Occurrence Of Extraintestinal Manifestations Research Articles

P782 Ustekinumab in Ulcerative colitis: a real-life effectiveness study across multiple Belgian centers (SULTAN)

Abstract Background Ulcerative colitis (UC) is a chronic inflammatory disease affecting the colon.1 Ustekinumab (UST), a monoclonal antibody against the p40 subunit of interleukin (IL) 12 and 23 has shown in the UNIFI trials to be effective and safe in patients with moderate-to-severe UC.2 Real-life data are still limited.3 The aim of this study was to assess the real-world effectiveness and safety of UST in patients with UC across Belgian hospitals. Methods In this multicentric, retrospective observational study, patients with UC who received UST from September 2020 onwards were included. Clinical and biochemical response was assessed at baseline, week 8, 16 and 52. The primary endpoint was steroid-free remission defined as partial Mayo score of ≤ 2 with no subscore > 1 at week 16. Secondary endpoints included clinical and biochemical response (defined respectively as a decrease in partial Mayo score ≥ 3 points and ≥ 3 plus a decrease in rectal bleeding score ≥ 1 or an absolute rectal bleeding score ≤ 1 and a decline of 50% or more in CRP and/or fecal calprotectin). Results 107 patients with moderate-severe UC (86% patients with ≥ S2 severity) were included across 16 participating centers. Median disease duration was 10 years (1-73y) and 69 (64%) of patients had previously failed 2 or more biologicals. At week 16, 35 patients reached the primary endpoint of steroid-free clinical remission (33%), while 67 had a clinical response (62.6%) (Fig 1). There was a statistically significant decline in partial mayo score (median at baseline 6.0 range (1-9); W16 2.0 (0-9, p<.001), CRP (3.85 mg/L (0.4-181) vs 3.15 (0.88-10.3); p<.001) and calprotectin (1040 (13-6000) vs 300 (3.8-2980); p<.001) (Fig 2 and 3). Biochemical response was seen in 41 patients (38%). No predictors for steroid-free remission could be identified. At the end of follow-up at week 52, 75 patients were still treated with UST (70%). Reasons for discontinuation were primary non-response (N=18 (17%), loss of response (N=8 (7.5%) and adverse events (N=2 (1.9%)). No predictor for UST failure could be identified. Eight patients needed to be referred for colectomy (7.5%). In 7 patients dose optimization via IV reinduction occurred. No difference in occurrence of extra-intestinal manifestations was noted during treatment, severe infections occurred in 1 patient (0.9%). No other new safety signals were observed. Conclusion In this multi-centric, real-life cohort with highly refractory UC patients, UST was associated with a clinical response rate of 63% at 16 weeks while steroid-free remission was achieved in 33% of patients. No important new safety signals were observed.

P527 Investigating fatigue in vedolizumab-treated patients with ulcerative colitis or Crohn’s disease from a Belgian registry

Abstract Background Vedolizumab (VDZ) has demonstrated remission in ulcerative colitis (UC) and Crohn’s disease (CD), but its impact on patient (pt) fatigue is not well understood. Herein we report interim fatigue analysis data from a Belgian registry of VDZ-treated pts. Methods Ad-hoc analysis from the prospective observational Belgian VDZ registry (started, November 2016; data cutoff, February 2019), a sub-study of the European VDZ post-authorization safety study (ENcePP EUPAS6469) included pts aged ≥18 years with UC or CD with ongoing VDZ intravenous therapy (≥2 weeks) at recruitment. At baseline (recruitment) and every 6 months, physicians collected data (follow-up was 3 years or 1 year after last dose if VDZ was discontinued [whichever occurred first] and pts completed the 13-Item Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale. Clinical remission was defined as Harvey-Bradshaw Index (HBI) score <5 for CD, and partial Mayo score (pMS) <2 with no individual subscore >1 for UC. This analysis explored the association (using generalized estimating equations) between all available FACIT-F total scores and baseline demographic, clinical, and treatment characteristics in the treatment analysis set (TAS; pts had ≥1 VDZ dose and ≥1 year of follow-up records). Results The registry enrolled 202 VDZ-treated UC and CD pts from 19 Belgian centres. TAS included 141 pts (UC 47, CD 94); median follow-up was 537 days; 140/141 pts had ≥1 FACIT-F score. In the UC and CD groups, respectively, 68% and 42% of pts were male; median (IQR) age at index date was 51 (37–59) and 40 (29–52); and baseline median (IQR) FACIT-F total score was 39 (32–46) and 32 (24–40). Lower FACIT-F score (more fatigue) was associated with higher pMS in UC (p<0.001), and higher HBI score (p=0.01) and having ongoing fistulas at baseline (p=0.01) in CD (Table). Less fatigue was associated with being in remission at baseline in both UC and CD (p<0.01). Being male was associated with less fatigue in the overall population and CD (p<0.01), but not in UC alone. Baseline occurrence of extra intestinal manifestations (EIMs) was associated with more fatigue in the overall group (p=0.037); however few pts (UC 4; CD 8) had EIMs. UC pts had less fatigue than CD pts (p=0.004). From baseline to month 24, the change in median (IQR) FACIT-F total score was -3.0 (-12.0 to 5.0) points for UC and 3.5 (-1.0 to 18.0) for CD. Conclusion These real-world data from a long-term registry study of VDZ-treated pts in Belgium demonstrate that higher pMS and HBI score, active fistulae, and EIM occurrence at baseline may be associated with more fatigue in IBD pts. Pts treated with VDZ had no significant change in FACIT-F total score over 24 months.

Extraintestinal Manifestations of Inflammatory Bowel Disease in Middle Eastern Patients

Background and AimsThe Inflammatory Bowel Diseases (IBDs), Crohn’s Disease (CD) and Ulcerative Colitis (UC), are gastrointestinal autoimmune disorders with many Extraintestinal Manifestations (EIMs). Previously reported incidences of EIMs in IBD patients have ranged from 10% to 50%. The large variation in occurrence of EIMs has been linked to genetic predisposition. Correlations between individual EIMs are unclear. Therefore, we aim to estimate the incidence of EIMs in a Middle Eastern cohort of patients with IBD and examine possible relationships with EIMs.Patients and MethodsWe conducted a retrospective study involving all patients included in the King Abdulaziz University IBD information system registry between 2013 and 2018. Data on demographics, disease characteristics, and EIMs were extracted and analyzed using descriptive statistics: the standard Student’s t-test and chi-squared test. Logistic regression analysis was used to examine associations using STATA software version 11.2 (StataCorp, TX, USA).ResultsWe reviewed the electronic medical files of 284 patients with confirmed IBD, of which 158 (55.6%) were females, the mean age was 27.8 (±15) years; 146 (51.4%) patients had CD and 138 (48.6%) UC. The overall incidence risk of EIMs was 138 (52.3%) over a mean duration of follow up of 7.3 (±3.9) years. The most common EIM was arthritis (33%), followed by aphthous ulcers (16%). Pyoderma gangrenosum occurred in 8% of patients and appeared to be specific for CD patients (p = 0.002), whereas Primary Sclerosing Cholangitis (PSC) was more specific for UC (p = 0.001). Certain EIMs appeared to occur together such as arthritis with PSC (p = 0.001). Regression analysis identified disease type (in favor of UC; odds ratio = 0.50, p = 0.03) and age at the time of diagnosis (odds ratio = 1.04, p = 0.001) as the only significant predictors of EIMs.ConclusionOur results demonstrate that more than half of IBD patients have at least one EIM. Contrary to what has often been reported, we found that EIMs occur more commonly in UC than CD. A multidisciplinary assessment is recommended as part of IBD management to improve overall health outcomes.

Extraintestinal manifestations and characteristics of ulcerative colitis in Xinjiang Uygur Autonomous Region

Objective To analyze the extraintestinal manifestations and clinical characteristics of patients with ulcerative colitis (UC) and to improve the knowledge, diagnosis and treatment of UC with extraintestinal manifestations. Methods From January 2013 to December 2017, at the Department of Gastroenterology, People′s Hospital of Xinjiang Uygur Autonomous Region, 260 hospitalized patients diagnosed as UC were collected. The demographic characteristics, clinical phenotypes and extraintestinal manifestations were analyzed. Chi square test was used for statistical analysis. Results Among 260 UC patients, 41.9% (109/260) had extraintestinal manifestations, including fatty liver (17.3%, 45/260), gallbladder stone (11.9%, 31/260), typeⅠperipheral arthritis (8.1%, 21/260), type Ⅱ peripheral arthritis (3.1%, 8/260), oral ulcer (4.6%, 12/260), erythema nodosum (3.8%, 10/260), irireitis (1.9%, 5/260), ankylosing spondylitis (1.5%, 4/260), sacroiliitis (1.5%, 4/260), pyoderma gangrenosum (0.4%, 1/260) and primary sclerosing cholangitis (0.4%, 1/260). Gender, ethnicity, age, history of intestinal surgery and body mass index (BMI) could affect the occurrence of extraintestinal manifestations in patients with UC (χ2=7.901, 4.318, 9.291, 8.162 and 10.397, all P<0.05). The incidence of joint lesions in Uygur UC patients was higher than that in Han UC patients (16.6%, 24/145 vs. 7.0%, 8/115), and the difference was statistically significant ( χ2=5.471, P=0.019). The incidence of extraintestinal manifestations in UC patients in the active phase was higher than that of UC patients in the inactive phase (52.9%, 92/174 vs. 19.8%, 17/86), and the difference was statistically significant (χ2=25.908, P<0.01). Conclusions UC is complicated with a variety of extraintestinal manifestations. The most commonly involved organs are liver and gallbladder, joint and oral cavity. The extraintestinal manifestations are more common in female, Uygur, patients with high BMI, youth, patients with a history of intestinal surgery and UC patients at the active phase. Key words: Colitis, ulcerative; Extra-intestinal manifestations; Clinical features

Incidence and Treatment of Patients Diagnosed With Inflammatory Bowel Diseases at 60 Years or Older in Sweden

Diagnosis of inflammatory bowel diseases (IBD) is increasing among elderly persons (60 years or older). We performed a nationwide population-based studyto estimate incidence and treatment of IBD. We identified all incident IBD cases in Sweden from 2006 through 2013 using national registers and up to 10 matched population comparator subjects. We collected data on the patients' health care contacts and estimated incidence rates, health service burden, pharmacologic treatments, extra-intestinal manifestations, and surgeries in relation to age of IBD onset (pediatric, <18 years; adults, 18-59 years; elderly, ≥60 years). Of 27,834 persons diagnosed with incident IBD, 6443 (23%) had a first diagnosis of IBD at 60 years or older, corresponding to an incidence rate of 35/100,000 person-years (10/100,000 person-years for Crohn's disease, 19/100,000 person-years for ulcerative colitis, and 5/100,000 person-years for IBDunclassified). During a median follow-up period of 4.2 years (range, 0-9 years), elderly patients had less IBD-specific outpatient health care but more IBD-related hospitalizations and overall health care use than adult patients withIBD.Compared with patients with pediatric or adult-onset IBD, elderly patients used fewer biologics and immunomodulators but more systemic corticosteroids. Occurrence of extra-intestinal manifestations was similar in elderly and adult patients, but bowel surgery was more common in the elderly (13% after 5 years vs 10% in adults) (P < .001). The absolute risk of bowel surgery was higher in the elderly than in the general population, but in relative terms, the risk increase was larger in younger age groups. In a nationwide cohort study in Sweden, we associated diagnosis of IBD at age 60 years or older with a lower use of biologicsand immunomodulators but higher absolute risk of bowel surgery, compared with diagnosis at a younger age. The large differences in pharmacologic treatment of adultsand elderly patients are not necessarily because of a milder course of disease and warrant further investigation.

Chronological Order of Appearance of Extraintestinal Manifestations Relative to the Time of IBD Diagnosis in the Swiss Inflammatory Bowel Disease Cohort.

Data evaluating the chronological order of appearance of extraintestinal manifestations (EIMs) relative to the time of inflammatory bowel disease (IBD) diagnosis is currently lacking. We aimed to assess the type, frequency, and chronological order of appearance of EIMs in patients with IBD. Data from the Swiss Inflammatory Bowel Disease Cohort Study were analyzed. The data on 1249 patients were analyzed (49.8% female, median age: 40 [interquartile range, 30-51 yr], 735 [58.8%] with Crohn's disease, 483 [38.7%] with ulcerative colitis, and 31 [2.5%] with indeterminate colitis). A total of 366 patients presented with EIMs (29.3%). Of those, 63.4% presented with 1, 26.5% with 2, 4.9% with 3, 2.5% with 4, and 2.7% with 5 EIMs during their lifetime. Patients presented with the following diseases as first EIMs: peripheral arthritis 70.0%, aphthous stomatitis 21.6%, axial arthropathy/ankylosing spondylitis 16.4%, uveitis 13.7%, erythema nodosum 12.6%, primary sclerosing cholangitis 6.6%, pyoderma gangrenosum 4.9%, and psoriasis 2.7%. In 25.8% of cases, patients presented with their first EIM before IBD was diagnosed (median time 5 mo before IBD diagnosis: range, 0-25 mo), and in 74.2% of cases, the first EIM manifested itself after IBD diagnosis (median: 92 mo; range, 29-183 mo). In one quarter of patients with IBD, EIMs appeared before the time of IBD diagnosis. Occurrence of EIMs should prompt physicians to look for potential underlying IBD.

P660 Crohn's disease course is not different in familial than in sporadic cases: A case-control population-based study

P660 Crohn’s disease course is not different in familial than in sporadic cases: A case control population-based study R. Gerard1 *, H. Sarter2, M. Fumery3, L. Dauchet4, E. Joyez4, F. Vasseur4, J.-F. Colombel5, D. Turck6, L. Peyrin-Biroulet7, G. Savoye8, C. Gower-Rousseau4,9. 1University and Hospital, Gastroenterology, Lille, France, 2University and Hospital, Epimad Registry Biostatistics EA 2694, Lille, France, 3University and Hospital, Gastroenterology, Amiens, France, 4University and Hospital, Epidemiology, Lille, France, 5Hemsley Inflammatory Bowel Disease Center, Icahn Medical School of Medicine at Mount Sinai, New-York, United States, 6University and Hospital, Paediatric, Lille, France, 7University and Hospital, Gastroenterology, Nancy, France, 8University and Hospital, Gastroenterology, Rouen, France, 9Health, Epidemiology, Lille, France Background: Having a first degree relative (siblings, children, parents) with Crohn’s disease (CD) is the main risk factor to develop the disease. This genetic risk could influence the natural history of the disease; particularly in multiplexes families (MF) defined by at least 3 members with CD linked at the first degree. The aim of our study was to compare disease course between patients with CD in MF and sporadic families. Methods: MF were identified in a French population-based study on inflammatory bowel disease (Epimad Registry). Each patient from MF was matched to at least one sporadic case also issued from this Registry. Matching criteria were: gender, age at CD diagnosis, phenotype at diagnosis (disease location and disease behaviour) according to Montreal classification [1] and date of CD diagnosis. Primary outcomes were assessed at the end of the follow up and included: disease extension, change of behaviour from inflammatory (B1) to complicated type of CD (structuring B2 and/or penetrating B3), occurrence of extra-intestinal manifestations (EIMs), the need for immunosuppressor (IS) treatment or anti-TNF biologic agent, and at least one intestinal resection. Case control comparisons were performed using a mixed model for multivariate analysis, adjusted to smoking status. Results: Fifty-nine patients belonging to 24 MF were included matched to 88 sporadic patients. The median follow-up was 16 years [Q1 = 12 Q3 = 20]. Patients from MF were significantly more often smokers or former smokers than controls (93% vs 53%, p < 0.05). No differences between MF and sporadic cases were observed regarding disease extension (75% vs 70%), change behaviour (56% vs 65%) or prevalence of EIMs (27% vs 31%). Similar proportions of sporadic cases and MF patients received at 10 and 20 years; (1) IS (46% vs 62% and 61% vs 73%, respectively), (2) anti-TNF therapy (14% vs 24% and 46% vs 52%, respectively), and (3) underwent surgical intestinal resection (42% vs 50% and 49% vs 57%, respectively). Conclusions: In this case control population-based study we find none difference in the CD disease course between patients from multiplex and sporadic families. These findings could suggest that genetic and environmental risk factors affecting the CD disease course are different from those affecting its occurrence.

Extraintestinal Manifestations of Pediatric Inflammatory Bowel Disease and Their Relation to Disease Type and Severity

Although it is known that extraintestinal manifestations (EIMs) commonly occur in pediatric inflammatory bowel disease (IBD), little research has examined rates of EIMs and their relation to other disease-related factors in this population. The purpose of this study was to determine the rates of EIMs in pediatric IBD and examine correlations with age, sex, diagnosis, disease severity, and distribution. Data were prospectively collected as part of the Pediatric IBD Collaborative Research Group Registry, an observational database enrolling newly diagnosed IBD patients <16 years old since 2002. Rates of EIM (occurring anytime during the period of enrollment) and the aforementioned variables (at baseline) were examined. Patients with indeterminate colitis were excluded from the analysis given the relatively small number of patients. One thousand nine patients were enrolled (mean age 11.6 +/- 3.1 years, 57.5% boys, mean follow-up 26.2 +/- 18.2 months). Two hundred eighty-five (28.2%) patients experienced 1 or more EIMs. Eighty-seven percent of EIM occurred within the first year. Increased disease severity at baseline (mild vs moderate/severe) was associated with the occurrence of any EIM (P < 0.001), arthralgia (P = 0.024), aphthous stomatitis (P = 0.001), and erythema nodosum (P = 0.009) for both Crohn disease (CD) and ulcerative colitis (UC) during the period of follow-up. Statistically significant differences in the rates of EIMs between CD and UC were seen for aphthous stomatitis, erythema nodosum, and sclerosing cholangitis. EIMs as defined in this study occur in approximately one quarter of pediatric patients with IBD. Disease type and disease severity were commonly associated with the occurrence of EIMs.

Variants at the 3p21 locus influence susceptibility and phenotype both in adults and early-onset patients with inflammatory bowel disease

To date, a number of high-profile studies have yielded over 50 inflammatory bowel disease (IBD) disease genes/loci. The polymorphisms rs9858542 (BSN) and rs3197999 (MST1), on 3p21 locus, have been found associated with susceptibility to IBD. We aimed to replicate these associations in adult and early-onset cohorts of IBD Italian patients, by analyzing also potential gene-gene interactions with variants in NOD2/CARD15, IL23R, ATG16L1, and IRGM genes, and investigating genotype-phenotype correlation. In all, 1808 patients with IBD, 855 with Crohn's disease (CD) and 953 with ulcerative colitis (UC), including 539 patients with their initial diagnosis <19 years of age, and 651 controls were analyzed for SNPs rs9858542 and rs3197999. BSN and MST1 were significantly associated with either CD (P(rs9858542) 2.5 x 10(-7); P(rs3197999) 3.9 x 10(-7)), and UC (P(rs9858542) = 3.1 x 10(-4); P(rs3197999) = 8 x 10(-4)). Prevalence of these variants was significantly increased in both adult and early-onset IBD patients. After stepwise logistic regression, the 2 variants were associated in adult UC with distal colitis (P(rs9858542) = 0.013, odds ratio [OR] = 2.04, 95% confidence interval [CI] = 1.16-3.59; P(rs3197999) = 0.018, OR 1.9, 95% CI 1.2-3.3), while the rs3197999 variant was inversely associated with occurrence of extraintestinal manifestations in adult CD(P = 0.017, OR 0.6, 95% CI 0.4-0.9). We confirmed the association of BSN and MST1 with IBD susceptibility, either in the adult or the early-onset cohorts. These variants appeared to influence either the distal location of the disease in the UC cohort and extraintestinal manifestations in CD patients.

Do HLA antigens predict the occurrence of extraintestinal manifestations of IBD?

Do HLA antigens predict the occurrence of extraintestinal manifestations of IBD?

Do HLA antigens predict the occurrence of extraintestinal manifestations of IBD?

Extraintestinal manifestations are commonly seen in (up to 40%) in patients with either ulcerative colitis (UC) or Crohn’s disease (CD). Many of them are associated with active disease (recurrent mouth ulcers, erythema nodosum, uveitis, Type 1, or reactive large joint arthropathy). Others pursue a clinical course independent of the intestinal disease (sacroiliitis, ankylosing spondylitis, Type 2 or small joint arthropathy, primary sclerosing cholangitis). Pyoderma gangrenosum usually occurs with active intestinal disease but can occasionally occur when the intestinal inflammation is largely in remission. For CD, both groups of these extraintestinal manifestations occur in patients with colonic involvement, and rarely occur when only small intestinal disease is present. Data on the HLA associations are limited both in terms of numbers of studies and numbers of patients studied. However, a particularly strong association has been found between the Class II allele DRB1*0103, and Type 1 arthropathy.1 Of patients with either UC or CD who develop the acute, large joint arthropathy in association with active disease, 38% of them carry this allele, compared with about 8% of UC patients as a whole, and only 2% of the healthy population. It is interesting to note that patients who develop a reactive arthropathy following infection (Salmonella, Campylobacter, Reiter’s syndrome) also have a high carriage rate of this allele. This allele is also associated with the risk of having recurrent mouth ulcers or uveitis, although less strongly compared with Type 1 arthropathy. Uveitis and recurrent mouth ulcers are also associated with HLA B27. Erythema nodosum has a particularly strong association with a polymorphism in the promoter region of the TNF gene (-1031C).2 There are further HLA associations with some of those extraintestinal manifestations that are independent of inflammatory bowel disease (IBD) activity. Ankylosing spondylitis (AS) occurs in 1%–2% of patients with IBD and differs from sporadic AS in having no gender association (compared with a marked male predominance in sporadic AS) and in having a weaker association with HLA B27 (60% compared with 90% in sporadic AS). Nevertheless, the association is highly significant. Patients with sacroiliitis only have a 22% risk of having HLA B27, a percentage that is little different from the normal control population. Patients with Type II arthropathy, a seronegative, symmetrical small joint disease, have a strong association with HLA B44. Data concerning primary sclerosing cholangitis (PSC) are conflicting. Most studies find an association with HLA DR3. In the largest study the haplotype HLA DRB1*0301, DQB1*0201 (the classical autoimmune haplotype) was found in 25% of patients with PSC and colitis, 16% of patients with pancolitis only, and 10% of controls (Cullen S, Chapmann RG, Jewell DP. Submitted). These data clearly indicate that individuals possessing certain HLA alleles are at risk of developing extraintestinal manifestations, should they have the misfortune of developing IBD. In contrast, they are unlikely to occur in patients with IBD who do not possess these alleles. Furthermore, these associations can explain why these manifestations often overlap in a single individual. The outstanding questions concern the mechanisms of pathogenesis. Since the HLA region on the short arm of chromosome 6 is a very gene-dense region, it cannot be assumed that the allelic associations that have been identified are the relevant genes as opposed to having identified an allele which is in linkage disequilibrium with a more relevant polymorphism in a neighboring gene. Until this problem has been overcome, functional studies to explore pathogenic mechanisms cannot sensibly begin.

Clinical features in familial cases of Crohn’s disease and ulcerative colitis in Italy: a GISC study

OBJECTIVE: Previous studies have reported genetic anticipation, genomic imprinting, and phenotypic concordance of some clinical features in familial cases of Crohn’s disease (CD) and ulcerative colitis (UC). The aim of our study was to investigate the phenotypic features of affected members in a large sample of CD and UC Italian families. METHODS: In a multicenter study, CD and UC families were recruited. Affected members were questioned about date of birth, gender, age at onset of symptoms and at diagnosis, location and extension of disease, occurrence of extraintestinal manifestations, use of steroids and/or of immunosuppressive drugs, need for resective surgery, and number of relapses per year (<1 yr or ≥1 yr). Statistical analysis was performed with χ 2, Fisher’s, Mann-Whitney U, and binomial probability tests, when appropriate. RESULTS: A total of 128 families with 270 affected members were studied: 35 were CD, 64 UC, and 29 mixed families (when UC and CD affected different members). In 99 of 128 families (77%), the diagnosis was concordant. In CD families, a high concordance for localization (46%), extraintestinal manifestations (67%), need for steroids (77%), need for immunosuppressive drugs (100%), need for surgery (29%), and relapse rate (36%) was found. In UC families, a high concordance for disease extension (33%), need for steroids (47%), and relapse rate (34%) was disclosed. A higher than expected concordance for ileal localization ( p < 0.4) in CD families and extensive colitis ( p < 0.05) in UC families was demonstrated. A generation difference of 15–20 yr in mean ages at onset of symptoms and at diagnosis was recorded. No features of more aggressive disease in subsequent generations and no differences in gender of transmitting parents and relatives were found. CONCLUSIONS: Our study shows a high rate of concordance for diagnosis and clinical features in UC and, especially, CD families. The disease occurred 15–20 yr earlier than in previous generations without features of increased severity.

Clinical features in familial cases of Crohn's disease and ulcerative colitis in Italy: a GISC study. Italian Study Group for the Disease of Colon and Rectum.

Previous studies have reported genetic anticipation, genomic imprinting, and phenotypic concordance of some clinical features in familial cases of Crohn's disease (CD) and ulcerative colitis (UC). The aim of our study was to investigate the phenotypic features of affected members in a large sample of CD and UC Italian families. In a multicenter study, CD and UC families were recruited. Affected members were questioned about date of birth, gender, age at onset of symptoms and at diagnosis, location and extension of disease, occurrence of extraintestinal manifestations, use of steroids and/or of immunosuppressive drugs, need for resective surgery, and number of relapses per year (< 1 yr or > or = 1 yr). Statistical analysis was performed with chi2, Fisher's, Mann-Whitney U, and binomial probability tests, when appropriate. A total of 128 families with 270 affected members were studied: 35 were CD, 64 UC, and 29 mixed families (when UC and CD affected different members). In 99 of 128 families (77%), the diagnosis was concordant. In CD families, a high concordance for localization (46%), extraintestinal manifestations (67%), need for steroids (77%), need for immunosuppressive drugs (100%), need for surgery (29%), and relapse rate (36%) was found. In UC families, a high concordance for disease extension (33%), need for steroids (47%), and relapse rate (34%) was disclosed. A higher than expected concordance for ileal localization (p < 0.4) in CD families and extensive colitis (p < 0.05) in UC families was demonstrated. A generation difference of 15-20 yr in mean ages at onset of symptoms and at diagnosis was recorded. No features of more aggressive disease in subsequent generations and no differences in gender of transmitting parents and relatives were found. Our study shows a high rate of concordance for diagnosis and clinical features in UC and, especially, CD families. The disease occurred 15-20 yr earlier than in previous generations without features of increased severity.

Extraintestinal manifestations of cotton-top tamarin colitis

A feature of human ulcerative colitis is the occurrence of extraintestinal manifestations of the disease: ankylosing spondylitis, peripheral arthropathy, iritis, iridoconjunctivitis, episcleritis and liver diseases (fatty liver, mild periportal chronic inflammation, and sclerosing cholangitis). More rarely, cholangiocarcinoma, hepatic abscesses, or cirrhosis are seen. The cotton-top tamarin (CTT) develops a noninfective spontaneously occurring colitis which closely resembles human ulcerative colitis clinically, endoscopically, histologically, and in response to treatment. This study evaluated liver and joint disease in CTTs with colitis. Livers from 100 cotton-top tamarins with ulcerative colitis were examined histologically at postmortem; 40 had varied pathology: steatosis (16), hepatitis (4), and abscess (4). Four animals had excessive portal fibrosis in the absence of significant inflammation and which resembled sclerosing cholangitis. Neither skeletal radiographs of 217 CTTs, including 43 that were >10 yr of age, nor histological examination of synovia from 10 knees, showed abnormalities. The findings of sclerosing cholangitis-like liver abnormalities strengthen the role of the CTT as a unique animal model of human ulcerative colitis.

HLA class II genes in primary sclerosing cholangitis and chronic inflammatory bowel disease: no HLA-DRw52a association in Swedish patients with sclerosing cholangitis.

The familial predisposition to chronic inflammatory bowel disease and the increased concordance rate in monozygotic twins with Crohn's disease, suggest that genetic factors influence disease susceptibility. A 100% association with the supertypic HLA class II specificity DRw52a was recently described in white North American patients with primary sclerosing cholangitis, with or without concurrent ulcerative colitis. HLA class II alleles of the DR, DQ, and DP subregions were determined by genomic typing techniques in a large group of Swedish patients with ulcerative colitis or Crohn's disease as well as in a series of patients with primary sclerosing cholangitis. No statistically significant HLA class II association was observed in any of the investigated diseases or when the patients were subgrouped according to disease site or occurrence of extraintestinal manifestations, except an insignificant increase of the DRw17, DQw2 haplotype in patients with primary sclerosing cholangitis. The failure to confirm the well established DRw17 association in Swedish patients with sclerosing cholangitis probably represents a statistical type II error. Furthermore, this study did not verify the recently described strong DRw52a association in sclerosing cholangitis--52% of the patients were DRw52a positive compared with 28% of the controls (p less than 0.05, pc NS). This discrepancy was probably caused by different typing techniques. The DRw52a specificity was determined directly by hybridising HLA-DRB3 genes, group specifically amplified by the polymerase chain reaction, with an allele specific oligonucleotide probe, whereas in the previously mentioned study DRw52a was assigned by indirect serological criteria, which overestimate the frequency of this allele.