Pierre Michetti

The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Current management

This paper is the second in a series of three publications relating to the European evidence-based consensus on the diagnosis and management of Crohns disease and concerns the management of active disease, maintenance of medically induced remission and surgery. The aims and methods of the ECCO Consensus, as well as sections on diagnosis and classification are covered in the first paper [van Assche et al. JCC 2009a]. The final paper covers post-operative recurrence, fistulating disease, the management of paediatric and adolescent IBD, pregnancy, psychosomatics, extraintestinal manifestations and complementary or alternative therapy for Crohns disease [Van Assche et al JCC 2009b]. #### Principal changes with respect to the 2006 ECCO guidelines The early use of azathioprine/mercaptopurine or methotrexate in combination with steroids is an appropriate option in moderately active localised ileocaecal CD. Anti-TNF therapy should be considered as an alternative for patients with objective evidence of active disease who have previously been steroid-refractory, steroid-dependent, or steroid-intolerant (based on Statement 5B). For those patients with severely active localised ileocaecal Crohns disease and objective evidence of active disease who have relapsed, anti-TNF therapy with or without an immunomodulator is an appropriate option [EL1a, RG B for infliximab]. For some patients who have infrequently relapsing disease, restarting steroids with an immunomodulator may be appropriate (based on Statement 5C). All currently available anti-TNF therapies appear to have generally similar efficacy and adverse-event profiles for inflammatory (‘luminal’) Crohns disease, so the choice depends on availability, route of delivery, patient preference, cost and national guidelines \[EL5, RG D\] (Statement 5I). Patients receiving azathioprine or mercaptopurine who relapse should be evaluated for adherence to therapy and have their dose optimised. Changing their maintenance therapy to methotrexate [EL1b RG B] or anti-TNF therapy [EL1a RGB] should be considered. Surgery should always be considered as an option in localised disease [EL4, …

European evidence based consensus on the diagnosis and management of Crohn’s disease: special situations

This third section of the European Crohn’s and Colitis Organisation (ECCO) Consensus on the management of Crohn’s disease concerns postoperative recurrence, fistulating disease, paediatrics, pregnancy, psychosomatics, extraintestinal manifestations, and alternative therapy. The first section on definitions and diagnosis reports on the aims and methods of the consensus, as well as sections on diagnosis, pathology, and classification of Crohn’s disease. The second section on current management addresses treatment of active disease, maintenance of medically induced remission, and surgery of Crohn’s disease.

Development of the Crohn's disease digestive damage score, the Lemann score.

Crohns disease (CD) is a chronic progressive destructive disease. Currently available instruments measure disease activity at a specific point in time. An instrument to measure cumulative structural damage to the bowel, which may predict long-term disability, is needed. The aim of this article is to outline the methods to develop an instrument that can measure cumulative bowel damage. The project is being conducted by the International Program to develop New Indexes in Crohns disease (IPNIC) group. This instrument, called the Crohns Disease Digestive Damage Score (the Lémann score), should take into account damage location, severity, extent, progression, and reversibility, as measured by diagnostic imaging modalities and the history of surgical resection. It should not be “diagnostic modality driven”: for each lesion and location, a modality appropriate for the anatomic site (for example: computed tomography or magnetic resonance imaging enterography, and colonoscopy) will be used. A total of 24 centers from 15 countries will be involved in a cross-sectional study, which will include up to 240 patients with stratification according to disease location and duration. At least 120 additional patients will be included in the study to validate the score. The Lémann score is expected to be able to portray a patients disease course on a double-axis graph, with time as the x-axis, bowel damage severity as the y-axis, and the slope of the line connecting data points as a measure of disease progression. This instrument could be used to assess the effect of various medical therapies on the progression of bowel damage. (Inflamm Bowel Dis 2011)

Effect of Whey-Based Culture Supernatant of Lactobacillus acidophilus (johnsonii) La1 on Helicobacter pylori Infection in Humans

Background: Specific strains of Lactobacillus acidophilus are known to inhibit intestinal cell adhesion and invasion by enterovirulent bacteria. As L. acidophilus can survive transiently in the human stomach, it may downregulate Helicobacter pylori infection. Methods: The ability of L. acidophilus (johnsonii) La1 supernatant to interfere with H. pylori bacterial growth, urease activity, and adhesion to epithelial cells was tested in vitro. Its effect on H. pylori infection in volunteers was monitored in a randomized, double-blind, controlled clinical trial, using a drinkable, whey-based, La1 culture supernatant. H. pylori infected volunteers were treated 14 days with 50 ml of La1 supernatant four times a day combined with either omeprazole 20 mg four times a day or with placebo. Infection was assessed by breath test, endoscopy, and biopsy sampling, performed at inclusion, immediately at the end of the treatment (breath test only), and 4 weeks after the end of the treatment. Results: La1 supernatant inhibited H. pylori growth in vitro, regardless of previous binding of H. pylori to epithelial cells. In 20 subjects (8 females, 12 males, mean age 33.1 years) a marked decrease in breath test values was observed immediately after treatment with La1 supernatant, both in the omeprazole and in the placebo group (median 12.3 vs. 28.8 and 9.4 vs. 20.4, respectively; p < 0.03). In both treatment groups, breath test values remained low 6 weeks after treatment (omeprazole treated 19.2, placebo treated 8.3; p < 0.03 vs. pretreatment), but the persistence of H. pylori infection was confirmed in gastric biopsies. Conclusion: La1 culture supernatant shown to be effective in vitro has a partial, acid-independent long-term suppressive effect on H. pylori in humans.

Oral immunization with urease and Escherichia coli heat-labile enterotoxin is safe and immunogenic in Helicobacter pylori–infected adults☆☆☆

BACKGROUND & AIMS Oral immunization with Helicobacter pylori urease can cure Helicobacter infection in animals. As a step toward therapeutic immunization in humans, the safety and immunogenicity of oral immunization with recombinant H. pylori urease were tested in H. pylori-infected adults. METHODS Twenty-six H. pylori-infected volunteers were randomized in a double-blind study to four weekly oral doses of 180, 60, or 20 mg of urease with 5 microg heat-labile enterotoxin of Escherichia coli (LT), LT alone, or placebo. Side effects and immune responses were evaluated weekly after immunization, and gastric biopsy specimens were obtained after 1 month and 6 months for histology and quantitative cultures. RESULTS Diarrhea was noted in 16 of 24 (66%) of the volunteers who completed the study. Antiurease serum immunoglobulin A titers increased 1. 58-fold +/- 0.37-fold and 3.66-fold +/- 1.5-fold (mean +/- SEM) after immunization with 60 and 180 mg urease, respectively, whereas no change occurred in the placebo +/- LT groups (P = 0.005). Circulating antiurease immunoglobulin A-producing cells increased in volunteers exposed to urease compared with placebo (38.9 +/- 13. 6/10(6) vs. 5.4 +/- 3.1; P = 0.018). Eradication of H. pylori infection was not observed, but urease immunization induced a significant decrease in gastric H. pylori density. CONCLUSIONS H. pylori urease with LT is well tolerated and immunogenic in H. pylori-infected individuals. An improved vaccine formulation may induce curative immunity.

Immunization of BALB/c mice against Helicobacter felis infection with Helicobacter pylori urease

BACKGROUND/AIMS Because Helicobacter pylori is a potentially dangerous human pathogen, the protective potential of oral immunization with H. pylori urease and its subunits was evaluated in an animal model. METHODS Mice were orally immunized with H. pylori sonicate, urease, or recombinant enzymatically inactive urease subunits and then challenged with Helicobacter felis. Control mice were sham-immunized. RESULTS H. felis colonization was present 5 days after challenge in 9 of 10 sham-immunized, 6 of 9 sonicate-immunized, and 3 of 10 urease-immunized animals (P = 0.031 vs. sham-immunized). Twelve days after challenge, urease B-immunized mice had a weaker colonization than sham-immunized controls, whereas urease A had no effect. After 70 days, most urease A- and urease B-immunized mice had cleared the colonization (10/17: P = 0.0019; 16/20: P = 0.00002 vs. sham-immunized). In urease B-immunized animals, protection was often associated with corpus gastritis. CONCLUSIONS Oral immunization with H. pylori urease protects mice against H. felis infection. Enzymatically inactive urease A and B subunits contain protective epitopes. It is unclear whether protection depends on the development of a mononuclear inflammatory response in the gastric corpus. Our observations should encourage the development of a human vaccine.

European evidence-based Consensus on the management of ulcerative colitis: Special situations

### 8.1 General Proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the procedure of choice for most patients with ulcerative colitis (UC) requiring colectomy.1 Pouchitis is a non-specific inflammation of the ileal reservoir and the most common complication of IPAA in patients with UC.2–7 Its frequency is related to the duration of the follow-up, occurring in up to 50% of patients 10 years after IPAA in large series from major referral centres.1–9 The cumulative incidence of pouchitis in patients with an IPAA for familial adenomatous polyposis is much lower, ranging from 0 to 10%.10–12 Reasons for the higher frequency of pouchitis in UC remain unknown. Whether the pouchitis more commonly develops within the first years after IPAA or whether the risk continues to increase with longer follow-up remains undefined. ECCO Statement 8A The diagnosis of pouchitis requires the presence of symptoms, together with characteristic endoscopic and histological abnormalities [EL3a, RGB]. Extensive colitis, extraintestinal manifestations (eg primary sclerosing cholangitis), being a non-smoker, p-ANCA positive serology, and non-steroidal anti-inflammatory drug use are possible risk factors for pouchitis [EL3b, RG D ]. #### 8.1.1 Symptoms After total proctocolectomy with IPAA, median stool frequency is 4 to 8 bowel movements1–4,13,14 with 700 mL of semiformed/liquid stool per day2,13,14. Symptoms related to pouchitis include increased stool frequency and liquidity, abdominal cramping, urgency, tenesmus and pelvic discomfort (2, 15). Rectal bleeding, fever, or extraintestinal manifestations may occur. Rectal bleeding is more often related to inflammation of the rectal cuff (“cuffitis”),16 than to pouchitis. Poor faecal incontinence may occur in the absence of pouchitis after IPAA, but is more common in patients with pouchitis. Symptoms of pouch dysfunction in patients with IPAA may be caused by conditions other than pouchitis, …

Favourable effect of an acidified milk (LC-1) on Helicobacter pylori gastritis in man

Objective The supernatant of Lactobacillus johnsonii La1 culture was shown to be bactericidal and to have a partial, acid-independent suppressive effect on Helicobacter pylori in humans. The aim of the present study was to investigate the effect of L. johnsonii La1-acidified milk (LC-1) on H. pylori infection. Design and methods Fifty-three volunteers infected with H. pylori as determined by positive 13C-urea breath test and positive serology were randomized to receive either LC-1 or a placebo 180 ml twice a day for 3 weeks. All subjects also received clarithromycin 500 mg bid during the last two weeks of acidified milk therapy. Oesophagogastroduodenoscopy and biopsies were performed at inclusion and repeated 4–8 weeks after the end of the treatment. H. pylori infection was confirmed by urease test and histology. H. pylori density and inflammation were scored using a modified Sydney classification. Results LC-1 ingestion induced a decrease in H. pylori density in the antrum (P = 0.02) and the corpus (P = 0.04). LC-1 also reduced inflammation and gastritis activity in the antrum (P = 0.02 and P = 0.01, respectively) and of activity in the corpus (P = 0.02). Clarithromycin eradicated H. pylori in 26% of the subjects; LC-1 did not improve the antibiotic effect. Conclusion These results suggest that H. pylori infection and gastritis can be down-regulated by LC-1.

Oral immunization with Helicobacter pylori urease B subunit as a treatment against Helicobacter infection in mice

BACKGROUND & AIMS Eradication of Helicobacter pylori infections in humans results in the healing of gastritis and gastric ulcers. This study used a mouse model to test whether oral vaccination can cure Helicobacter infection and gastritis. METHODS Mice were infected with Helicobacter felis. Three weeks after infection, the mice were orally immunized with H. pylori urease B subunit. Control mice were simultaneously infected but sham immunized. RESULTS Three to 8 weeks after oral immunization of H. felis-infected mice with recombinant H. pylori urease B subunit, the infection cleared and there was no evidence of gastritis. Vaccinated mice remained protected against two consecutive H. felis challenges. CONCLUSIONS These results show that the lack of natural immunity against Helicobacter can be overcome by oral immunization and that vaccination offers a novel therapeutic approach to Helicobacter-induced gastritis.

The Wiskott-Aldrich syndrome protein is required for the function of CD4+CD25+Foxp3+ regulatory T cells

The Wiskott-Aldrich syndrome, a primary human immunodeficiency, results from defective expression of the hematopoietic-specific cytoskeletal regulator Wiskott-Aldrich syndrome protein (WASP). Because CD4+CD25+Foxp3+ naturally occurring regulatory T (nTreg) cells control autoimmunity, we asked whether colitis in WASP knockout (WKO) mice is associated with aberrant development/function of nTreg cells. We show that WKO mice have decreased numbers of CD4+CD25+Foxp3+ nTreg cells in both the thymus and peripheral lymphoid organs. Moreover, we demonstrate that WKO nTreg cells are markedly defective in both their ability to ameliorate the colitis induced by the transfer of CD45RBhi T cells and in functional suppression assays in vitro. Compared with wild-type (WT) nTreg cells, WKO nTreg cells show significantly impaired homing to both mucosal (mesenteric) and peripheral sites upon adoptive transfer into WT recipient mice. Suppression defects may be independent of antigen receptor–mediated actin rearrangement because both WT and WKO nTreg cells remodeled their actin cytoskeleton inefficiently upon T cell receptor stimulation. Preincubation of WKO nTreg cells with exogenous interleukin (IL)-2, combined with antigen receptor–mediated activation, substantially rescues the suppression defects. WKO nTreg cells are also defective in the secretion of the immunomodulatory cytokine IL-10. Overall, our data reveal a critical role for WASP in nTreg cell function and implicate nTreg cell dysfunction in the autoimmunity associated with WASP deficiency.