A rare cause of peripheral arthralgia in inflammatory bowel disease: multifocal osteonecrosis.

Osteonecrosis (ON) is characterized by an infarction of osseous tissue in the subchondral regions of the bone. We report the case of a young male patient with ulcerative colitis (UC) developing severe and multifocal, large joint ON resulting in severe disability. Since typical symptoms of ON, like joint pain, might be misinterpreted as common extraintestinal manifestations, ON might easily be overlooked in patients with inflammatory bowel disease (IBD). Plain radiographs detect only advanced cases, MRI is the diagnostic method of choice with a specificity and sensitivity of > 90 %. We discuss the incidence of ON specifically in IBD and provide an update on risk factors like treatment with corticosteroids (CS), although ON has been reported in IBD patients without previous CS treatment. Apart from that, underlying inflammation, thromboembolic events and genetic risk factors might be involved in ON development supporting the hypothesis of a complex cascade. Causative therapies for ON are not available, and surgical interventions like trepanning, core decompression and prosthetic replacement are often necessary. Our intention is to direct attention to this severe complication in the differential work-up of joint pain in IBD patients.

Vandetanib therapy in medullary thyroid cancer.

The U.S. Food and Drug Administration (FDA) approved vandetanib in April 2011 for the treatment of unresectable, locally advanced or metastatic medullary thyroid cancer (MTC). In Europe it was approved in March 2012, but only for the treatment of aggressive and symptomatic MTC. This small molecule is a tyrosine kinase inhibitor of several growth factors involved in cellular proliferation and angiogenesis, including the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptors 2 and 3 (VEGFR-2, VEGFR-3). In addition, vandetanib is an inhibitor of the RET (rearranged during transfection) gene, a proto-oncogene often mutated in familial MTC. Since MTC is a rare disease, for which no previous medical therapies are approved, vandetanib is the first drug shown to be effective in a large phase III trial treating patients with metastatic or locally advanced MTC. Common adverse events are diarrhea, nausea, hypertension, headache and QT prolongation that are manageable and are commonly outweighed by the benefits of vandetanib in terms of delaying disease progression and inducing tumor response.

Diffuse gastric cancer with peritoneal carcinomatosis can mimic Crohn's disease.

In some cases the diagnosis of gastric cancer is difficult and the endoscopic presentation may be misleading. Diffuse type gastric carcinoma with peritoneal metastasis may present primarily with abdominal pain, colonic infiltration and/or diarrhea, thus other differential diagnoses like Crohn's disease (CD) may be considered at first. Therefore intensive diagnostic work-up is important. We report two cases of gastric cancer with ascites due to peritoneal carcinomatosis who were first diagnosed as CD. The patients were hospitalized in different institutions for weight loss, abdominal pain and nausea. The first colonoscopy, upper endoscopy with multiple biopsies and ascites puncture were negative for malignant disease, but macroscopic lesions resembling CD were described. Both patients were released on a prednisolone-based treatment for suspected CD. They presented to our hospital for further evaluation due to persistent symptoms. Neither lower nor upper endoscopy were suggestive of CD and endoscopic ultrasound was suspicious of malignancy in one case. Histology was diagnostic and showed gastric infiltration by a poorly differentiated adenocarcinoma. Diffuse type gastric cancer (gastric linitis plastica) with peritoneal metastasis may mimic certain clinical, endoscopic and CT imaging features of CD. Repeated biopsies and endoscopic investigations are often necessary to confirm a malignant process, especially in case of an inconclusive clinical and endoscopic picture. Endoscopic ultrasound may be useful to evaluate the risk of malignancy in patients with macroscopic suspicion of malignancy and negative biopsies.

Mesenteric fat - control site for bacterial translocation in colitis?

In Crohn's disease bacteria could be detected in the adjacent mesenteric fat characterized by hypertrophy of unknown function. This study aimed to define effector responses of this compartment induced by bacterial translocation during intestinal inflammation. Dextran sulfate sodium-induced colitis served as a model of intestinal inflammation. Translocation of peptides and bacteria into mesenteric fat was evaluated. Innate functions of mesenteric fat and epithelium were characterized at whole tissue, cellular, and effector molecule levels. Orally applied peptides translocated in healthy wild-type (WT) mice. Bacterial translocation was not detected in healthy and acute but increased in chronic colitis. Mesenteric fat from colitic mice released elevated levels of cytokines and was infiltrated by immune cells. In MyD88(-/-) mice bacterial translocation occurred in health and increased in colitis. The exaggerated cytokine production in mesenteric fat accompanying colonic inflammation in WT mice was less distinct in MyD88(-/-) mice. In vitro studies revealed that fat not only increases cytokine production following contact with bacterial products, but also that preadipocytes are potent phagocytes. Colonic inflammation is accompanied by massive cytokine production and immune cell infiltration in adjacent adipose tissue. These effects can be considered as protective mechanisms of the mesenteric fat in the defense of bacterial translocation.

CCR7 deficiency causes diarrhea associated with altered ion transport in colonocytes in the absence of overt colitis.

The chemokine receptor CCR7 is a central regulator in the maintenance of cellular homeostasis of mucosal tissues. CCR7⁻/⁻ mice develop autoimmune gastritis and exocrinopathy accompanied by the formation of mucosal tertiary lymphoid follicles. Here we found that CCR7-deficient mice frequently suffered from chronic diarrhea linked with increased gastrointestinal motility and the development of severe anorectal prolapse. Enhanced formation of intestinal lymphoid follicles was associated with an elevated proportion of activated colonic T cells and increased production of the cytokine interleukin (IL)-1ß. To uncover the pathomechanisms of diarrhea in CCR7⁻/⁻ mice, colonic epithelial barrier and ion channel activities were analyzed in Ussing chambers. Although overt acute colitis was absent, CCR7 deficiency resulted in reduced electrogenic sodium absorption and colonic chloride secretion. As it is known that IL-1ß regulates epithelial sodium channel (ENaC) activity, these data imply a causal link between CCR7 expression, IL-1ß level, and Na⁺ malabsorption owing to altered ENaC expression and diarrhea.

Proliferation rate but not mismatch repair affects the long-term response of colon carcinoma cells to 5FU treatment.

The role of mismatch repair (MMR) in the response of colon carcinoma cells to 5-fluorouracil (5FU) is not well understood. In most of the in vitro studies only short-term response was investigated. We focussed here on the influence of MMR status on the mechanism of the short- and long-term response to clinically relevant 5FU concentrations by using isogenic or semiisogenic cell line pairs expressing/nonexpressing the hMLH1 protein, an important component of the MMR system. We show that the lower survival of MMR-proficient than of MMR-deficient cells in the clonogenic survival assay is due to a more frequent early cell arrest and to subsequent senescence. By contrast, the long-term cell growth after treatment, which is also affected by long-term arrest and senescence, is independent from the MMR status. The overall effect on the long-term cell growth is a cumulative result of cell proliferation rate-dependent growth inhibition, apoptosis and necrotic cell death. The main long-term cytotoxic effect of 5FU is the inhibition of growth while apoptosis and the necrotic cell death are minor contributions.

The synthetic hydroxyproline-containing collagen analogue (Gly-Pro-Hyp)10 ameliorates acute DSS colitis.

In experimental models of and humans with intestinal inflammation, increased levels of the matrix-degrading gelatinases MMP-2 and -9 in inflamed tissues can be detected. The synthetic collagen analogue (Gly-Pro-Hyp)10, (GPO)10, has been identified as a relevant binding structure for proMMP-2/-9 and promotes enzymatic activity of proMMP-2. Since targeted MMP strategies might offer promising anti-inflammatory treatment options, we for the first time studied in vivo actions exerted by (GPO)10 applying an acute dextrane sulfate sodium (DSS) induced colitis model. Seven-day intraperitoneal (GPO)10 treatment ameliorated clinical symptoms and histopathological colonic changes as compared to placebo controls with severe colitis. (GPO)10-treated mice displayed a diminished influx of neutrophils, and T- and B-lymphocytes into their colonic mucosa whereas numbers of regulatory T-cells and regenerative cells were higher as compared to placebo controls. Furthermore, IL-6 secretion was down-regulated in ex vivo colonic biopsies derived from (GPO)10-treated mice whereas higher concentrations of the anti-inflammatory cytokine IL-10 in extra-intestinal compartments such as MLN and spleen could be detected. Strikingly, influx of inflammatory cells into lungs was abolished following (GPO)10 application. We therefore propose (GPO)10 as a promising effective and safe treatment option of intestinal and extra-intestinal inflammatory conditions in humans.

UDCA slows down intestinal cell proliferation by inducing high and sustained ERK phosphorylation.

Ursodeoxycholic acid (UDCA) attenuates colon carcinogenesis in humans and in animal models by an unknown mechanism. We investigated UDCA effects on normal intestinal epithelium in vivo and in vitro to identify the potential chemopreventive mechanism. Feeding of mice with 0.4% UDCA reduced cell proliferation to 50% and suppressed several potential proproliferatory genes including insulin receptor substrate 1 (Irs-1). A similar transcriptional response was observed in the rat intestinal cell line IEC-6 which was then used as an in vitro model. UDCA slowed down the proliferation of IEC-6 cells and induced sustained hyperphosphorylation of ERK1/ERK2 kinases which completely inhibited the proproliferatory effects of EGF and IGF-1. The hyperphosphorylation of ERK1 led to a transcriptional suppression of the Irs-1 gene. Both, the hyperphosphorylation of ERK as well as the suppression of Irs-1 were sufficient to inhibit proliferation of IEC-6 cells. ERK1/ERK2 inhibition in vitro or ERK1 elimination in vitro or in vivo abrogated the antiproliferatory effects of UDCA. We show that UDCA inhibits proliferation of nontransformed intestinal epithelial cells by inducing a sustained hyperphosphorylation of ERK1 kinase which slows down the cell cycle and reduces expression of Irs-1 protein. These data extend our understanding of the physiological and potentially chemopreventive effects of UDCA and identify new targets for chemoprevention.

[Infectious enteritis]. / Enteritis infectiosa.

Infectious diarrhea belongs to the most frequent infections worldwide and can be elicited by a wide array of microbial pathogens. In developed countries transmission occurs much more frequently from contaminated food as compared to direct person-to-person contact, except for enteric viruses which can also be transmitted by aerosol formation after vomiting. In Germany, more than 90% of cases are caused by the four pathogens Norovirus, Rotavirus, Campylobacter and Salmonella. Therapy of infectious diarrhea is mainly supportive. In cases with a severe or prolonged course, signs of inflammation, bloody stool, immunosuppression, comorbidity and in suspected outbreaks, fecal microbial analysis should be performed and a specific therapy should be considered if indicated.

[Luminal gastroenterology and inflammation]. / Luminale Gastroenterologie und Entzündung.

Luminal inflammation of the intestine is a trigger of numerous gastrointestinal and non-gastrointestinal diseases. Several mechanisms have an impact on luminal inflammation, such as antibiotic or immunosuppressive therapies. In this paper recent data and new therapeutic approaches are reported concerning gastrointestinal and non-gastrointestinal diseases, for example eosinophilic esophagitis, irritable bowel syndrome, Crohn's disease and hepatic encephalopathy. In addition, recommendations are provided for the concurrent medication with proton pump inhibitors (PPIs) with respect to cardiovascular and gastrointestinal complications in patients in whom dual antiplatelet therapy including clopidrogel is indicated. Finally, an outlook is given on new and interesting therapeutic concepts in clostridium difficile colitis.

[What has been confirmed in the treatment of inflammatory bowel disease?]. / Was ist gesichert in der Therapie chronisch entzündlicher Darmerkrankungen?

The therapy of inflammatory bowel diseases is currently guided by clinical variables. An escalation of immunosuppressive therapy is required in case of treatment failure. However, clinical remission does not necessarily imply mucosal healing. In parallel to the treatment of rheumatoid arthritis a novel concept is emerging suggesting that an early anti-inflammatory treatment can reduce structural changes in inflammatory bowel diseases. The studies supporting this novel therapeutic strategy that mucosal healing might build the future therapeutic goal will be discussed. In order to adjust the therapy, risk factors indicating a complicated disease course will be identified, resulting in the development of an individual disease course. The benefit of these strategies will be discussed together with therapy-associated complications.

Use of methotrexate in patients with inflammatory bowel diseases.

Methotrexate (MTX) is one of the immunosuppressants commonly used in inflammatory bowel diseases. There is very good evidence for its use in patients with steroid-dependent or steroid-refractory Crohn's disease for induction as well as maintenance of remission. Optimal dose as well as mode of application is still a matter of debate. The only large randomised controlled trials used 25 mg/wk for induction and 15 to 25 mg/wk for maintenance of remission, both applied intramuscularly. Current guidelines recommend methotrexate in patients with extensive disease, steroid-refractory, and steroid-dependent disease. They even suggest MTX for patients with infrequent relapses in the need of repetitive corticosteroid therapy. In clinical practice it is mainly used in patients who failed treatment with thiopurines (azathioprine or 6-mercaptopurine) or who are intolerant to these drugs. MTX can also be used in paediatric patients, whereas the evidence for its effectiveness in fistulising disease is very weak. Two small studies did not prove that MTX is efficacious in ulcerative colitis. Even though case series suggest otherwise, its use is not recommended by current guidelines for patients with ulcerative colitis.

[New therapeutic approaches to special diseases of the small intestine]. / Neue therapeutische Ansätze bei speziellen Erkrankungen des Dünndarms.

Numerous reports on fundamental research and clinical studies have appeared in the past 1-2 decades which have contributed decisively to understanding inflammatory diseases of the small intestine. Illustrated by the examples of Crohn's disease, celiac disease, refractory sprue, and Whipple's disease, the rationale and evidence for treatment approaches are presented that are based on these pathophysiological findings. Emphasis is placed on modulation of the intestinal flora with antibiotics and probiotics as well as immunomodulatory/immunosuppressive measures with so-called biological agents. Future treatment options that directly intervene in the disease process are discussed.

Diagnostic value of confocal endomicroscopy in celiac disease.

BACKGROUND: Improved endoscopic screening with targeted biopsies might enhance diagnostic yield in celiac disease. Confocal endomicroscopy (CEM) allows high-resolution in vivo histological analysis. We compared the endomicroscopic findings during ongoing endoscopy with the histological findings graded according to the Marsh classification. METHODS: Twenty-four patients with celiac disease and six patients with celiac disease that was refractory on a gluten-free diet were examined using CEM. The duodenal mucosa was evaluated by CEM and by conventional histological analysis in respect of villous atrophy, crypt hyperplasia, and increased numbers of intraepithelial lymphocytes (IELs > 40 / 100 enterocytes). The CEM results were assessed as to sensitivity, specificity, and interobserver variability. A Marsh classification score determined by CEM was compared to that obtained by histology. Thirty patients undergoing routine upper gastrointestinal endoscopy were used as controls. RESULTS: Conventional histology showed villous atrophy and crypt hyperplasia in 23 and increased numbers of IELs in 27 of the 30 patients with celiac disease. With CEM, villous atrophy, crypt hyperplasia, and increased IELs were respectively identified in 17, 12, and 22 of the 30 patients. The agreement of the findings on CEM with those of conventional histology was good in relation to villous atrophy (sensitivity 74 %) and increased numbers of IELs (sensitivity 81 %), but inadequate in relation to crypt hyperplasia (sensitivity 52 %). The kappa values for determination of interobserver variability were 0.90 for villous atrophy, 1.00 for crypt hyperplasia, and 0.84 for IEL detection. In the 30 control patients, normal duodenal architecture was found by both histology and endomicroscopy, indicating an overall specificity of 100 %. CONCLUSION: The assessment of duodenal histology by CEM in patients with celiac disease is sensitive and specific in determining increased numbers of IELs and villous atrophy, but insufficient in respect of crypt hyperplasia. For routine use of CEM in patients with celiac disease, the technique would need to be improved.

Immune modulation by non-hodgkin lymphoma in a patient with two primary intestinal T-cell lymphomas and long-standing celiac disease.

Tumors may influence immunologic reactions. Here, we report on a 72-year-old patient who suffered from celiac disease (CD) that had been diagnosed 20 years before. Under a normal diet but without any evidence of enteropathy or CD-associated antibodies, the patient developed a jejunal T-cell lymphoma. It was resected due to perforation and four courses of IMVP-16 were added. The patient started and kept a strict gluten-free diet (GFD). Two years later, he presented with weight loss and a clonally divergent refractory sprue type II with loss of antigen (CD8; T-cell receptor-beta) expression in intraepithelial lymphocytes. At this time point, he showed high titers of CD-associated antibodies, although he was on a strict GFD. This case report highlights several questions: the missing enteropathy under a gluten-containing diet supports the notion of immune suppression in malignant diseases, especially non-Hodgkin lymphoma. Secondly, the patient developed an early form of a second independent T-cell lymphoma (refractory sprue type II) under a strict GFD, then with CD-associated antibodies, which raises the question whether the clonal intraepithelial lymphocytes were stimulating antibody production. Thus, the single detection of CD-associated antibodies in patients with CD is not itself proof of noncompliance with GFD.

[Updated German S3-guideline regarding the diagnosis of Crohn's disease--implementation of radiological modalities]. / Aktualisierte S 3-Leitlinie zur Diagnostik des Morbus Crohn--radiologische Untersuchungstechniken.

The recently updated German S 3-guideline regarding the diagnosis and treatment of Crohn's disease incorporates several changes concerning the radiological approach compared to the former guideline. This article focuses on guideline-based radiological imaging techniques for patients with Crohn's disease. The new guideline is also compared to former European and German guidelines in the context of recently published radiological literature.