Maternal and foetal adverse events with tumour necrosis factor-alpha inhibitors in inflammatory bowel disease.

BACKGROUND: Transplacental transfer of tumour necrosis factor-alpha (TNF-α) inhibitors has been shown in mothers receiving therapy for inflammatory bowel disease (IBD). AIM: To examine reports of adverse events of these medications in pregnancy. METHODS: Individual Safety Reports of adverse events (Jan 2003-June 2012) were accessed from the Food and Drug Administration Adverse Event Reporting System. The study data set was constructed by searching for cases with an indication for medication usage of IBD. The data set was then queried for key terms indicating pregnancy, followed by elimination of cases with potentially teratogenic exposures (FDA category X concomitant medications) as well exposures to study medications through partner or if the medications were discontinued prior to pregnancy. Logistic regression analysis was performed to detect signals for maternal/foetal adverse events with TNF-α inhibitors and/or thiopurines (compared to aminosalicylates). RESULTS: A total of 1097 individual Safety Reports in pregnant IBD patients were identified with the majority reported among patients receiving TNF-α inhibitor monotherapy (783 cases, 71.4%). Thiopurine monotherapy (OR 2.55, CI 0.95-6.88) and in combination with TNF-α inhibitors (OR 0.97, CI 0.49-1.93) were not associated with increased odds of maternal/foetal adverse events. Decreased odds for maternal/foetal adverse events were seen with TNF-α inhibitor monotherapy (overall) and specifically with certolizumab monotherapy (OR 0.11, CI 0.05-0.23). CONCLUSIONS: In this analysis of adverse events from the Food and Drug Administration Adverse Event Reporting System, use of thiopurine monotherapy or in combination with TNF-α inhibitors was not associated with an increase in maternal/foetal adverse events. Certolizumab monotherapy was associated with a decrease in maternal/foetal adverse events.

Blockade of arginine vasotocin signaling reduces aggressive behavior and c-Fos expression in the preoptic area and periventricular nucleus of the posterior tuberculum in male Amphiprion ocellaris.

Many marine fishes change sex in response to social cues when the dominance hierarchy is perturbed. Arginine-vasotocin (AVT) and the mammalian homolog arginine vasopressin are neuropeptides involved in social and reproductive behaviors across vertebrate taxa. The goal of this study was to determine whether AVT signaling influences aggression and expression of c-Fos, a marker of neuroplasticity, in key brain regions of the social decision circuit in Amphiprion ocellaris clownfish, a species where behavioral dominance precedes gonadal sex change from male to female. In experiment 1, juvenile clownfish (average mass 2.5g) were paired together in a tank (a total of 24 pairs), matched approximately for size with one fish randomly receiving either an intraperitoneal injection of the arginine vasopressin V1a receptor antagonist (Manning compound) or saline vehicle, and evaluated for aggressive and submissive behaviors over a 10-min period. The second experiment was a repeat of the first using five pairs of mature, reproductive males, except the animals interacted for 90-min immediately followed by euthanasia for immunohistochemical detection of c-Fos protein. Numbers of c-Fos-positive cells were quantified in the preoptic area of the hypothalamus (POA), the anterior tuberal nucleus (aTn), and periventricular nucleus of the posterior tuberculum (TPp). Manning compound significantly reduced aggression and the probability of winning the contest relative to saline (vehicle) controls. In experiment 2, saline-treated fish displayed approximately twice as many c-Fos-positive cells in the POA and 25% more in the TPp than the Manning-treated fish, no differences were observed in the aTn. Taken together, results suggest AVT signaling is necessary for aggressive behavior and expression of neuroplasticity in the POA and TPp that likely contributes to behavioral dominance and hence, sex change in A. ocellaris.

Neurological events with tumour necrosis factor alpha inhibitors reported to the Food and Drug Administration Adverse Event Reporting System.

BACKGROUND: The association between inhibition of tumour necrosis factor alpha (TNF-α) and new onset of neurological adverse events (AEs) is unclear. AIMS: To evaluate neurological AEs with TNF-α inhibitors reported to the Food and Drug Administration Adverse Event Reporting System (FAERS) utilising a standardised scoring tool for drug-induced AEs. METHODS: A search of FAERS for neurological AEs (January 1, 2000 to December 31, 2009) reported with infliximab, adalimumab, certolizumab and etanercept was performed. Full-text reports were accessed using the Freedom of Information Act and scored using Naranjo score, while accounting for temporal association, previous conclusive reports of the neurological AE with any TNF-α inhibitor, and alternate explanations including underlying disease, concomitant medications and comorbidities, such as diabetes mellitus. RESULTS: There were 772 reports. Most were in patients who had rheumatoid arthritis (393, 50.9%) followed by inflammatory bowel disease (140, 18.1%). No significant differences in age or gender were seen between IBD patients compared with rheumatological diseases (P = 0.584 and P = 0.055 respectively). Etanercept was reported most (327, 42.4%) followed by infliximab (276, 35.8%) (P = 0.008). Peripheral neuropathy was the most common neurological AE (296 reports, 38.3%) followed by central nervous system and/or spinal cord demyelination (153 reports, 19.8%). Majority (551, 71.4%) of the reports were of 'possible' AE with the remaining 'probable' AE and none identified as 'definite' AE. CONCLUSION: While several neurological AEs have been described, definite association between de novo development of these AEs and exposure to TNF-α inhibitors was not established using the Naranjo score.

Increased risk of osteoporosis-related fractures in patients with irritable bowel syndrome.

UNLABELLED: We sought to determine whether patients with irritable bowel syndrome (IBS) have an increased risk of osteoporosis and related fractures using the Nationwide Emergency Department Sample (NEDS). Patients with IBS had increased adjusted odds of osteoporosis and osteoporotic fractures compared to the non-IBS control group, controlling for known risk factors for osteoporosis. Screening measures to identify osteoporosis in this group are advised. INTRODUCTION: Ulcerative colitis, Crohn's disease, and celiac disease have well-described augmented risk of osteoporosis and related fractures. We sought to determine whether IBS also indicates an increased risk of osteoporosis and related fractures. METHODS: The 2008 NEDS database was used to determine the adjusted odds of osteoporosis and related fractures in IBS patients. Only fractures (pathologic wrist (733.12), vertebrae (733.13), and femur fractures (733.14), traumatic wrist (813.x), vertebrae (805.x-806.x), and hip fractures (820.x-821.x)) with a secondary diagnosis of osteoporosis (733.0x) were included in the analysis. A multivariate logistic regression analysis was performed, controlling for known risk factors for osteoporosis and related fractures. RESULTS: We identified 317,857 ED visits in patients with a diagnosis of IBS. Of these, 17,752 carried a diagnosis of osteoporosis and 694 IBS patients had a concurrent diagnosis of a pathologic fracture of the wrist, hip, or vertebrae. A total of 1,503 IBS patients had a concurrent diagnosis of a traumatic fracture of the wrist, hip, or vertebra. Overall, patients with IBS had an increased adjusted odds of osteoporosis (odds ratio (OR) 4.28, 95% confidence interval (CI) 4.21-4.35) and osteoporotic fractures (OR 2.36, CI 2.26-2.47) compared to the non-IBS control group. The highest adjusted odds of fracture was seen at the wrist (OR 2.41, CI 2.10-2.77 compared to controls). CONCLUSIONS: IBS patients are at an increased risk of osteoporosis and related fractures. Screening measures to identify osteoporosis and prevent fractures are advised.