Olga Merino

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.

Liver dysfunction related to hepatitis B and C in patients with inflammatory bowel disease treated with immunosuppressive therapy

Background There is no information about the frequency of liver dysfunction in patients with inflammatory bowel disease (IBD) treated with immunosuppressants and infected with hepatitis B (HBV) and/or C virus (HCV). Aim To assess the influence of immunosuppressants on the course of HBV and HCV infection in IBD. Methods Patients with IBD with HBV and/or HCV infection from 19 Spanish hospitals were included. Clinical records were reviewed for the type of immunosuppressant used, treatment duration, liver function tests and viral markers before, during and after each immunosuppressant. Logistic and Cox regression analysis were used to identify predictors of outcome. Results 162 patients were included; 104 had HBV markers (25 HBsAg positive) and 74 had HCV markers (51 HCV-RNA positive), and 16 patients had markers of both infections. Liver dysfunction was observed in 9 of 25 HBsAg positive patients (36%), 6 of whom developed hepatic failure. Liver dysfunction in HCV was observed in 8 of 51 HCV-RNA positive patients (15.7%), and only one developed hepatic failure. The frequency and severity of liver dysfunction was significantly higher in HBV-infected patients than in HCV-infected patients (p=0.045 and p=0.049, respectively). Treatment with ≥2 immunosuppressants was an independent predictor of HBV reactivation (OR 8.75; 95% CI 1.16 to 65.66). The majority of patients without reactivation received only one immunosuppressant for a short period and/or prophylactic antiviral treatment. No definite HBV reactivations were found in anti-HBc positive patients lacking HBsAg. Conclusion Liver dysfunction in patients with IBD treated with immunosuppressants is more frequent and severe in those with HBV than in HCV carriers and is associated with combined immunosuppression.

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.

Adalimumab induction and maintenance therapy for patients with ulcerative colitis previously treated with infliximab

Aliment Pharmacol Ther 2011; 33: 340–348

Thiopurine methyl-transferase activity and azathioprine metabolite concentrations do not predict clinical outcome in thiopurine-treated inflammatory bowel disease patients

Aliment Pharmacol Ther 2011; 34: 544–554

Adalimumab induction and maintenance therapy for ulcerative colitis patients previously treated with Infliximab.

Aliment Pharmacol Ther 2011; 33: 340–348

Smoking does influence disease behaviour and impacts the need for therapy in Crohn′s disease in the biologic era

Recently, the notion that smoking may adversely affect Crohn′s disease (CD) outcomes has been challenged by the suggestion that the widespread use of immunosuppressants and anti‐TNF drugs might offset the adverse effects of tobacco.

Long-term durability of response to adalimumab in Crohn's disease†

Background: Adalimumab is an effective treatment for Crohns disease (CD), but may also be associated with loss of response. Few reports provide insight into the durability of treatment of CD with adalimumab for periods longer than 12 months in clinical practice. Aims: To evaluate the long‐term durability of adalimumab maintenance treatment and to identify predictive factors associated with loss of response. Methods: CD patients who initially responded to adalimumab were evaluated in a historical cohort study. Maintenance of long‐term response was estimated using Kaplan–Meier analysis. Cox regression analysis was performed to identify potential predictive factors for loss of efficacy. Results: In all, 380 CD patients were included (mean age, 38 years; 52% female). Of these, 43% had ileocolic CD, 50% inflammatory CD, and 41% perianal CD. Median follow‐up with adalimumab was 8 months (range, 4–75 months). The annual risk of loss of response to adalimumab was 18% per patient‐year of follow‐up. Twenty‐eight percent of patients were anti‐TNF‐naïve and 72% anti‐TNF‐experienced. The loss of efficacy was 8% per patient‐year of follow‐up in the anti‐TNF‐naïve patients and 22% in the anti‐TNF‐experienced group (P < 0.01). In the multivariate analysis, the presence of extraintestinal manifestations (hazard ratio [HR] = 1.7; 95% confidence interval [CI] = 1.02–2.9) and previous experience with other anti‐TNF agents (HR = 2.5,95% CI = 1.2–5.3) were associated with higher risk of loss of efficacy. Conclusions: A relevant proportion of CD patients on long‐term adalimumab lost response. The risk of loss of response was higher (more than 2‐fold) in anti‐TNF‐experienced than in anti‐TNF‐naïve patients (22% vs. 8% per patient‐year of treatment). Having extraintestinal manifestations seems to increase the risk of loss of efficacy. (Inflamm Bowel Dis 2011;)

Observational study on the efficacy of adalimumab for the treatment of ulcerative colitis and predictors of outcome.

BACKGROUND Information on efficacy and predictors of response to adalimumab in ulcerative colitis (UC) clinical practice is limited. AIM Assessment of response to adalimumab and its predictors in an observational cohort study. METHODS Retrospective cohort study based on data obtained from ENEIDA registry. All patients diagnosed with UC treated with adalimumab were included. Response to adalimumab was evaluated at weeks 12, 28, and 54 according to the partial Mayo score, and requirement of colectomy until end of follow-up. RESULTS 48 patients with UC treated with adalimumab were included; 39 (81.3%) had previously received infliximab. Response rates at weeks 12, 28 and 54 were 70.8%, 43.2% and 35% respectively. Response to prior treatment with infliximab was the only predictive factor of response to adalimumab at week 12, which was obtained in 90% of infliximab remitters, 53.8% of responders and 33.3% of primary non-responders (p=0.01). Colectomy was required in 11 patients (22.9%), after a mean time of 205 days. The only clinical independent predictor of colectomy was non-response to adalimumab at week 12: colectomy rates were 5/34 (14.7%) in responders and 6/14 (42.9%) in non-responders (p=0.035), time free of colectomy was significantly reduced in non-responders (p=0.01). Adalimumab withdrawal due to adverse events occurred in 4.2% of patients. CONCLUSION This study shows that adalimumab is an effective treatment in patients with UC. If used as a second anti-TNF, previous achievement of remission with the first anti-TNF predicts response, and failure to achieve response at week 12 predicts colectomy.

Does smoking influence Crohn's disease in the biologic era? The TABACROHN study.

Background:While most studies have found a negative effect of smoking on Crohns disease (CD) phenotype, more recent data have failed to reproduce this association, which might be due to a current wider use of thiopurines and biologic therapy. The TABACROHN study aimed at defining the impact of smoking on CD in the largest published series. Methods:This multicenter cross-sectional study included 1170 CD patients. Patients were classified as nonsmokers, current smokers, or former smokers according to their present smoking status. Clinical data regarding disease characteristics, treatment, and complications were collected. Results:Smokers were more frequently under maintenance treatment when compared to nonsmokers. In addition, current smokers presented higher use of biologic drugs compared to nonsmokers. Tobacco exposure and a higher tobacco load were independent predictors of need for maintenance treatment and stenosing phenotype, respectively. Conclusions:In the era of early and widespread use of immunosuppressants and biologics, tobacco exposure is an independent predictor of need for maintenance treatment, specifically biologic therapy. The wider use of biologics and immunosuppressants could account for the existence of no major differences in disease behavior and complications between nonsmokers and current smokers.