Laszlo Lakatos, Tunde Pandur, Gyula David, 1^st Department of Medicine, Csolnoky F. Province Hospital, Veszprem
Zsuzsanna Balogh, Department of Medicine, Grof Eszterhazy Hospital, Papa
Pal Kuronya, Department of Infectious Diseases, Magyar Imre Hospital, Ajka
Arpad Tollas, Department of Medicine, Municipal Hospital, Varpalota
Peter Laszlo Lakatos, 1^st Department of Medicine, Semmelweis University, Budapest, Hungary
Correspondence to: Laszlo Lakatos, MD, 1st Department of Medicine, Csolnoky F. Province Hospital, Korhaz u.1, Veszprem, H-8200 Hungary.  laklaci@hotmail.com
Telephone: +36-20-911-9339    Fax: +36-1-313-0250
Received: 2003-06-21    Accepted: 2003-08-02

Abstract
AIM: IBD is a systemic disease associated with a large number of extraintestinal manifestations (EIMs). Our aim was to determine the prevalence of EIMs in a large IBD cohort in Veszprem Province in a 25-year follow-up study.

METHODS: Eight hundred and seventy-three IBD patients were enrolled (ulcerative colitis/UC/: 619, m/f: 317/302, mean age at presentation: 38.3 years, average disease duration: 11.2 years; Crohn’s disease/CD/: 254, m/f: 125/129, mean age at presentation: 32.5 years, average disease duration: 9.2 years). Intestinal, extraintestinal signs and laboratory tests were monitored regularly. Any alteration suggesting an EIMs was investigated by a specialist.

RESULTS: A total of 21.3 % of patients with IBD had EIM (UC: 15.0 %, CD: 36.6 %). Age at presentation did not affect the likelihood of EIM. Prevalence of EIMs was higher in women and in CD, ocular complications and primary sclerosing cholangitis (PSC) were more frequent in UC. In UC there was an increased tendency of EIM in patients with a more extensive disease. Joint complications were more frequent in CD (22.4 % vs UC 10.2 %, P<0.01). In UC positive family history increased the risk of joint complications (OR:3.63). In CD the frequency of type-1 peripheral arthritis was increased in patients with penetrating disease (P=0.028). PSC was present in 1.6 % in UC and 0.8 % in CD. Dermatological complications were present in 3.8 % in UC and 10.2 % in CD, the rate of ocular complications was around 3 % in both diseases. Rare complications were glomerulonephritis, autoimmune hemolytic anaemia and celiac disease.

CONCLUSION: Prevalence of EIM in Hungarian IBD patients is in concordance with data from Western countries. The high number of EIM supports a role for complex follow-up in these patients.

Lakatos L, Pandur T, David G, Balogh Z, Kuronya P, Tollas A, Lakatos PL. 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(10):2300-2307
http://www.wjgnet.com/1007-9327/9/2300.asp

INTRODUCTION
Ulcerative colitis (UC) and Crohn’s disease (CD) are chronic inflammatory diseases of undetermined origin. Inflammatory bowel disease (IBD) is a multifactorial polygenic disease with probable genetic heterogeneity. In this hypothesis, the disease may develop in a genetically predisposed host as a consequence of altered mucosal barrier and disregulated immune response to environmental, in particular enteric antigens, resulting in continuous immune-mediated inflammation^[1-4]. IBD predominantly affects the gastrointestinal system but it is associated with a large number of extraintestinal manifestations (EIMs)^[5]. Some disorders parallel the activity of the bowel disease but for a number of these conditions, their courses run independently of the course of the intestinal disease^[6,7]. Furthermore, there has been some variance in the literature as to whether these EIMs are more associated with CD or UC. In the classical study of Greenstein et al.^[8] EIMs were classified as colitis associated, small bowel associated and none specific manifestations.
     EIMs contribute significantly to morbidity and mortality. Defining specific associations of immune mediated diseases in extraintestinal sites and IBD may be helpful in the better understanding of the pathogenesis of IBD.
     The pathogenesis of EIMs is also multifactorial. The role of genetic factors is supported by family and candidate (e.g. certain HLA) gene studies^[9-11]. The role of humoral immunity is supported by the higher prevalence of autoantibodies in the presence of EIMs, especially pANCA in primary sclerosing cholangitis (PSC). The immunological and clinical connections between these diseases and IBD have never been fully elucidated.
      In this study we aimed to define the prevalence of EIMs in a 25-year follow up study in Hungarian IBD patients. We sought to determine if any of the EIMs was more likely associated with CD or UC, with male or female gender in a follow-up study. Possible associations between EIMs and location and disease behaviour were also investigated.

MATERIALS AND METHODS
Eight hundred and seventy-three IBD patients followed-up at the Out- and Inpatient Gastroenterology Units of the Csolnoky F. Province Hospital in Veszprem Province were enrolled. This hospital is the secondary referral center for IBD patients in the province.
     The data of the 619 UC patients (male/female: 317/302) are summarized in Table 1. The age at presentation varied between 9 and 80 years (average: 38.3 years). Average disease duration was 11.2 years (1-56 years). The location of UC according to the known greatest extent was proctitis in 117, left sided colitis in 304 (including 171 patients with proctosigmoiditis), subtotal (98) and pancolitis (100) in 198 cases. Two hundred and fifty-four CD patients were included (125 males, 129 females). Average age at presentation was 32.5 years (12-80 years). According to the Vienna classification 192 patients were classified as A1, while 62 as A2. Disease duration was 9.2 years (1-40 years). Location of CD was ileal (L1) in 60, colonic (L2) in 81 and ileocolonic (L3) in 113 cases. Patients with upper GI manifestation had lower GI disease as well and they were classified according to their lower GI disease. According to the disease behavior 83 of our CD patients were defined as non-stricturing non-penetrating, 62 as stricturing and 105 as penetrating. Fifty-eight patients of the 95 penetrating cases had parallel strictures. Patients with indeterminate colitis were excluded.

Table 1  Clinical data of IBD patients

In Crohn’s disease (CD). Location: L1: terminal ileum, L2: colonic, L3: ileocolonic, behaviour: B1: non stricturing-non penetrating, B2: stricturing, B3: penetrating.

    Patients in remission were followed-up twice per year. Patients who relapsed were followed-up or hospitalised according to the actual disease activity. Special interest was dedicated to the presence of EIM. Screening of EIMs was not performed, therefore the number of EIMs may have been underestimated. Routine follow-up consisted of assessment of patient’s complaints, physical examination and laboratory testing.
     Any alteration suggesting an EIMs was investigated by a specialist. In this study we did not assess the association between disease activity and the presence of EIM. Major EIMs studied in this report were axial and peripheral arthropathies (including ankylosing spondylitis), aseptic femoral head necrosis, primary sclerosing cholangitis (PSC), small duct cholangitis, autoimmune hepatitis, erythema nodosum, pyoderma gangrenosum, chronic urticaria, acute anterior uveitis, iritis, episcleritis, conjunctivitis, autoimmune hemolytic anaemia (AIHA), immune thrombocytopenic purpura (ITP), celiac disease, myositis, and glomerulonephritis.
     Joint involvements were classified as peripheral and/or axial arthropathies. Peripheral arthropathies were divided into two subgroups according to the classification of Orchard et al^[13]. Type-1 arthritis is an acute self-limiting pauciarticular (less than 5 joints) arthropathy typically affecting large joints. It is associated with other EIMs and its course parallels with the activity of the bowel disease. In contrast, type 2 arthritis is a chronic bilateral, symmetrical polyarticular arthropathy affecting five or more small joints. Its course runs independently of the course of the intestinal disease. Axial arthropathies are divided into sacroileitis and ankylosing spondylitis (SPA). Its incidence is 20-times higher than that in the normal population^[14]. Rheumatologists investigated sacroileitis and ankylosing spondylitis cases. Laboratory testing (rheumatoid factor), X-ray and since 1997 MRI examinations were done.
     Patients with elevated liver function tests (LFT, aminotransferases, cholestatic enzymes) were followed-up more cautiously. In patients with chronic or progressive elevation of enzyme levels liver biopsy and/or endoscopic retrograde cholangiopancreatography (ERCP) examination was done if patient gave informed consent. The diagnosis of PSC was based on elevated liver function tests, ERCP and consistent histology findings. Small duct PSC was diagnosed if histology suggested PSC, but ERCP could not verify the diagnosis^[15,16]. Cholelithiasis, cirrhosis and focal nodular hyperplasia (FNH) were excluded from hepatobiliary manifestations.
     In patients with verified thrombosis, blood samples were examined for hypercoagulability including in almost all cases analysis of plasminogen, proteins C and S activity and factor V Leiden mutation.
     Patients with glomerulonephritis were followed-up by nephrologists as well. Diagnosis was based on clinical and chemical data and congruent histology findings. Ureteral obstruction was diagnosed by cystoscopy and urography, CT or MRI. If the alteration suggested fistulae in the urinary tract, cytography was also performed.

Statistical analysis
For statistical comparison of the data, Statistica 6.0 (Statsoft Inc, USA) was used. Normality was tested by Shapiro-Wilk’s W test. x² test with Yates correction was used to compare groups and odds ratios were calculated.

RESULTS
The prevalence of major (joint, hepatobiliary, ocular and cutaneous) and all EIMs determined in this study are shown in Table 2. Major EIMs were apparent more frequently in CD than in UC (36.6 % vs 15.0 %, P<0.001). EIMs were more frequent in patients with a disease duration for more than 10 years in both CD (22.1 % vs 48.9 %, P=0.003) and UC (22.1 % vs 10.4 %, P<0.001).

Table 2  Prevalence of extraintestinal manifestations (EIM) in IBD

     The prevalence of EIMs was higher in CD except ocular complications and PSC (P<0.001 for joint, hepatobiliary and cutaneous manifestations, Tables 3 and 4). In general, EIMs were more frequent in women except hepatobiliary manifestations and arthropathies in UC patients.
     All major EIMs were more prevalent in more extensive UC (Table 5). There was a tendency of increased frequency of joint manifestations in CD patients with colonic involvement (L2 and L3: 23.7 %) compared to patients with only ileal disease (18.3 %, P=NS, Table 5). The prevalences of hepatobiliary, ocular and cutaneous manifestations were not different according to disease location.

Table 3  Age at presentation and prevalence of major extraintestinal manifestations in patients with IBD

A1: age at presentation <40 yrs, A2: age at presentation ≥40 yrs.

Table 4A  Familial IBD and association with extraintestinal manifestations

Table 4B  Familial IBD and association with extraintestinal manifestations

Table 5  Prevalence of extraintestinal manifestations in ulcerative colitis and Crohn’s disease according to location and disease behaviour

     Age at presentation (A1: <40 years, A2: =40 years) did slightly affect the prevalence of EIMs (Table 3). Joint manifestations were more prevalent in CD patients with earlier disease onset (OR: 1.96, 95 % CI: 1.01-4.21). The same tendency was observed for cutaneous manifestations.
      Familial disease was seen in 3.9 % of patients with UC and 12.2 % of patients with CD (Tables 4A-B). Joint manifestations were more frequent in UC patients with familial disease (OR: 3.63, 95 % CI: 1.43-9.31) than without. The same tendency was seen in UC patients (OR: 1.9, 95 % CI: 0.87-4.14) and  ocular manifestations were found in familial UC cases.

Table 6A  Joint manifestations in IBD patients

*Two female patients with ulcerative colitis had rheumatoid arthritis.

Table 6B  Joint manifestations in IBD according to location and disease behaviour

*One patient with proctitis and one with pancolitis had rheumatoid athritis.

     Joint manifestations were more frequent in CD than in UC (P<0.001, Tables 6A-B.). There was a tendency of increased frequency of joint manifestations in women with CD (26.4 % vs 18.4 %, OR: 1.58, 95 % CI: 0.87-2.87). Axial arthritis (10.2 % vs 3.2 %, P=0.0001) and type 1(11.4 % vs 2.7 %, P=0.0001) arthritis were more frequent in CD, with equal prevalence of type-2 arthritis. In UC joint manifestations were almost three-fold more frequent in patients with pancolitis compared to proctitis and left sided colitis cases (P<0.002 for both, Table 5). In CD a tendency of increased frequency of joint manifestations was observed in patients with colonic involvement (L2 and L3: 23.7 %) or stricturing/penetrating disease (26.3 %) compared to patients with ileal only disease (18.3 %) or non-stricturing non-penetrating disease behavior (14.9 %, Table 6B). An increased frequency of type 1 arthritis was observed in patients with penetrating compared to non-stricturing non-penetrating disease (P=0.028), the same tendency was observed in patients with or without colonic involvement. Type-1 arthritis affected more frequently the joints of the lower extremities (most frequently the knee and ankle), while type-2 arthritis was more common in the joints of the upper extremities.
     Hepatobiliary manifestations are summerised in Table 7. PSC was diagnosed in 10 patients with UC and only 2 patients with CD. Small duct PSC was diagnosed in 8 and 6 cases, respectively. Non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) was diagnosed in 9.4 % of UC patients and 19.3 % of CD patients (P<0.0001). These patients had unexplained abnormal liver function tests (viral hepatitis, autoimmune, drug or alcohol induced disease, extrahepatic obstruction excluded). Liver biopsy was performed in 22/107 cases, which identified NAFLD or NASH in almost all cases. US proved hepatomegaly in 13/107 (12.1 %). Progression to cirrhosis was not observed in these patients during follow-up.

Table 7  Hepatobiliary manifestations in IBD patients

*One female patient had autoimmune hepatitis. NAFLD: non-alcoholic fatty liver disease, NASH: non-alcoholic steatohepatitis.

      Cutaneous manifestations were seen in 10.2 % of the patients with CD and 3.9 % of the patients with UC (Tables 8A-B). Cutaneous manifestations were more common in women in both UC (male/female: 5.0 %/2.8 %) and CD (13.2 %/7.2 %, OR: 1.95, 95 % CI: 0.85-4.48). Erythema nodosum and pyoderma gangrenosum were the most frequent manifestations. In UC cutaneous manifestations were more frequent in more extensive disease (7.6 % in pancolitis vs 2.1 % in proctitis or left sided colitis, P=0.002).
     Ocular manifestations were apparent in approximately 3.0 % of UC and CD patients (Table 9). The prevalence was more frequent in women in both UC (P=0.009, OR: 4.37, 95 % CI: 1.51-12.6) and CD (OR:3.0, 95 % CI=0.67-8). Conjunctivitis, acute anterior uveitis and scleritis were the most frequent manifestations. Ocular manifestations developed mostly during the early years of the disease. In UC more than half of the patients with ocular complication had pancolitis (6.1 % in pancolitis vs 1.9 % in left sided colitis or proctitis, P=0.01).
      Iron deficiency anaemia was seen in 35.8 % of CD patients and in one fourth of UC patients (Tables 10A-C). It was more frequent in women in UC (32.1 % vs 19.6 %, P<0.001, OR=1.95, 95 % CI: 1.35-2.81). Chronic anaemia was more frequent in patients with CD (9.6 % vs 17.7 %, P<0.001). The prevalence of macrocytic anaemia was around 4 % in both diseases. It was also observed more frequently in patients with ileocolonic disease than without it (P=0.03). The same tendency was observed according to disease behaviour; chronic anaemia tended to be more frequent in patients with stricturing or penetrating disease (P=0.06, Table 10C). AIHA developed in four UC patients.

Table 8A  Cutaneous manifestations in patients with ulcerative colitis (n=619)