Uma Mahadevan

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.

Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease.

BACKGROUND & AIMS Some women with inflammatory bowel disease require therapy with tumor necrosis factor (TNF) antagonists during pregnancy. It is not clear whether these drugs are transferred to the fetus via the placenta and then cleared, or whether structurally different TNF antagonists have different rates of transfer. METHODS We studied 31 pregnant women with inflammatory bowel disease receiving infliximab (IFX, n = 11), adalimumab (ADA, n = 10), or certolizumab (CZP, n = 10). Serum concentrations of the drugs were measured at birth in the mother, infant, and in cord blood, and then monthly in the infant until the drugs were undetectable. Drug concentrations in the cord and the infant at birth were compared with those of the mother. RESULTS Concentrations of IFX and ADA, but not CZP, were higher in infants at birth and their cords than in their mothers. The levels of CZP in infants and their cords were less than 2 μg/mL. The median level of IFX in the cord was 160% that of the mother, the median level of ADA in the cord was 153% that of the mother, and the median level of CZP in the cord was 3.9% that of the mother. IFX and ADA could be detected in the infants for as long as 6 months. No congenital anomalies or serious complications were reported. CONCLUSIONS The TNF antagonists IFX and ADA are transferred across the placenta and can be detected in infants at birth; the drugs were detected in infants up to 6 months after birth. CZP has the lowest level of placental transfer, based on levels measured in cords and infants at birth, of the drugs tested.

The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD With the European Crohn's and Colitis Organisation: Pregnancy and Pediatrics

Women with inflammatory bowel disease (IBD) have similar rates of fertility to the general population, but have an increased rate of adverse pregnancy outcomes compared with the general population, which may be worsened by disease activity. Infertility is increased in those undergoing ileal pouch–anal anastomosis. Anti-tumor necrosis factor therapy in pregnancy is considered to be low risk and compatible with use during conception in men and women and during pregnancy in at least the first two trimesters. Infliximab (IFX) and certolizumab pegol are also compatible with breastfeeding, but safety data for adalimumab (ADA) are awaited. The safety of natalizumab during pregnancy is unknown. For children with Crohns disease (CD), IFX is effective at inducing and maintaining remission. Episodic therapy is not as effective as scheduled infusions. Disease duration in children does not appear to affect the efficacy of IFX. IFX promotes growth in prepubertal and early pubertal Crohns patients. It is also effective for the treatment of extraintestinal manifestations. ADA is effective for children with active CD and for maintaining remission, even if they have lost response to IFX, although there are fewer data. Vaccination of infants exposed to biological therapy in utero should be given at standard schedules during the first 6 months of life, except for live-virus vaccines such as rotavirus. Inactivated vaccines may be safely administered to children with IBD, even when immunocompromised.

Ciprofloxacin or metronidazole for the treatment of perianal fistulas in patients with Crohn's disease: a randomized, double-blind, placebo-controlled pilot study.

Background: Although metronidazole and ciprofloxacin are used to treat perianal Crohns disease (CD), no placebo‐controlled trials have been performed. Methods: We performed a placebo‐controlled pilot trial to evaluate the efficacy and safety of metronidazole and ciprofloxacin in patients with perianal CD. Twenty‐five patients with CD and actively draining perianal fistulas were randomized to receive ciprofloxacin 500 mg, metronidazole 500 mg, or placebo twice daily for 10 weeks. Remission and response of perianal fistulas were defined as closure of all fistulas and closure of at least 50% of fistulas that were draining at baseline, respectively. The primary endpoint was remission at 10 weeks. Results: Ten patients were randomized to ciprofloxacin, 7 to metronidazole, and 8 to placebo. Remission at week 10 occurred in 3 patients (30%) treated with ciprofloxacin, no patients (0%) treated with metronidazole, and 1 patient (12.5%) treated with placebo (P = 0.41). Response at week 10 occurred in 4 patients (40%) treated with ciprofloxacin, 1 patient (14.3%) treated with metronidazole, and 1 patient (12.5%) treated with placebo (P = 0.43). Termination of the trial prior to week 10 occurred in 1 patient (10%) treated with ciprofloxacin, 5 patients (71.4%) treated with metronidazole, and 1 patient (12.5%) treated with placebo (P < 0.02). No serious adverse events occurred. Conclusion: Remission and response occurred more frequently in patients treated with ciprofloxacin but the differences were not significant in this pilot study. Ciprofloxacin was well tolerated.

Diagnosis and management of pouchitis

The disease pouchitis was first reported by Kock 1 in 1977 as an inflammatory condition of the continent ileal reservoir (Kock pouch) in patients who had undergone proctocolectomy. The Kock pouch was later replaced by the ileal pouch anal anastomosis (IPAA, also known as the ileoanal pouch) which was independently described by Parks and Utsunomiya 2,3 in 1980. The ileoanal pouch is now the surgical option of choice in patients with familial adenomatous polyposis (FAP) and ulcerative colitis (UC) with either dysplasia or disease refractory to medical therapy. Pouchitis is the most common long-term complication of IPAA in UC. 4 This review discusses the diagnostic criteria, cause, and management of acute and chronic pouchitis.

865 PIANO: A 1000 Patient Prospective Registry of Pregnancy Outcomes in Women With IBD Exposed to Immunomodulators and Biologic Therapy

Close Monitoring of CRP and Fecal Calprotectin is Able to Predict Clinical Relapse in Patients With Crohns Disease in Remission After Infliximab Withdrawal. a Sub-Analysis of the Stori Study Nicolas de Suray, Julia Salleron, Gwenola Vernier-Massouille, Jean-Charles Grimaud, Yoram Bouhnik, David Laharie, Jean-Louis Dupas, Helene PillantLe Moult, Laurence Picon, Michel Veyrac, Mathurin Flamant, Guillaume Savoye, Raymond Jian, Martine De Vos, Eric Piver, Jean-Frederic Colombel, Edouard Louis

Adalimumab use in pregnancy

Infliximab, a chimeric antibody to tumour necrosis factor alpha (TNF-α), has demonstrated efficacy for the induction and maintenance of remission in patients with Crohn’s disease.1,2 Antibodies to the chimeric component of infliximab can lead to infusion reactions and possible loss of response.3 A human recombinant monoclonal antibody to TNF-α, adalimumab, has recently demonstrated safety and efficacy for induction of remission in Crohn’s disease.4 It has also been effective in patients who have lost response to infliximab.5 Currently, this drug is FDA approved for the treatment of rheumatoid arthritis but it is being administered off label to patients with Crohn’s disease who …

IL-22+ CD4+ T Cells Are Associated with Therapeutic Trichuris trichiura Infection in an Ulcerative Colitis Patient

IL-22+ CD4+ cells are associated with Trichuris trichiura infection in an ulcerative colitis patient. It Wiggles and Jiggles and Tickles Inside Although we all know that the old lady from the famed nursery rhyme swallowed the spider to catch the fly, no one knows why she swallowed the fly. We do know why the patient described in the study by Broadhurst et al. swallowed some worms—more specifically eggs of the helminth Trichuris trichiura—to treat his ulcerative colitis. What remains unknown are the root causes of ulcerative colitis, a form of inflammatory bowel disease. Now, Broadhurst et al. not only provide insight into the physiological effects of helminth infection on ulcerative colitis, they also glean some hints about potential targets for treating the underlying disease. Ulcerative colitis is characterized by open sores or ulcers in the lining of the colon. The disease is associated with defects in immune regulation and is usually treated with immunosuppressive drugs. Parasitic worms, or helminths, modulate the immune response to survive within the guts of hosts. Because ulcerative colitis is more common in developed countries than in regions of the world with endemic helminth infections, researchers have proposed that ingestion of the worms may provide relief for colitis patients. The study by Broadhurst et al. examines the potential mechanism that governs the relationship between parasitic whipworms and ulcerative colitis in a patient who ingested T. trichiura in lieu of other forms of treatment. They found that tissue that is actively affected by colitis has high numbers of immune cells that express the inflammatory cytokine interleukin-17 (IL-17) in the absence of the mucosal–healing cytokine IL-22. However, after helminth exposure, the disease went into remission, and IL-22–producing immune cells predominated. The authors then further profiled the molecular signals associated with ulcerative colitis in the presence and absence of helminth infection. This approach revealed that active ulcerative colitis is associated with an inflammatory signal, whereas helminth infection was associated with increased carbohydrate and steroid metabolism. These profiles suggest new targets for treating ulcerative colitis, although care must be taken because helminth infection sometimes results in an inflammatory response similar to that seen in inflammatory bowel disease. As with the old lady who swallowed the fly, we must be cautious that the treatment is not worse than the disease. No one wants to swallow a horse. Ulcerative colitis, a type of inflammatory bowel disease, is less common in countries endemic for helminth infections, suggesting that helminth colonization may have the potential to regulate intestinal inflammation in inflammatory bowel diseases. Indeed, therapeutic effects of experimental helminth infection have been reported in both animal models and clinical trials. Here, we provide a comprehensive cellular and molecular portrait of dynamic changes in the intestinal mucosa of an individual who infected himself with Trichuris trichiura to treat his symptoms of ulcerative colitis. Tissue with active colitis had a prominent population of mucosal T helper (TH) cells that produced the inflammatory cytokine interleukin-17 (IL-17) but not IL-22, a cytokine involved in mucosal healing. After helminth exposure, the disease went into remission, and IL-22–producing TH cells accumulated in the mucosa. Genes involved in carbohydrate and lipid metabolism were up-regulated in helminth-colonized tissue, whereas tissues with active colitis showed up-regulation of proinflammatory genes such as IL-17, IL-13RA2, and CHI3L1. Therefore, T. trichiura colonization of the intestine may reduce symptomatic colitis by promoting goblet cell hyperplasia and mucus production through TH2 cytokines and IL-22. Improved understanding of the physiological effects of helminth infection may lead to new therapies for inflammatory bowel diseases.

European evidenced-based consensus on reproduction in inflammatory bowel disease

Inflammatory bowel diseases (IBD) typically affect patients in their reproductive years. It has been shown that reproductive issues are of key concern to IBD patients,1 especially women.2 In this respect, it is important to note that IBD patients remain voluntary childless more frequently than non-IBD controls.1,3,4 A recent study reported that IBD patients refrain from having children due the concerns about the adverse reproductive outcome.1 Fear of side-effects of the medication on the child and medical advice given by physicians, were the most important reasons for voluntary childlessness in this study. The treatment of IBD patients wishing to conceive is surrounded with uncertainties both for the parents to be and the treating physician. This guideline is developed to address these uncertainties and to promote a European perspective on reproduction in inflammatory bowel disease patients. The strategy to reach consensus involved the following steps: 1. The development of questions that should be covered by these pregnancy guidelines. Participants were asked to review these questions and when necessary to adjust or add questions. 2. The participants met in London in November to agree on the questions 3. The participants performed a systematic literature search of their topic with the appropriate key words using Medline/Pubmed and the Cochrane database, as well as their own files. The evidence level was graded (Table 1) according to the Oxford Centre for Evidence-Based medicine 5. 4. Provisional statements of the participants were written and the participants met in Prague in February 2010 to agree on the statements. This was done by projecting the statements and revising them on screen until a consensus was reached. Consensus was defined as agreement by > 80% of the participants. Each recommendation was graded as stated above. 5. The final document on each topic was written by the …

Systematic review and meta-analysis on the effects of thiopurines on birth outcomes from female and male patients with inflammatory bowel disease

Background:Inflammatory bowel disease (IBD) affects people during their prime reproductive years. The thiopurines (6-mercaptopurine and azathioprine), commonly used for induction and maintenance of remission, are U.S. Food and Drug Administration (FDA) pregnancy category D, raising concern for fetal risk. We performed a systematic review and meta-analysis to evaluate the effects of thiopurine exposure during pregnancy or at the time of conception on three measures of fetal risk in women and men with IBD. Methods:A systematic search of PubMed and Web of Science using a combination of Mesh and text terms was performed to identify studies reporting birth outcomes from IBD women and men exposed to thiopurines within 3 months of conception and/or during pregnancy. A meta-analysis was performed using the random effects model to pool estimates and report odds ratio (OR) for three outcomes in women: low birth weight (LBW), preterm birth, and congenital abnormalities and one in men: congenital abnormalities. Results:In women with IBD exposed to thiopurines, the pooled ORs for LBW, preterm birth, and congenital abnormalities were 1.01 (95% confidence interval [CI] 0.96, 1.06), 1.67 (95% CI 1.26, 2.20), and 1.45 (95% CI 0.99, 2.13), respectively. In men, the pooled OR for congenital abnormality was 1.87 (95% CI 0.67, 5.25). Conclusions:Thiopurine exposure in women with IBD was not associated with LBW or congenital abnormalities, but was associated with preterm birth. Exposure in men at the time of conception was not associated with congenital abnormalities.