Vedolizumab exposure in pregnancy: outcomes from clinical studies in inflammatory bowel disease.

BACKGROUND: Vedolizumab is a gut-selective immunoglobulin G1 monoclonal antibody to α4 ß7 integrin for the treatment of Crohn's disease (CD) and ulcerative colitis (UC). Prospective clinical studies of vedolizumab in pregnancy have not been conducted; therefore, existing safety data of vedolizumab in pregnancy were examined. AIM: To assess pregnancy outcomes in females and partners of males who received vedolizumab. METHODS: All pregnancy data collected during the clinical programme (from 14 May 2007 to 27 June 2013) and in the post-marketing setting (to 19 November 2015) were analysed. RESULTS: Across six studies, there were 27 pregnancies in female participants and 19 pregnancies in partners of male participants. Among 24 vedolizumab-treated females (23 with CD/UC, one healthy volunteer), there were 11 live births, five elective terminations, four spontaneous abortions and four undocumented outcomes. A congenital corpus callosum agenesis anomaly was reported in one live birth from a healthy volunteer with extensive obstetric history exposed to single-dose vedolizumab 79 days before estimated conception. Of 19 pregnancies in partners of male participants, there were 11 live births, two spontaneous abortions, three elective terminations and three undocumented outcomes. Post-marketing reports recorded 81 pregnancies, resulting in four live births, 11 spontaneous abortions and 66 pregnancies that were on-going or reported undocumented outcomes. CONCLUSIONS: Initial analysis, limited by sample size and follow-up, identified no new safety concerns for pregnancy outcomes in females directly or indirectly exposed to vedolizumab. However, vedolizumab should be used during pregnancy only if the benefits to the mother outweigh the risks to the mother/unborn child.

Cognitive impairment and reduced quality of life among old-age groups in Southern Urban India: home-based community residents, free and paid old-age home residents.

AIM: The purpose of the study were (i) to screen for cognitive impairment using Mini-Mental Status Examination among three old-age groups based on dwelling types in Chennai, India i.e. residential paid old-age homes, residential free (charitable) homes and home-based community-dwelling residents; (ii) secondly to investigate factors (demographic, psychological, medical and disability) associated with cognitive impairment in the these old-age; (iii) third, to investigate the independent association between cognitive impairment and health-related quality of life (QOL) among elderly across aged care dwelling types. METHODS: A total of 499 elderly from three old-age groups were interviewed in this cross-sectional study (173 elderly home-based community-dwellers, 176 paid-home and 150 free-home residents). All the participants were interviewed for their socio-economic condition, medical morbidity, self-reported worry and anxiety, disability and QOL. RESULTS: 42.7% free-home elderly residents were found to have cognitive impairment, whereas 32.4% of paid-home and 21.9% of community-dwelling elderly had cognitive impairment. The residents of free-home were less educated, had lower income and reported higher incidence of worry, anxiety, disability and poor QOL than community-dwelling or paid-home residents. Increasing age, low education, female gender, high blood pressure and disability were associated with cognitive impairment. Cognitive impairment had significant negative effect on their health-related QOL (b = -0.10, P = 0.01), independent of age, gender, education, chronic illness and dwelling type. CONCLUSION: The burden of cognitive impairment was high in all aged-care dwelling types in urban India; with free charitable home residents being worse affected. Cognitive impairment was associated with disability and poor health-related QOL in these age-care settings.

The Toronto Consensus Statements for the Management of Inflammatory Bowel Disease in Pregnancy

"BACKGROUND & AIMS: The management of inflammatory bowel disease (IBD) poses a particular challenge during pregnancy because the health of both the mother and the fetus must be considered. METHODS: A systematic literature search identified studies on the management of IBD during pregnancy. The quality of evidence and strength of recommendations were rated using the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. RESULTS: Consensus was reached on 29 of the 30 recommendations considered. Preconception counseling and access to specialist care are paramount in optimizing disease management. In general, women on 5-ASA, thiopurine, or anti-tumor necrosis factor (TNF) monotherapy for maintenance should continue therapy throughout pregnancy. Discontinuation of anti-TNF therapy or switching from combination therapy to monotherapy may be considered in very select low-risk patients. Women who have a mild to moderate disease flare while on optimized 5-ASA or thiopurine therapy should be managed with systemic corticosteroid or anti-TNF therapy, and those with a corticosteroid-resistant flare should start anti-TNF therapy. Endoscopy or urgent surgery should not be delayed during pregnancy if indicated. Decisions regarding cesarean delivery should be based on obstetric considerations and not the diagnosis of IBD alone, with the exception of women with active perianal Crohn's disease. With the exception of methotrexate, the use of medications for IBD should not influence the decision to breast-feed and vice versa. Live vaccinations are not recommended within the first 6 months of life in the offspring of women who were on anti-TNF therapy during pregnancy. CONCLUSIONS: Optimal management of IBD before and during pregnancy is essential to achieving favorable maternal and neonatal outcomes"

Intentional infliximab use during pregnancy for induction or maintenance of remission in Crohn's disease.

AIM: To study the effects of infliximab on pregnancy and foetal outcome. METHODS: We conducted a retrospective chart review of women with Crohn's disease treated intentionally with infliximab during pregnancy. The primary outcome measure was the occurrence of congenital malformations. Secondary outcome measures were the rate of premature birth, low-birth weight, small for gestational age infants, intrauterine growth retardation and caesarean section. RESULTS: Ten women were identified. Eight women received maintenance infliximab infusions throughout their pregnancy and two women received their initial infliximab infusions during pregnancy. All 10 pregnancies ended in live births. No infants had congenital malformations, intrauterine growth retardation or small for gestational age parameters. Three infants were premature and one had low-birth weight. Eight women had a caesarean section. CONCLUSIONS: This is the first reported series of intentional infliximab use throughout pregnancy. These data, combined with other studies of inadvertent use of infliximab during pregnancy, suggest that the benefits of infliximab in achieving response and maintaining remission in mothers with Crohn's disease may outweigh the risk to the foetus of exposure to the drug. Further prospective data collection will be helpful to confirm these findings.

Fistula response to methotrexate in Crohn's disease: a case series.

BACKGROUND: Controlled trials have demonstrated the efficacy of methotrexate in the induction and maintenance of remission in luminal Crohn's disease; however, its effect on fistulizing disease is unknown. AIM: To describe the response to methotrexate therapy in a series of patients with fistulizing Crohn's disease. METHODS: A retrospective chart review was conducted of all patients with Crohn's disease receiving methotrexate in one practice. The response of patients with fistulizing and luminal disease was assessed using clinical and laboratory criteria. Fistula response was categorized as either complete or partial closure. RESULTS: Thirty-seven courses of methotrexate therapy were given to 33 patients with luminal and/or fistulizing Crohn's disease. In 16 patients with fistulas, four (25%) had complete closure, five (31%) had partial closure and all had failed or were intolerant to 6-mercaptopurine therapy. Overall, response to methotrexate was seen in 23 of 37 (62%) treatment courses in patients with luminal and/or fistulizing Crohn's disease. Two of the 33 patients (6%) had a significant adverse event. CONCLUSIONS: In this case series, 56% of patients with Crohn's fistulas on methotrexate showed a complete or partial response to therapy. Further studies are needed to confirm the role of methotrexate alone, and in combination with other therapies, for the treatment of fistulizing Crohn's disease.

Evolving medical therapies for Crohn's disease.

Medical therapy for Crohn's disease has changed dramatically over the past few years. Physicians have become increasingly willing to use traditional immunosuppressive agents such as azathioprine/6-mercaptopurine (6-MP) and methotrexate as well as new biologic therapies such as infliximab. Azathioprine, 6-MP, and methotrexate have demonstrated efficacy in induction and maintenance of remission in Crohn's disease. 6-MP has also demonstrated efficacy in the pediatric population and possibly as first-line therapy. As use of the purine metabolites grows, therapeutic drug monitoring for efficacy and toxicity will become an emerging area of interest. With respect to the biologic therapies, infliximab is increasingly used to treat patients with difficult disease; however, knowledge is still evolving regarding optimal dosing schedules and the significance of immune reactions to the compound. A humanized anti-tumor necrosis factor antibody, CDP571, may be less immunogenic. Interleukin-10 did not consistently demonstrate benefit in Crohn's disease. Similarly, antisense to intracellular adhesion molecule 1 (ISIS 2302) was not efficacious when administered either subcutaneously or intravenously. Finally, growth hormone has shown promising results in a small trial.

Infliximab for the treatment of orofacial Crohn's disease.

Orofacial manifestations of Crohn's disease can be difficult to diagnose and treat. We report a case in which the orofacial lesions occurred 7 years prior to the diagnosis of underlying inflammatory bowel disease. The patient was refractory to mesalamine and systemic corticosteroids but responded to infliximab, the chimeric monoclonal antibody to tumor necrosis factor (TNF-alpha). A review of the literature of the orofacial granulomatoses is presented as well.

Intravenous azathioprine in severe ulcerative colitis: a pilot study.

OBJECTIVE: Azathioprine use in acute ulcerative colitis has been limited by its perceived long onset of action. The aim of this study was to determine the safety and clinical effect of an i.v. loading dose of azathioprine in the setting of severe steroid refractory ulcerative colitis. METHODS: Nine hospitalized patients with severe steroid refractory ulcerative colitis were enrolled. Patients 1-3 received 20 mg/kg i.v. azathioprine over 36 h. Patients 4-6 received 40 mg/kg i.v. azathioprine over 36 h. Patients 7-9 received 40 mg/kg i.v. azathioprine as three 8-h infusions over 3 days. Clinical remission was defined as steroid withdrawal and an Ulcerative Colitis Disease Activity Index score of 0. The Inflammatory Bowel Disease Questionnaire was obtained at each visit. White blood cell concentrations and erythrocyte concentrations of 6-thioguanine were obtained. RESULTS: Five of nine patients (56%) had a response and avoided colectomy. Three of nine patients (33%) met the definition for clinical remission. Response was seen within 4 wk. The mean 6-thioguanine concentration for those five patients at 12 wk after infusion was 148.2 pmol/8 x 10(8). Two patients had transient leukopenia and one had transient hepatotoxicity. CONCLUSIONS: Intravenous azathioprine appears to be safe and of clinical benefit in inducing response and avoiding colectomy in severe steroid refractory ulcerative colitis. Data from an i.v. azathioprine trial in Crohn's disease suggests oral dosing alone may obtain the same results. The role of oral dosing alone in severe ulcerative colitis and the role of azathioprine metabolite levels in monitoring efficacy should be investigated further.

Cloning and expression of an acyl-CoA dehydrogenase from Mycobacterium tuberculosis.

A gene from Mycobacterium tuberculosis coding for acyl-CoA dehydrogenase was cloned, overexpressed and characterized on the basis of enzyme activity with various chain length substrates. The results show that the protein is a medium chain acyl-CoA dehydrogenase (MCADH). The mycobacterium protein expressed appears to be unique, since by comparison, the active site glutamic acid of the protein does not lie in the same position as other well characterized MCADH, but in a position present in long chain and isovaleryl acyl-CoA dehydrogenases (LCADH and IVDH).