Scandinavian Journal of Gastroenterology

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Association of extraintestinal manifestations and anaemia with disease outcomes in patients with inflammatory bowel disease Zsuzsanna Vegh, Zsuzsanna Kurti, Lorant Gonczi, Petra Anna Golovics, Barbara Dorottya Lovasz, Istvan Szita, Mihaly Balogh, Tunde Pandur, Stephan R Vavricka, Gerhard Rogler, Laszlo Lakatos & Peter Laszlo Lakatos To cite this article: Zsuzsanna Vegh, Zsuzsanna Kurti, Lorant Gonczi, Petra Anna Golovics, Barbara Dorottya Lovasz, Istvan Szita, Mihaly Balogh, Tunde Pandur, Stephan R Vavricka, Gerhard Rogler, Laszlo Lakatos & Peter Laszlo Lakatos (2016): Association of extraintestinal manifestations and anaemia with disease outcomes in patients with inflammatory bowel disease, Scandinavian Journal of Gastroenterology, DOI: 10.3109/00365521.2016.1140807 To link to this article: http://dx.doi.org/10.3109/00365521.2016.1140807

Published online: 16 Feb 2016.

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Date: 21 February 2016, At: 12:43

SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY, 2016 http://dx.doi.org/10.3109/00365521.2016.1140807

ORIGINAL ARTICLE

Association of extraintestinal manifestations and anaemia with disease outcomes in patients with inflammatory bowel disease Zsuzsanna Vegha,b, Zsuzsanna Kurtia, Lorant Gonczia, Petra Anna Golovicsa, Barbara Dorottya Lovasza, Istvan Szitab, Mihaly Baloghc, Tunde Pandurb, Stephan R Vavrickad, Gerhard Roglerd, Laszlo Lakatosb and Peter Laszlo Lakatosa 1st Department of Medicine, Semmelweis University, Budapest, Hungary; bDepartment of Medicine, Csolnoky Ferenc Province Hospital, Veszprem, Hungary; cDepartment of Medicine, Grof Eszterhazy Hospital, Papa, Hungary; dDepartment of Medicine, Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland

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a

ABSTRACT

ARTICLE HISTORY

Objective The association between extraintestinal manifestations (EIMs) and disease activity suggest a common pathogenetic link with inflammatory bowel disease (IBD). We report on the association of EIMs and anaemia with long-term disease outcomes, including treatment steps, hospitalization, and surgery in the prospective population-based IBD inception cohort from Veszprem province. Methods Data of 678 incident IBD patients (Crohn’s disease/ulcerative colitis(CD/UC): 331/347) diagnosed from 1st January 2000 to 31st December 2012 were analyzed (CD: m/f: 176/155, median age at diagnosis: 28, IQR: 21–40 years, disease duration: 6, IQR: 2–9 years; UC: m/f: 200/147, median age at diagnosis: 36, IQR: 26–50 years, duration: 7, IQR: 4–10 years). Results EIMs were present in 30% of the CD and 17.3% of the UC patients. In CD, female gender (p ¼ 0.02) need for steroid (p 50.001) and azathioprine (AZA) (p ¼ 0.02), while in UC, young age at onset (p ¼ 0.03), extensive disease (p ¼ 0.003), female gender (p ¼ 0.07), need for steroids (p50.001) and AZA (p ¼ 0.004) and need for IBD-related hospitalization (p ¼ 0.01) were associated with the presence of EIMs. Anaemia was present in 56.7% of the CD and 30.2% of the UC patients. In both CD and UC anaemia was associated with age at onset (pCD ¼ 0.001, pUC ¼ 0.04), disease location/ extent (pCD ¼ 0.02, pUC50.001), steroid and AZA use (for both pCD,UC50.001), need for surgery/ colectomy (pCD50.001, pUC ¼ 0.002) and hospitalization (pCD ¼ 0.004, pUC50.001) and in CD, it was associated with anti TNF therapy(p ¼ 0.002). Conclusions The presence of EIMs was associated with disease phenotype in UC and with treatment strategy in both CD and UC. Additionally, anaemia was associated with hospitalization and surgery in both CD and UC, suggesting that EIMs and anaemia may be helpful in stratifying disease severity in IBD.

Received 10 November 2015 Revised 4 January 2016 Accepted 7 January 2016 Published online 11 February 2016 KEYWORDS

Anaemia; disease outcome; extraintestinal manifestations; inflammatory bowel disease

Introduction Inflammatory bowel diseases (IBD) including Crohn’s disease (CD)and ulcerative colitis (UC)are chronic diseases primarily affecting the digestive tract but they are often associated with extraintestinal manifestations (EIMs) with prevalence rates reported from 6.2 to 38.1%.[1–6] The variation in the prevalence of EIMs can be explained by the differences in the study design and methodology. As an example, one of the lowest prevalence (6.2%) was reported in the population-based study by Bernstein et al., where EIMs were identified through voluntary registered ICD-9-CM (International Classification of Diseases, 9th Revision, Clinical

CONTACT Zsuzsanna Vegh ß 2016 Taylor & Francis

[email protected]

Modification) codes in the University of Manitoba IBD Database.[1] In contrast, in the prospective cohort study by the Swiss Inflammatory Bowel Disease Cohort Study Group (SIBDCS) conducted in 2010, 43% of CD and 31% of UC patients had at least one EIM, while in the recent study by the same study group investigating the prevalence and chronological appearance of EIMs relative to the time of IBD diagnosis, EIMs occurred in 33.7% of the CD and 21.7% of the UC patients median 9 years after the diagnosis.[3,4] However, the SIBDCS is not populationbased and may contain a center bias. Nevertheless, similar findings were reported in the population-based

1st Department of Medicine, Semmelweis University, Budapest, Koranyi S 2A, H-1083, Hungary

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study published by our study group in 2003 with prevalence rates of 36.6% and 15% in CD and in UC in patients diagnosed between 1997 and 2001 with a mean follow-up of 11.2 years.[5] For the different types of EIMs several classifications are used. Greenstein et al. classified the EIMs as ‘‘colitis related’’ (joint, skin, mouth, and eye disease), ‘‘small bowel related’’ (malabsorption, gallstones, kidney stones, non-calculous hydronephrosis, and hydroureter), and none specific manifestations (osteoporosis, liver disease, peptic ulcer, and amyloidosis).[6] Some EIMs parallel the disease activity suggesting a common pathogenetic link in IBD, but there are EIMs, which run a course independently from the intestinal activity.[7,8] However, the association of EIMs with disease outcomes including hospitalization and surgery has not been studied yet. Anaemia is the most common complication in patients with IBD. The recent systematic review by Filmann et al. on the prevalence of anaemia in IBD in European countries reported an overall prevalence of 24% (95% confidence interval, 18–31) in IBD with more than half of the patients (57%) having iron-deficiency anaemia.[9] The prevalence was significantly higher in patients with CD (p ¼ 0.01, odds ratio 0.77) and in patients with active disease (p50.0001, odds ratio 2.72) compared to UC patients and patients in remission. In the recent study by Koutroubakis et al. conducted at an IBD center, anaemia was associated with disease activity (p50.0001) and recurrent or persistent anaemia for 3 or more years was independently associated with hospitalizations (p50.01) and IBD-surgeries (p ¼ 0.01).[10] In this study, our aim was to investigate the prevalence and association of EIMs and anaemia with longterm disease outcomes, including treatment steps, hospitalization, and surgery in the population-based inception IBD cohort from Veszprem province diagnosed between 2000 and 2012 in the biological era.

Methods A total of 678 new patients diagnosed with IBD from 2000 to 2012 in the population based inception cohort from Veszprem province were included. The disease characteristics are summarized in (Table 1). Patients were diagnosed in seven general hospitals and gastroenterology outpatients units in Veszprem province. The provincial IBD register data were centralized in Veszprem. The disease phenotype was assessed by a questionnaire completed by the clinician at the time of diagnosis and updated yearly, as necessary. IBD diagnoses were generated in each hospital and outpatient unit and were reviewed thoroughly, using the Lennard– Jones criteria.[11] Disease behavior and location in CD

Table 1. Disease characteristics of patients with inflammatory bowel disease from the Veszprem province database diagnosed from 2000 to 2012. Crohn’s disease No. of patients Male/female Median age at diagnosis, yr (IQR) Median disease duration, yr (IQR) Disease location/extent

Disease behavior at diagnosis Perianal disease Smoking status (never/current/former) Total steroid exposure Total AZA exposure Total anti-TNF exposure Surgical resection/colectomy

331 176/155 28 (21–40) 6 (2–9) L1:115 (35%) L2:105 (32%) L3:108 (32%) L4:3 (1%) B1:82 (55%) B2:66 (20%) B3:83 (25%) 59 (18%) 147 (44%)/138 (42%)/46 (14%) 194 (59%) 197 (60%) 27 (8%) 121 (37%)

Ulcerative colitis 347 200/147 36 (26–50) 7 (4–10) E1:96 (28%) E2:153 (44%) E3:96 (28%) – – 223 (64%)/43 (13%)/81 (23%) 135 (39%) 59 (17%) 26 (8%) 13 (4%)

IQR: interquartile range; L1: ileal; L2: colonic; L3: ileocoloni; L4: isolated upper disease; B1: non-stricturing, non-penetrating; B2: stricturing; B3: penetrating; E1: proctitis; E2: left-sided colitis; E3: extensive colitis.

and disease extent in UC were classified according to the Montreal classification.[12] The change in disease behavior was defined as the change from B1 (non-stricturing, non-penetrating) to either B2 and/or B3 (stricturing and/ or penetrating) disease during the follow-up period. Cases with indeterminate colitis were excluded from the study. Patients’ data regarding smoking status, perianal disease, and EMIs were collected and updated prospectively. Both in-and outpatient records were collected and comprehensively reviewed. A more detailed description of our data collection method, case ascertainment, and follow-up strategy of the Veszprem Province IBD Group was published in our previous studies.[13,14] Any condition suggesting an EIM was investigated by a specialist: rheumatologic EIMs as peripherial arthritis, axial arthropathy including ankylosing spondylitis were diagnosed by rheumatologists, cutaneous EIMs as erythema nodosum and pyoderma gangraenosum by dermatologists and ocular EIMs as uveitis and iridocyclitis by ophthalmologists. Primary sclerosing cholangitis was excluded from this study due to known association with significant but different outcomes including hepatic transplantation and colorectal cancer (CRC) and low overall prevalence. Furthermore, it is known that hepatobiliary manifestations are associated with less severe disease course in IBD. For the diagnosis of anaemia the definitions from the World Health Organization (WHO) were used.[15] Patients’ data regarding medical therapy (5-ASA, steroid, immunosuppressive and biological therapy) were registered throughout their disease course.

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Short-term corticosteroid therapy was used in case of clinical exacerbations. Azathioprine therapy has been used as a maintenance treatment in patients with steroid-dependent, steroid-refractory or fistulizing disease. Methotrexate therapy was used only in selected cases as a second-line immunosuppressive therapy. Infliximab therapy has been used in selected cases since the late-1990s, while there is easier access to this biological drug from 2004. Since 2008, infliximab and adalimumab have become much easier accessible. All-cause and IBD-related hospitalizations (including medical-surgical complications) were registered throughout the disease course from the time of diagnosis. Surgery was performed for emergent indications (e.g., obstructive symptoms, hemorrhage), and for failure to respond to medical therapy. Surgical resections were performed by the same leading IBD surgeon and all cases were discussed between the IBD specialist and the IBD surgeon. Due to the regulations of the National Health Fund, patients were monitored by an IBD specialist at a specialized gastroenterology center every 6 months resulting in a close patient-specialist relationship.[14] In referral patients, disease phenotype, course, and hospitalization events were captured retrospectively at the time of the referral visit and prospectively thereafter. For statistical analyses SPSS software v. 20.0 (Chicago, IL) was used. Frequency distributions were performed for categorical data and calculation of medians and interquartile ranges for continuous variables. Differences between groups were analyzed by 2-test, and 2-test with Yates correction for categorical variables, and for time-dependent outcomes Kaplan–Meier survival curves were plotted and Log-rank test was performed.

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Association between EIMs/anaemia and disease characteristics/treatment strategy/disease outcomes (with variables with a p50.2 in univariate analysis) was also tested by using logistic regression analysis. A p value of 5 0.05 was considered as significant.

Ethics and consent The study protocol was approved by Semmelweis University Regional and Institutional Committee of Science and Research Ethics and the Csolnoky F. Province Hospital Institutional Committee of Science and Research Ethics.

Results Extraintestinal manifestations and their association with disease phenotype and clinical outcomes in CD EIMs were present in 100 (30%) of the CD patients (male/female: 56/44). The factors associated with EIMs in CD and UC are presented in (Table 2). In addition, the association between EIMs and need for steroids and need for AZA remained significant in a logistic regression model (psteroid50.001, pAZA ¼ 0.01, including gender age, duration, disease location as additional variables). Age at onset (p ¼ 0.06), disease location (p ¼ 0.42), smoking (p ¼ 0.08), perianal disease (p ¼ 0.54), presence of internal fistula (p ¼ 0.27), anti-TNF use (p ¼ 0.08) and need for surgery (p ¼ 0.22) showed no association with the presence of EIMs in CD. In Kaplan–Meier analysis, the cumulative probability of IBD-related hospitalization was not associated with the presence of EIMs (pLogRank ¼ 0.592).

Table 2. Factors associated with EMIs and anaemia in patients with Crohn’s disease and ulcerative colitis. EIM CD Age at onset Female gender Disease location Need for steroid Need for AZA Need for anti-TNF Need for IBD-related hospitalization Need for resective surgery UC Age at onset Female gender Disease extent Need for steroid Need for AZA Need for IBD-related hospitalization Need for colectomy

Anaemia

OR

CI (95%)

p

OR

CI (95%)

p

– 1.7 – 3.03 1.68 – – –

– 1.06–2.72 – 1.79–5.13 1.03–2.75 – – –

0.06 0.02 0.42 50.001 0.03 0.09 0.69 0.38

– 0.83 – 2.40 3.39 4.87 2.24 2.79

– 0.54–1.28 – 1.53–3.76 2.14–5.37 1.65–14.43 1.28–3.91 1.72–4.51

0.001 0.39 0.02 50.001 50.001 0.002 0.004 50.001

1.77 1.57 3.58 3.1 2.57 2.12 –

1.005–3.082 0.90–2.77 1.37–9.30 1.74–5.51 1.35–4.89 1.18–4.16 –

0.03 0.07

0.602 – 4.70 5.45 3.81 4.68 5.58

0.37–0.98 – 2.16–10.18 3.32–8.94 2.13–6.79 2.65–8.24 1.68–18.55

0.04 0.55 50.001 50.001 50.001 50.001 0.002

0.003 pmultiple EIMs¼0.05 50.001 pmultiple EIMs50.001 0.004 pmultiple EIMs50.001 0.01 0.57

EIM: extraintestinal manifestation; CD: Crohn’s disease; UC: ulcerative colitis; AZA: azathioprine; IBD: inflammatory bowel disease; OR: Odds ratio; CI: confidence interval.

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Similarly, neither the presence nor the number of EIMs was associated with the time to disease behavior change (pLogRankpresence ¼ 0.762; pLogRankmultiple ¼ 0.636).

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Extraintestinal manifestations and their association with disease phenotype and clinical outcomes in UC EIMs were present in 60 (17.3%) UC patients. The factors associated with EIMs in UC are presented in (Table 2). In addition, the association between EIMs and need for steroids and need for AZA remained significant in a logistic regression model (psteroid50.001, pAZA ¼ 0.002, including gender age, duration, extent as additional variables). Presence of multiple EIMs was associated with disease extent, steroid, and AZA use (Table 2). There was no association between the presence of EIMs and smoking (p ¼ 0.79) and colectomy (p ¼ 0.57). In Kaplan–Meier analysis, the presence of EIMs was associated with the cumulative probability of IBD-related hospitalization in UC patients (Figure 1).

Anaemia and its association with disease phenotype and clinical outcomes in IBD The prevalence of anaemia was 56.7% in CD and 30.2% in UC patients. The factors associated with anaemia in CD and UC are shown in (Table 2). In addition, the association between anaemia and need for steroids and

Figure 1. The cumulative probability of first IBD-related hospitalization in ulcerative colitis patients with/without EMIs, pLogRank ¼ 0.002.

need for AZA remained significant in a logistic regression model in both CD and UC (CD: psteroid50.001, pAZA50.001; UC: psteroid50.001, pAZA ¼ 0.001, including gender age, duration, extent as additional variables). In Kaplan–Meier analysis, anaemia was associated with the time to disease behavior change and time to major IBD-related surgery in CD (Figure 2) and with the time to IBD-related hospitalization in both CD and UC (Figure 3). In contrast, there was no association with gender and smoking status either in CD or UC.

Discussion In the present prospective, population-based study of IBD patients in Veszprem province, Hungary, the presence of EIMs was associated with disease phenotype in UC, while with the treatment strategy with both CD and UC. Of importance, anaemia was associated with disease phenotype, treatment steps, and disease outcomes (including hospitalization and surgery) in both CD and UC. The prevalence of EIMs in CD and UC observed in our study was in line with most of the population-based studies. In the recent study by the EC-IBD Study Group the cumulative prevalence of the first EIM was 16.9% with higher prevalence rates of immune-mediated EIMs observed in CD compared to UC over a median followup time of 10.1 years in the population-based inception cohort of IBD patients (20.1% vs. 10.4%; p50.001).[16] We found a higher prevalence of anaemia in CD patients compared to UC patients (56.7% vs. 30.2%), in concordance with the earlier results from by our group, with iron-deficiency anaemia diagnosed as the most common anaemia type in IBD (CD: 35.8%, UC: 25.9%).[5] The prevalence of anaemia was higher in CD but it was comparable in UC compared to the recent meta-analysis on the prevalence of anaemia in IBD in Europe, where the overall prevalence of anaemia was 27% (95% CI ¼ 19–35) in CD and 21% (95%CI ¼ 15–27) in UC.[9] Our finding was in line with the prevalence rates found in the population-based study of the IBSEN study group, where 48.4% of the CD vs. 20.2% of the UC patients had anaemia at diagnosis (p50.001) and the prevalence of anaemia decreased over the 10-year follow-up period except for women with CD.[17] In the IBD Cohort of Uppsala Region cohort (ICURE) anaemia was more common in CD patients compared to UC patients at the time of diagnosis (42% versus 24%, p50.0001), but the difference disappeared after one year (18% vs. 18%, p ¼ NS).[18] The presence of EIMs was associated with a more severe disease phenotype in UC patients, in concordance with the findings of the EC-IBD Study Group [16] and of

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Figure 2. (A) The cumulative probability of disease behavior change in Crohn’s disease patients with/without anaemia, pLogRank50.001. (B) The cumulative probability of major IBD-related surgery in Crohn’s disease patients with/without anaemia, pLogRank50.001.

Figure 3. (A) The cumulative probability of first IBD-related hospitalization in Crohn’s disease with/without anaemia, pLogRank ¼ 0.001. (B) The cumulative probability of first IBD-related hospitalization in ulcerative colitis with/without anaemia, pLogRank ¼ 0.001.

the study conducted by our study group on the prevalence of EIMs in IBD in 2003.[5] In the SIBDCS analysis by Vavricka et al. [3] active disease was associated with the presence of EIMs in CD patients in multiple logistic regression analysis (OR ¼ 1.95, 95%CI ¼ 1.17–3.23, p ¼ 0.01), while in our study there

was an association of EIMs with treatment strategy (higher AZA exposure) but not with disease location/ behavior or family history of IBD. In this study, anaemia was associated with the behavior change from B1 (non-stricturing, none-penetrating) to B2/B3 (stricturing/penetrating) disease

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behavior but not with disease location. In the Norwegian IBSEN study [17] the use of steroids was associated with anaemia in UC, while at the 1-and 5-year follow-up visits and at the 5-and 10-year visits in CD patients. In the recent study by Koutroubakis et al. [10] anaemia was associated with disease activity (p50.0001), need for hospitalizations (p50.01) and IBD-surgeries (p ¼ 0.01) However, these results are not comparable to the findings of our population-based study, because they are representing the prevalence of EIMs and their association with disease outcomes in an IBD center. In the SIBDCS analysis by Voegtlin et al. [19] comparing the prevalence of anaemia in tertiary referral centers and gastroenterologic practices to the general population, the frequency of anaemia was higher in tertiary referral centers compared to gastroenterologic practices and healthy controls (28.8% vs. 12.9% vs. 3.4%; p50.01). Furthermore, significantly more patients had active disease in referral centers compared to gastroenterologic practices (36% vs. 23%, p ¼ 0.032). Authors are aware of possible limitations of this study; the prevalence of EIMs might have been underestimated with missed mild cases, since they were investigated by specialists only in the presence of suggestive symptoms and referral by the gastroenterologist. In contrast, the strength of this study is the prospective follow-up and population-based setting. Furthermore, patients had close contact with their specialist having follow-up visit at least every 6 months due to the regulations of the National Health Fund. The Veszprem Province register was started in 1977 with long-term prospective data capture and the majority of the gastrointestinal (GI) specialists including the IBD center specialists in Veszprem were unchanged during the follow-up period. In conclusion, EIMs were associated with treatment strategy in both CD and UC and with disease extent in UC. In addition, anaemia was associated with disease phenotype, treatment strategy and hospitalization and surgery requirements in both CD and UC suggesting that EIMs and anaemia may be helpful in defining long-term disease severity and outcomes in IBD.

Disclosure statement For all authors no conflicts of interest and no source of funding were declared.

Reference [1] Bernstein CN, Blanchard JF, Rawsthorne P, et al. The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study. Am J Gastroenterol. 2001;96:1116–1122.

[2] Veloso FT, Carvalho J, Magro F. Immune-related systemic manifestations of inflammatory bowel disease. A prospective study of 792 patients. J Clin Gastroenterol. 1996;23:29–34. [3] Vavricka SR, Brun L, Ballabeni P, et al. Frequency and risk factors for extraintestinal manifestations in the Swiss inflammatory bowel disease cohort. Am J Gastroenterol. 2011;106:110–119. [4] Vavricka SR, Rogler G, Gantenbein C, et al. Chronological order of appearance of extraintestinal manifestations relative to the time of IBD diagnosis in the Swiss inflammatory bowel disease cohort. Inflamm Bowel Dis. 2015;21:1794–1800. [5] Lakatos L, Pandur T, David G, et al. Association of extraintestinal manifestations of inflammatory bowel disease in a province of Western Hungary with disease phenotype: results of a 25-year follow-up study. World J Gastroenterol. 2003;9:2300–2307. [6] Greenstein AJ, Janowitz HD, Sachar DB. The extraintestinal complications of Crohn’s disease and ulcerative colitis: a study of 700 patients. Medicine. 1976;55: 401–412. [7] Lamers CB. Treatment of extraintestinal complications of ulcerative colitis. Eur J Gastroenterol Hepatol. 1997;9: 850–853. [8] Ljung T, Staun M, Grove O, et al. Pyoderma gangrenosum associated with Crohn disease: effect of TNF-alpha blockade with infliximab. Scand J Gastroenterol. 2002;37:1108–1110. [9] Filmann N, Rey J, Schneeweiss S, et al. Prevalence of anaemia in inflammatory bowel diseases in European countries: a systematic review and individual patient data meta-analysis. Inflamm Bowel Dis. 2014;20:936–945. [10] Koutroubakis IE, Ramos-Rivers C, Regueiro M, et al. Persistent or recurrent anaemia is associated with severe and disabling inflammatory bowel disease. Clin Gastroenterol Hepatol. 2015;13:1760–1766. [11] Lennard-Jones JE. Classification of inflammatory bowel disease. Scand J Gastroenterol. 1989;24:2–6. [12] Satsangi J, Silverberg MS, Vermeire S, et al. The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut. 2006;55:749–753. [13] Lakatos L, Kiss LS, David G, et al. Incidence, disease phenotype at diagnosis, and early disease course in inflammatory bowel diseases in Western Hungary, 2002-2006. Inflamm Bowel Dis. 2011;17:2558–2556. [14] Lakatos PL, Golovics PA, David G, et al. Has there been a change in the natural history of Crohn’s disease? Surgical rates and medical management in a population-based inception cohort from Western Hungary between 1977–2009. Am J Gastroenterol. 2012;107:579–588. [15] World Health Organization. Iron deficiency anaemia assessment, prevention and control a guide for programme managers. Report; 2011. Report No.: WHO/NHP/01.3. [16] Isene R, Bernklev T, Høie O, et al. Extraintestinal manifestations in Crohn’s disease and ulcerative colitis: results from a prospective, population-based

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European inception cohort. Scand J Gastroenterol. 2015;50:300–305. [17] Høivik ML, Reinisch W, Cvancarova M, et al. IBSEN study group. Anaemia in inflammatory bowel disease: a population-based 10-year follow-up. Aliment Pharmacol Ther. 2014 Jan;39:69–76. [18] Sjo¨berg D, Holmstro¨m T, Larsson M, et al. Anaemia in a population-based IBD cohort (ICURE):

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still high prevalence after 1 year, especially among pediatric patients. Inflamm Bowel Dis. 2014;20:2266–2270. [19] Voegtlin M, Vavricka SR, Schoepfer AM, et al. Prevalence of anaemia in inflammatory bowel disease in Switzerland: a cross-sectional study in patients from private practices and university hospitals. J Crohns Colitis. 2010;4:642–648.

Association of extraintestinal manifestations and anaemia with disease outcomes in patients with inflammatory bowel disease.

The association between extraintestinal manifestations (EIMs) and disease activity suggest a common pathogenetic link with inflammatory bowel disease ...
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