Microscopic colitis in Denmark and Sweden: incidence, putative risk factors, histological assessment and endoscopic activity.

OBJECTIVE: The significantly higher incidence rates of microscopic colitis (MC) in Denmark compared to Sweden remains unexplained. METHODS: Consecutive patients with newly diagnosed MC in the neighbouring regions of Skåne in 2011-2015 and Zealand in 2010-2016 were prospectively identified. Data on large bowel endoscopies and biopsies rates were retrieved. Information on putative factors were obtained from registers and literature. Interobserver agreement between pathologists from both regions on 40 blinded hematoxylin and eosin (H&E)-stained colon biopsies (collagenous colitis (CC), lymphocytic colitis (LC), non-specific inflammation and normal) was evaluated using kappa statistics. RESULTS: The mean annual incidence per 105 inhabitants in Skåne and Zealand 2010-2015 was 5.9 (95% CI 4.6-7.3) versus 16.4 (95% confidence intervals (95% CI) 13.6-19.2) for CC and 2.7 (95% CI 1.0-4.3) versus 11.1 (95% CI 8.8-13.4) for LC, respectively. Number of endoscopies with biopsy per 1000 and the rate of MC per endoscopy with biopsy was higher in Zealand (34-52/1000) than in Skåne (12-21/1000). The kappa value for overall agreement between pathologists was good (0.72; 95% CI 0.64-0.79). Prescription of proton pump inhibitors and selective serotonin reuptake inhibitors was higher in Skåne in the relevant age groups and prescription of non-steroidal anti-inflammatory drugs and smoking rate higher in Zealand. Alcohol consumption was higher in Denmark than in Sweden. CONCLUSION: The incidence of MC and number of cases per colonic biopsy was higher in Zealand and could not be readily explained by endoscopy or biopsy rates, differences in histological assessment or putative risk factors.

Individualized Therapy Is a Long-Term Cost-Effective Method Compared to Dose Intensification in Crohn's Disease Patients Failing Infliximab.

BACKGROUND: In Crohn's disease patients failing infliximab therapy, interventions defined by an algorithm based on infliximab and anti-infliximab antibody measurements have proven more cost-effective than intensifying the infliximab regimen. AIM: This study investigated long-term economic outcomes at the week 20 follow-up study visit and after 1 year. Clinical outcomes were assessed at week 20. METHODS: Follow-up from a 12-week, single-blind, clinical trial where patients with infliximab treatment failure were randomized to infliximab intensification (5 mg/kg every 4 weeks) (n = 36), or algorithm-defined interventions (n = 33). Accumulated costs, expressed as mean costs per patient, were based on the Danish National Patient Registry. RESULTS: At the scheduled week 20 follow-up study visit, response and remission rates were similar in all study subpopulations between patients treated by the algorithm or by infliximab intensification. However, the sum of healthcare costs related to Crohn's disease was substantially lower (31 %) for patients randomized to algorithm-based interventions than infliximab intensification in the intention-to-treat population: $11,940 versus $17,236; p = 0.005. For per-protocol patients (n = 55), costs at the week 20 follow-up visit were even lower (49 %) in the algorithm group: $8,742 versus $17,236; p = 0.002. Figures were similar for patients having completed the 12-week trial as per protocol (50 % reduction in costs) (n = 45). Among patients continuing the allocated study intervention throughout the entire 20-week follow-up period (n = 29), costs were reduced by 60 % in algorithm-treated patients: $7,056 versus $17,776; p < 0.001. Cost-reduction percentages remained stable throughout one year. CONCLUSION: Economic benefit of algorithm-based interventions at infliximab failure is maintained throughout 1 year.

Course of Disease in Patients with Microscopic Colitis: A European Prospective Incident Cohort Study.

BACKGROUND AND AIMS: The disease course of microscopic colitis [MC] is considered chronic but benign. However, this assumption is based on mainly retrospective studies, reporting on incomplete follow-up of selective cohorts. Systematic, prospective and unbiased data to inform patients and healthcare professionals on the expected course of the disease and real-life response to therapy are warranted. METHODS: A prospective, pan-European, multi-centre, web-based registry was established. Incident cases of MC were included. Data on patient characteristics, symptoms, treatment and quality of life were systematically registered at baseline and during real-time follow-up. Four disease course phenotypes were discriminated and described. RESULTS: Among 381 cases with complete 1-year follow-up, 49% had a chronic active or relapsing disease course, 40% achieved sustained remission after treatment and 11% had a quiescent course. In general, symptoms and quality of life improved after 3 months of follow-up. A relapsing or chronic active disease course was associated with significantly more symptoms and impaired quality of life after 1 year. CONCLUSIONS: A minority of MC patients follow a quiescent disease course with spontaneous clinical improvement, whereas the majority suffer a chronic active or relapsing disease course during the first year after diagnosis, with persisting symptoms accompanied by a significantly impaired quality of life.

European guidelines on microscopic colitis: United European Gastroenterology and European Microscopic Colitis Group statements and recommendations.

INTRODUCTION: Microscopic colitis is a chronic inflammatory bowel disease characterised by normal or almost normal endoscopic appearance of the colon, chronic watery, nonbloody diarrhoea and distinct histological abnormalities, which identify three histological subtypes, the collagenous colitis, the lymphocytic colitis and the incomplete microscopic colitis. With ongoing uncertainties and new developments in the clinical management of microscopic colitis, there is a need for evidence-based guidelines to improve the medical care of patients suffering from this disorder. METHODS: Guidelines were developed by members from the European Microscopic Colitis Group and United European Gastroenterology in accordance with the Appraisal of Guidelines for Research and Evaluation II instrument. Following a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the certainty of the evidence. Statements and recommendations were developed by working groups consisting of gastroenterologists, pathologists and basic scientists, and voted upon using the Delphi method. RESULTS: These guidelines provide information on epidemiology and risk factors of microscopic colitis, as well as evidence-based statements and recommendations on diagnostic criteria and treatment options, including oral budesonide, bile acid binders, immunomodulators and biologics. Recommendations on the clinical management of microscopic colitis are provided based on evidence, expert opinion and best clinical practice. CONCLUSION: These guidelines may support clinicians worldwide to improve the clinical management of patients with microscopic colitis.

Risk of osteoporosis in microscopic colitis.

OBJECTIVES: Patients with microscopic colitis (MC) have several risk factors for osteoporosis. The prevalence of osteopenia and osteoporosis in MC is unknown. The primary purpose of this study was to evaluate bone mineral status in MC. METHODS: Patients with MC and disease activity within the last 2 years were included. Bone turnover markers were analyzed and bone mineral density (BMD) was measured with Dual Energy X-ray Absorptiometry (DXA) at inclusion and after one year. Medical history, demographics, risk factors for osteoporosis, disease activity and treatment with cumulative budesonide dosage at least 3 years before inclusion was registered. Adrenal function was tested by adrenocortico-tropic hormone (ACTH) and an ACTH stimulation test at inclusion. Results were compared with age and sex-matched controls. RESULTS: Fifty MC patients (44 women) were included. Median age 67 (range 45-93); median disease duration 28 month (range 2-163); median cumulative budesonide dosage 702 mg (range 0-5400). No difference in number of patients with osteoporosis or osteopenia and BMD was detected between groups. The bone mineral formation marker specific alkaline phosphatase was lower in MC than controls 12 (5-69) µg/l versus 16 (10-35) µg/l (p < 0.005). Patients more often smoked (34% versus 10%, p = 0.001). Disease duration and cumulative budesonide dose was associated with lower BMD and T-score in hip (Spearman's rho; p < 0.05) with a cut of point of 2500 mg budesonide predicting osteopenia. Budesonide treatment did not affect adrenal gland function. CONCLUSION: The risk of osteoporosis in patients with MC is not increased. However, DXA scan is recommended in MC patients with known risk factors or active disease requiring longstanding budesonide treatment. Supplementation of calcium and vitamin-D in patients treated with budesonide is recommended.

Probiotic treatment of collagenous colitis: a randomized, double-blind, placebo-controlled trial with Lactobacillus acidophilus and Bifidobacterium animalis subsp. Lactis.

BACKGROUND: Probiotic treatment may be effective in diseases involving gut microflora and intestinal inflammation. In collagenous colitis (CC), a potential pathogenic role of the gut microflora has been proposed. The effect of probiotic treatment in CC is unknown. Our aim was to investigate the clinical effect of treatment with Lactobacillus acidophilus LA-5 and Bifidobacterium animalis subsp. lactis BB-12 (AB-Cap-10) in patients with CC. MATERIALS AND METHODS: Patients with CC and diarrhea were in a double-blind placebo-controlled study randomized (2:1) to AB-Cap-10 or placebo for 12 weeks. The primary end point was reduction in bowel frequency per week of >or=50%. Secondary end points were changes in bowel frequencies, stool consistency, stool weight, histopathology, and abdominal bloating and pain. RESULTS: Twenty-nine patients were randomized: 21 to probiotics and 8 to placebo. Reduction in bowel frequency per week of >or=50% occurred in 6 of 21 (29%) and in 1 of 8 (13%) patients receiving probiotic and placebo, respectively (P = 0.635). No differences between treatments were observed regarding the secondary end points. Post hoc analysis showed a median reduction in bowel frequency per week from 32 (range 18-84) to 23 (range 11-56; P < 0.005), a reduction in number of days with liquid stools per week from 6 days (range 0-7 days) to 1 day (range 0-7 days; P < 0.005), and an increase in number of days with solid stools per week (P < 0.05) in the AB-Cap-10 group. CONCLUSIONS: AB-Cap-10 had no significant effect on the chosen end points. Post hoc analysis demonstrated amelioration of clinical symptoms in the AB-Cap-10 group, indicating that probiotic treatment may potentially influence the disease course of CC.

Implications of Infliximab Treatment Failure and Influence of Personalized Treatment on Patient-reported Health-related Quality of Life and Productivity Outcomes in Crohn's Disease.

BACKGROUND: This study assessed the effects of infliximab (IFX) treatment failure on patient-reported outcomes and explored the influence of using personalized treatment in this situation. METHODS: Sixty-nine Crohn's disease patients with IFX treatment failure were randomized to an intensified IFX regimen (n = 36) or personalized treatment defined by IFX and anti-IFX antibodies (n = 33). Health-related quality of life evaluated with the Short Inflammatory Bowel Disease Questionnaire (IBDQ) and productivity evaluated with the Work Productivity and Activity Impairment Questionnaire (WPAI:CD) were assessed at treatment failure and after 4, 8, 12 and 20 weeks. RESULTS: Median IBDQ score at manifestation of IFX treatment failure was 40 and improved markedly in responders by 11 at weeks 4 and 8 (p < 0.001) and by 13 at weeks 12 and 20 (p < 0.001). Non-responders improved modestly at weeks 12 and 20 (increase of median 4, p < 0.05). Overall activity impairment was high at IFX failure (median 70%) and decreased substantially in responders (40-50%, p < 0.001) and to a lesser extent in non-responders (15-40%, p < 0.05). In employed patients (55%), absenteeism was negligible during the entire study period. However, median presenteeism was 40% at manifestation of IFX failure and decreased only among responders across time (decrease 10-30%, p < 0.05). Although anti-tumour necrosis factor (TNF) therapy was discontinued in most patients handled by personalized treatment, IBDQ and WPAI:CD scores were similar in these patients compared with patients routinely dose-intensified on IFX. CONCLUSION: Regaining low disease activity after IFX failure is necessary for minimizing patient impairment and indirect disease-related costs. A personalized treatment strategy does not have a negative influence on patient-reported outcomes.

Changes in serum trough levels of infliximab during treatment intensification but not in anti-infliximab antibody detection are associated with clinical outcomes after therapeutic failure in Crohn's disease.

BACKGROUND AND AIMS: Intensification of the infliximab (IFX) regimen is recommended if the treatment effect is inadequate. However, the rationale for this is not well defined as the underlying mechanisms vary. The aim of this study was to explore the association between changes in serum IFX and anti-IFX antibodies (Abs) after IFX intensification and clinical outcomes. METHODS: We performed a post hoc analysis of a randomized clinical trial including 42 Crohn's disease patients with IFX treatment failure, all treated with an intensified IFX regimen (5mg/kg every 4 week) for 12 weeks. Trough serum IFX and anti-IFX Ab concentrations were measured by a homogeneous mobility shift binding assay (HMSA) and a functional cell-based reporter gene assay (RGA) at treatment failure and the end of the trial. RESULTS: Twenty-one patients (50%) regained clinical response on the intensified IFX regimen. The increase in serum trough levels of IFX during treatment intensification was higher among responders than non-responders (RGA, 8.8 versus 3.0 µg/mL, p = 0.035; HMSA, 9.9 versus 4.7 µg/mL, p = 0.040), and differentiated patients by clinical outcome (RGA, area under receiver operating characteristic curve [AUC] 0.75 [0.53-0.97], p = 0.035; HMSA, AUC 0.74 [0.53-0.95], p = 0.042). All responders exhibited an IFX increase ≥2.6 µg/mL (sensitivity 100%, specificity 50%). Anti-IFX Abs detected by HMSA in 13 patients (32%) were often non-functional and became undetectable during IFX intensification. However, even functional anti-IFX Abs detected by RGA in six patients (15%) became undetectable. CONCLUSION: Increase in IFX levels following treatment intensification was associated with improved clinical outcomes, indicating insufficient drug levels in a subgroup of patients. Anti-IFX Abs may become undetectable during treatment intensification, suggesting lowered production or the formation of immune complexes.

The use of shared medication record as part of medication reconciliation at hospital admission is feasible.

INTRODUCTION: Medication reconciliation improves congruence in cross sectional patient courses. Our regional electronic medical record (EMR) integrates the shared medication record (SMR) which provides full access to current medication and medication prescriptions for all citizens in Denmark. We studied whether our SMR integration could facilitate medication reconciliation. MATERIAL AND METHODS: Patients admitted to the emergency department for hospitalization were randomised to consultation using EMR with or without the integrated SMR access. Observed time used for medication reconciliation was the primary efficacy parameter. RESULTS: A total of 62 consecutive patient consultations were randomised including 39 with more than five prescriptions. EMR had data from previous consultations for 46 patients, 59 patients provided information on medication. In all, 18 junior physicians in early postgraduate medical training each participated with a median of three consultations (range 1-9). Time expenditure for medicine reconciliation was 5:27 min.:sec. (range: 2:00-15:37) with access to SMR integration and 4:15 min.:sec. (1:15-12:00) without SMR access. The number of active medicine prescriptions was eight and nine, respectively. Incorporating SMR did not increase the work load. Physicians judged the SMR integration and workflow as being useful. Patients unambiguously sup-ported physicians' use of SMR in this setting. CONCLUSION: Integration of information on individuals' medication from a national SMR into a hospital EMR was feasible and useful, and it did not increase time expenditure for medication reconciliation. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

Drug insight: aminosalicylates for the treatment of IBD.

Sulfasalazine and mesalazine (also known as mesalamine; 5-aminosalicylic acid) preparations have for many years been used for the treatment of IBD (i.e. ulcerative colitis and Crohn's disease), for both active disease and the control of remission. It has also been suggested that mesalazine is a chemoprophylactic agent that protects against the development of colorectal cancer. This Review focuses on the latest clinical evidence for the use of these aminosalicylates for the treatment of IBD, and concludes that sulfasalazine and mesalazine are useful for the treatment of both active and quiescent ulcerative colitis, whereas they have no clinical effect on either active or inactive Crohn's disease. Furthermore, evidence is lacking that mesalazine per se is a chemoprophylactic agent.

H+/amino acid transporter 1 (PAT1) is the imino acid carrier: An intestinal nutrient/drug transporter in human and rat.

BACKGROUND AND AIMS: Amino acid (and related drug) absorption across the human small intestinal wall is an essential intestinal function. Despite the revelation of a number of mammalian genomes, the molecular identity of the classic Na(+)-dependent imino acid transporter (identified functionally in the 1960s) remains elusive. The aims of this study were to determine whether the recently isolated complementary DNA hPAT1 (human proton-coupled amino acid transporter 1), or solute carrier SLC36A1, represents the imino acid carrier; the Na(+) -dependent imino acid transport function measured at the brush-border membrane of intact intestinal epithelia results from a close functional relationship between human proton-coupled amino acid transporter-1 and N(+) /H(+) exchanger 3 (NHE3). METHODS: PAT1 function was measured in isolation ( Xenopus laevis oocytes) and in intact epithelia (Caco-2 cell monolayers and rat small intestine) by measurement of amino acid and/or H(+) influx. Tissue and membrane expression of PAT1 were determined by reverse-transcription polymerase chain reaction and immunohistochemistry. RESULTS: PAT1-specific immunofluorescence was localized exclusively to the luminal membrane of Caco-2 cells and human and rat small intestine. The substrate specificity of hPAT1 is identical to that of the imino acid carrier. In intact epithelia, PAT1-mediated amino acid influx is reduced under conditions in which NHE3 is inactive. CONCLUSIONS: The identification in intact epithelia of a cooperative functional relationship between PAT1 (H(+) /amino acid symport) and NHE3 (N(+) /H(+) exchange) explains the apparent Na + dependence of the imino acid carrier in studies with mammalian intestine. hPAT1 is the high-capacity imino acid carrier localized at the small intestinal luminal membrane that transports nutrients (imino/amino acids) and orally active neuromodulatory agents (used to treat affective disorders).