Mireia Peñalva

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.

Anti-inflammatory effects of pancreatitis associated protein in inflammatory bowel disease

Background and aims: Increased pancreatitis associated protein (PAP) mRNA has been reported in active inflammatory bowel disease (IBD). The aims of the current study were to characterise PAP production in IBD and the effects of PAP on inflammation. Patients and methods: Serum PAP levels were determined in healthy controls (n = 29), inflammatory controls (n = 14), and IBD patients (n = 171). Ex vivo PAP secretion in intestinal tissue was measured in 56 IBD patients and 13 healthy controls. Cellular origin of PAP was determined by immunohistochemistry. The effects of exogenous PAP on nuclear factor κB (NFκB) activation, proinflammatory cytokine production, and endothelial adhesion molecule expression were also analysed ex vivo. Results: Patients with active IBD had increased serum PAP levels compared with controls, and these levels correlated with clinical and endoscopic disease severity. Ex vivo intestinal PAP synthesis was increased in active IBD and correlated with endoscopic and histological severity of inflammatory lesions. PAP localised to colonic Paneth cells. Incubation of mucosa from active Crohn’s disease with PAP dose dependently reduced proinflammatory cytokines secretion. PAP prevented TNF-α induced NFκB activation in monocytic, epithelial, and endothelial cells and reduced proinflammatory cytokine mRNA levels and adhesion molecule expression. Conclusions: PAP is synthesised by Paneth cells and is overexpressed in colonic tissue of active IBD. PAP inhibits NFκB activation and downregulates cytokine production and adhesion molecule expression in inflamed tissue. It may represent an anti-inflammatory mechanism and new therapeutic strategy in IBD.

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.

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.

Effectiveness of infliximab after adalimumab failure in Crohn's disease.

AIM To evaluate the effectiveness of infliximab as a second-line therapy in Crohns disease patients after adalimumab failure. METHODS A historical cohort study in a community-based gastroenterology practice evaluated Crohns disease patients treated with infliximab (induction plus maintenance) after adalimumab failure. Patients were identified using a large Spanish database (ENEIDA). RESULTS We included 15 Crohns disease patients who received infliximab after adalimumab failure. Five patients discontinued adalimumab due to loss of response, 3 due to adverse events and 7 due to partial response. After infliximab therapy was started, all patients who had interrupted adalimumab due to loss of efficacy regained response. All patients who discontinued adalimumab due to adverse events responded to infliximab and maintained this response; one of these patients had an uneventful course on infliximab, but 2 developed adverse events. None of the 7 patients who interrupted adalimumab due to partial response reached remission with infliximab. CONCLUSION Switching from adalimumab to infliximab may be useful in patients who develop adverse effects or loss of response, however, the benefit of infliximab in primary nonresponders was not established.

Disease severity in familial cases of IBD

BACKGROUND Phenotypic traits of familial IBD relative to sporadic cases are controversial, probably related to limited statistical power of published evidence. AIM To know if there are phenotype differences between familial and sporadic IBD, evaluating the prospective Spanish registry (ENEIDA) with 11,983 cases. METHODS 5783 patients (48.3%) had ulcerative colitis (UC) and 6200 (51.7%) Crohns disease (CD). Cases with one or more 1st, 2nd or 3rd degree relatives affected by UC/CD were defined as familial case. RESULTS In UC and CD, familial cases compared with sporadic cases had an earlier disease onset (UC: 33 years [IQR 25-44] vs 37 years [IQR 27-49]; p<0.0001); (CD: 27 years [IQR 21-35] vs 29 years [IQR 22-40]; p<0.0001), higher prevalence of extraintestinal immune-related manifestations (EIMs) (UC: 17.2% vs 14%; p=0.04); (CD: 30.1% vs 23.6%; p<0.0001). Familial CD had higher percentage of ileocolic location (42.7% vs 51.8%; p=0.0001), penetrating behavior (21% vs 17.6%; p=0.01) and perianal disease (32% vs 27.1%; p=0.003). Differences are not influenced by degree of consanguinity. CONCLUSION When a sufficiently powered cohort is evaluated, familial aggregation in IBD is associated to an earlier disease onset, more EIMs and more severe phenotype in CD. This feature should be taken into account at establishing predictors of disease course.

Su1132 Toxicity and Mortality Related to the Use of Ciclosporin in Steroid Refractory Ulcerative Colitis: A Multicentric Nationwide Study (ENEIDA)

years. Among the included patients, 4,734 used thiopurines with median duration of one year. Numbers of lymphoma cases identified were 119 and 18 among non-users and while using thiopurines respectively. The incidence rate of lymphoma among those who never used thiopurines was 0.6 compared to 0.9, 1.6, 1.6, 5, 8.9 per 1000 person-year for the 1st, 2nd, 3th, 4th and .4 years of thiopurine use respectively (Figure). The incidence rates of the fourth and more than four years were significantly different from the incidence rate of non-users, yielding HR of lymphoma of 8 and 14 for the fourth year and more than four year of thiopurines use respectively (p,0.001). Conclusion: In this nationwide cohort of UC patients, the incidence rate of lymphoma significantly increased after the third year of cumulative exposure to thiopurines.

W1275 Long-Term Durability of Response to Adalimumab Treatment in Crohn's Disease

Long-Term Durability of Response to Adalimumab Treatment in Crohns Disease Maria Chaparro, Julian Panes, V. Garcia, Olga Merino, Pilar Nos, Eugeni Domenech, Mireia Penalva, Esther Garcia-Planella, Maria Esteve, Joaquin Hinojosa, Montserrat Andreu, Fernando Munoz, Ana Gutierrez, Juan L. Mendoza, Jesus Barrio, Manuel Barreiro, Isabel Vera, Pere Vilar, Jose Luis Cabriada, Miguel A. Montoro, Xavier Aldeguer Mante, Cristina Saro, Javier P. Gisbert