[Use of specific antidotes in DOAC-associated severe gastrointestinal bleeding - an expert consensus - Antagonozation of direct oral anticoagulants in gastrointestinal hemorrhages]. / Einsatz von spezifischen Antidots bei DOAK-assoziierter schwerer gastrointestinaler Blutung ­ ein Expertenkonsensus.

Gastrointestinal (GI) bleeding is one of the most common complications associated with the use of direct oral anticoagulants (DOAC). Clear algorithms exist for the emergency measures in (suspected) GI bleeding, including assessing the medication history regarding anti-platelet drugs and anticoagulants as well as simple coagulation tests during pre-endoscopic management. Platelet transfusions, fresh frozen plasma (FFP), or prothrombin complex concentrate (4F-PCC) are commonly used for optimizing the coagulation status. For severe bleeding under the thrombin inhibitor dabigatran, idarucizumab is available, and for bleeding under the factor Xa inhibitors rivaroxaban or apixaban, andexanet alfa is available as specific antidotes for DOAC antagonization. These antidotes represent emergency drugs that are typically used only after performing guideline-compliant multimodal measures including emergency endoscopy. Antagonization of oral anticoagulants should be considered for severe gastrointestinal bleeding in the following situations: (1) refractory hemorrhagic shock, (2) endoscopically unstoppable bleeding, or (3) nonavoidable delays until emergency endoscopy for life-threatening bleeding. After successful (endoscopic) hemostasis, anticoagulation (DOACs, vitamin K antagonist, heparin) should be resumed timely (i.e. usually within a week), taking into account individual bleeding and thromboembolic risk.

Association between adverse effects under azathioprine therapy and inosine triphosphate pyrophosphatase activity in patients with chronic inflammatory bowel disease.

BACKGROUND: Inosine triphosphate pyrophosphatase (ITPA) catalyzes the pyrophosphohydrolysis of inosine triphosphate to inosine monophosphate. Recently, single-nucleotide polymorphisms in the ITPA gene, associated with decreased enzyme activity, have been reported. Some clinical studies have demonstrated that the 94C>A mutation is linked to flu-like symptoms, rash, and pancreatitis during azathioprine (AZA) therapy and to early AZA discontinuation. In this study, we investigated whether the enzyme phenotype is also related to adverse effects (AEs). METHODS: Patients suffering from inflammatory bowel disease who were treated with AZA (N=160; age 43±12 years) were included. Data were categorized into quartiles according to the ITPA activity. Information about the therapeutic regimen, AEs [leucopenia, increased hepatic enzymes (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase), flu-like symptoms, and pancreatitis], cotherapy, and comorbidity was obtained from the responsible clinicians and patients by using a standardized questionnaire. ITPA activity was measured by a validated high-performance liquid chromatography procedure. In patients with decreased ITPA activity, the 94C>A and IVS2+21A>C genotypes were determined. RESULTS: AEs were reported significantly more often for patients with low ITPA activity than for patients with high ITPA activity; the highest odds ratio for occurrence of AEs was found to be below a threshold of 59.9 µmol/(gHb·h) [hemoglobin (Hb)]. Decreased ITPA activities [particularly <89.2 µmol/(gHb·h)] were frequently accompanied by leucopenias, whereas very low enzyme activities [<37.3 µmol/(gHb·h)] were associated with a higher incidence of increased liver enzymes. CONCLUSIONS: The results demonstrate a relationship between low ITPA activity and AEs and support the idea that the determination of ITPA phenotype might be an appropriate alternative to genotyping.

Clinical trial: a novel high-dose 1 g mesalamine suppository (Salofalk) once daily is as efficacious as a 500-mg suppository thrice daily in active ulcerative proctitis.

BACKGROUND: Mesalamine suppositories are first-line therapy in active ulcerative proctitis; the standard regime still recommends multiple doses per day. The primary objective of this study was to show the noninferiority of once-daily administration of a novel 1 g mesalamine suppository versus thrice-daily administration of the 0.5 g mesalamine suppository. METHODS: This was a single-blind (investigator-blinded), randomized, multicenter, comparative, Phase III clinical trial. Patients with mild to moderately active ulcerative proctitis inserted either one mesalamine 1 g suppository at bedtime or one mesalamine 0.5 g suppository thrice daily over a 6-week period. The primary endpoint was rate of remission (Disease Activity Index below 4). RESULTS: In all, 354 patients were evaluable for safety and per-protocol analysis. The new regimen demonstrated noninferiority: The percentage of patients with remission was 87.9% for the once-daily 1 g mesalamine suppository and 90.7% for the thrice-daily 0.5 g mesalamine suppository. Each regimen resulted in prompt cessation of clinical symptoms (e.g., median time to ≤3 stools per day (all without blood): 5 days in the 1 g mesalamine once-daily and 7 days in the 0.5 g mesalamine thrice-daily group). Patients preferred applying suppositories once a day. CONCLUSIONS: In active ulcerative proctitis the once-daily administration of a 1 g mesalamine suppository is as effective and safe, yet considerably more convenient, than the standard thrice-daily administration of a 0.5 g mesalamine suppository.

Increased insulin resistance and beta cell activity in patients with Crohn's disease.

BACKGROUND: Pancreatitis and exocrine pancreatitic insufficiency have been described as extraintestinal manifestations of inflammatory bowel disease. In this study, we investigated whether the endocrine pancreatic function is also disturbed in patients with inflammatory bowel disease. METHODS: Seventeen patients with Crohn's disease and 13 healthy volunteers participated in the study. We analyzed the plasma insulin response in a 75-g oral glucose tolerance test. Glucose and insulin levels were determined at time 0 (fasting levels) and 30, 60, 90, 120, 180, 240, and 300 min after glucose uptake. Insulin resistance and beta cell function (BCF) were analyzed by calculating respective indices. RESULTS: Fasting and oral glucose-tolerance test glucose levels appeared to be similar in patients with Crohn's disease and in the controls. Impaired fasting glucose, impaired glucose tolerance, and/or overt diabetes mellitus were not observed in the volunteers. Insulin as well as the index for BCF were significantly increased in patients with Crohn's disease. In addition, insulin resistance was shown to be significantly elevated in Crohn's disease. CONCLUSIONS: Patients with Crohn's disease reveal an increased insulin secretion caused by an enhanced BCF, which may be induced by an up-regulated enteropancreatic axis. This hypersecretion may override the insulin resistance given by the chronic inflammatory state.

Interferon-beta-1a for the treatment of steroid-refractory ulcerative colitis: a randomized, double-blind, placebo-controlled trial.

BACKGROUND & AIMS: We performed a randomized, double-blind, placebo-controlled, multicenter trial to investigate the efficacy and safety of recombinant interferon-beta-1a (rIFN-beta-1a) in outpatients with active steroid-refractory ulcerative colitis. METHODS: Ninety-one randomized patients subcutaneously received 3 MIU rIFN-beta-1a (group A, n = 32), 1 MIU rIFN-beta-1a (group B, n = 30), or placebo (group C, n = 29) 3 times a week over a period of 8 weeks in addition to standard therapy. An intention-to-treat analysis was performed to evaluate the efficacy and safety of treatment. RESULTS: In all 3 groups, the median prestudy clinical activity index (CAI) was 10. In 18 of 32 patients (56%) in group A, in 11 of 30 patients (36%) in group B, and in 10 of 29 patients (34%) in group C, a reduction of the CAI of 6 points or greater (response) was achieved (differences were not statistically significant). Complete response (reduction of CAI to < or =4) was achieved in 56%, 30%, and 38% of patients in groups A, B, and C, respectively. Compared with baseline, the median endoscopic index had been reduced by 5, 3, and 4 points in groups A, B, and C, respectively. Steroid reduction was 12 mg in group A, 6 mg in group B, and 10 mg in group C. Identical side effects occurred in all 3 groups. Seven serious adverse events were reported (1 in group A and 6 in group C). All were unrelated to therapy as judged by the investigating physicians. CONCLUSIONS: rIFN-beta-1a was safe but not significant, at the dosage and/or duration of treatment used, in steroid-refractory ulcerative colitis. Further studies are indicated.

Crohn's disease patient characteristics in a tertiary referral center: comparison with patients from a population-based cohort.

OBJECTIVES: Data on the clinical presentation, effects of therapy and prognosis of patients with Crohn's disease are often based on patients from specialized referral centers. We assessed the extent of the selection based on the clinical and demographic characteristics. METHODS: All patients with Crohn's disease presenting to the University Hospital of Regensburg (Medical Department) were analyzed retrospectively with respect to demographic and disease specific characteristics. Only patients diagnosed <2 years before presentation were included in the main analysis. The original data from a population-based, prospectively assembled incidence cohort were available for comparison (EC-IBD, northern centers only, n=475). Age at diagnosis, disease location and behavior were categorized according to the Vienna classification. Differences were examined using chi-square tests. MAIN RESULTS: At the referral center, 394 patients were treated within a 5-year period. Of these, 116 patients fulfilled the inclusion criteria for the comparative analysis. Sixteen percent of the referral patients were diagnosed at age 40 or older, as compared with 32% in the population-based group (P<0.004). The distribution of disease location, sex, smoking behavior and positive family history was similar in both groups. Among the referral patients, more had fistulas (39% versus 20%, P<0.001). Also, more patients were receiving steroids (49% versus 27%) or other immunosuppressive therapy (12% versus 4%). The selection effects increase with duration of disease. CONCLUSIONS: Patients with late onset of disease, inflammatory only disease behavior and no need for immunosuppression are under-represented at a tertiary referral center.

Controlled, open, randomized multicenter trial comparing the effects of treatment on quality of life, safety and efficacy of budesonide foam and betamethasone enemas in patients with active distal ulcerative colitis.

BACKGROUND/AIMS: There is evidence of a higher quality of life with foams as compared with enemas. The purpose of this study was to assess the effect of treatment with budesonide foam or betamethasone enema on the quality of life and the clinical outcome in patients with distal ulcerative colitis. METHODOLOGY: In an open multicenter trial, patients with active distal ulcerative colitis were randomized to receive 2 mg/50 mL budesonide foam or 5 mg/100 mL betamethasone enema. Primary outcome variable was the change in the mean Life Quality Index. Therapeutic efficacy was determined by clinical activity, endoscopical and histological indices. RESULTS: 38 patients were included in the study. The decrease of the mean Life Quality Index was more pronounced in the budesonide group. No significant difference in the efficacy of treatment was observed for both groups. Betamethasone suppressed the plasma cortisol level in the majority of the patients (87%) compared to only 22% of the patients receiving budesonide. CONCLUSIONS: The quality of life is not significantly different in patients during treatment with budesonide foam or betamethasone enema for active distal ulcerative colitis. However, while having comparable clinical efficacy budesonide foam has less effect on the plasma cortisol level thus potentially minimizing steroid side effects.

Functional expression of the interleukin-11 receptor alpha-chain and evidence of antiapoptotic effects in human colonic epithelial cells.

A tissue-protective effect of interleukin-11 (IL-11) for the intestinal mucosa has been postulated from animal models of inflammatory bowel disease (IBD). Despite the fact that the clinical usefulness of the anti-inflammatory effects of this cytokine is presently investigated in patients with IBD, there are no data available regarding the target cells of IL-11 action and the mechanisms of tissue protection within the human colonic mucosa. IL-11 responsiveness is restricted to cells that express the interleukin-11 receptor alpha-chain (IL-11Ralpha) and an additional signal-transducing subunit (gp130). In this study, we identified the target cells for IL-11 within the human colon with a new IL-11Ralpha monoclonal antibody and investigated the functional expression of the receptor and downstream effects of IL-11-induced signaling. Immunohistochemistry revealed expression of the IL-11Ralpha selectively on colonic epithelial cells. HT-29 and colonic epithelial cells (CEC) constitutively expressed IL-11Ralpha mRNA and protein. Co-expression of the signal-transducing subunit gp130 was also demonstrated. IL-11 induced signaling through triggering activation of the Jak-STAT pathway without inducing anti-inflammatory or proliferative effects in colonic epithelial cells. However, IL-11 stimulation resulted in a dose-dependent tyrosine phosphorylation of Akt, a decreased activation of caspase-9, and a reduced induction of apoptosis in cultured CEC. In HLA-B27 transgenic rats treated with IL-11, a reduction of apoptotic cell numbers was found. This study demonstrates functional expression of the IL-11Ralpha restricted on CEC within the human colonic mucosa. IL-11 induced signaling through triggering activation of the Jak-STAT pathway, without inducing anti-inflammatory or proliferative effects. The beneficial effects of IL-11 therapy are likely to be mediated by CEC via activation of the Akt-survival pathway, mediating antiapoptotic effects to support mucosal integrity.

[Suspected cases of severe side effects after infliximab (Remicade) in Germany]. / Verdachtsfälle schwerwiegender Nebenwirkungen nach Infliximab (Remicade) aus Deutschland.

BACKGROUND: Remicade is a chimeric, human-murine, monoclonal antibody. Remicade was approved in the EU in August 1999 for the treatment of active refractory Crohn's disease, and for treating fistulas in subjects with refractory Crohn's disease, and in December 2000 for preventing disease progression in subjects with methotrexate-resistant rheumatoid arthritis. In May 2003, infliximab was approved in the EU for the treatment of ankylosing spondylitis in patients with severe symptoms and elevated serologic parameters of inflammation, who have been refractory to standard treatment. RESULTS: On the basis of the so-called spontaneous capture, the Paul Ehrlich Institute was notified of 44 adverse drug reactions leading to the death of the patient after the application of infliximab in Germany. 18 of these patients had rheumatoid arthritis, eight Crohn's disease, 13 graft-versus-host disease, and five other diseases. 24 of those patients had sepsis or serious infections. According to the manufacturer, 20,000 patients have been treated in Germany with infliximab. DISCUSSION AND CONCLUSION: We discuss, in this article, the question of causal relation with the medication and make recommendations for the safe use of infliximab.

Response to infliximab treatment in Crohn's disease is not associated with mutations in the CARD15 (NOD2) gene: an analysis in 534 patients from two multicenter, prospective GCP-level trials.

Infliximab induces remission in 30-40% of patients with active Crohn's disease. Treatment response is a stable trait over repeated doses yet the clinical predictors of response are still unknown. Recently, three variants in the CARD15 gene have been identified as major genetic risk factors for Crohn's disease. Single nucleotide polymorphisms (SNPs) 8, 12 and 13, have been shown to be independently associated with Crohn's disease susceptibility. The aim of the present study was to investigate these variants in relation to the therapeutic efficacy of infliximab. SNPs were genotyped (TaqMan) in two cohorts ( n= 90 and n= 444 (ACCENT I)) of active Crohn's disease patients (CDAI 220-450). The patients were recruited from independent multicenter trials conducted according to GCP. At the start of both trials, patients received a single infusion of open label infliximab (5 mg/kg bodyweight). The genotypic and allelic frequencies of each SNP were significantly associated with Crohn's disease in comparison to 370 healthy controls as reported previously. Response to infliximab (drop in CDAI 70 points or remission, respectively) was not associated with the genetic variants in the CARD15 gene in either cohort. The subsequent negative findings in a two-cohort model exclude SNPs 8, 12 and 13 of the CARD15 gene as predictors for therapeutic response to infliximab treatment.

Prior bowel resections, perianal disease, and a high initial Crohn's disease activity index are associated with corticosteroid resistance in active Crohn's disease.

OBJECTIVES: Some patients with Crohn's disease (CD) do not respond to corticosteroid therapy. Furthermore, corticosteroids frequently cause side effects. Thus, predictive parameters for treatment refractoriness would be helpful for treatment decisions. METHODS: A total of 300 patients with active CD (i.e., with a Crohn's Disease Activity Index [CDAI] >200) entered the study. Treatment started with 60-100 mg/day prednisolone equivalent, which was then tapered to 10-15 mg/day within 6 wk and maintained at that dose for another 4 wk. After 10 wk of treatment, response to steroids was defined by a CDAI <150, steroid resistance by a CDAI always > or =150 and steroid dependency by a relapse after dose reduction. Of 239 eligible patients, 196 were responders, 26 were steroid resistant, and 17 were steroid dependent. RESULTS: Prior bowel resections, a high initial CDAI, and perianal disease were associated with steroid resistance. Of the steroid resistant patients 53.9% were bowel-resected compared to 20.4% of the responders (relative risk = 3.63; 95% CI = 1.79-7.36). Perianal disease was observed in 42.3% of steroid resistant patients versus 21.9% of responders (relative risk = 2.28; 95% CI = 1.12-4.66) and initial CDAI was 347+/-91 in resistant patients versus 301+/-81 in responders (p < 0.05). Parameters for steroid dependent patients were not significantly different from those of responders. CONCLUSIONS: In this study (thus far the largest study for the evaluation of predictive factors for treatment refractoriness to corticosteroids in CD), only prior bowel resection, perianal disease, and a high initial CDAI were found to be predictive of resistance to steroid treatment.

Screening for osteoporosis in patients with inflammatory bowel disease by using urinary N-telopeptides.

BACKGROUND: Patients with inflammatory bowel disease are at increased risk of osteoporosis. DESIGN AND METHODS: We carried out a prospective study of bone mineral density and biochemical markers of bone metabolism like osteocalcin and urinary N-telopeptides in 72 patients with inflammatory bowel disease and evaluated if one of these markers detects osteoporosis. In addition, bone mineral density and N-telopeptides were analysed retrospectively in a second series of 93 patients with inflammatory bowel disease in order to assess predictive values found in the first patient group in an independent sample. RESULTS: Multiple linear regression showed that N-telopeptides (P < 0.0001) and total white blood cell count (P = 0.006) correlated negatively with the bone mineral density of the lumbar spine and only N-telopeptides (P = 0.005) correlated negatively with the bone mineral density of the femoral neck. Using receiver operator characteristic curves N-telopeptide concentrations of > 40 (30) nmol N-telopeptides/mmol creatinine were chosen as best cut-off values to exclude osteoporosis at the lumbar spine (femoral neck). Using these cut-off values a negative predictive value of 100% (100%) and a positive predictive value of 37.5% (27.9%) were found in the first group, and a negative predictive value of 95.2% (96%) and a positive predictive value of 15.6% (23.3%) in the second, independent group of patients. CONCLUSION: Our data suggest that N-telopeptide levels could be used as a tool for the screening of osteoporosis and for selecting those inflammatory bowel disease patients where bone mineral density measurement is indicated.

Uncoupling of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis in inflammatory bowel disease?

In inflammatory diseases such as Crohn's disease (CD) and ulcerative colitis (UC), one would expect that TNF or IL-6 stimulates the hypothalamus, which activates the hypothalamus-autonomic nervous system (HANS) axis and the hypothalamic-pituitary-adrenal (HPA) axis in a parallel fashion. The study was initiated in order to investigate the parallelism of the HANS and HPA axes. We measured a typical marker of the HANS axis (neuropeptide Y, NPY) and of the HPA axis (serum cortisol). Plasma NPY was positively correlated with serum cortisol in control subjects (R(Rank)=0.259, p=0.026), which is a sign for the parallel activation of the two axes in healthy subjects. However, serum cortisol was not correlated with plasma NPY in CD or UC patients. In the active CD or UC, inclusion of patients with and without prior prednisolone therapy revealed a negative correlation between the serum cortisol and plasma NPY (CD: R(Rank)=-0.285, p<0.05; UC: R(Rank)=-0.510, p<0.01). This study demonstrates that the two stress axes seem to act in a parallel fashion in control subjects but are uncoupled in IBD patients. Uncoupling of these two axes may be partly due to prior corticosteroid therapy, whereas inverse coupling is a result of simultaneous corticosteroid therapy. It is discussed how the uncoupling of the two anti-inflammatory stress axes can appear.