The Pathogenesis of Extraintestinal Manifestations: Implications for IBD Research, Diagnosis, and Therapy.

This article reports on the sixth scientific workshop of the European Crohn's and Colitis Organisation [ECCO] on the pathogenesis of extraintestinal manifestations [EIMs] in inflammatory bowel disease [IBD]. This paper has been drafted by 15 ECCO members and 6 external experts [in rheumatology, dermatology, ophthalmology, and immunology] from 10 European countries and the USA. Within the workshop, contributors formed subgroups to address specific areas. Following a comprehensive literature search, the supporting text was finalized under the leadership of the heads of the working groups before being integrated by the group consensus leaders.

Genetic polymorphisms associated with smoking behaviour predict the risk of surgery in patients with Crohn's disease.

BACKGROUND: Smoking is a strong environmental factor leading to adverse outcomes in Crohn's disease, but a more benign course in ulcerative colitis. Several single nucleotide polymorphisms (SNPs) are associated with smoking quantity and behaviour. AIM: To assess whether smoking-associated SNPs interact with smoking to influence the clinical course of inflammatory bowel diseases. METHODS: Genetic and prospectively obtained clinical data from 1434 Swiss inflammatory bowel disease cohort patients (821 Crohn's disease and 613 ulcerative colitis) were analysed. Six SNPs associated with smoking quantity and behaviour (rs588765, rs1051730, rs1329650, rs4105144, rs6474412 and rs3733829) were combined to form a risk score (range: 0-12) by adding the number of risk alleles. We calculated multivariate models for smoking, risk of surgery, fistula, Crohn's disease location and ulcerative colitis disease extent. RESULTS: In Crohn's disease patients who smoke, the number of surgeries was associated with the genetic risk score. This translates to a predicted 3.5-fold (95% confidence interval: 2.4- to 5.7-fold, P<.0001) higher number of surgical procedures in smokers with 12 risk alleles than individuals with the lowest risk. Patients with a risk score >7 had a significantly shorter time to first intestinal surgery. The genetic risk score did not predict surgery in ulcerative colitis or occurrence of fistulae in Crohn's disease. SNP rs6265 was associated with ileal disease in Crohn's disease (P<.05) and proctitis in ulcerative colitis (P<.05). CONCLUSIONS: SNPs associated with smoking quantity is associated with an increased risk for surgery in Crohn's disease patients who smoke. Our data provide an example of genetics interacting with the environment to influence the disease course of inflammatory bowel disease.

Impact of the early use of immunomodulators or TNF antagonists on bowel damage and surgery in Crohn's disease.

BACKGROUND: The impact of early treatment with immunomodulators (IM) and/or TNF antagonists on bowel damage in Crohn's disease (CD) patients is unknown. AIM: To assess whether 'early treatment' with IM and/or TNF antagonists, defined as treatment within a 2-year period from the date of CD diagnosis, was associated with development of lesser number of disease complications when compared to 'late treatment', which was defined as treatment initiation after >2 years from the time of CD diagnosis. METHODS: Data from the Swiss IBD Cohort Study were analysed. The following outcomes were assessed using Cox proportional hazard modelling: bowel strictures, perianal fistulas, internal fistulas, intestinal surgery, perianal surgery and any of the aforementioned complications. RESULTS: The 'early treatment' group of 292 CD patients was compared to the 'late treatment' group of 248 CD patients. We found that 'early treatment' with IM or TNF antagonists alone was associated with reduced risk of bowel strictures [hazard ratio (HR) 0.496, P = 0.004 for IM; HR 0.276, P = 0.018 for TNF antagonists]. Furthermore, 'early treatment' with IM was associated with reduced risk of undergoing intestinal surgery (HR 0.322, P = 0.005), and perianal surgery (HR 0.361, P = 0.042), as well as developing any complication (HR 0.567, P = 0.006). CONCLUSIONS: Treatment with immunomodulators or TNF antagonists within the first 2 years of CD diagnosis was associated with reduced risk of developing bowel strictures, when compared to initiating these drugs >2 years after diagnosis. Furthermore, early immunomodulators treatment was associated with reduced risk of intestinal surgery, perianal surgery and any complication.

PTPN2 controls differentiation of CD4⁺ T cells and limits intestinal inflammation and intestinal dysbiosis.

Loss-of-function variants within the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) are associated with increased risk for Crohn's disease (CD). A disturbed regulation of T helper (Th) cell responses causing loss of tolerance against self- or commensal-derived antigens and an altered intestinal microbiota plays a pivotal role in CD pathogenesis. Loss of PTPN2 in the T-cell compartment causes enhanced induction of Th1 and Th17 cells, but impaired induction of regulatory T cells (Tregs) in several mouse colitis models, namely acute and chronic dextran sodium sulfate colitis, and T-cell transfer colitis models. This results in increased susceptibility to intestinal inflammation and intestinal dysbiosis which is comparable with that observed in CD patients. We detected inflammatory infiltrates in liver, kidney, and skin and elevated autoantibody levels indicating systemic loss of tolerance in PTPN2-deficient animals. CD patients featuring a loss-of-function PTPN2 variant exhibit enhanced Th1 and Th17 cell, but reduced Treg markers when compared with PTPN2 wild-type patients in serum and intestinal tissue samples. Our data demonstrate that dysfunction of PTPN2 results in aberrant T-cell differentiation and intestinal dysbiosis similar to those observed in human CD. Our findings indicate a novel and crucial role for PTPN2 in chronic intestinal inflammation.

Colorectal polypectomy during insertion and withdrawal or only during withdrawal? A randomized controlled trial.

BACKGROUND AND STUDY AIMS: Removal of colorectal polyps is routinely performed during withdrawal of the endoscope. However, polyps detected during insertion of the colonoscope may be missed at withdrawal. We aimed to evaluate whether polypectomy during both insertion and withdrawal increases polyp detection and removal rates compared with polypectomy at withdrawal only, and to assess the duration of both approaches. PATIENTS AND METHODS: Patients were included into the study when the first polyp was detected, and randomized into two groups; in group A, polyps ≤ 10 mm in diameter were removed during insertion and withdrawal of the colonoscope, while in group B, these polyps were removed at withdrawal only. Main outcome measures were duration of colonoscopy, number of polyps detected during insertion but not recovered during withdrawal, technical ease, patient discomfort, and complications. RESULTS: 150 patients were randomized to group A and 151 to group B. Mean (± standard deviation [SD]) duration of colonoscopy did not differ between the groups (30.8 ± 15.6 min [A] vs. 28.5 ± 13.8 min [B], P = 0.176). In group A 387 polyps (mean 2.58 per colonoscopy) were detected and removed compared with 389 polyps detected (mean 2.58 per colonoscopy) in group B of which 376 were removed (13 polyps were missed, mean size [SD] 3.2 [1.3] mm; 7.3 % of patients). Patient tolerance was similar in the two groups. CONCLUSIONS: Removal of polyps ≤ 10 mm during withdrawal only is associated with a considerable polyp miss rate. We therefore recommend that these polyps are removed during both insertion and withdrawal.

[New options for helicobacter pylori antibiotic treatment]. / Neue Möglichkeiten der Helicobacter-pylori-Behandlung mit Antibiotika.

Helicobacter plays a central role in the pathogenesis of several gastric diseases and its eradication has a therapeutic or prophylactic effect in many clinical situations. However, treatment of Helicobacter infection can be challenging and the frequently recommended clarithromycin based triple therapy fails in more than 20% of patients. Reasons for treatment failure include antibiotic resistances and bacterial persistence in an acidic stomach, for instance due to rapid metabolization of the proton pump inhibitor by the host. Therapeutic efficiency can be improved by a therapy tailored for an individual patient and the respective pathogen. In an alternative approach the antibiotic therapy can be intensified leading to a sequential or concomitant therapy. These and other strategies tested only in single studies can achieve eradication in 90 % and up to over 95 % of patients, respectively, and should be used more often in clinical practice.

Diagnosing lactase deficiency in three breaths.

BACKGROUND: Lactose hydrogen breath tests (H(2)-BTs) are widely used to diagnose lactase deficiency, the most common cause of lactose intolerance. The main time-consuming part of the test relates to the sampling frequency and number of breath samples. AIM: Evaluate sensitivities and specificities of two- and three-sample breath tests compared with standard breath sampling every 15 min. METHODS: Lactose H(2)-BT with probes samples every 15 min served as gold standard. Sensitivity, specificity, positive and negative predictive value of two-sample tests (0-60 min, 0-90 min or 0-120 min) and three-sample tests (0-60-90 min, 0-60-120 min or 0-90-120 min) were calculated. RESULTS: Among 1049 lactose H(2)-BT performed between July 1999 and December 2005, 337 (32%) had a positive result. Two-sample tests had sensitivity and specificity of 52.5 and 100.0% (0-60 min), 81.9 and 99.7% (0-90 min), and 92.6 and 99.2% (0-120 min), respectively. Three-sample tests had sensitivity and specificity of 83.4 and 99.7% (0-60-90 min), 95.0 and 99.2% (0-60-120 min), and 95.0 and 98.9% (0-90-120 min), respectively. CONCLUSION: A three-sample breath test (baseline, 60/90 min and 120 min) has excellent sensitivity and specificity for lactase deficiency. Lactose H(2)-BT can be simplified but not shortened to <2 h.

Air suctioning during colon biopsy forceps removal reduces bacterial air contamination in the endoscopy suite.

BACKGROUND AND STUDY AIMS: Bacterial contamination of endoscopy suites is of concern; however studies evaluating bacterial aerosols are lacking. We aimed to determine the effectiveness of air suctioning during removal of biopsy forceps in reducing bacterial air contamination. PATIENTS AND METHODS: This was a prospective single-blinded trial involving 50 patients who were undergoing elective nontherapeutic colonoscopy. During colonoscopy, endoscopists removed the biopsy forceps first without and then with suctioning following contact with the sigmoid mucosa. A total of 50 L of air was collected continuously for 30 seconds at 30-cm distance from the biopsy channel valve of the colonoscope, with time starting at forceps removal. Airborne bacteria were collected by an impactor air sampler (MAS-100). Standard Petri dishes with CNA blood agar were used to culture Gram-positive bacteria. Main outcome measure was the bacterial load in endoscopy room air. RESULTS: At the beginning and end of the daily colonoscopy program, the median (and interquartile [IQR] range) bioaerosol burden was 4 colony forming units (CFU)/m (3) (IQR 3 - 6) and 16 CFU/m (3) (IQR 13 - 18), respectively. Air suctioning during removal of the biopsy forceps reduced the bioaerosol burden from a median of 14 CFU/m (3) (IQR 11 - 29) to a median of 7 CFU/m (3) (IQR 4 - 16) ( P = 0.0001). Predominantly enterococci were identified on the agar plates. CONCLUSION: The bacterial aerosol burden during handling of biopsy forceps can be reduced by applying air suction while removing the forceps. This simple method may reduce transmission of infectious agents during gastrointestinal endoscopies.

Recent advances in the etiology and treatment of Crohn's disease.

Significant advances have been achieved in the understanding of the pathogenesis of Crohn's disease (CD). A number of susceptibility genes have been detected by large genome wide screening-approaches. We do not completely understand the function of most of these genetic variants, however, there is good evidence that most of them are associated with the recognition and detection of luminal bacteria as well as defence against this microbiota. The important role of intestinal bacteria for the onset of CD is now clear. The intestinal bacteria and other "environmental" factors certainly contribute to CD pathogenesis: the respective genetic variations now termed as "susceptibility factors" exist since ten thousands of years. However, the incidence of CD is largely dependent on factors such as childhood hygiene or socioeconomic status; factors that are determined by living conditions and environment. New therapeutic concepts emerge from these insights. The most important progress in recent years certainly is the introduction of biologics in the therapy of CD. TNF blockers have been shown to be very effective for the control of complicated disease courses. However, more time will be needed until the concepts on pathogenesis evolve into new therapeutics that are introduced into clinical routine and guidelines. The hygiene hypothesis has led to the administration of helminths to CD patients to modulate the intestinal immune system. Another new approach is to improve the mucosal barrier function, which has been shown to be impaired in CD patients.

[Early gastric cancer--or not]. / Magenfrühkarzinom oder doch nicht?

A 46-year old female patient presented with non-specific epigastric discomfort that had been present for 6 months. Endoscopic work-up showed a small gastric polyp and biopsy samples revealed adenocarcinoma. There was no evidence of metastatic disease or penetration of the muscle layer on endosonography, rating the tumor as early gastric cancer. Endoscopic submucosal dissection was unsuccessful due to bleeding complications and the patient was treated with subtotal gastrectomy. Surprisingly, the final histological diagnosis revealed a highly differentiated neuroendocrine tumor and the initial diagnosis had to be revised.

[Diffuse abdominal pain and eosinophilia]. / Diffuse Bauchschmerzen und Eosinophilie.

Eosinophilic gastroenteritis is a rare clinical condition of unknown aetiology and heterogenic etiopathology. Important differential diagnoses are intestinal parasitic infections, hypereosinophilic syndrome, malignancies such as lymphoma and allergic diseases. The diagnosis can be made in most cases by patient history, routine laboratory testing and endoscopic biopsies or paracentesis. Patients with only mild diarrhea can be treated with antidiarrheal medications. More symptomatic patients are usually treated with corticosteroids.

Bedside sonographic control for positioning enteral feeding tubes: a controlled study in intensive care unit patients.

BACKGROUND AND STUDY AIM: The correct placement of an enteral feeding tube in the duodenum in critically ill patients is usually controlled radiographically. However, a direct bedside method that obviates the need for exposure to radiation would be preferable. The aim of this study was to demonstrate the usefulness of bedside sonographic position control for placing enteral feeding tubes in critically ill patients. PATIENTS AND METHODS: After placement of the enteral feeding tube, the position of the tip was determined using bedside transabdominal ultrasound. Native ultrasound was enhanced by injection of air bubbles into the feeding tube. The tube was regarded as being correctly positioned when the tube was visualized within the second or third parts of the duodenum. Plain abdominal radiographs with contrast served as the gold standard test. RESULTS: A total of 76 consecutive examinations were analyzed. In 12 patients, access to the upper abdominal wall was not possible because of open wounds; in another 13 patients who had undergone extensive abdominal surgery, the duodenum could not be identified and so no conclusion could be reached regarding the position of the tube. In 51/76 patients (67 %) ultrasound identified the duodenum and it was possible to determine the position of the tube (46 true positives and 2 true negatives); the position was incorrectly diagnosed in three patients. The sensitivity was 96 % (95 %CI 87 % - 98 %) and the specificity was 50 % (95 %CI 36 % - 65 %), with a positive predictive value of 94 %. CONCLUSIONS: Bedside sonographic control of the positioning of enteral feeding tubes is very sensitive and can be a valuable alternative to radiological control, especially in patients without open abdominal wounds, external installations, or extensive abdominal surgery.

Pneumocystis carinii pneumonia in chronic lymphocytic leukaemia.

Pneumocystis carinii pneumonia in patients with chronic lymphocytic leukaemia (CLL) who have not been treated with fludarabin are rare, although clinically relevant CD4 T-cell depletion can occur in longstanding CLL without prior treatment with purine analogues. A 52 year old woman is reported who was on long term treatment with chlorambucil and taking a short course of prednisone for familial CLL before she developed progressive dyspnoea, and P carinii pneumonia was diagnosed in bronchoalveolar lavage fluid. Despite treatment with high dose co-trimoxazole the patient died.

Efficacy of laser treatment of tattoos using lasers emitting wavelengths of 532 nm, 755 nm and 1064 nm.

BACKGROUND: Multifunctional laser devices can be used to treat tattoos successfully. OBJECTIVES: To report the efficacy of laser treatment in professional, amateur, accidental and permanent make-up tattoos from our own experience and to compare it with the literature. METHODS: We retrospectively studied 74 consecutive patients with professional, amateur, make-up and accidental tattoos between June 1998 and November 2000. Patients were treated with a Q-switched Nd:YAG laser (wavelengths of 532 nm and 1064 nm), a Q-switched alexandrite laser (755 nm) and a variable pulse Nd:YAG laser (532 nm). RESULTS: Fourteen patients (19%) achieved a complete response (>95% lightening of treated tattoos), 23 (31%) an excellent response (76-95% lightening) and 21 (28%) a good response (51-75% lightening). Sixteen patients (22%) showed only a slight improvement (< or =50% lightening). Make-up tattoos and blue-black professional tattoos were most successfully treated. Multicoloured professional tattoos needed more treatments (mean +/- SD 5.7 +/- 5.4) in comparison with single-colour tattoos (3.5 +/- 2.0). The amateur tattoos needed fewer treatments (2.8 +/- 1.1) in comparison with professional tattoos. With accidental tattoos the results depended on the particles which had penetrated the skin. In contrast to literature reports, newer tattoos showed a trend to better treatment results than older tattoos. CONCLUSIONS: Using modern Q-switched lasers, tattoos are removed successfully with minimal risk of scarring and permanent pigmentary alterations. Even multicoloured tattoos can be treated successfully and with a low rate of side-effects.

Pulmonary granulomas after tumour necrosis factor alpha antagonist therapy.

Tumour necrosis factor alpha (TNFalpha) antagonists are an established therapeutic option in Crohn's disease and rheumatoid arthritis. In recently published studies these agents have been used with great success, but little is known about any side effects or long term consequences. They increase the frequency of infections with mycobacteria, where TNFalpha is thought to be an important host defence factor. We describe one patient who was treated with TNFalpha antagonists and later developed pulmonary granulomas with caseating necrosis without detection of mycobacteria or any other pathogens. Possible mechanisms involved in this newly recognised side effect are discussed.

[Diabetic ketoacidosis and hyperosmolar hyperglycemia. 24 consecutive cases]. / Diabetische Ketoazidose und hyperosmolare Hyperglykämie - 24 konsekutive Fälle -

BACKGROUND: Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemia (HH) remain life-threatening complications of diabetes mellitus. Herein, we evaluated a standardized protocol for the therapy of acute hyperglycemic crises. PATIENTS AND METHODS: Retrospective study of patients treated in a medical intensive care unit for acute and severe hyperglycemia. Therapy was standardized according to internal guidelines effective for all treating physicians. RESULTS: 24 diabetic patients (11 men, 13 women, age 54 +/- 16 years, 11 DKA, 13 HH) were included into this study. All except one patient in the DKA-group had diabetes mellitus type 1. All patients with HH had diabetes mellitus type 2. Patients with DKA were significantly younger and complained more often about nausea and vomiting compared to the HH-group. Infections were the major cause for acute hyperglycemia followed by non-compliance. The arterial pH-value in the DKA-group was lower than in the HH-group (7,07 +/- 0,12 vs. 7,36 +/- 0,05). The length of stay in the intensive care unit was 1,8 +/- 1,2 days in patients with DKA and 2,2 +/- 1,2 days in patients with HH. The length of stay in the hospital was 11,5 +/- 5,9 days in patients with DKA and 18,3 +/- 10,9 days in patients with HH. No patient died during hospitalization. CONCLUSION: This study emphasizes the relevance of standardized written guidelines for the therapy of acute hyperglycemic crises in diabetic patients.

Contrast media triggering cutaneous graft-versus-host disease.

Adverse reactions to iodinated contrast media are varied and known to develop in patients with asthma and a history of allergy. We describe three successful allogeneic bone marrow transplantation (BMT) patients, who all developed dermal graft-versus-host disease (GVHD) after receiving contrast media. Cutaneous GVHD triggered by contrast media has not been reported to date and has implications for the assessment, monitoring and treatment of patients during the post-transplant period.