[Transition medicine-structural solutions]. / Transitionsmedizin ­ strukturelle Lösungsansätze.

Young adults suffering from chronic diseases represent a critical subgroup of patients that after reaching legal age have to be transferred to the colleagues from adult medicine. Thus in this patient group two evident problems come together: first, the adolescence phase that presents a challenge for any young adult and second, the transition to the novel structure and environment of adult medicine. It has been recognized for Germany that there are significant deficits for this transition phase. These deficits have already been addressed by other countries through the introduction of so-called transition clinics. In this article, we will summarize the challenges of this transition phase and the resulting points and needs that will have to be addressed by a structured program for transition. As an example, the Berliner TransitionsProgramm (BTP) will be presented where a framework structure is provided that allows for the transition of various chronic diseases. The BTP accompanies the transition process for a two-year time period by providing a framework structure consisting of transition consultations, a transition booklet, a structured summary of the previous disease course as well as a case manager who assures that the included patients stay within the program and do not get lost to assure treatment continuity. In addition, the program succeeded, at least from some insurance companies, in obtaining financial reimbursement for this time-consuming effort. Thus in our view, the BTP functions as role model for transition medicine in Germany.

Risk for lower intestinal perforations in patients with rheumatoid arthritis treated with tocilizumab in comparison to treatment with other biologic or conventional synthetic DMARDs.

OBJECTIVE: To investigate the risk of developing lower intestinal perforations (LIPs) in patients with rheumatoid arthritis (RA) treated with tocilizumab (TCZ). METHODS: In 13 310 patients with RA observed in the German biologics register Rheumatoid Arthritis: Observation of Biologic Therapy, 141 serious gastrointestinal events possibly associated with perforations were reported until 31 October 2015. All events were validated independently by two physicians, blinded for treatment exposure. RESULTS: 37 LIPs (32 in the colon/sigma) were observed in 53 972 patient years (PYs). Only two patients had a history of diverticulitis (one in TCZ). Age, current/cumulative glucocorticoids and non-steroidal anti-inflammatory drugs were significantly associated with the risk of LIP. The crude incidence rate of LIP was significantly increased in TCZ (2.7/1000 PYs) as compared with all other treatments (0.2-0.6/1000 PYs). The adjusted HR (ref: conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs)) in TCZ was 4.48 (95% CI 2.0 to 10.0), in tumour necrosis factor-α inhibitor (TNFi) 1.04 (0.5 to 2.3) and in other biologic DMARDs 0.33 (0.1 to 1.4). 4/11 patients treated with TCZ presented without typical symptoms of LIP (acute abdomen, severe pain). Only one patient had highly elevated C reactive protein (CRP). One quarter of patients died within 30 days after LIP (9/37), 5/11 under TCZ, 2/13 under TNFi and 2/11 under csDMARD treatment. CONCLUSIONS: The incidence rates of LIP under TCZ found in this real world study are in line with those seen in randomised controlled trials of TCZ and higher than in all other DMARD treatments. To ensure safe use of TCZ in daily practice, physicians and patients should be aware that, under TCZ, LIP may occur with mild symptoms only and without CRP elevation.

Co-morbidities and bleeding in elderly patients with haemophilia-A survey of the German, Austrian and Swiss Society of Thrombosis and Haemostasis Research (GTH).

BACKGROUND: Nowadays patients with haemophilia survive longer due to improvements in haemophilia care. It has been hypothesized that the bleeding type and frequency may vary with age and are influenced by co-morbidities and co-medication in elderly patients. OBJECTIVES: To investigate a large group of patients older than 60 years of age with haemophilia concerning haemophilia treatment, bleeding pattern changes, co-morbidities, co-medication, bleeding sites and patient mortality. METHODS: A retrospective multi-centre data collection study was initiated on behalf of the German, Austrian and Swiss Society of Thrombosis and Haemostasis Research (GTH). Parameters of interest were investigated over the 5 years prior to study entry. RESULTS: A total of 185 haemophilia patients (mean age, 69.0±7.0 years, 29% with severe haemophilia) were included in the study. Regular prophylaxis was performed in 30% of the patients with severe haemophilia. In total, the annual bleeding rate was 2.49 and in patients with severe haemophilia 5.61, mostly caused by joint bleeds. Hypertension was the most common co-morbidity, but it occurred significantly less frequently than in an age-matched general population older than 70 years; 12% of the patients suffered from ischaemic heart disease, and 13% of the patients received anticoagulant or antiplatelet therapy. Within the observation period, 17% of the patients with severe haemophilia developed a higher frequency of bleeding symptoms, which was significantly associated with the use of antiplatelet or anticoagulant drugs. CONCLUSIONS: The most common co-morbidity of the patient population was hypertension, a considerable part had ischemic heart disease and antiplatelet or anticoagulant drugs.

Faecal microbiota transplantation-A clinical view.

Faecal microbiota transplantation has gained increasing attention over the last decade as various phenotypes could be transferred from a donor to a recipient in different animal models. Clinically, however, the sole indication with evidence from a randomized placebo controlled trial is refractory Clostridium difficile infection. Despite revealing successful clinical outcomes, questions concerning regulatory affairs, the identification of the best donor, the optimal mixture of the transplant as well as the preferred route of administration remain to be clarified even for this indication. Initiated by the idea that alterations in the composition of the intestinal microbiota are associated with intestinal inflammation in inflammatory bowel disease, several studies investigated whether faecal microbiota transplantation would be an equally suitable approach for these devastating disorders. Indeed, the available data indicate changes in the microbiota composition following faecal microbial transplantation depending on the degree of intestinal inflammation. Furthermore, first data even provide evidence that the transplantation of an "optimized" microbiota induces clinical remission in ulcerative colitis. However, despite these intriguing results it needs to be considered that not only "a cure of inflammation", but also risk factors and phenotypes including obesity can be transferred via faecal microbiota transplantation. Thus, a deeper understanding of the impact of a distinct microbiota composition is required before "designing" the optimal faecal microbiota transplant.

[Biosimilars in inflammatory bowel disease]. / Biosimilars in der Behandlung chronisch entzündlicher Darmerkrankungen.

After the expiry date of the patent protection for Infliximab in 2013, the biosimilar CT­P13 was approved for indications in Crohn's disease and ulcerative colitis in adults as well as in children. The approval has been based on two randomized clinical studies indicating equivalence for the biosimilar with regard to pharmacokinetics, efficacy, as well as side-effects. The clinical experience since, in addition to multiple non-randomized studies, indicate a comparable efficacy and immunogenicity of the Infliximab biosimilar CT-P13 in inflammatory bowel disease. Thus, the introduction of the biosimilar as primary therapy seems to be justified. Tight monitoring of the safety of biosimilars with regard to efficacy and side effects has to be ensured.

[Efficacy, tolerability, and safety of cannabinoids in gastroenterology: A systematic review]. / Wirksamkeit, Verträglichkeit und Sicherheit von Cannabinoiden in der Gastroenterologie : Eine systematische Übersichtsarbeit.

BACKGROUND: The medical use of cannabis is discussed in gastroenterology for inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS), and chronic pancreatitis. MATERIALS AND METHODS: A systematic literature search until March 2015 was performed in the databases Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, www.cannabis-med.org , and clinicaltrials.gov. Randomized controlled trials (RCT) investigating herbal cannabis and/or pharmaceutical cannabinoids in IBD, IBS, or chronic pancreatitis with a study duration of ≥ 4 weeks and a sample size of at least n = 10 per study arm were identified. Clinical outcomes comprised efficacy (pain, nausea, appetite/weight, diarrhea, health-related quality of life, and remission rates for IBD), tolerability (drop-out rate due to side effects), and safety (severe side effects). Methodology quality of RCTs was evaluated with the Cochrane Risk of Bias Tool. RESULTS: Only one RCT treating 21 patients with Crohn's disease and herbal cannabis was identified. The study revealed no significant differences of remission rate because of low statistical power. However, there was a clear tendency for less abdominal pain and improved appetite with medical cannabis. The methodological risk of the study was high. Furthermore, results of two RCTs investigating synthetic cannabis in IBD and chronic pancreatitis, respectively, have not yet been released. No RCT for IBS was found. Several case reports described cannabis-induced acute pancreatitis. CONCLUSIONS: Cannabis may be useful for symptom relief in Crohn's disease such as pain, nausea, and loss of appetite. However, studies with high methodological quality, sufficient sample size, and study duration are mandatory to determine potential therapeutic effects and risks of cannabis in gastroenterology. Currently, use of tetrahydrocannabinol to alleviate symptoms such as pain and appetite loss in Crohn's disease should only be considered in individual patients after failure of established medical therapies and only after careful risk-benefit assessment.

[Current position on Vedolizumab for ulcerative colitis and Crohn's disease]. / Vedolizumab bei Colitis ulcerosa und Morbus Crohn: eine Standortbestimmung.

Vedolizumab, the first drug in the class of anti-integrin molecules, is newly approved for ulcerative colitis and Crohn's disease and can be prescribed in Germany since mid-2014. By a specific receptor binding a relatively gut-selective mode of action was achieved without the known side effects of the systemic immunosuppression of the anti-TNF-alpha antibodies. According to the present data the safety profile of Vedolizumab appears to be more favorable than that of the anti-TNF- alpha therapy. Vedolizumab is suitable for induction therapy in patients with ulcerative colitis and Crohn's disease, however the kinetic of response compared with the anti-TNF-alpha antibodies seems to be slower. For maintenance therapy the Vedolizumab data show a deep and sustained remission in patients initially responding to induction therapy with a lower loss of efficacy in the long-term treatment known from the anti-TNF-alpha therapy. On the basis of currently available data the efficacy of Vedolizumab in ulcerative colitis appears to be slightly better than in Crohn's disease.

Therapy of complicated Crohn's disease during pregnancy--an interdisciplinary challenge.

BACKGROUND: Severe courses of Crohn's disease (CD) during pregnancy are rare. However, if occurring, the risk of miscarriage and low birth weight is increased. At present, only limited data is available on the treatment of CD during pregnancy. In particular, there are no standard guidelines for surgical therapy. Nevertheless, surgery is often unavoidable if complications during the course of the disease arise. PURPOSE: This study provides a critical overview of conventional and interventional treatment options for CD complications during pregnancy and analyses the surgical experience gained thus far. For illustrative purposes, clinical cases of three young women with a severe clinical course during pregnancy are presented. METHODS: After treatment-refractory for conservative and interventional measures, surgery remained as the only treatment option. In all cases, a split stoma was created after resection to avoid anastomotic leaks that would endanger the lives of mother and child. The postoperative course of all three patients was uneventful, and pregnancy remained intact until delivery. No further CD specific medication was required before birth. CONCLUSIONS: The management of CD patients during pregnancy requires close interdisciplinary co-operation between gastroenterologists, obstetricians, anaesthetists and visceral surgeons. For the protection of mother and child treatment should thus be delivered in a specialised centre. This article demonstrates the advantages of surgical therapy by focusing on alleviating CD complaints and preventing postoperative complications.

[Azathioprine in Crohn's disease therapy--guidance against the background of recent studies]. / Azathioprin in der Therapie des Morbus Crohn--eine Standortbestimmung vor dem Hintergrund aktueller Studien.

Thiopurines (azathioprine and 6-mercaptopurine) are the most frequently used drugs in the treatment of patients with Crohn's disease. In current guidelines published by the German Society of Gastroenterology, Nutritional and Metabolic Diseases (DGVS) in 2014 and by the European Crohn´s and Colitis Organisation (ECCO) in 2010 different indications have been suggested. However, efficacy of azathioprine has been substantially questioned by recent publications in adults as well as in children examining the efficacy of early initiation of this treatment. These articles were published after release of the aforementioned guidelines. Therefore, in this survey recently published data are discussed on the background of our knowledge on the efficacy of azathioprine and 6-mercaptopurine developed in many years, and suggestions for the future use of these substances in the treatment of patients with Crohn's disease will be provided.

[Etiopathogenesis of chronic inflammatory bowel diseases. Role of the immune system]. / Ätiopathogenese chronisch-entzündlicher Darmerkrankungen. Rolle des Immunsystems.

The challenge of the mucosal immune system is to develop tolerance toward intestinal antigens. Considering the quantity of bacteria that continuously attack the intestinal barrier, one can only imagine the complexity involved. To master this task, a tight network between the intestinal microbiota, the barrier, immune cells of the lamina propria as well as the adjacent mesenteric fat tissue is required. The key pathways involved have been revealed by the genome-wide association studies as well as functional data from experimental models. However, although knowledge with regard to the pathogenesis of chronic inflammatory bowel disease has been increasing continuously over recent decades, the current therapeutic strategies are limited to controlling the pro-inflammatory effector phase rather than achieving cure. The best example is cytokine neutralizing antibodies. The present review aims to describe the role of the various cell populations within the intestinal wall for disease pathogenesis and, thus, identify possible therapeutic strategies.

[Chronic inflammatory bowel diseases. Clinical aspects and new therapy approaches]. / Chronisch-entzündliche Darmerkrankungen. Klinische Aspekte und neue Therapieansätze.

There is a continuously increasing incidence in inflammatory bowel diseases affecting mostly young people who are in a vulnerable phase of life. Thus, early diagnosis and initiation of an effective therapeutic regimen is critical in order to maintain a good quality of life. In Germany, the standard therapeutic strategy is an accelerated step up approach, including the introduction of early immunosuppressive therapy if required. Although novel therapeutic strategies have found their way into clinical use there is still a substantial subgroup of patients where effective therapy is lacking. The future introduction of anti-adhesion molecule antibodies might provide a realistic option for this subgroup. Equally important is the availability of predictive markers allowing stratification of patients into subgroups at the time of diagnosis. Assuming that the CD8(+) T cell transcriptome approach will be confirmed in prospective trials, personalized therapy in patients with inflammatory bowel disease will be the next step.

Primary brain tumours and specific serum immunoglobulin E: a case-control study nested in the European Prospective Investigation into Cancer and Nutrition cohort.

BACKGROUND: Case-control studies suggest that patients with allergic diseases have a lower risk of developing glioma but not meningioma or schwannoma. However, those data can be differentially biased. Prospective studies with objective measurements of immunologic biomarkers, like immunoglobulin E (IgE), in blood obtained before cancer diagnosis could help to clarify whether an aetiological association exists. METHODS: The present case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) measured specific serum IgE as a biomarker for the most common inhalant allergens in 275 glioma, 175 meningioma and 49 schwannoma cases and 963 matched controls using the ImmunoCAP specific IgE test. Subjects with an IgE level ≥0.35 kUA/l (kilo antibody units per litre) were classified as sensitized by allergens. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by adjusted conditional logistic regression models for each tumour subtype. The effect of dose-response relationship was assessed in five increasing IgE level categories to estimate P-values for trend. RESULTS: The risk of glioma was inversely related to allergic sensitization (OR = 0.73; 95% CI 0.51-1.06), especially pronounced in women (OR = 0.53; 95% CI 0.30-0.95). In dose-response analyses, for high-grade glioma, the lowest OR was observed in sera with the highest IgE levels (P for trend = 0.04). No association was seen for meningioma and schwannoma. CONCLUSION: The results, based on serum samples prospectively collected in a cohort study, provide some support for the hypothesis that individuals with allergic sensitization are at reduced risk of glioma and confirm results from previous case-control studies.

[Desmopressin parenteral in patients with VWD1, VWD 2A and thrombocytopathy]. / Desmopressin parenteral bei VWD1, VWD 2A und Thrombozytopathie. Biologische und klinische Ansprechbarkeit.

UNLABELLED: Desmopressin (DDAVP, Minirin® parenteral), which induces the release of von-Willebrand factor from endogenous stores, is indicated in von Willebrand disease type 1 (VWD 1). In the present study effectiveness of DDAVP was tested and side effects were recorded in patients with VWD 1, von Willebrand disease type 2 (VWD 2) or thrombocytopathy (TCP). PATIENTS, METHODS: Subjects were analysed prior to and after Minirin parenteral infusion (0.4 µg/kg body weight (b.w.) over 60 minutes) for partial thromboplastin time (PTT, seconds), ADP/epinephrine triggered platelet-function analyzer (PFA-100) occlusion time (seconds), factor VIII activity (FVIII, %), VWF as ristocetin cofactor activity (VWF:RCo, %) and VWF antigen (VWF:Ag, %). Side effects of DDAVP during operative interventions were recorded per questionnaires by the patients. RESULTS: The mean ± standard deviation dose (n = 165 patients) of Minirin parenteral administered was 0.37 ± 0.02 µg/kg b.w., most often upcoming dental operations (57%) necessitated testing. Coagulation parameters of patients with VWD 1 or TCP normalised in almost all patients, but only in approximately 50% of patients with VWD 2 respectively. Appraisal of effectiveness of Minirin parenteral as good was 96% in case of VWD 1 and 95 % in case of TCP. During minor surgeries (n = 23) in 91% of the patients no complications and in 2 patients (9%) postoperative haemorrhages without need for further interventions occurred, but 83% of the patients reported adverse reactions in the questionnaires, although Minirin parenteral was well tolerated by all patients during DDAVP efficacy tests. CONCLUSION: Desmopressin is well tolerated and affective in patients with VWD 1 and thrombocytopathy.

Inhibitor-immunology-study. Evaluation of inhibitor development in haemophilia B.

UNLABELLED: The development of inhibitors in haemophilia B is one of the most important complications of replacement therapy, affecting mortality and morbidity. Inhibitor development is based on complex immunological factors, and to date, only little is known about its underlying mechanisms. Here, we present first results of the haemophilia B group of our Inhibitor-Immunology study. PATIENTS, METHODS: So far we have analysed 15 patients with haemophilia B. Four of them developed a high titre inhibitor; the remaining 11 had no inhibitor. We evaluated 9 SNPs in 8 genes (CD40, CTLA-4 , IL-1ß, IL-10, TLR2 , TLR4, TLR9, TNF-α). We compared the distribution of these alleles between inhibitor and non-inhibitor haemophilia B patients and between haemophilia B patients and a normal male control population. HLA typing was performed in all patients. Results, discussion: There appears to be a trend towards a skewed distribution of TLR 9, IL-10 and CTLA4 alleles in haemophilia B patients. Due to the limited number these differences are, however, not statistically significant. The t-test of all patients with inhibitor versus without inhibitor was significant for HLA-A*03 and DPB1*0401 and borderline for DRB1*0201.