Esther Garcia-Planella

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.

Cytomegalovirus infection in ulcerative colitis: A prospective, comparative study on prevalence and diagnostic strategy

Background: Cytomegalovirus (CMV) infection has been reported in ulcerative colitis (UC), especially in severe, steroid‐refractory disease. However, its role in steroid‐refractoriness remains unknown. Our goals were to evaluate the prevalence of CMV disease in UC, the best diagnostic strategy, and the influence of disease activity and/or treatment in its development. Methods: Prospective, observational study including 114 subjects with active UC requiring intravenous steroids, steroid‐refractory UC, inactive UC on mesalamine, inactive UC on azathioprine, and healthy controls. CMV antibodies, pp65‐antigenemia, and rectal biopsies for hematoxylin and eosin staining, immunohistochemistry, and CMV‐pp67 mRNA were performed. These procedures were repeated after medical treatment only in patients with active UC. CMV disease was defined by the presence of inclusion bodies and/or positive immunohistochemistry in colonic biopsies. Results: CMV disease was found in 6 steroid‐refractory, CMV‐IgG‐positive UC patients but not among controls, inactive UC, or steroid‐responding UC patients. In 5 out of the 6 patients, CMV disease was diagnosed after 7–10 days on cyclosporine. Conclusions: CMV disease in UC only affects seropositive, steroid‐refractory UC patients. Steroid/cyclosporine treatment together with disease activity may predispose to latent colonic CMV reactivation. The impact of antiviral therapy on the clinical outcome of these patients remains to be elucidated.

Safety of thiopurine therapy in inflammatory bowel disease: long-term follow-up study of 3931 patients.

Background:To evaluate the safety of thiopurines in patients with inflammatory bowel disease. To identify predictive factors associated with the development of thiopurine-induced adverse events. Methods:Long-term incidence of adverse events was estimated in patients from a prospectively maintained Spanish nationwide database using Kaplan–Meier analysis. Cox regression analysis was performed to identify potential predictive factors of adverse events. Results:Three thousand nine hundred and thirty-one patients were included. Ninety-five percent of patients were on azathioprine. The median follow-up with thiopurines was 44 months (range, 0–420). Adverse events occurred at a median of 1 month after starting treatment. The cumulative incidence of adverse events was 26%, with an annual risk of 7% per patient-year of treatment. Most frequent adverse events were nausea (8%), hepatotoxicity (4%), myelotoxicity (4%), and pancreatitis (4%). Four patients had lymphoma. Female and Crohns disease increased the risk of having nausea. The risk of hepatotoxicity was lower in females and higher in Crohns disease. The risk of myelotoxicity was significantly higher in patients treated with mercaptopurine and in females. The risk of pancreatitis was higher in Crohns disease. Overall, 17% of patients discontinued thiopurine treatment due to adverse events. Thirty-seven percent of these patients started thiopurines again and 40% of them had adverse events again. Conclusions:As many as 1 of 4 patients on thiopurine therapy had adverse events during follow-up. A relatively high proportion of patients (17%) had to discontinue the treatment with thiopurines due to adverse events. However, more than half of patients that restarted thiopurine treatment after its discontinuation due to adverse events tolerated it. Several predictive factors for some adverse events have been identified.

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

Azathioprine without oral ciclosporin in the long-term maintenance of remission induced by intravenous ciclosporin in severe, steroid-refractory ulcerative colitis

Background : Intravenous ciclosporin is considered to be the only alternative to avoid surgery in severe, steroid‐refractory ulcerative colitis. In responders, some authors recommend a switch to oral ciclosporin to act as a ‘bridge’ until the therapeutic action of azathioprine is achieved for maintenance treatment.

Clinical evolution of luminal and perianal Crohn's disease after inducing remission with infliximab: how long should patients be treated?

Background:  Few data are available regarding the evolution of Crohns disease after discontinuing a successful course of infliximab.

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.

Epidemiological risk factors in microscopic colitis: a prospective case-control study.

Background:The cause of collagenous colitis (CC) and lymphocytic colitis (LC) is unknown and epidemiological risk factors for CC and LC are not well studied. The aim was to evaluate in a case–control study epidemiological risk factors for CC and LC. Methods:In all, 120 patients with CC, 70 with CL, and 128 controls were included. For all cases and controls information was prospectively recorded. A binary logistic regression analysis was performed separately for CC and LC. Results:Independent associations observed with the diagnosis of CC were: current smoking (odds ratio [OR], 2.4), history of polyarthritis (OR, 20.8), and consumption of lansoprazole (OR, 6.4), low-dose aspirin (OR, 3.8), beta-blockers (OR, 3.6), and angiotensin II receptor antagonists (OR 0.20). In the case of LC they were: current smoking (OR, 3.8), associated autoimmune diseases (OR, 8), and consumption of sertraline (OR, 17.5), omeprazole (OR 2.7), low-dose aspirin (OR, 4.7), and oral antidiabetic drugs (OR, 0.14). Conclusions:The consumption of drugs, current smoking, and associated autoimmune diseases were independently associated with the risk of microscopic colitis.