Saturday, June 14, 2014
CHICAGO (FRONTLINE MEDICAL NEWS) – Treating diarrhea-predominant irritable bowel syndrome with mesalazine for 12 weeks failed to improve stool frequency or other symptoms, compared with placebo, in a multicenter, randomized double-blind trial with 115 patients. Stool frequency decreased in both groups from a mean of four bowel movements per day to three per day by weeks 11 and 12. Mesalazine (also known as mesalamine or 5-aminosalicylic acid) also produced no significant differences, compared with placebo, in secondary outcomes, including abdominal pain scores, stool consistency, satisfactory relief of symptoms of irritable bowel syndrome (IBS), anxiety, depression, or Patient Health Questionnaire–12 Somatic Symptoms scores, Dr. Ching Lam reported at the annual Digestive Disease Week. Patients took 2 g/day of mesalazine or placebo for 1 week and then increased the dose to 2 g b.i.d. if they could tolerate it. All were adults with diarrhea-predominant IBD who had completed a prerandomization 2-week stool diary showing a stool frequency of at least three per day for more than 2 days per week and a stool consistency of at least 25% type 5-7 and less than 25% type 1-2 on the Bristol Stool Form Scale. All underwent a baseline colonoscopy/sigmoidoscopy before randomization to exclude patients with microscopic or inflammatory colitis. The study also excluded patients who were taking NSAIDs or other drugs that affect gut motility and patients with a history of abdominal surgery or renal or liver impairment. The study initially randomized 136 patients, but 11 in the mesalazine group and 10 on placebo were excluded from the intent-to-treat analysis of results because they withdrew consent, were lost to follow-up, or had an incomplete stool diary at weeks 11-12, or because results were not available due to adverse events, said Dr. Lam of Nottingham (England) University. Clinicians had been interested in mesalazine for diarrhea-predominant IBS because small randomized, controlled pilot studies and some open-label studies had suggested that the drug might improve IBS symptoms of abdominal pain and stool frequency and consistency, especially in patients with postinfectious IBS. The drug is approved to treat ulcerative colitis and some other bowel diseases. Those earlier studies also suggested that mesalazine might reduce the numbers of mast cells in unselected cohorts of patients with IBS. In the current study, a subgroup of patients did show elevations in “mast cell percent area stained,” and this correlated weakly with urgency and stool consistency, but mesalazine treatment did not reduce the mast cell percent area stained, Dr. Lam reported. An analysis of results for a small subgroup of patients with postinfectious IBS suggested that mesalazine may benefit them, “but this requires a larger, adequately powered study to confirm,” she said. Better phenotyping of the heterogeneous group of patients with IBS and diarrhea would help evaluate any new treatments, she added. British government agencies funded the trial. Several of Dr. Lam’s coinvestigators reported financial associations with multiple pharmaceutical companies.
Posted by Dr. Walid Y. Farah at 11:01 AM
CHICAGO (FRONTLINE MEDICAL NEWS) – Women with inflammatory bowel disease can safely continue monotherapy with azathioprine/6-mercaptopurine or antitumor necrosis–alpha agents during pregnancy to maintain remission, according to an analysis of 1,289 women and 1,039 live births. Infants exposed to azathioprine/6 MP and anti-TNF-alpha agents achieve developmental milestone scores at rates similar to unexposed infants and do not have higher rates of congenital anomalies, lead author Dr. Uma Mahadevan said at the annual Digestive Disease Week. Overall, there were 55 congenital anomalies, with 21 diagnosed at birth. Events were similar among infants with in utero exposure to azathioprine, anti-TNF agents, combination therapy, and those with no drug exposure (12 vs. 17 vs. 7 vs. 19 events). Exposure was defined as any use of azathioprine/6 MP or the anti-TNF-alpha agents infliximab (Remicade), adalimumab (Humira), or certolizumab pegol (Cimzia) at any time from 3 months prior to conception to the end of the pregnancy. Nine women had exposure to the recombinant monoclonal antibody natalizumab (Tysabri) and were included in the anti-TNF agents group. The analysis was based on the PIANO registry, a prospective cohort of pregnant women with IBD who were followed by telephone or in-person questionnaire at every trimester, at delivery, at 4, 9, and 12 months after delivery, and annually for the first 4 years of their child’s life. Seven women received their diagnosis of IBD during pregnancy, 59.4% had Crohn’s disease, 38.3% ulcerative colitis, and 2.3% were indeterminate. Two-thirds of women reported breastfeeding, with unexposed women significantly more likely to breastfeed than women with exposure to azathioprine, anti-TNF agents, or combination therapy (85% vs. 65% vs. 71% vs. 61%; P less than .0001). After controlling for drug exposure, breastfeeding was not associated with an increased risk of infant infection or reduced height or weight, reported Dr. Mahadevan, with the University of California San Francisco. Infants exposed to combination therapy, however, had higher rates of preterm birth, after adjustment for none/mild vs. moderate/severe IBD activity (odds ratio, 2.6; P less than .05). Infants exposed to combination therapy who were born to mothers with ulcerative colitis also had increased rates of preterm birth (odds ratio, 4.9), low birth weight (OR, 6.1), and NICU stay (OR, 3.9). One possible reason for this signal is that women with ulcerative colitis in the PIANO registry, as well as two other studies, have more disease activity during pregnancy, Dr. Mahadevan suggested. Another possibility is that mothers with ulcerative colitis may have low levels of untreated inflammation. With just 161 women available for analysis, the PIANO investigators previously reported a significant increase in infant infections at 12 months of age in those exposed to combination infliximab or adalimumab plus azathioprine. Most anti-TNF agents cross the placenta in the second and third trimester, which has raised concerns about immune system development and risk of subsequent infections. In the current analysis, there was no increase in infant infections when the investigators looked at all anti-TNF drugs. “But when we removed certolizumab from the analysis, it was significant just as it was 2 years ago,” Dr. Mahadevan said in an interview. “Certolizumab is not actively transported across the placenta. Fortunately, the majority of the infections were minor, including otitis media and upper respiratory infections.” Developmental milestones Overall, infants exposed to azathioprine or anti-TNF agents were found to achieve developmental milestones at rates similar to unexposed infants of mothers with IBD based on Denver Childhood Developmental Test and Ages and Stages Questionnaire scores, she said. After controlling for preterm birth, the mean developmental milestone score at 4 months was 0.92 for infants with no drug exposure, with a nonsignificant mean delta difference of 0.01, 0.01, 0.00 points for infants exposed to azathioprine, anti-TNF agents, and combination therapy, respectively. In a surprising twist, infants exposed to anti-TNF agents alone actually had significantly better scores at 12 months than unexposed infants, bettering the average score of 0.81 in the unexposed group by a mean delta of 0.02 points (P = .01), Dr. Mahadevan said. “I wouldn’t interpret this data [as indicating] that biologics make your baby smarter. I think the key thing is that it doesn’t make it worse,” she remarked. “When you see the deltas, they are pretty small.” On the Ages and Stages Questionnaire, the biologic group had significantly better mean scores than the unexposed group for gross motor skills at 36 months (55.94 vs. 47.53; P = .01), gross motor skills at 48 months (60 vs. 51.20; P = .02), fine motor skills at 48 months (53.50 vs. 42.11; P = .01), and personal/social interaction at 48 months (58 vs. 51.93; P = .04). The azathioprine-exposed group always had better scores than the unexposed group, Dr. Mahadevan said. Where it was statistically significant was for personal/social interaction at 24 months (50.75 vs. 47.34; P = .04), problem solving at 36 months (mean 52.04 vs. 48.66; P = .05), and problem solving at 48 months (mean 59.92 vs. 57.66; P = .02). Dr. Mahadevan observed that the data may change because not all infants have reached each time point and may not reflect outcomes in lower socioeconomic groups since more than 90% of women were of similar socioeconomic and educational status. Still, the findings are reassuring in the absence of any randomized controlled trials. A recent report found children born to mothers with IBD had higher rates of attention-deficit hyperactivity disorder and gross motor abnormalities (J. Crohns Colitis 2013;7:542-50), while a case series reported normal neuropsychological development in 25 consecutive children exposed in utero to TNF-alpha inhibitors (Inflamm. Bowel Dis. 2014;20:495-501), she noted. A recent systematic review of 58 articles or abstracts also found no association between TNF-alpha inhibitor use during pregnancy with IBD and adverse pregnancy outcomes, congenital abnormalities, or infections in the first year of life (BMC Medicine 2013;11:174). The study was supported by the Crohn’s and Colitis Foundation of America. Dr. Mahadevan reported serving as an advisor for Janssen-Cilag, AbbVie, Takeda, and UCB Pharma, and receiving research grants from Prometheus Laboratories and GlaxoSmithKline.
Posted by Dr. Walid Y. Farah at 10:56 AM