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ABSTRACT: Ulcerative colitis (UC) is a prevalent inflammatory bowel disease of the colonic mucosa affecting approximately 20,000-25,000 Danes. Apart from subgroups with early onset, extensive and long-standing inflammation, or primary sclerosing cholangitis the risk of developing colorectal cancer is of the same magnitude as in the background population. The symptoms are usually diarrhoea including bloody stools, rectal tenesmi, anaemia, and fatigue. This review is an update on diagnostics and treatment strategies of relevance for clinicians, and as UC often affects patients during their peak reproductive years, emphasis is additionally put on the management of pregnant patients with UC.
Ugeskrift for laeger 05/2013; 175(20):1412-1416.
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ABSTRACT: The use of thiopurines as immunosuppression for the treatment of refractory or chronic active inflammatory bowel disease is established for both Crohn's disease and ulcerative colitis. Nevertheless, many questions remain concerning the optimal treatment regimens of azathioprine, 6-mercaptopurine and thioguanine. We will briefly summarize dose recommendations, indications for thiopurine therapy and side effects which are relevant in clinical practice. We discuss some currently debated topics, including the combination of azathioprine and allopurinol, switching of thiopurine therapy in case of side effects, the use of azathioprine in pregnancy, the infection risk using thiopurines and the evidence when to stop thiopurines. Excellent reviews have been published on the thiopurine metabolic pathway which will not be discussed here in detail.
World Journal of Gastroenterology 02/2013; 19(7):1040-8. · 2.47 Impact Factor
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ABSTRACT: Use of the immunomodulators thiopurines and methotrexate (MTX) in the treatment of inflammatory bowel disease (IBD), i.e., Crohn's disease and ulcerative colitis (UC), is considered to be good clinical practice. However, despite being administered to a considerable number of IBD patients over the years, questions remain about the most rational treatment regimens of azathioprine (AZA), 6-mercaptopurine (6-MP), and MTX, and results from a range of recent studies necessitate increased attention to how to optimize the use of these immunomodulators. First and foremost, it is of utmost importance to define the subgroup of IBD patients in need of immunomodulators, including those in need of combination therapy with biologic agents, especially because some side effects may be rather severe. Second, colorectal cancer is observed more often in IBD patients than in the background population. However, a recent nationwide Dutch study pointed to a preventive effect of thiopurines. Finally, the need for an appropriate approach to the discontinuation of immunomodulators is emphasized. Since controversy continues regarding the most appropriate use of immunomodulators, this paper is focusing on pharmacokinetics, pharmacogenetics, and therapeutic blood testing, as well as the occurrence of adverse events, when using AZA, 6-MP, and MTX in an attempt to determine a more up-to-date and rational treatment regimen in IBD.
The Journal of Clinical Pharmacology 02/2013; · 2.91 Impact Factor
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ABSTRACT: Intestinal epithelial cell (IEC) death signalling through the Fas receptor is impaired in active ulcerative colitis (UC). This is possibly due to the activation of cytoprotective pathways resulting in limitation of the tissue injury secondary to inflammation. We hypothesized that inflammatory signalling like the nuclear factor (NF)-κB or mitogen activated protein kinase (MAPK) pathways could be involved in (a) the modification of Fas mediated apoptosis responses and (b) the regulation of the Fas receptor inhibitor cellular FLICE-like inhibitory protein (c-FLIP). Phospho-ERK was upregulated in IECs in active UC as well as IECs exposed to pro-inflammatory cytokines in vitro. Similarly, the short form of c-FLIP (c-FLIP(S)) was found to be upregulated in IECs from patients with active UC. c-FLIP(S) was the main splice variant found in both HT-29 cells and primary human IECs. Both splice variants were induced by TNF-α, IL-1β and IFN-γ, while IL-10 induced c-FLIP(L) expression; TNF-α also induced c-FLIP(S) in primary IECs. Inhibition of NF-κB, JNK and p38 pathways did not affect c-FLIP expression, whereas ERK inhibition by MEK1 RNA silencing and pharmacologic inhibitors decreased c-FLIP(S) expression. Similarly, ERK - but not NF-κB - inhibited Fas ligand and TNF-α-mediated apoptosis responses in both cell line experiments and primary IECs. The present study identifies the MEK-ERK pathway as a major regulator of apoptosis in IECs during flares of UC and an inducer of c-FLIP(S). The results explain the resistance to receptor mediated epithelial apoptosis in active UC. Oncogenic c-FLIP could promote propagation of DNA-damaged IECs and contribute to cancer development in UC.
Journal of Molecular Medicine 02/2013; · 4.67 Impact Factor
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ABSTRACT: Ulcerative colitis (UC) is a colonic inflammatory condition with a substantial impact on the quality of life of affected persons. The disease carries a cumulative risk of need of colectomy of 20-30% and an estimated cumulative risk of colorectal cancer of 18% after 30 years of disease duration. With the introduction of the tumor necrosis factor-alpha inhibitors for the treatment of UC, it has become increasingly evident that the disease course is influenced by whether or not the patient achieves mucosal healing. Thus, patients with mucosal healing have fewer flare-ups, a decreased risk of colectomy, and a lower probability of developing colorectal cancer. Understanding the mechanisms of mucosal wound formation and wound healing in UC, and how they are affected therapeutically is therefore of importance for obtaining efficient treatment strategies holding the potential of changing the disease course of UC. This review is focused on the pathophysiological mechanism of mucosal wound formation in UC as well as the known mechanisms of intestinal wound healing. Regarding the latter topic, pathways of both wound healing intrinsic to epithelial cells and the wound-healing mechanisms involving interaction between epithelial cells and other cells of the mucosa are discussed. The biochemistry of wound healing in UC provides the basis for the subsequent description of how these pathways are affected by the current medications, and what can be learnt on how to design future treatment regimens for UC based on targeting mucosal healing.
Advances in clinical chemistry 01/2013; 59:101-23. · 3.20 Impact Factor
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ABSTRACT: Crohn's disease (CD) is one of main disease entities under the umbrella term chronic inflammatory bowel disease. The etiology of CD involves alterations in genetic, microbiological, and immunological factors. This review is devoted to the role of the bacterial wall compound muramyl dipeptide (MDP) for the activation of inflammatory pathways involved in the pathogenesis of CD. The importance of this molecule is underscored by the fact that (1) MDP, which is found in most Gram-negative and -positive bacteria, is able to trigger several immunological responses in the intestinal system, and (2) that alterations in several mediators of the MDP response including-but not restricted to-nucleotide oligomerization domain 2 (NOD2) are associated with CD. The normalization of MDP signaling is one of several important factors that influence the intestinal inflammatory response, a fact which emphasizes the pathogenic importance of MDP signaling for the pathogenesis of CD. The important aspects of NOD2 and non-NOD2 mediated effects of MDP for the development of CD are highlighted, as well as how alterations in these pathways might translate into the development of new therapeutic strategies.
Cellular and Molecular Life Sciences CMLS 12/2012; · 6.57 Impact Factor
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Cathrine Jespersgaard,
Peder Fode,
Marianne Dybdahl,
Ida Vind, Ole Haagen Nielsen,
Claudio Csillag,
Pia Munkholm,
Ben Vainer,
Lene Riis,
Margarita Elkjaer,
Natalia Pedersen,
Elisabeth Knudsen,
Paal Skytt Andersen
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ABSTRACT: Background and Purpose of StudyExtensive copy number variation is observed for the DEFA1A3 gene encoding alpha-defensins 1–3. The objective of this study was to determine the involvement of alpha-defensins in colonic
tissue from Crohn’s disease (CD) patients and the possible genetic association of DEFA1A3 with CD.
MethodsTwo-hundred and forty ethnic Danish CD patients were included in the study. Reverse transcriptase PCR assays determined DEFA1A3 expression in colonic tissue from a subset of patients. Immunohistochemical analysis identified alpha-defensin peptides in
colonic tissue. Copy number of DEFA1A3 and individual alleles, DEFA1 and DEFA3, were compared with those for controls, by use of combined real-time quantitative PCR and pyrosequencing, and correlated with
disease location.
ResultsInflammatory-dependent mRNA expression of DEFA1A3 (P<0.001), and the presence of alpha-defensin peptides, were observed in colonic tissue samples. Higher DEFA1A3 gene copy number (CD: mean copy number, 7.2 vs. controls 6.7; P<0.001) and individual DEFA1 alleles (CD mean copy number 5.6 vs. controls 5.1; P<0.01) were associated with CD, with strong association with colonic location (P<0.001).
ConclusionsAlpha-defensins are involved in the inflammation of CD, with local mRNA and peptide expression. In combination with the findings
that a high DEFA1A3 copy number is significantly linked to CD, these results suggest that a high DEFA1A3 copy number might be important in hindering the normal inflammatory response in CD, particularly colonic CD.
KeywordsCrohn’s disease–Colonic tissue–Copy number variation–Defensin–Genetic association–Real-time PCR
Digestive Diseases and Sciences 04/2012; 56(12):3517-3524. · 2.12 Impact Factor
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ABSTRACT: High levels of pro-inflammatory cytokines are linked to inflammatory bowel disease (IBD). The transcription factor Caudal-related homeobox transcription factor 2 (CDX2) plays a crucial role in differentiation of intestinal epithelium and regulates IBD-susceptibility genes, including meprin 1A (MEP1A). The aim was to investigate the expression of CDX2 and MEP1A in colitis; to assess if they are regulated by tumor necrosis factor-α (TNF-α), and finally to reveal if CDX2 is involved in a TNF-α-induced down-regulation of MEP1A.
Expression of CDX2 and MEP1A was investigated in colonic biopsies of ulcerative colitis (UC) patients and in dextran sodium sulfate (DSS)-induced colitis. CDX2 protein expression was investigated by immunoblotting and immunohistochemical procedures. CDX2 and MEP1A regulation was examined in TNF-α-treated Caco-2 cells by reverse transcription-polymerase chain reaction and with reporter gene assays, and the effect of anti-TNF-α treatment was assessed using infliximab. Finally, in vivo CDX2-DNA interactions were investigated by chromatin immunoprecipitation.
The CDX2 and MEP1A mRNA expression was significantly decreased in active UC patients and in DSS-colitis. Colonic biopsy specimens from active UC showed markedly decreased CDX2 staining. TNF-α treatment diminished the CDX2 and MEP1A mRNA levels, a decrease which, was counteracted by infliximab treatment. Reporter gene assays showed significantly reduced CDX2 and MEP1A activity upon TNF-α stimulation. Finally, TNF-α impaired the ability of CDX2 to interact and activate its own, as well as the MEP1A expression.
The present results indicate that a TNF-α-mediated down-regulation of CDX2 can be related to suppressed expression of MEP1A during intestinal inflammation.
Biochimica et Biophysica Acta 02/2012; 1822(6):843-51. · 4.66 Impact Factor
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ABSTRACT: Analyzing data obtained from genome-wide gene expression experiments is challenging due to the quantity of variables, the need for multivariate analyses, and the demands of managing large amounts of data. Here we present the R package pcaGoPromoter, which facilitates the interpretation of genome-wide expression data and overcomes the aforementioned problems. In the first step, principal component analysis (PCA) is applied to survey any differences between experiments and possible groupings. The next step is the interpretation of the principal components with respect to both biological function and regulation by predicted transcription factor binding sites. The robustness of the results is evaluated using cross-validation, and illustrative plots of PCA scores and gene ontology terms are available. pcaGoPromoter works with any platform that uses gene symbols or Entrez IDs as probe identifiers. In addition, support for several popular Affymetrix GeneChip platforms is provided. To illustrate the features of the pcaGoPromoter package a serum stimulation experiment was performed and the genome-wide gene expression in the resulting samples was profiled using the Affymetrix Human Genome U133 Plus 2.0 chip. Array data were analyzed using pcaGoPromoter package tools, resulting in a clear separation of the experiments into three groups: controls, serum only and serum with inhibitor. Functional annotation of the axes in the PCA score plot showed the expected serum-promoted biological processes, e.g., cell cycle progression and the predicted involvement of expected transcription factors, including E2F. In addition, unexpected results, e.g., cholesterol synthesis in serum-depleted cells and NF-κB activation in inhibitor treated cells, were noted. In summary, the pcaGoPromoter R package provides a collection of tools for analyzing gene expression data. These tools give an overview of the input data via PCA, functional interpretation by gene ontology terms (biological processes), and an indication of the involvement of possible transcription factors.
PLoS ONE 01/2012; 7(2):e32394. · 4.09 Impact Factor
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ABSTRACT: Adherent-invasive Escherichia coli (AIEC) are reported to inhabit the gut mucosa in Crohn's disease (CD), however, little is known about the importance of host factors for the interplay between AIEC and the human gut. To examine if differences in bacterial adhesion patterns are disease associated, the AIEC-prototype strain LF82 was evaluated for its ability to adhere to ileal and colonic biopsies from CD and healthy controls (HC). Moreover, the efficacy of the non-pathogenic E. coli Nissle 1917 (ECN) in averting LF82 adhesion to ileal mucosa was assessed. Similar numbers of LF82 adhered to biopsies from CD and HC. A significantly greater LF82 attachment to ileal versus colonic mucosa was found in HC (P < 0.01), however, not in CD. ECN did not reduce the adhesion of LF82 to ileal specimens in CD or HC. These results show that enhanced bacterial adhesion ability is unlikely to play any significant role in CD, thus implying that other host protective factors may be impaired in CD. Further, exclusion of LF82 attachment by ECN co-incubation does not appear to represent a relevant treatment regimen.
Microbial Pathogenesis 09/2011; 51(6):426-31. · 1.94 Impact Factor
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ABSTRACT: A systematic review to evaluate the efficacy of 5-aminosalicylates for induction of remission or clinical response in patients with mild to moderately active Crohn's disease is described. The effect of either high (3 to 4.5 g/day) or low dose (1 to 2 g/day) 5-aminosalicylic acid was similar to that of placebo. Overall, sulfasalazine was not superior to placebo and was inferior to glucocorticoids for the treatment of mild to moderately active Crohn's disease. Neither published nor unpublished data support any use of 5-aminosalicylates for the treatment of Crohn's disease.
Ugeskrift for laeger 08/2011; 173(35):2110-3.
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ABSTRACT: We here present a method based on qRT-PCR to quantify E. coli LF82 in intestinal human samples. Two different primer-probe sets were designed to detect LF82, and a third to target total E. coli. The assay showed high robustness and specificity for detection of LF82 in the presence of intestinal tissue.
Journal of microbiological methods 07/2011; 86(1):111-4. · 2.43 Impact Factor
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Cathrine Jespersgaard,
Peder Fode,
Marianne Dybdahl,
Ida Vind, Ole Haagen Nielsen,
Claudio Csillag,
Pia Munkholm,
Ben Vainer,
Lene Riis,
Margarita Elkjaer,
Natalia Pedersen,
Elisabeth Knudsen,
Paal Skytt Andersen
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND AND PURPOSE OF STUDY: Extensive copy number variation is observed for the DEFA1A3 gene encoding alpha-defensins 1-3. The objective of this study was to determine the involvement of alpha-defensins in colonic tissue from Crohn's disease (CD) patients and the possible genetic association of DEFA1A3 with CD.
Two-hundred and forty ethnic Danish CD patients were included in the study. Reverse transcriptase PCR assays determined DEFA1A3 expression in colonic tissue from a subset of patients. Immunohistochemical analysis identified alpha-defensin peptides in colonic tissue. Copy number of DEFA1A3 and individual alleles, DEFA1 and DEFA3, were compared with those for controls, by use of combined real-time quantitative PCR and pyrosequencing, and correlated with disease location.
Inflammatory-dependent mRNA expression of DEFA1A3 (P < 0.001), and the presence of alpha-defensin peptides, were observed in colonic tissue samples. Higher DEFA1A3 gene copy number (CD: mean copy number, 7.2 vs. controls 6.7; P < 0.001) and individual DEFA1 alleles (CD mean copy number 5.6 vs. controls 5.1; P < 0.01) were associated with CD, with strong association with colonic location (P < 0.001).
Alpha-defensins are involved in the inflammation of CD, with local mRNA and peptide expression. In combination with the findings that a high DEFA1A3 copy number is significantly linked to CD, these results suggest that a high DEFA1A3 copy number might be important in hindering the normal inflammatory response in CD, particularly colonic CD.
Digestive Diseases and Sciences 06/2011; 56(12):3517-24. · 2.12 Impact Factor
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ABSTRACT: One of the most serious complications of ulcerative colitis is the development of colorectal cancer. Screening patients with ulcerative colitis by standard histological examination of random intestinal biopsy samples might be inefficient as a method of cancer surveillance. This Review focuses on the current understanding of the pathogenesis of ulcerative colitis-associated colorectal cancer and how this knowledge can be transferred into patient management to assist clinicians and pathologists in identifying patients with ulcerative colitis who have an increased risk of colorectal cancer. Inflammation-driven mechanisms of DNA damage, including the generation and effects of reactive oxygen species, microsatellite instability, telomere shortening and chromosomal instability, are reviewed, as are the molecular responses to genomic stress. We also discuss how these mechanisms can be translated into usable biomarkers. Although progress has been made in the understanding of inflammation-driven carcinogenesis, markers based on these findings possess insufficient sensitivity or specificity to be usable as reliable biomarkers for risk of colorectal cancer development in patients with ulcerative colitis. However, screening for mutations in p53 could be relevant in the surveillance of patients with ulcerative colitis. Several other new biomarkers, including senescence markers and α-methylacyl-CoA-racemase, might be future candidates for preneoplastic markers in ulcerative colitis.
Nature Reviews Gastroenterology & Hepatology 06/2011; 8(7):395-404. · 8.10 Impact Factor
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ABSTRACT: Many transcription factors are known to control transcription at several promoters, while others are only active at a few places. However, due to their importance in controlling cellular functions, aberrant transcription factor function and inappropriate gene regulation have been shown to play a causal role in a large number of diseases and developmental disorders. Inflammatory bowel disease (IBD) is characterized by a chronically inflamed mucosa caused by dysregulation of the intestinal immune homeostasis. The aetiology of IBD is thought to be a combination of genetic and environmental factors, including luminal bacteria. The Caudal-related homeobox transcription factor 2 (CDX2) is critical in early intestinal differentiation and has been implicated as a master regulator of the intestinal homeostasis and permeability in adults. When expressed, CDX2 modulates a diverse set of processes including cell proliferation, differentiation, cell adhesion, migration, and tumorigenesis. In addition to these critical cellular processes, there is increasing evidence for linking CDX2 to intestinal inflammation. The aim of the present paper was to review the current knowledge of CDX2 in regulation of the intestinal homeostasis and further to reveal its potential role in inflammation.
Biochimica et Biophysica Acta 03/2011; 1812(3):283-9. · 4.66 Impact Factor
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ABSTRACT: The mammalian family of mitogen-activated protein kinases (MAPKs) is activated by diverse extracellular and intracellular stimuli, and thereby they play an essential role in connecting cell-surface receptors to changes in transcriptional programs. The MAPK signaling pathways regulate a wide range of cellular activities and have been implicated in the pathogenesis of several diseases, including inflammatory bowel disease (IBD). This review summarizes recent findings on the regulatory mechanism of MAPK signaling pathways, focusing on nuclear targets and their role in IBD. Finally, it summarizes how these signaling pathways have been exploited for the development of therapeutics and discuss the current knowledge of potential MAPK inhibitors and their anti-inflammatory effects in clinical trials related to IBD.
Clinica chimica acta; international journal of clinical chemistry 03/2011; 412(7-8):513-20. · 2.54 Impact Factor
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ABSTRACT: The complex and yet unknown etiology of Crohn's disease (CD) might consist of various disease endophenotypes, each of which represent their own pathogenesis. This review focuses on the disease endophenotype linked to polymorphisms in the nucleotide-binding oligomerization domain containing 2 (NOD2) protein and on the importance of established adherent-invasive E. coli (AIEC) in ileal mucosa. To date, there are several reports pointing to the implications of NOD2 polymorphisms in epithelial and immunological responses against microbes, but the pathological significance of NOD2 mutations in CD is not yet clarified. The enhanced number of pathogenic E. coli in the ileal mucosa of CD as compared to healthy controls may result from a genetically based failure in one of the intestinal bacteria sensing systems, like NOD2, making the ileal epithelium more prone to colonization with microbes harboring specific properties such as AIEC. Increasing the focus on defining subgroups of patients with similar disease initiations, mechanisms of action, and manifestations in CD may be pivotal for the development and implementation of future individualized treatment strategies of benefit for the single patient at an early stage.
Inflammatory Bowel Diseases 02/2011; 17(11):2392-401. · 4.86 Impact Factor
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ABSTRACT: The introduction of biological agents (i.e. antitumour necrosis factor-α and anti-integrin treatments) for the treatment of inflammatory bowel disease (IBD) [i.e. Crohn's disease (CD) and ulcerative colitis] has led to a substantial change in the treatment algorithms and guidelines, especially in CD. However, many questions still remain about the true efficacy and the best treatment regimens. Thus, a need for further treatment options still exists as up to 40% of IBD patients treated with the presently available biologicals do not have positive clinical responses. Better patient selection might maximize the clinical benefit for those in most need of an effective therapy to avoid disabling disease whilst also minimizing the complications associated with therapy. Further, the 'trough-level strategy' may help clinicians to optimize therapy and to avoid loss of response and/or immunogenicity. The idea behind this dosage regimen is that correct dosing must ensure that the patient's lowest level of drug concentration (i.e. the trough level) occurring just before the next drug administration is high enough for the full effect to be seen. Controversy continues regarding the appropriate use of biologicals; therefore, in this review, we focus on considerations that might lead to a more rational strategy for antitumour necrosis factor-α agents in IBD, emphasizing the situations in which the risks may outweigh the benefits. Finally, the need for an appropriate strategy for stopping biological treatment is discussed.
Journal of Internal Medicine 01/2011; 270(1):15-28. · 5.48 Impact Factor
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ABSTRACT: Ulcerative colitis (UC) is believed to carry a predisposition to colorectal cancer (CRC) development. International clinical guidelines suggest that UC patients should have a colonoscopy performed every year or up to every third year from approximately eight years after diagnosis for early detection of CRC/dysplasia. However, according to the Danish epidemiological data available, such recommendations are dubious. The present mini review focuses on this matter for the UC population in Denmark.
Ugeskrift for laeger 10/2010; 172(43):2960-2.
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ABSTRACT: Abstract Extraintestinal manifestations occur rather frequently in inflammatory bowel disease (IBD), e.g. ulcerative colitis (UC) and Crohn's disease (CD). The present paper provides an overview of the epidemiology, clinical characteristics, diagnostic process, and management of rheumatic, metabolic, dermatologic (mucocutaneous), ophthalmologic, hepatobiliary, hematologic, thromboembolic, urinary tract, pulmonary, and pancreatic extraintestinal manifestations related to IBD. Articles were identified through search of the PubMed and Embase databases, the Cochrane Library, and the web sites of the European Agency for the Evaluation of Medicinal Products (EMEA) and the US Food and Drug Administration (FDA) (cut-off date October 2009). The search terms 'Crohn's disease', 'inflammatory bowel disease', or 'ulcerative colitis' were combined with the terms 'adalimumab', 'anemia', 'arthritis', 'bronchiectasis', 'bronchitis', 'cutaneous manifestations', 'erythema nodosum', 'extraintestinal manifestations', 'hyperhomocysteinemia', 'infliximab', 'iridocyclitis', 'lung disease', 'ocular manifestations', 'osteomalacia', 'pancreatitis', 'primary sclerosing cholangitis', 'renal stones', 'sulfasalazine', 'thromboembolism', and 'treatment'. The search was performed on English-language reviews, practical guidelines, letters, and editorials. Articles were selected based on their relevance, and additional papers were retrieved from their reference lists. Since some of the diseases discussed are uncommon, valid evidence of treatment was difficult to obtain, and epidemiologic data on the rarer forms of extraintestinal manifestations are scarce. However, updates on the pathophysiology and treatment regimens are given for each of these disorders. This paper offers a current review of original research papers and randomized clinical trials, if any, within the field and makes an attempt to point out practical guidelines for the diagnosis and treatment of various extraintestinal manifestations related to IBD.
Annals of medicine 03/2010; 42(2):97-114. · 3.52 Impact Factor
