Bernd Bokemeyer

Azathioprine-induced Acute Pancreatitis in Patients with Inflammatory Bowel Diseases--A Prospective Study on Incidence and Severity.

Background and Aims: Azathioprine [AZA] is recommended for maintenance of steroid-free remission in inflammatory bowel disease IBD. The aim of this study has been to establish the incidence and severity of AZA-induced pancreatitis, an idiosyncratic and major side effect, and to identify specific risk factors. Methods: We studied 510 IBD patients [338 Crohn’s disease, 157 ulcerative colitis, 15 indeterminate colitis] with initiation of AZA treatment in a prospective multicentre registry study. Acute pancreatitis was diagnosed in accordance with international guidelines. Results: AZA was continued by 324 [63.5%] and stopped by 186 [36.5%] patients. The most common cause of discontinuation was nausea [12.2%]. AZA-induced pancreatitis occurred in 37 patients [7.3%]. Of these: 43% were hospitalised with a median inpatient time period of 5 days; 10% had peripancreatic fluid collections; 24% had vomiting; and 14% had fever. No patient had to undergo nonsurgical or surgical interventions. Smoking was the strongest risk factor for AZA-induced acute pancreatitis [p < 0.0002] in univariate and multivariate analyses. Conclusions: AZA-induced acute pancreatitis is a common adverse event in IBD patients, but in this study had a mild course in all patients. Smoking is the most important risk factor.

Mesalazine in left-sided ulcerative colitis: Efficacy analyses from the PODIUM trial on maintenance of remission and mucosal healing

BACKGROUND AND AIMnLeft-sided colitis is the most prevalent subtype of ulcerative colitis, a chronic inflammatory disease of the colon. The standard of care for mild-to-moderate ulcerative colitis is mesalazine. The PODIUM study compared a once daily to a twice daily dosing regimen of a slow-release mesalazine (Pentasa®); here we assess the efficacy, in terms of maintenance of remission and mucosal healing, of both regimens in patients with left-sided disease.nnnPATIENTS AND METHODSnEligible patients were randomised to once daily (1×2 g) or twice daily (2×1 g) oral treatment with mesalazine, for 12 months. Disease activity was assessed clinically and endoscopically at baseline and at 12 months using the Ulcerative Colitis Disease Activity Index, without endoscopic assessment at months 4 and 8.nnnRESULTSnThe study met the primary endpoint of non-inferiority in terms of remission, for once daily versus twice daily dosing, in patients with left-sided ulcerative colitis; an 8% difference was reported in the 12-month clinical and endoscopic remission rates (69% [95% CI: 59.5-76.5] and 61% [95% CI: 51.4-69.6] with once daily and twice daily dosing, respectively; p=0.310). Mucosal healing scores after 12 months were 0 or 1 for 84.4% of the once daily and 78.8% of the twice daily population. Slow-release mesalazine was well tolerated in both dosing regimens, with no difference in reported adverse events.nnnCONCLUSIONSnOnce daily slow-release mesalazine is similarly effective to the standard twice daily schedule in patients with left-sided ulcerative colitis for the maintenance of remission in mild-to-moderate disease.

Parameters of a severe disease course in ulcerative colitis

AIMnTo detect high risk patients with a progressive disease course of ulcerative colitis (UC) requiring immunosuppressive therapy (IT).nnnMETHODSnA retrospective, multicenter analysis of 262 UC patients from eight German tertiary inflammatory bowel disease centres was performed. Patients were divided into two groups depending on the patients need to initiate immunosuppressive therapy in the disease course. A comparison between the two groups was made with regard to demographics, clinical and laboratory parameters obtained within three months after UC diagnosis and the response to first medical therapy. Using this data, a prognostic model was established to predict the individual patients probability of requiring an immunosuppressive therapy.nnnRESULTSnIn 104 (39.7%) out of 262 patients, UC therapy required an immunosuppressive treatment. Patients in this group were significantly younger at time of diagnosis (HR = 0.981 ± 0.014 per year, P = 0.009), and required significantly more often a hospitalisation (HR = 2.5 ± 1.0, P < 0.001) and a systemic corticosteroid therapy at disease onset (HR = 2.4 ± 0.8, P < 0.001), respectively. Response to steroid treatment was significantly different between the two groups of patients (HR = 5.2 ± 3.9 to 50.8 ± 35.6 compared to no steroids, P = 0.016 to P < 0.001). Furthermore, in the IT group an extended disease (HR = 3.5 ± 2.4 to 6.1 ± 4.0 compared to proctitis, P = 0.007 to P = 0.001), anemia (HR = 2.2 ± 0.8, P < 0.001), thrombocytosis (HR = 1.9 ± 1.8, P = 0.009), elevated C-reactive protein (CRP) (HR = 2.1 ± 0.9, P < 0.001), and extraintestinal manifestations in the course of disease (HR = 2.6 ± 1.1, P = 0.004) were observed. Six simple clinical items were used to establish a prognostic model to predict the individual risk requiring an IT. This probability ranges from less than 2% up to 100% after 5 years. Using this, the necessity of an immunosuppressive therapy can be predicted in 60% of patients. Our model can determine the need for an immunosuppressive drug therapy or if a watch and wait approach is reasonable already early in the treatment course of UC.nnnCONCLUSIONnUsing six simple clinical parameters, we can estimate the patients individual risk of developing a progressive disease course.

Predictors for subsequent need for immunosuppressive therapy in early Crohn's disease

BACKGROUND AND AIMSnThe clinical course of Crohns disease (CD) is highly variable with a subgroup of patients developing a progressive disease course necessitating immunosuppressive therapy (IT). However, reliable, stable and non-invasive individual clinical parameters in order to identify patients at risk for undergoing subsequent IT have not been sufficiently established. We therefore aimed to identify such clinical parameters.nnnMETHODSnA retrospective, multicenter analysis of CD patients from 6 German tertiary IBD centers was performed. Patients were classified into two groups depending on requiring IT or not. Personal data, clinical and laboratory parameters during the first 3 months after CD diagnosis and effects of initial medical therapy were compared between these two groups.nnnRESULTSnIn 218 (61.8%) of the 353 patients the CD course necessitated IT. Those patients were significantly younger at symptom onset and diagnosis, and required significantly more often a systemic corticosteroid therapy. Furthermore, significant differences in serological markers of inflammation were observed. Age, gender and the effect of initial steroid therapy were used to develop a prognostic model predicting the individual probability of necessitating IT.nnnCONCLUSIONSnThe simple clinical items age at diagnosis, gender, and need for systemic steroid therapy can predict a progressive disease course in early CD. Our model based on these parameters allows an individualized estimation of each patients risk to develop a progressive disease course. Thereby, our model can help in deciding if patients will need immunosuppressive drugs early in the disease course or if a careful watch and wait strategy is justified.

Predictive factors for sustained virological response after treatment with pegylated interferon α-2a and ribavirin in patients infected with HCV genotypes 2 and 3.

Background Previous trials have often defined genotype 2 and 3 patients as an “easy to treat” group and guidelines recommend similar management. Aims The present study looks for differences between the two genotypes and analyzes predictive factors for SVR. Methods Prospective, community-based cohort study involving 421 physicians throughout Germany. The analysis includes 2,347 patients with untreated chronic HCV genotype 2 (nu200a=u200a391) and 3 (nu200a=u200a1,956) infection treated with PEG-IFN α-2a plus ribavirin between August 2007 and July 2012. Results When compared with genotype 2 patients, those with genotype 3 were younger, had a shorter duration of infection, lower values of total cholesterol, LDL cholesterol and BMI, a higher frequency of drug use as infection mode and male gender (p<0.0001, respectively), and a higher APRI score (p<0.005). SVR was higher in genotype 2 when compared with genotype 3 (64.7% vs. 56.9%, pu200a=u200a0.004). By multivariate analysis of genotype 2 patients, low baseline γ -GT and RVR predicted SVR. In genotype 3 age ≤45 years, cholesterol>130 mg/dl, a low APRI score, and a γ-GT ≥3-times ULN, RVR, and RBV starting dose were associated with SVR by multivariate analysis. Conclusions The present study corroborates that liver fibrosis is more pronounced in genotype 3 vs. 2. SVR is higher in genotype 2 versus genotype 3 partly because of follow-up problems in genotype 3 patients, in particular in those infected by drug use. Thus, subgroups of genotype 3 patients have adherence problems and need special attention also because they often have significant liver fibrosis. Trial Registration Verband Forschender Arzneimittelhersteller e.V., Berlin, Germany ML21645 ClinicalTrials.gov NCT02106156

Randomized Open-Label Phase 1 Study of the Pharmacokinetics of Ferric Maltol in Inflammatory Bowel Disease Patients with Iron Deficiency

BackgroundIron deficiency anemia (IDA) is a common complication of inflammatory bowel disease (IBD). Oral ferric maltol improves and normalizes hemoglobin (Hb) in patients with IBD.AimThis open-label, randomized Phase 1 study evaluated the pharmacokinetics of ferric maltol and its effect on iron indices in IBD patients with iron deficiency (with or without anemia).MethodsIron deficient adult IBD patients received ferric maltol 30, 60, or 90xa0mg twice daily during an 8-day period. Pharmacokinetics and iron uptake were assessed on days 1 and 8.ResultsTwenty-four patients were included: 13 with Crohn’s disease and 11 with ulcerative colitis (mean age 39xa0years; 67xa0% female, mean Hb 13.0xa0g/dL; mean reticulocyte Hb content (CHr) 31.9xa0pg; mean ferritin 13.9xa0µg/L). Plasma maltol and maltol glucuronide increased rapidly at all doses, reaching maximum plasma concentration (Cmax) 1.0–1.5xa0h post-dose and declining to baseline after 3–6xa0h. Maltol and maltol glucuronide exposure (area under the concentration–time curve; AUC) appeared dose proportional with twice-daily dosing, with higher exposure to maltol glucuronide vs. maltol. Mean day 8/day 1 ratios for Cmax and AUC0–t indicated no accumulation after 7xa0days of twice-daily dosing. Serum iron and transferrin saturation (TSAT) increased with all doses (maximum values at 1.5–3.0xa0h post-dose). Serum ferritin and CHr increased by day 8, with greater improvements with 60 and 90xa0mg twice-daily doses than with 30xa0mg twice-daily doses.ConclusionsThe key constituents of ferric maltol showed predictable pharmacokinetics, with no accumulation over 7xa0days and increased iron uptake and storage over time at 30–90xa0mg twice-daily doses.

Quality of care in inflammatory bowel disease: results of a prospective controlled cohort study in Germany (NET IBD )

Background/aims Patients with inflammatory bowel disease (IBD) need comprehensive, interdisciplinary and cross-sectoral health care. In Germany, evidence-based care pathways have been developed to improve the quality of care of IBD patients. We aimed to evaluate the effects of the implementation of some of these recommendations on patient-related outcomes. Methods In a region of North Germany, outpatients with IBD were recruited by gastroenterologists (intervention group). Three activities based on the recommendations of the IBD pathways were implemented, namely, 1) patient participation in a questionnaire-based assessment of 22 somatic and psychosocial problems combined with individualized care recommendations (patient activation procedure); 2) patient invitation to participate in a 2-day patient education program and 3) invitation to their gastroenterologists to participate in periodic interdisciplinary case conferences. For the control group, IBD patients receiving standard care at gastroenterology practices outside the specified region were recruited by their doctors. At baseline, 6- and 12-month follow-up, study patients were invited to complete questionnaires. Generic health-related quality of life, social participation and self-management skills were the main outcomes. Results At baseline, 349 patients were included in the study (intervention group: 189; control group: 160); 142 patients from the former and 140 from the latter group returned completed questionnaires at the 12-month follow-up. Over time, improvement in health-related quality of life and social participation was similar in both groups. Participants of the intervention group demonstrated improved self-management skills and more often followed steroid-free medication regimens. Conclusion In a real-world clinical context, patient activation procedure combined with patient education and case conferences was less effective than expected. The observed beneficial effects, however, encourage the evaluation of more intensive and addressee-centered activities.

Biosimilars bei „Chronisch Entzündlichen Darmerkrankungen (CED)“: Erfahrungen und Einschätzungen deutscher Gastroenterologen

The European Medicines Agency (EMA) recently approved the first anti-TNF-alpha biosimilar for infliximab (CT-P13) (trade names: Inflectra® and Remsima®) in Germany. Over the past year, German gastroenterologists gained experience treating IBD-patients with infliximab biosimilars (IFX-biosimilars). To evaluate their experiences and opinions on biosimilars, we conducted a nationwide online survey among German gastroenterologists. Our results are based on the assessment of 449 questionnaires. Although 61u200a% of the participants had already prescribed IFX-biosimilars, about two thirds of these participating gastroenterologists with IFX-biosimilar prescription stated their experience as based on fewer than 10 IBD-patients treated with IFX-biosimilars. Only 15u200a% considered themselves to be very experienced with biosimilars. The lower price in comparison to the originator is seen as the most important advantage of biosimilars (71u200a%). More than two thirds of the survey participants requested specific gastroenterological trials and registries to increase the data available on biosimilars in IBD-patients (68u200a%).

Azathioprine allows glucocorticoid withdrawal – post hoc results of a prospective study in patients with inflammatory bowel diseases

Backgroundu2002Azathioprine is recommended as first-line immunosuppressant in patients with steroid-dependent inflammatory bowel diseases (IBDs). However, data on steroid withdrawal after induction therapy in IBD patients are sparse. Methodsu2002In this post-hoc analysis of a prospective multicenter study, we analyzed the proportion and clinical characteristics of 324 azathioprine-tolerant patients as to whether they could terminate the glucocorticoid therapy after initiation of treatment with azathioprine. Resultsu2002Systemic steroid therapy was required in 190 patients (58.6u200a%) at baseline and in 40 patients (12.3u200a%) at the end of the follow-up period (pu200a<u200a0.001). The median daily dose was 30u200amg at baseline and 10u200amg at follow-up.u200aAt baseline, only 122 patients (37.2u200a%) were advised to take at least the lowest recommended dose of 2u200amg/kg per day. At follow-up, 221 patients (68.2u200a%) were prescribed at least the recommended maintenance dosage. Conclusionu2002The majority of patients with thiopurine-naïve IBDs that needed systemic steroids at baseline were able to discontinue steroids after 3u200a-u200a6 months of azathioprine therapy. These data support the continued high value of azathioprine in the immunosuppressive therapy of IBD.

Ustekinumab – eine Standortbestimmung

The present review by the IBD-Dach group provides a comprehensive summary of the mode of action, clinical development, approval, efficacy and safety aspects of the novel anti-p40 antibody Ustekinumab. The review provides current data, including the large clinical trials as well as smaller case series and work outside the field of inflammatory bowel diseases for shedding more light into special situations. Together, the data indicate that Ustekinumab shows clinical efficacy as well as a good safety profile for the treatment of Crohns disease.