Michael Manz

Serum Protein Electrophoresis: An Underused but Very Useful Test

Serum protein electrophoresis is used in clinical practice to identify patients with multiple myeloma and other serum protein disorders. It is an inexpensive and easy-to-perform screening procedure. Electrophoresis separates serum proteins based on their physical properties and identifies morphologic patterns in response to acute and chronic inflammation, various malignancies, liver or renal failure, and hereditary protein disorders. For gastroenterologists, the use of serum protein electrophoresis may be helpful in the diagnosis of both common diseases with unusual presentations and rare disorders with typical presentations. Therefore, it represents an ideal screening tool.

Efficacy and safety of certolizumab pegol induction therapy in an unselected Crohn's disease population: Results of the FACTS survey†

Background: Switzerland was the first country to approve certolizumab pegol (Cimzia, CZP) for the treatment of patients with moderate to severe Crohns disease (CD) in September 2007. This phase IV study aimed to evaluate the efficacy and safety of CZP in a Swiss multicenter cohort of practice‐based patients. Methods: Baseline and Week 6 evaluation questionnaires were sent to all Swiss gastroenterologists in hospitals and private practices. Disease activity was assessed with the Harvey–Bradshaw Index (HBI) and adverse events were evaluated according to WHO guidelines. Results: Fifty patients (31 women, 19 men) were included; 56% had complicated disease (stricture or fistula) and 52% had undergone prior CD‐related surgery. All patients had prior exposure to systemic steroids, 96% to immunomodulators, 78% to infliximab, and 50% to adalimumab. A significant decrease in HBI was observed at Week 6 (versus Week 0) following induction therapy with CZP 400 mg subcutaneously at Weeks 0, 2, and 4 (12.6 ± 4.7 Week 0 versus 6.2 ± 4.4 Week 6, P < 0.001). Response and remission rates at Week 6 were 54% and 40%, respectively. We identified 8/11 CD patients undergoing a 50% fistula response (P = 0.021). The frequency of adverse drug reactions attributed to CZP was 6%. CZP was continued in 80% of patients beyond Week 6. Conclusions: In a population of CD patients with complicated disease behavior, CZP induced a response and remission in 54% and 40% of patients, respectively. This series provides the first evidence of the effectiveness of CZP in perianal fistulizing CD. Inflamm Bowel Dis 2010

First-Line Therapies in Inflammatory Bowel Disease

Background and Aims: Medical therapy of inflammatory bowel disease (IBD) is becoming more complex, given the increasing choice of drugs to treat Crohn’s disease (CD) and ulcerative colitis (UC). We aimed to summarize the current guidelines for first-line treatments in IBD. Methods: An extensive literature search with focus on the guidelines of the European Crohn’s and Colitis Organisation for the diagnosis and treatment of CD and UC was performed. First-line treatments were defined as the following drug categories: 5-aminosalicylates, budesonide, systemic steroids, azathioprine, 6-mercaptopurine, methotrexate, infliximab, adalimumab and certolizumab pegol. The following drug categories were not included: cyclosporine and tacrolimus (not yet approved by Swissmedic for IBD treatment). Results: Treatment recommendations for the following clinically frequent situations are presented according to disease severity: ileocecal CD, colonic CD, proximal small bowel CD and perianal CD. For UC the following situations are presented: ulcerative proctitis, left-sided colitis and pancolitis. Conclusions: We provide a summary on the use of first-line therapies for clinically frequent situations in patients with CD and UC.

Efficacy and safety of certolizumab pegol in an unselected crohn's disease population: 26-week data of the FACTS II survey†

Background: Certolizumab pegol (Cimzia, CZP) was approved for the treatment of Crohns disease (CD) patients in 2007 in Switzerland as the first country worldwide. This prospective phase IV study aimed to evaluate the efficacy and safety of CZP over 26 weeks in a multicenter cohort of practice‐based patients. Methods: Evaluation questionnaires at baseline, week 6, and week 26 were completed by gastroenterologists in hospitals and private practices. Adverse events were evaluated according to World Health Organization (WHO) guidelines. Results: Sixty patients (38F/22M) were included; 53% had complicated disease (stricturing or penetrating), 45% had undergone prior CD‐related surgery. All patients had prior exposure to systemic steroids, 96% to immunomodulators, 73% to infliximab, and 43% to adalimumab. A significant decrease of the Harvey‐Bradshaw Index (HBI) was observed under CZP therapy (12.2 ± 4.9 at week 0 versus 6.3 ± 4.7 at week 6 and 6.7 ± 5.3 at week 26, both P < 0.001). Response and remission rates were 70% and 40% (week 6) and 67% and 36%, respectively (week 26). The complete perianal fistula closure rate was 36% at week 6 and 55% at week 26. The frequency of adverse drug reactions attributed to CZP was 5%. CZP was continued in 88% of patients beyond week 6 and in 67% beyond week 26. Conclusions: In a population of CD patients with predominantly complicated disease behavior, CZP proved to be effective in induction and maintenance of response and remission. This series provides the first evidence of CZPs effectiveness in perianal fistulizing CD in clinical practice. (Inflamm Bowel Dis 2011;)

Therapy of steroid-resistant inflammatory bowel disease.

Background and Aims: Although systemic corticosteroids are successfully administered for the induction of clinical response and remission in the majority of patients with inflammatory bowel disease (IBD) presenting with a flare, a proportion of these patients demonstrate a primary nonresponse to steroids or in the case of an initial response, they develop a resistance or a steroid dependence. Long-term therapy with corticosteroids for treatment of IBD should be avoided, given the high frequency of adverse treatment effects. Knowledge about treatment strategies in case of steroid nonresponse is therefore highly relevant. Methods: A systematic literature research was performed using Medline and Embase to summarize the currently recommended treatment strategies for steroid-resistant IBD. Results: Treatment of steroid-resistant Crohn’s disease is based on the introduction of immunomodulators such as azathioprine, 6-mercaptopurine or methotrexate, the anti-TNF drugs infliximab, adalimumab and certolizumab pegol. In the case of steroid resistance in ulcerative colitis, aminosalicylates, the above-mentioned immunomodulators, infliximab, adalimumab or calcineurin inhibitors such as ciclosporin or tacrolimus may be administered. Conclusion: This review summarizes the current evidence for treating steroid-resistant IBD.

Topical therapies in inflammatory bowel disease.

Due to misunderstandings about their effectiveness and feasibility, topical (or rectal) therapies with aminosalicylates (5-aminosalicylic acid, 5-ASA) and steroids are often underused in patients with ulcerative colitis (UC). However, many of these patients could be treated solely with rectal/topical therapies, or could benefit from them in combination with oral therapies. We review the evidence for topical therapies containing 5-ASA and budesonide in UC and discuss how these therapies can be optimized in daily practice, thereby improving compliance. Finally, we provide a brief summary of studies on the use of other topical treatments in UC, the results of which were both promising and negative.

Monitoring colonoscopy withdrawal time significantly improves the adenoma detection rate and the performance of endoscopists.

BACKGROUND AND STUDY AIMS The recommended minimum withdrawal time for screening colonoscopy is 6 minutes. Adenoma detection rates (ADRs) increase with longer withdrawal times. We aimed to compare withdrawal times and ADRs of endoscopists unaware of being monitored vs. aware. PATIENTS AND METHODS Seven experienced gastroenterologists prospectively performed 558 screening colonoscopies during a 9-month period in a Swiss University hospital. Colonoscopy withdrawal times were first measured without the gastroenterologists’ knowledge of being monitored (n = 355 colonoscopies) and then with their knowledge (n = 203 colonoscopies). RESULTS The median withdrawal time when gastroenterologists were unaware of being monitored was 4.5 minutes (interquartile range [IQR] 4 – 5.5 minutes) without intervention and 6 minutes (IQR 4 – 9 minutes) with intervention, increasing significantly to 7.3 minutes (IQR 6.5 – 9 minutes) and 8 minutes (IQR 7 – 11 minutes), respectively, when they were aware of being monitored (P < 0.001 both for colonoscopies with and without intervention). The ADR increased from 21.4 % when the gastroenterologists were unaware of being monitored to 36.0 % when they were aware (P < 0.001). In the multivariate regression model, the endoscopists knowing they were being monitored was the strongest factor associated with ADR (odds ratio 4.417; 95 % confidence interval [CI] 2.241 – 8.705; P < 0.001). CONCLUSIONS Colonoscopy withdrawal time in unmonitored gastroenterologists is shorter than recommended and increases with awareness of monitoring. ADR significantly increases when gastroenterologists are aware of being monitored. Implementation of systematic monitoring, and analysis of withdrawal time and ADR for each endoscopist may help to increase the ADR.

Treatment algorithm for moderate to severe ulcerative colitis

The care for a patient with ulcerative colitis (UC) remains challenging despite the fact that morbidity and mortality rates have been considerably reduced during the last 30 years. The traditional management with intravenous corticosteroids was modified by the introduction of ciclosporin and infliximab. In this review, we focus on the treatment of patients with moderate to severe UC. Four typical clinical scenarios are defined and discussed in detail. The treatment recommendations are based on current literature, published guidelines and reviews, and were discussed at a consensus meeting of Swiss experts in the field. Comprehensive treatment algorithms were developed, aimed for daily clinical practice.

Deregulation of transcription factors controlling intestinal epithelial cell differentiation; a predisposing factor for reduced enteroendocrine cell number in morbidly obese individuals

Morbidly obese patients exhibit impaired secretion of gut hormones that may contribute to the development of obesity. After bariatric surgery there is a dramatic increase in gut hormone release. In this study, gastric and duodenal tissues were endoscopically collected from lean, and morbidly obese subjects before and 3 months after laparoscopic sleeve gastrectomy (LSG). Tissue morphology, abundance of chromogranin A, gut hormones, α-defensin, mucin 2, Na+/glucose co-transporter 1 (SGLT1) and transcription factors, Hes1, HATH1, NeuroD1, and Ngn3, were determined. In obese patients, the total number of enteroendocrine cells (EEC) and EECs containing gut hormones were significantly reduced in the stomach and duodenum, compared to lean, and returned to normality post-LSG. No changes in villus height/crypt depth were observed. A significant increase in mucin 2 and SGLT1 expression was detected in the obese duodenum. Expression levels of transcription factors required for differentiation of absorptive and secretory cell lineages were altered. We propose that in obesity, there is deregulation in differentiation of intestinal epithelial cell lineages that may influence the levels of released gut hormones. Post-LSG cellular differentiation profile is restored. An understanding of molecular mechanisms controlling epithelial cell differentiation in the obese intestine assists in the development of non-invasive therapeutic strategies.

Limited value of fecal calprotectin in patients with liver cirrhosis

Fecal calprotectin (FC) is an established biological marker of colonic inflammation [1] that is also useful to detect peptic lesions in the upper intestinal tract [2,3]. However, little is known about the value of FC in patients with liver cirrhosis. In one report, higher FC levels have been found with increasing Child– Pugh classification [4]. Elevation of portal pressure may change intestinal hemodynamics and render the mucosa more vulnerable to damage. Patients with liver cirrhosis are therefore at higher risk for peptic mucosal lesions. However, the ability of FC to detect mucosal lesions in the upper intestinal tract in cirrhotic patients has never been systematically examined. Accordingly, we aimed to investigate the diagnostic value of FC in patients with liver cirrhosis. In 55 consecutive patients with liver cirrhosis (25 alcoholic, 16 viral hepatitis, 8 non-alcoholic steatohepatitis, 3 primary biliary cirrhosis, 1 each hemochromatosis, antitrypsin deficiency and cryptogenic cirrhosis; 43 Child A, 12 Child B), FC levels were measured in stool samples collected within 24 h before esophagogastrojejunoscopy (EGD) using an enzyme-linked immunosorbent assay (Bühlmann AG, Schönenbuch, Switzerland). EGD was done for esophageal varices in 44 patients, for epigastric pain in 5 patients, in 2 patients to rule out gastric cancer and in 1 each for reflux, dysphagia, irondeficiency anemia and diarrhea. If EGD was normal but calprotectin values elevated (>50 mg/g), patients received colonoscopy (20 colonoscopies, 36% of all patients). The final diagnoses were adjudicated blinded to FC levels. The local ethics committee approved the study and all patients provided written informed consent. The presence of a peptic lesion in the upper GI tract was the primary end point. Among the study population, patients with peptic lesions (45%) had higher FC levels than patients without (p = 0.02, Table I). No correlation existed between the occurrence of peptic lesions and the presence of portal hypertension (p = 0.84) or higher Child–Pugh class (p = 0.31). Receiver operating characteristics curve for FC to identify peptic lesions showed an area under the curve (AUC) of 0.69 (95% CI 0.55– 0.80) with an optimal cut-off at 64 mg/g.Using this cutoff yielded a sensitivity of 80% and a specificity of 67% with positive and negative likelihood ratios of 2.4 (95% CI 1.7–3.3) and 0.19 (95% CI 0.1–0.8), respectively. The overall accuracy of the test was 73%. Patients with liver cirrhosis often have important comorbidities and EGD should be performed only if necessary. Unfortunately, patient selection for endoscopy based on symptoms is not reliable [5,6] and therefore a non-invasive test such as FC would be clinically useful. In our study, patients with peptic lesion had higher FC levels. However, compared with patients with normal liver function [3], FC in cirrhotic patients did not reliably identify mucosal lesions in the upper intestinal tract. In conclusion, our study shows that the diagnostic value of FC to detect mucosal lesions in patients with liver cirrhosis is only moderate.