Míriam Mañosa

Safety of Thiopurines and Anti-TNF-α Drugs During Pregnancy in Patients With Inflammatory Bowel Disease

OBJECTIVES:The safety of thiopurines and anti-tumor necrosis factor-α (TNF-α) drugs during pregnancy remains controversial, as the experience with these drugs in this situation is limited. Our aim is to assess the safety of thiopurines and anti-TNF-α drugs for the treatment of inflammatory bowel disease (IBD) during pregnancy.METHODS:Retrospective, multicenter study in IBD patients. Pregnancies were classified according to the therapeutic regimens during pregnancy or during the 3 months before the conception: non-exposed group, pregnancies exposed to thiopurines alone (group A), and pregnancies exposed to anti-TNF-α drugs (group B). An unfavorable Global Pregnancy Outcome (GPO) was considered if pregnancy developed with obstetric complications in the mother and in the newborn.RESULTS:A total of 187 pregnancies in the group A, 66 pregnancies in the group B, and 318 pregnancies in the non-exposed group were included. The rate of unfavorable GPO was different among the three groups (31.8% in non-exposed group, 21.9% in group A, and 34.8% in group B), being lower in pregnancies under thiopurines than among non-exposed (P=0.01). The rate of pregnancy complications was similar among the three groups (27.7% in non-exposed, 20.9% in group A, and 30.3% in group B). The rate of neonatal complications was different among the three groups (23.3% in non-exposed group, 13.9% in group A, and 21.2% in group B), being lower in pregnancies under thiopurines than among non-exposed (P=0.01). In the multivariate analysis, the treatment with thiopurines (odds ratio=0.6; 95% confidence interval=0.4–0.9, P=0.02) was the only predictor of favorable GPO, whereas maternal age >35 years at conception was the only predictor of unfavorable GPO. The treatment with anti-TNF-α drugs was not associated with an unfavorable GPO.CONCLUSION:The treatment with thiopurines and anti-TNF-α drugs does not seem to increase the risk of complications during pregnancy and does seem to be safe for the newborn.

Medication-Taking Behavior in a Cohort of Patients with Inflammatory Bowel Disease

Recent studies have shown a low adherence rate to maintenance treatment in patients with inflammatory bowel disease (IBD). We sought to assess the medication-taking behavior in a cohort of patients with IBD. We prospectively included IBD patients from the outpatient clinic who agreed to answer a questionnaire about prescribed treatment and adherence. Physicians registered clinical data including prescribed medications. Two hundred fourteen patients (115 Crohns disease/99 ulcerative colitis) were included. The most prescribed medications were oral mesalazine (56.5%) and immunomodulators (41.1%). Forty-three percent of patients admitted to occasionally forgetting to take their medication but only 7.5% of them did it voluntary. Oral mesalazine and azathioprine were the drugs with the poorest compliance, with nonadherence rates of 45% and 25% of the total prescribed doses, respectively. The only factor associated with a better adherence was a more complicated course of the disease—steroid dependency, steroid refractoriness, need for infliximab treatment, hospitalization, or surgery (P=.02). Twenty percent of patients admitted to self-medicating. An important proportion of patients with IBD admit to forget some doses of the prescribed medication in the setting of a specialized unit of a referral centre.

Infliximab salvage therapy after failure of ciclosporin in corticosteroid-refractory ulcerative colitis: a multicentre study

Aliment Pharmacol Ther 2012; 35: 275–283

Long-term durability of infliximab treatment in Crohn's disease and efficacy of dose "escalation" in patients losing response.

Background The efficacy of infliximab therapy in patients with Crohns disease (CD) is unknown beyond 12 months. For patients who lose their initial response, consideration can be given to dose “escalation” to regain therapeutic benefit. Aim Our primary goal was to evaluate the long-term durability of maintenance infliximab treatment. The secondary goals were to identify potential predictors of loss of infliximab efficacy, to evaluate the response to infliximab escalation, and the safety of the treatment with infliximab with and without escalation of dose. Methods CD patients treated with infliximab with response to an induction regimen were evaluated. Maintenance of long-term response was estimated using Kaplan-Meier analysis. The effect of specific variables was calculated using logistic regression analysis. Efficacy of dose escalation in patients who lose response to infliximab was analyzed. Results Three hundred and nine CD patients were included. The mean follow-up time with infliximab treatment was 41 months, and the majority (95%) were on concomitant immunosuppressive therapy. The annual risk of loss of response to infliximab was 12% per patient-year of treatment. After loss of response, 41% of patients were managed with infliximab therapy escalation. After the first intensified dose, 56% of patients achieved remission and 40% partial response. Concurrent immunomodulators enhanced and smoking decreased the proportion of patients who maintained response (P<0.05). Conclusions A relevant proportion of CD patients on long-term infliximab treatment loss response. After loss of response, a high proportion of these patients initially respond to infliximab dose escalation. Concurrent immunomodulators may increase and smoking may decrease maintenance of response.

Omega-3 fatty acids and inflammatory bowel diseases – a systematic review

BACKGROUND & AIM Despite their well known anti-inflammatory actions, the clinical usefulness of omega-3 PUFA in inflammatory bowel disease is controversial. We aimed to systematically review the available data on the performance of omega-3 PUFA as therapeutic agents in these patients. METHODS Electronic databases were systematically searched for RCT of fish oil or omega-3 PUFA therapy in both active and inactive ulcerative colitis or Crohns disease, without limitation on either the length of therapy or the form it was given, including nutritional supplements and enteral formula diets. Eligible articles were assessed for methodological quality on the basis of the adequacy of the randomisation process, concealment of allocation, blinding of intervention and outcome, possible biases, and completeness of follow-up. The five-point Oxford quality score was calculated. RESULTS A total of 19 RCT were finally selected for this review. Overall, available data do not allow to support the use of omega-3 PUFA supplementation for the treatment of both active and inactive inflammatory bowel disease. Negative results are quite consistent in trials assessing the use of omega-3 PUFA to maintain disease remission, particularly ulcerative colitis, and to a lesser extent Crohns disease. Trials on their use in active disease do not allow to draw firm conclusions mainly because the heterogeneity of design (ulcerative colitis) or their short number (Crohns disease). In most trials, the appropriateness of the selected placebo is questionable. CONCLUSION The present systematic review does not allow to make firm recommendations about the usefulness of omega-3 PUFA in inflammatory bowel disease.

Impact of azathioprine on the prevention of postoperative Crohn's disease recurrence: Results of a prospective, observational, long-term follow-up study

Background: Postoperative recurrence (PR) occurs early after intestinal resection in >75% of Crohns disease (CD) patients. No well‐established strategy for long‐term PR prevention is available. The aim was to prospectively evaluate the long‐term endoscopic and clinical outcomes of postoperative CD on maintenance treatment with azathioprine (AZA), especially in patients who developed endoscopic lesions confined to the ileocolic anastomosis. Methods: Long‐term AZA therapy (2–2.5 mg/kg/day) was initiated immediately after surgery in 56 consecutive patients who underwent a curative intestinal resection. Clinical and biological assessments every 3 months, as well as yearly endoscopic evaluation, were performed until the end of the study or clinical PR (CPR). Results: Thirty‐seven patients (70%) showed mucosal lesions at endoscopy after a median of 12 months (range 12–60); however, in 15 of these patients lesions were confined to the anastomosis and only 6 showed endoscopic progression, but none of them developed CPR. Among the remaining 22 patients with endoscopic PR (EPR), 23% suffered a CPR during follow‐up. Thirty percent of patients remained free of EPR after a median follow‐up of 33 months (range 12–84). The cumulative probability of EPR was 44%, 53%, 69%, and 82%, at 1, 2, 3, and 5 years, respectively. No predictive factors of EPR were found. Conclusions: Early postoperative use of AZA seems to delay EPR development in comparison to historical series or placebo groups in randomized controlled trials. Although usually considered as endoscopic recurrence, those lesions confined to the ileocolonic anastomosis are not likely to progress or to become symptomatic in the short term.

Infliximab Rescue Therapy after Cyclosporin Failure in Steroid-Refractory Ulcerative Colitis

Background: Cyclosporin (CsA) and infliximab (IFX) have proven efficacy in avoiding colectomy in patients with steroid-refractory ulcerative colitis (UC). Aim: To assess the clinical outcome of patients treated with IFX after CsA failure for acute steroid-refractory flares of UC. Methods: Medical records of patients with a steroid-refractory UC flare who did not respond to CsA or relapsed soon after hospital discharge, and who followed rescue therapy with IFX, were reviewed retrospectively. Results: Sixteen patients were included, 69% with extensive UC. Thirteen patients had moderate-to-severe disease activity at the time IFX was started. Median time between CsA discontinuation and the first IFX infusion was 19 days. Thirteen patients completed an induction regimen, and 6 of them followed scheduled maintenance treatment with IFX. After a median time of follow-up from the first IFX infusion of 195 days, 6 patients (37.5%) required colectomy. Median time for colectomy was 47 days. There were no deaths or malignancies, and only one septic complication was recorded. Conclusions: IFX rescue therapy might avoid short-term colectomy in a proportion of steroid-refractory UC patients who do not respond to CsA, but systematic use of sequential rescue therapy is not recommended until more data about its safety profile is available.

Efficacy of infliximab rescue therapy in patients with chronic refractory pouchitis: A multicenter study

Background: Despite medical therapy, 30% of patients with ulcerative colitis (UC) need to undergo surgery. Around 50% of patients with proctocolectomy with ileal pouch–anal anastomosis (IPAA) develop complications of the pouch. Clinical evidence for the use of infliximab (IFX) in refractory pouchitis is limited. The aim of this study was to report efficacy of IFX in these patients. Methods: A retrospective, multicenter study was designed. Patients older than 18 years with chronic refractory pouchitis treated with IFX (5 mg/kg) were included. Short‐term IFX efficacy was evaluated at week 8 and mid‐term efficacy at weeks 26 and 52. Complete response was defined as cessation of diarrhea and urgency and partial response as marked clinical improvement but persisting symptoms. The modified Pouchitis Disease Activity Index (mPDAI) without endoscopy was calculated when available. Results: Thirty‐three consecutive UC patients with chronic refractory pouchitis were included (18 male, mean age 45 years, range 21–67). At week 8, 21% patients achieved complete response and 63% showed partial clinical response. At weeks 26 and 52, 33% and 27% achieved complete response and 33% and 18% showed partial clinical response, respectively. Thirteen patients (39%) withdrew treatment (four for lack of efficacy, four for loss of response and five for adverse events). None of the potential factors analyzed had an influence on response to IFX. Conclusions: IFX was effective in the short‐ and mid‐term in patients with chronic refractory pouchitis. However, medication had to be discontinued in a high number of patients. (Inflamm Bowel Dis 2011;)

Addition of metronidazole to azathioprine for the prevention of postoperative recurrence of Crohn's disease: a randomized, double-blind, placebo-controlled trial.

Background:Endoscopic recurrence occurs in up to 80% of patients with Crohn’s disease 1 year after intestinal resection. Imidazole antibiotics, thiopurines, and particularly their combination have proven efficacy in preventing endoscopic recurrence. The aim of the study was to compare the efficacy of the addition of metronidazole (for 3 months after the surgical treatment) to azathioprine for the prevention of postsurgical endoscopic recurrence. Methods:A pilot study was made of 50 patients with Crohn’s disease undergoing intestinal resection with ileocolic anastomosis and treated with 2 to 2.5 mg/kg of azathioprine per day for 1 year. The patients were randomized to receive additional 15 to 20 mg/kg of metronidazole per day or placebo for the first 3 months (n = 25 per arm). Endoscopic assessment was performed 6 and 12 months after the surgical resection. The primary end point was the prevention of endoscopic recurrence as defined by a Rutgeerts score of <2 at 6 months. The initial sample size had an 80% statistical power in detecting an absolute risk reduction of ≥30%. Results:Endoscopic recurrence occurred in 28% and 44% of the patients at 6 months (P = 0.19) and in 36% and 56% (P = 0.15) at 12 months in the metronidazole and placebo groups, respectively. No statistically significant differences were found between the treatment groups regarding severe endoscopic recurrence (Rutgeerts score ≥ 3) at 6 and 12 months. Likewise, there were no differences in the rate of adverse events between the treatment groups. Conclusions:The addition of metronidazole to azathioprine did not significantly reduce the risk of endoscopic recurrence beyond azathioprine alone in this study but does not worsen its safety profile.

Infliximab safety profile and long-term applicability in inflammatory bowel disease: 9-year experience in clinical practice

Aliment Pharmacol Ther 31, 553–560