Jörg C. Hoffmann

Updated German Guideline on Diagnosis and Treatment of Ulcerative Colitis, 2011

! Hintergrund Die Colitis ulcerosa (CU) ist neben dem Morbus Crohn die wichtigste chronisch-entzundliche Darmerkrankung (CED). Die Inzidenz fur die Colitis ulcerosa liegt in Deutschland bei bei 3,0–3,9 pro 100000 Einwohner [1, 2]. Die Pravalenz durfte in der westlichen Welt derzeit bei 160– 250 pro 100000 Einwohner liegen [3, 4]. Der hochste Gipfel der alterspezifischen Inzidenz liegt bei den 16bis 25-Jahrigen, wenn auch die Verteilung uber die Altersdekaden weit gleichmasiger ist als fruher beschrieben wurde [2]. Somit beginnt fur die meisten Patienten ihre Erkrankung wahrend der Schulzeit oder der Berufausbildung und dauert wahrend ihres gesamten beruflichen Lebens an. Daraus folgt, dass durch die Erkrankung nicht nur direkte Kosten (Medikamente, Arztbesuche, Operationen, Krankenhausaufenthalte etc.), sondern auch umfangreiche indirekte Kosten (Rente, Arbeitsausfalle etc.) entstehen. Es ist davon auszugehen, dass bei Patienten mit CU ca. die Halfte der Gesamtkosten den indirekten Kosten zuzuordnen sind [5]. An direkten medizinischen Kosten wurden dabei zuletzt zwischen 2500 und 5000€ pro Inhaltsverzeichnis! Hintergrund Die Colitis ulcerosa (CU) ist neben dem Morbus Crohn die wichtigste chronisch-entzündliche Darmerkrankung (CED). Die Inzidenz für die Colitis ulcerosa liegt in Deutschland bei bei 3,0–3,9 pro 100000 Einwohner [1, 2]. Die Prävalenz dürfte in der westlichen Welt derzeit bei 160– 250 pro 100000 Einwohner liegen [3, 4]. Der höchste Gipfel der alterspezifischen Inzidenz liegt bei den 16bis 25-Jährigen, wenn auch die Verteilung über die Altersdekaden weit gleichmäßiger ist als früher beschrieben wurde [2]. Somit beginnt für die meisten Patienten ihre Erkrankung während der Schulzeit oder der Berufausbildung und dauert während ihres gesamten beruflichen Lebens an. Daraus folgt, dass durch die Erkrankung nicht nur direkte Kosten (Medikamente, Arztbesuche, Operationen, Krankenhausaufenthalte etc.), sondern auch umfangreiche indirekte Kosten (Rente, Arbeitsausfälle etc.) entstehen. Es ist davon auszugehen, dass bei Patienten mit CU ca. die Hälfte der Gesamtkosten den indirekten Kosten zuzuordnen sind [5]. An direkten medizinischen Kosten wurden dabei zuletzt zwischen 2500 und 5000€ pro Inhaltsverzeichnis

Through the endoscope balloon dilation of ileocolonic strictures: prognostic factors, complications, and effectiveness

Background/aimsAbout half of all Crohn’s disease (CD) patients undergo surgery at some point, many because of strictures. An alternative possibility is to dilate strictures endoscopically. However, little is known about prognostic factors.Patients and methodsThirty-two patients with primary CD (n = 2), radiogenic strictures (n = 1), or postoperative strictures (27 because of CD; 2 after resection because of cancer), were planned to undergo colonoscopic dilatation of which 25 patients were dilated (10 men; 15 women; median age 48). Length of stenosis, diameter of stricture, balloon size, smoking status, ulcer in the stricture, passage postdilatation, hemoglobin level, complications, redilatation, and subsequent surgery were recorded. Only patients with at least 6 months follow up were included.ResultsFive out of 32 patients had no stenosis, marked inflammation, or fistulas adjacent to the stricture. One patient each had a long stricture (8cm) or a filiform stenosis ruling out dilatation [technical success, 25/27 (92.6%)]. Among these 25 patients, 39 colonoscopies with 51 dilatations were performed. After a single dilatation, 52% were asymptomatic while 48% needed another intervention, half of them surgery. Bleeding without need for transfusion occurred in 3 out of 39 colonoscopies and one perforation required surgery. Significant prognostic factors were smoking and ulcers in the stricture (P < 0.05 each). Some ulcers led to intussusception requiring surgery in spite of good dilatation results.ConclusionThrough the endoscope balloon stricture dilatation is a relatively safe and often effective treatment modality in ileocolonic strictures. The presence of ulcers in the stricture have a worse outcome as do smokers.

Human peripheral γδ T cells possess regulatory potential

Deficiency in γδ T cells aggravates colitis in animal models suggesting that γδ T cells have regulatory properties. Therefore, proliferation, suppression and cytokine secretion of human γδ T cells were determined in vitro. Human peripheral γδ T cells were isolated from the whole blood of healthy donors by magnetic antibody cell sorting technology. The proliferation after CD3/CD28 stimulation was measured by 3[H]thymidine incorporation. Interferon‐γ (IFN‐γ), interleukin‐2 (IL‐2), transforming growth factor‐β (TGF‐β) and IL‐10 concentrations were measured by enzyme‐linked immunosorbent assay; TGF‐β messenger RNA was also measured by reverse transcription–polymerase chain reaction. The expression of latency associated peptide (LAP), a TGF‐β complex component, intracellular cytokine content and T helper cell proliferation were measured by flow cytometry. Human γδ T cells showed poor proliferation upon CD3/CD28 stimulation and suppressed T helper cell growth stronger than CD4+ CD25+ T cells, although γδ T cells were FOXP3 negative. They secreted little IL‐2 but high concentrations of IFN‐γ, IL‐10 and TGF‐β. When looking at LAP expression the Vδ1 subset was found to be the main TGF‐β producer compared to Vδ2 T cells. Taken together, peripheral γδ T cells have in vitro a more potent regulatory potential than CD4+ CD25+ cells regarding T helper cell suppression. This is most likely the result of strong TGF‐β secretion, particularly by the Vδ1 subset.

Human peripheral gammadelta T cells possess regulatory potential.

Deficiency in γδ T cells aggravates colitis in animal models suggesting that γδ T cells have regulatory properties. Therefore, proliferation, suppression and cytokine secretion of human γδ T cells were determined in vitro. Human peripheral γδ T cells were isolated from the whole blood of healthy donors by magnetic antibody cell sorting technology. The proliferation after CD3/CD28 stimulation was measured by 3[H]thymidine incorporation. Interferon‐γ (IFN‐γ), interleukin‐2 (IL‐2), transforming growth factor‐β (TGF‐β) and IL‐10 concentrations were measured by enzyme‐linked immunosorbent assay; TGF‐β messenger RNA was also measured by reverse transcription–polymerase chain reaction. The expression of latency associated peptide (LAP), a TGF‐β complex component, intracellular cytokine content and T helper cell proliferation were measured by flow cytometry. Human γδ T cells showed poor proliferation upon CD3/CD28 stimulation and suppressed T helper cell growth stronger than CD4+ CD25+ T cells, although γδ T cells were FOXP3 negative. They secreted little IL‐2 but high concentrations of IFN‐γ, IL‐10 and TGF‐β. When looking at LAP expression the Vδ1 subset was found to be the main TGF‐β producer compared to Vδ2 T cells. Taken together, peripheral γδ T cells have in vitro a more potent regulatory potential than CD4+ CD25+ cells regarding T helper cell suppression. This is most likely the result of strong TGF‐β secretion, particularly by the Vδ1 subset.

γδ T lymphocytes: a new type of regulatory T cells suppressing murine 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis

BackgroundThe intestinal immune system is continuously challenged by antigen without becoming dysregulated. However, injury of the mucosa by, i.e. dextran sulphate sodium causes severe inflammation in γδ T-cell-deficient mice. We therefore asked whether γδ T cells have regulatory functions.Materials and methodsγδ T cells were isolated from spleens and mesenteric lymph nodes of C57BL/6 wild-type (wt) mice. Proliferation and cytokine secretion of γδ T cells were quantified by [3H] thymidine incorporation and ELISA. Additionally, proliferation of carboxyfluorescein diacetate succinimidylester-labelled CD4+ T cells cocultured with γδ T cells was analysed by flow cytometry. Finally, γδ T cells from wt or interleukin-10 transgenic (IL-10tg) mice were transferred into congenic mice with 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis.Resultsγδ T cells were hyporesponsive to CD3/CD28 stimulation and suppressed CD4+ T-cell proliferation (up to 66 ± 7% suppression) in vitro. Further, the preventive transfer of wt or IL-10tg γδ T cells ameliorated TNBS-induced colitis resulting in prolonged survival and reduced histological damage (1.5 ± 0.4 and 1.3 ± 0.2, respectively vs. 3.8 ± 0.3 in untransferred mice, p < 0.05). This was accompanied by reduced TNF-α and increased IL-10 and TGF-β secretion from intestinal and splenic lymphocytes.ConclusionsMurine γδ T cells are a new type of regulatory T cells in vitro and act protective on mouse TNBS-induced colitis in vivo. Future studies have to define the underlying mechanism and to investigate whether γδ T cells can be used for immunotherapy of human inflammatory bowel disease.

Gadofluorine M-enhanced magnetic resonance imaging of inflammatory bowel disease: quantitative analysis and histologic correlation in a rat model.

Objectives:To determine the colonic mural enhancement in a rat model of inflammatory bowel disease (IBD) using gadofluorine M- and diethylenetriamine pentaacetic acid (Gd-DTPA)-enhanced magnetic resonance (MR) imaging, and to correlate the degree of enhancement with the histopathologic severity of the disease. Materials and Methods:This study was approved by our hospitals institutional animal care and use committee. A total of 44 rats with 2 grades (mild, n = 17; and severe, n = 27) of dinitrobenzene sulfonic acid (DNBS)-induced IBD and 13 rats without IBD, were examined using a 2.4-T, small animal MR scanner. T2- and T1-weighted MR images were acquired, and sequential T1-weighted MR imaging was then performed immediately and again 15, 45, 60, and 90 minutes, and 24 hours after intravenous -injection of either gadofluorine M- or Gd-DTPA (0.1 mmol Gd/kg body weight). The signal-to-noise ratios and enhancement ratios (ER) of the colon wall were measured. For paired and group comparisons of the histopathology and MR imaging data, the Wilcoxon- and the Mann-Whitney U tests were used, and the multifactorial analysis of variance test was used to compare the time courses of the ERs. Results:Gadofluorine M injection resulted in significant differences in the ER of noninflamed, mildly inflamed, and severely inflamed colon wall at any time up to 24 hours after contrast injection (ER at 24 hours 2.0 ± 1.2; 10.1 ± 4.3; and 49.7 ± 10.8, respectively; P < 0.01). After Gd-DTPA injection, significant differences were observed in the ER of inflamed and noninflamed bowel at 15, 45, and 60 minutes (P < 0.01); however, no significant differences in mildly and severely inflamed bowel were observed at any time. In contrast to Gadofluorine M, there was no prolonged contrast enhancement in the inflamed colon wall after intravenous injection of Gd-DTPA (ER at 24 hours 1.6 ± 1.3; 3.4 ± 2.7; and 3.3 ± 1.6, respectively; n.s.). Conclusions:Gadofluorine M-enhanced MR imaging shows a higher correlation of the wall enhancement and histopathology grading in an IBD rat model than does Gd-DTPA-enhanced imaging.

αCD2 mAb treatment safely attenuates adoptive transfer colitis

Increased proliferation, defective apoptosis, and cytokine dysregulation of T lymphocytes are thought to be important for the pathogenesis of inflammatory bowel disease. Since these phenomena can be corrected by αCD2 mAb, we asked whether CD2 directed immunotherapy safely prevents and/or ameliorates adoptive transfer colitis. Colitis was induced by transfer of CD4+ T cell blasts to syngenic RAG1−/− mice or CD45RBhigh CD4+ T cells to SCID mice. The αCD2 mAb 12-15 or rat IgG was given, starting either initially or upon first signs of colitis. Disease activity was assessed by clinical monitoring, microscopic scoring, hemoccult, endoscopy, and blood count analysis. Cytokine production of stimulated LPL was measured by ELISA and cell proliferation by [3H]-thymidine incorporation. Parasite control was analyzed in a murine model of infection with Toxoplasma gondii. The αCD2 mAb significantly increased mean survival time when starting at transfer of blasts (survival >35 days: αCD2 69% vs 0% of controls, P<0.001). In the SCID colitis model hematochezia and macroscopic colitis were delayed. When used in established T-cell blast colitis, the benefit was less pronounced, even in combination with dexamethasone (mean survival±s.e.m.: αCD2+dexa: 13.5±2.9 vs dexa+IgG: 6.3±1.0, P<0.05). In the preventive experiment the αCD2 mAb markedly reduced IL-2 secretion and T-cell proliferation. The immune response towards Toxoplasma gondii was not impaired. These studies show for the first time that CD2 directed immunotherapy can attenuate or delay adoptive transfer colitis and ameliorate established colitis. Most likely inhibition of IL-2 secretion and T-cell proliferation are responsible for these effects. Still, immune defence towards T. gondii is maintained.

Targeting human CD2 by the monoclonal antibody CB.219 reduces intestinal inflammation in a humanized transfer colitis model

The cell adhesion molecule CD2 facilitates antigen-independent T-cell activation and CD2 deficiency or blockade reduces intestinal inflammation in murine models. We here aimed to evaluate the therapeutic potential of monoclonal antibodies (mAb) specific for human CD2 in colitis treatment. Transfer colitis induced by naïve CD4(+) T cells expressing human CD2 was treated with anti-human CD2 mAb. The mAb CB.219 protected from severe colitis in a preventive treatment regimen, while therapeutic treatment ameliorated intestinal inflammation. Diminished intestinal tissue damage was paralleled by a profound suppression of lamina propria lymphocytes to produce pro-inflammatory cytokines and tumor necrosis factor α as well as the neutrophil chemoattractant CXC motif ligand 1 and the CC chemokine ligand 3. Furthermore, infiltration with macrophages and T cells was low. Thus, reduced intestinal inflammation in our humanized colitis model by targeting CD2 on T cells with the mAb CB.219 suggests a novel approach for colitis treatment.

[The German competence network inflammatory bowel disease (KNCED) -- network research leads to the identification of the cause of disease and to the improvement in patient care].

ZusammenfassungDas Kompetenznetz chronisch entzündliche Darmerkrankungen (KN-CED) ist eines von mittlerweile 17 Kompetenznetzen, die vom Bundesministerium für Bildung und Forschung (BMBF) gefördert werden. Es handelt sich hierbei um vernetzte Forschungsverbünde zu definierten Krankheitsbildern, die durch eine hohe Erkrankungshäufigkeit oder Sterberate gekennzeichnet sind bzw. einen hohen Kostenfaktor darstellen. Projektträger der Kompetenznetze ist das Deutsche Zentrum für Luft- und Raumfahrt (DLR e. V.). Die zentrale Organisationsstruktur ist die Telematikplattform für medizinische Forschungsnetze (TMF e. V.).Das KN-CED ist ein Forschungsverbund, der sich zum Ziel gesetzt hat, die beiden chronisch verlaufenden und derzeit noch unheilbaren Krankheitsentitäten Morbus Crohn und Colitis ulcerosa in ihrer Gesamtheit zu erforschen. Dazu gehören insbesondere die Untersuchung von Krankheitsursachen, die Etablierung neuer Therapieverfahren bzw. Optimierung von bestehenden Therapieformen und die Versorgungsforschung.Um dieses Ziel zu erreichen, ist das Kompetenznetz sowohl in nationale als auch internationale Forschungsverbünde integriert und wird durch die nationale Patientenvereinigung DCCV sowie von Industriepartnern unterstützt.Eine Verstetigung der geschaffenen Strukturen wird durch den Verein „Kompetenznetz CED“ vorangetrieben.Kernstück der Forschung im Kompetenznetz sind u. a. die geschaffenen Core Facilities mit den Schwerpunkten Molekulargenetik, Tier- und Zellmodelle sowie Serummarker.Die zentrale Datenbank des Kompetenznetzes, die Biodaten von mittlerweile mehr als 4 000 Patienten speichert, stellt eine der weltweit größten Biodatenbanken zum Thema CED überhaupt dar.Die erfolgreiche Zusammenarbeit innerhalb der vernetzten Strukturen des Kompetenznetzes spiegelt sich in zahlreichen Publikationen wider. So konnten z. B. zwei der mittlerweile drei bekannten Krankheitsgene von Morbus Crohn identifiziert werden. Auch wurden unter Beteiligung des Kompetenznetzes nationale Leitlinien für die Diagnostik und Therapie von CED erstellt.Das Kompetenznetz betreibt zudem eine kooperative Gemeinschaft von Studienzentren, innerhalb deren wesentliche Therapieentwicklungen u. a. im Bereich neuer biotechnologischer Medikamente stattfinden.Die Analyse der bestehenden Versorgungsstrukturen sowie die Entwicklung von Organisationsstandards für Patienten mit CED runden die Forschung innerhalb des Kompetenznetzes ab und unterstreichen den Anspruch, umfassende Antworten auf die Probleme zu finden, die mit den Krankheitsbildern Morbus Crohn und Colitis ulcerosa verbunden sind.AbstractThe competence network chronic inflammatory bowel disease (KN-CED) is one of 17 networks of competence initiated by the German Federal Ministry of Education and Research (BMBF). These networks are concerned with disease patterns which are characterized by their high frequency, high mortality rate or which present a large expense factor. The project-executing organization is the German Center for Air and Space Travel (DLR e. V.). The central structure of organization is the Telematic Platform for medical Networks (TMF e. V.).Aim of the KN-CED is to investigate, in their complexity, the incurable chronic diseases ulcerative colitis and Crohn’s disease, particularly with regard to the causes of disease, the establishment of new therapy standards as well as patient care.To achieve this goal, the competence network is integrated into both national and international research associations and is also backed by the national self-help group DCCV and the pharmaceutical industry.Principal items of the competence network are the core facilities and their main focus on molecular genetics, animal and cell models and serum markers. Having stored the data of more than 4,000 patients so far, the central database of the competence network is one of the largest databases worldwide with regard to inflammatory bowel disease (IBD).The successful cooperation within the network is reflected in numerous publications. Thus, two of the three known genes of Crohn’s disease were identified. Also with the participation of the competence network national guidelines for the diagnosis and therapy of IBD were generated.Furthermore, the competence network operates study centers where significant therapeutic developments in the field of biotechnological drugs are taking place.The analysis of existing structures of care as well as the development of standards of organization for patients with IBD top the research within the competence network and emphasize the claim to find comprehensive answers to the questions connected with IBD.

[Clinical practice guideline on diagnosis and treatment of Crohn's disease - summary for the general practitioner].

The German clinical practice guideline on diagnosis and therapy of Crohns disease is the result of an evidence-based consensus conference under the auspices of the German Gastroenterologic Society and the Competence Network IBD. This article will summarize the recommendations most important for the general practitioner.Crohns disease is diagnosed in cooperation with a gastroenterologist who is performing endoscopy and possibly ultrasound. Uncomplicated relapses can nevertheless be successfully treated at the office of a family physician - mostly with steroids. Steroids are not appropriate for long-term treatment though. In those cases an early treatment with immunosuppressants in collaboration with a gastroenterologist is required. Cooperation with several different sub specialists is necessary when surgery is required as well as for the treatment of fistula, psychosomatic aspects and extraintestinal manifestations.ZusammenfassungDie Leitlinie „Diagnostik und Therapie des Morbus Crohn“ ist das Ergebnis einer evidenzbasierten Konsensuskonferenz, die von der Deutschen Gesellschaft für Verdauungs- und Stoffwechselkrankheiten zusammen mit dem Kompetenznetz Chronisch entzündliche Darmerkrankungen ausgerichtet wurde. Hier sollen die für die praktische Arbeit von Internisten und Hausärzten wesentlichen Empfehlungen zusammengetragen werden.Während die initiale Diagnostik wegen der apparativen Untersuchungen die Zusammenarbeit mit einem endoskopierenden Kollegen erfordert, kann der unkomplizierte Schub in der hausärzlichen Praxis zumeist mit Steroiden erfolgreich behandelt werden. Für die Langzeittherapie sind Steroide aber ungeeignet. Hier sollte rechtzeitig eine Therapie mit Immunsuppressiva in Zusammenarbeit mit einem Gastroenterologen erfolgen. Bei notwendigen Operationen, der Therapie von Fisteln, psychosomatischen Aspekten und extraintestinalen Manifestationen ist die Zusammenarbeit mit Fachärzten verschiedener anderer Disziplinen notwendig.AbstractThe German clinical practice guideline on diagnosis and therapy of Crohn’s disease is the result of an evidence-based consensus conference under the auspices of the German Gastroenterologic Society and the Competence Network IBD. This article will summarize the recommendations most important for the general practitioner.Crohn’s disease is diagnosed in cooperation with a gastroenterologist who is performing endoscopy and possibly ultrasound. Uncomplicated relapses can nevertheless be successfully treated at the office of a family physician – mostly with steroids. Steroids are not appropriate for long-term treatment though. In those cases an early treatment with immunosuppressants in collaboration with a gastroenterologist is required. Cooperation with several different sub specialists is necessary when surgery is required as well as for the treatment of fistula, psychosomatic aspects and extraintestinal manifestations.