in the onset of nti TNF therpy between men nd women is tht the use of immunosuppressive nd biologicl drugs is generlly voided in women of childbering ge. In our nlysis, significntly higher number of men receiving TNF inhibitors in the second nd third decdes of life my support this hypothesis. Although TNF inhibitors nd thiopurines re generlly considered sfe during pregnncy (nd only TNF inhibitors should be stopped in the third trimester), with the risk of miscrrige nd other obstetricl complictions rther being incresed by disese ctivity itself s opposed to the medictions used to sustin remission, there is still high risk of tretment discontinution mong pregnnt women. 26 Moreover, in Polnd, the NFZ hs declred pregnncy contrindiction to biologicl therpy, with reimbursement regultions providing tht the therpy must be stopped in women who become pregnnt while receiving TNF inhibitors. This might be the reson why women re less likely to receive biologics erly in the course of the disese. Our dt thus demonstrte n lrming trend, given strictly defined window of opportunity in biologicl therpy in IBD, during which the use of TNF inhibitors is the most effective nd sfe. 27 Post hoc nlyses from lrge clinicl trils hve shown tht ptients with shorter disese durtion hd better response to nti TNF therpy thn those with longer disese durtion. 6 Recently, Ppmichel et l 10 hve shown tht shorter period between dignosis of CD nd the strt of nti TNF therpy is ssocited with long term remission ( medin period of pproximtely 10 yers) fter discontinution of infliximb on chieving clinicl remission. 10 Thus, the observed dely in the nti TNF therpy dministrtion in Polish women my compromise the chnces for good outcomes. In our study, we lso observed lower medin BMI in women strting nti TNF tretment s compred with men (20.6 kg/m 2 vs 22.6 kg/m 2 ). This difference cnnot be explined by demogrphic trends lone becuse, ccording to recent pooled nlysis of popultion studies from 200 countries (including Polnd), the ge stndrdized men BMI in Polish women in 2014 ws 25.8 kg/m 2 (95% CI, ), which is 1.1 kg/m 2 lower thn in Polish men (26.9 kg/m 2 ; 95% CI, ). 28 As weight loss is one of the key symptoms of CD ctivity, our results my indicte tht women hve more serious disese thn men t the strt of nti TNF therpy, which is novel finding. As concerns the CDAI, we did not observe sex relted differences, but, s noted bove, the CDAI must exceed 300 points in Polnd for the tretment to be strted unless the indiction for tretment is refrctory perinl disese. Our study hs severl limittions. First, the study smple ws reltively smll, s compred with cohorts from other countries. However, to our knowledge, our cohort study ws the first to describe the use of TNF inhibitors in country with limited ccess to biologics. To vlidte the SATIMOS study dt on the ge nd sex of ptients, we retrieved the NFZ dt, which confirmed our results. Second, we did not collect dt on pst pregnncies nd deliveries in our femle ptients, which might otherwise hve helped us explin the observed differences in therpy between women nd men. Third, we lcked dt on the ptients involvement in tretment decision mking, so we could not consider this fctor in our nlysis. However, one of the possible explntions for our results might be tht women re less frequently willing to give consent to more ggressive tretment, s compred with men. In conclusion, we showed tht women with CD in Polnd re less likely to receive TNF inhibitors thn men, nd receive them t stge of the disese tht is lredy so dvnced s to possibly compromise tretment outcomes. There hve been single reports in the literture suggesting tht femle sex might lso be ssocited with more limited use of immunosuppressive nd biologicl drugs in other countries. We do not know whether this merely reflects limited ccess to TNF inhibitors or is ssocited with some other culturl or physicin- or ptient relted fctors. More prospective studies re thus needed to explore this importnt phenomenon, with view to optimizing therpy outcomes in ptients with IBD regrdless of sex. Acknowledgments The following gstroenterologists re cknowledged for prticiption in dt collection: Tomsz Arłukowicz (Olsztyn), Piotr Brszczewski (Lublin), Ann Boduł (Łódź), Mgdlen Chruścielewsk Kiliszek (Wrszw), Młgorzt Ferenc (Olsztyn), Mciej Kowlski (Włocłwek), Lilin Łykowsk Szuber (Poznń), Ew Młeck Pns (Łodź), Agnieszk Meder (Bydgoszcz), Milen Pdysz (Łódź), Ann Pietrzk (Wrszw), nd Krystyn Stec Michlsk (Łódź). The uthors would like to thnk Mrs. Pulin Wieszczy for the sttisticl nlysis. Funding This work ws supported by dontion to the Intestinl Section of the Polish Society of ORIGINAL ARTICLE Possible undertretment of women with Crohn disese in Polnd 679

7 Gstroenterology provided by Egis nd covering the cost of mngement of the electronic dtbse used in this study. Contribution sttement EZ, PE, JK, MK, nd MW J conceived the ide for the study. PE, MK, MW J, RT W, DM, ID K, AŚ, AL, MB, nd MG collected the dt nd criticlly reviewed the mnuscript. PE nd EZ drfted the mnuscript. EZ is the gurntor of the rticle nd pproved the finl mnuscript. All uthors red nd pproved the finl version of the mnuscript. Conflict of interest PE received lecture fee(s) from Abbvie; other conflict, Astells. MK received lecture fee(s) from Abbvie, Alvogen, nd Tked; other conflict, Ferring, Alvogen, nd Abbvie. RT W received lecture fee(s) from Abbvie nd Tked; other conflict, Ferring. ID K: other conflict, Astells, Ferring, Abbvie, MSD, nd Tked. JK received lecture fee(s) from Egis nd Abbvie. MB: other conflict, Olympus. EZ received lecture fee(s) from Egis; other conflict, Astells, Tked, nd Jnnsen Cilg. REFERENCES 1 Vogelr L, Spijker AV, vn der Woude CJ. The impct of biologics on helth relted qulity of life in ptients with inflmmtory bowel disese. Clin Exp Gstroenterol. 2009; 2: Peyrin Biroulet L, Hrmsen WS, Tremine WJ, et l. Surgery in popultion bsed cohort of Crohn s disese from Olmsted County, Minnesot ( ). Am J Gstroenterol. 2012; 107: Vester Andersen MK, Prosberg MV, Jess T, et l. Disese course nd surgery rtes in inflmmtory bowel disese: popultion bsed, 7 yer follow up study in the er of immunomodulting therpy. Am J Gstroenterol. 2014; 109: Molnder P, Sipponen T, Kemppinen H, et l. Achievement of deep remission during scheduled mintennce therpy with TNFlph blocking gents in IBD. J Crohns Colitis. 2013; 7: Neurth MF, Trvis SP. Mucosl heling in inflmmtory bowel diseses: systemtic review. Gut. 2012; 61: Peyrin Biroulet L, Bressenot A, Kmpmn W. Histologic remission: the ultimte therpeutic gol in ulcertive colitis? Clin Gstroenterol Heptol. 2014; 12: Eder P, Linke K, Witowski J. Updte on the mechnisms of ction of ntitnf lph ntibodies nd their clinicl implictions in inflmmtory bowel disese. Pol Arch Med Wewn. 2016; 126: Trivedi I, Hnuer SB. Blncing the risks nd benefits of biologic therpy in inflmmtory bowel diseses. Expert Opin Drug Sf. 2015; 14: Ousslh A, Evesque L, Lhrie D, et l. A multicenter experience with infliximb for ulcertive colitis: outcomes nd predictors of response, optimiztion, colectomy, nd hospitliztion. Am J Gstroenterol. 2010; 105: Ppmichel K, Vnde Csteele N, Gils A, et l. Long term outcome of ptients with Crohn s disese who discontinued infliximb therpy upon clinicl remission. Clin Gstroenterol Heptol. 2015; 13: Gomollón F, Dignss A, Annese V, et l. 3rd Europen Evidence bsed Consensus on the Dignosis nd Mngement of Crohn s Disese 2016: Prt 1: Dignosis nd Medicl Mngement. J Crohns Colitis. 2017; 11: Rencz F, Pentek M, Bortlik M, et l. Biologicl therpy in inflmmtory bowel diseses: Access in Centrl nd Estern Europe. World J Gstroenterol. 2015; 21: Dignss A, Lindsy JO, Sturm A, et l. Second Europen evidence bsed consensus on the dignosis nd mngement of ulcertive colitis prt 2: current mngement. J Crohns Colitis. 2012; 6: Molodecky NA, Soon IS, Rbi DM, et l. Incresing incidence nd prevlence of the inflmmtory bowel diseses with time, bsed on systemtic review. Gstroenterology. 2012; 142: Jkubowski A, Zgorowicz E, Krszewsk E, et l. Rising hospitliztion rtes for inflmmtory bowel disese in Polnd. Pol Arch Intern Med. 2014; 124: Dotson JL, Bricker JB, Kppelmn MD, et l. Assessment of sex differences for tretment, procedures, complictions, nd ssocited conditions mong dolescents hospitlized with Crohn s disese. Inflmm Bowel Dis. 2015; 21: Zelinkov Z, vn der Woude CJ. Gender nd Inflmmtory Bowel Disese. J Clin Cell Immunol. 2014; 5: Vvrick SR, Brun L, Bllbeni P, et l. Frequency nd risk fctors for extrintestinl mnifesttions in the Swiss inflmmtory bowel disese cohort. Am J Gstroenterol. 2011; 106: Bert F, Glorieus E, Reeners C, et l. Adlimumb dose escltion nd dose de escltion success rte nd predictors in lrge ntionl cohort of Crohn s ptients. J Crohns Colitis. 2013; 7: Juillert P, Pittet V, Vder JP, et l. Infliximb for Crohn s disese in the Swiss IBD Cohort Study: clinicl mngement nd ppropriteness. Eur J Gstroenterol Heptol. 2010; 22: Schnitzler F, Fidder H, Ferrnte M, et l. Long term outcome of tretment with infliximb in 614 ptients with Crohn s disese: results from single centre cohort. Gut. 2009; 58: Lesuis N, Befrits R, Nyberg F, et l. Gender nd the tretment of immune medited chronic inflmmtory diseses: rheumtoid rthritis, inflmmtory bowel disese nd psorisis: n observtionl study. BMC Med. 2012; 10: Blumenstein I, Herrmnn E, Filmnn N, et l. Femle ptients suffering from inflmmtory bowel diseses re treted less frequently with immunosuppressive mediction nd hve higher disese ctivity: subgroup nlysis of lrge multi centre, prospective, internet bsed study. J Crohns Colitis. 2011; 5: Lw ST, Li KK. Gender relted differences in clinicl course of Crohn s disese in n Asin popultion: retrospective cohort review. Arq Gstroenterol. 2014; 51: Lee GJ, Kppelmn MD, Boyle B, et l. Role of sex in the tretment nd clinicl outcomes of peditric ptients with inflmmtory bowel disese. J Peditr Gstroenterol Nutr. 2012; 55: vn der Woude CJ, Ardizzone S, Bengtson MB, et l. The second Europen evidenced bsed consensus on reproduction nd pregnncy in inflmmtory bowel disese. J Crohns Colitis. 2015; 9: Mgro F, Elikim R. Are we on our wy to chnge our mode of thinking nd treting inflmmtory bowel disese ptients? Ann Gstroenterol. 2014; 27: NCD Risk Fctor Collbortion (NCD RisC). Trends in dult body mss index in 200 countries from 1975 to 2014: pooled nlysis of 1698 popultion bsed mesurement studies with 19.2 million prticipnts. Lncet. 2016; 387: