Effectiveness and Safety of the Sequential Use of a Second and Third Anti-TNF Agent in Patients With Inflammatory Bowel Disease: Results From the Eneida Registry.

BACKGROUND: The effectiveness of the switch to another anti-tumor necrosis factor (anti-TNF) agent is not known. The aim of this study was to analyze the effectiveness and safety of treatment with a second and third anti-TNF drug after intolerance to or failure of a previous anti-TNF agent in inflammatory bowel disease (IBD) patients. METHODS: We included patients diagnosed with IBD from the ENEIDA registry who received another anti-TNF after intolerance to or failure of a prior anti-TNF agent. RESULTS: A total of 1122 patients were included. In the short term, remission was achieved in 55% of the patients with the second anti-TNF. The incidence of loss of response was 19% per patient-year with the second anti-TNF. Combination therapy (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.8-3; P < 0.0001) and ulcerative colitis vs Crohn's disease (HR, 1.6; 95% CI, 1.1-2.1; P = 0.005) were associated with a higher probability of loss of response. Fifteen percent of the patients had adverse events, and 10% had to discontinue the second anti-TNF. Of the 71 patients who received a third anti-TNF, 55% achieved remission. The incidence of loss of response was 22% per patient-year with a third anti-TNF. Adverse events occurred in 7 patients (11%), but only 1 stopped the drug. CONCLUSIONS: Approximately half of the patients who received a second anti-TNF achieved remission; nevertheless, a significant proportion of them subsequently lost response. Combination therapy and type of IBD were associated with loss of response. Remission was achieved in almost 50% of patients who received a third anti-TNF; nevertheless, a significant proportion of them subsequently lost response.

Autologous haematopoietic stem cell transplantation in refractory Crohn's disease: Experience in our centre. / Trasplante de precursores hematopoyéticos en enfermedad de Crohn refractaria: experiencia en nuestro centro.

INTRODUCTION: Autologous haematopoietic stem cell transplantation (AHSCT) is an accepted treatment in refractory Crohn's disease (CD). MATERIAL AND METHODS: Data on patients with refractory CD subjected to AHSCT are collected at the Hospital Universitario Ramón y Cajal in Madrid and the results obtained are described retrospectively. RESULTS: Seven patients in total have received AHSCT due to refractory CD in our centre. Three patients (43%) presented with clinical and endoscopic remission; one patient (14%) clinical improvement without remission and three patients (43%) remained active with the need to restart treatment in the assessment of the initial response to the AHSCT (after six months). Symptoms recurred in five of the seven patients (71%) and all of them had to restart medical treatment after an average of 13.8 months (range: 3-30 months). Only one patient needed surgery after the AHSCT. At the end of the follow-up, after a mean of 48 months (range: 17-78 months), 5/7 (71%) of the patients were in clinical remission with or without treatment. CONCLUSION: AHSCT may be a promising therapeutic option for patients with refractory CD. Its usefulness lies in the fact that it can produce clinical remission without treatment in some patients, but also that it can make the disease treatable, obtaining a response to certain treatments in patients who had previously lost it.

Trasplante de microbiota fecal: indicaciones, metodología y perspectivas futuras / Faecal microbiota transplantation: indications, methodology and future prospects

La microbiota intestinal se define como el conjunto de microorganismos que habitan de forma natural en el tubo digestivo. Bacterias, hongos y virus se incluyen dentro de este ente fisiológico que va mucho más allá de ser un mero espectador pasivo de la mucosa intestinal. La microbiota interviene de forma activa en la homeostasis y su desregulación se ha relacionado con múltiples enfermedades de naturaleza infecciosa, metabólica y autoinmunitaria. El trasplante de microbiota fecal (TMF) consiste en la introducción de una solución de materia fecal debidamente procesada procedente de un donante sano en el tracto gastrointestinal de otro individuo con el fin de manipular las características de la microbiota del receptor. Aunque pueda parecer algo novedoso, los primeros casos se remontan a la época de la China Imperial; no obstante, no ha sido hasta los últimos 20 años cuando el interés y la actividad investigadora en este campo se han multiplicado de forma exponencial. Fruto de este trabajo el TMF constituye hoy en día una herramienta eficaz y validada en casos refractarios de diarrea por C. Difficile. Aunque la evidencia científica es menor, ya existen ensayos clínicos que evalúan su beneficio en la enfermedad inflamatoria intestinal y en el síndrome metabólico. Lo atractivo de su mecanismo fisiopatológico, la sencillez del procedimiento y su bajo coste lo sitúan como un tratamiento prometedor en múltiples enfermedades extradigestivas. El objetivo de esta revisión es resumir de una forma concisa, rigurosa y actualizada las indicaciones, metodología y seguridad del TMF.

The intestinal microbiota is defined as the set of organisms that live in the digestive tract. Bacteria, fungi and viruses are included in a physiological entity that goes far beyond being a passive spectator of the intestinal mucosa. The microbiota is actively involved in homeostasis and its imbalance has been linked to multiple infectious, metabolic and autoimmune diseases. Fecal microbiota transplantation (FMT) consists in the introduction of a solution made with processed stool from a healthy donor into the gastrointestinal tract of another individual in order to manipulate the characteristics of the receiver microbiota. Although it may seem new, the first cases date back to the days of Imperial China; however, it was not until the past 20 years when the interest and research in this field have grown exponentially. Nowadays, TMF is an effective and validated treatment in refractory cases of C.difficile diarrhea. Although the scientific evidence is less, there are clinical trials evaluating its benefit in inflammatory bowel disease and metabolic syndrome. The appeal of its pathophysiological mechanism, the simplicity of the procedure and its low cost place FMT as a promising treatment for multiple extraintestinal diseases. The objective of this review is to summarize in a concise, thorough and updated form its indications, methodology and safety.

Does active smoking really influence the course of Crohn's disease? A retrospective observational study.

BACKGROUND: Active smoking has been associated with a higher risk of developing Crohn's disease (CD). However, its impact on clinical outcomes has been controversial among studies. AIMS: To evaluate the influence of active smoking on initial manifestations of CD, the development of disease-related complications, and therapeutic requirements. METHODS: Patients diagnosed with CD within a ten-year period (1994-2003) were identified. Clinical and therapeutic features until October 2008 or loss of follow-up were recorded. Smoking status was assessed at each major disease-related event (e.g. penetrating and stricturing complications, perianal disease, intestinal resection, introduction of immunomodulators or biological agents). RESULTS: A total of 259 patients were included in the study with a median follow-up period of 91 months. At diagnosis, 50.5% were active smokers and only 12% of them quit smoking during follow-up, mostly after a major disease-related event occurred. Smoking at diagnosis was not associated with a particular CD presentation. Active smoking did not influence the development of strictures, intraabdominal and perianal penetrating complications, or increased resectional surgery, biological therapy or immunomodulators requirements. CONCLUSIONS: Patients who develop CD while smoking seem to have a similar disease course to those who never smoked.

Adalimumab is effective in long-term real life clinical practice in both luminal and perianal Crohn's disease. The Madrid experience.

OBJECTIVE: To evaluate effectiveness and safety of adalimumab in CD patients of the Madrid area and identify predictors of response. METHODS: Multicenter retrospective survey of all CD patients treated with adalimumab in 9 hospitals of the Madrid area (Spain). Univariate and multivariate analysis of predictors of response was performed. RESULTS: 174 patients included (50% males) with a median follow-up of 40 weeks. 30% had active perianal fistulizing disease at the beginning of the therapy with adalimumab. 59% had been previously treated with infliximab, being the lost of response (42.2%) the most frequent cause of withdrawal of the drug. 33% of patients needed dose escalation from every-other week to every week. The median time for this dose escalation was 33 weeks (range 2-120). The percentages of complete response at 4 weeks, 6 months and end of follow-up were 63, 70 and 63% in luminal disease and 49, 50 and 41% in perianal disease respectively. The prevalence of adverse events was 18% (most frequent was: 5 abscesses) causing the withdrawal of the drug in 21% of them. CONCLUSIONS: Adalimumab is effective and safe for the management of CD, even in refractory cases to infliximab.

Factors that modify therapy adherence in patients with inflammatory bowel disease.

OBJECTIVES: Inflammatory bowel disease is associated with a high risk of deficient adherence to therapy. Our study was designed to analyze the adherence to treatment in a specialized inflammatory bowel disease clinic, and to study which factors could influence it. METHODS: 107 consecutive patients (64% Crohn's disease, 36% ulcerative colitis) filled up an anonymous survey with data on demography, disease, therapy and a self-applied adherence declaration. RESULTS: A 69% (95%CI: 60-77%) showed some type of non-adherence. A 66% (95 CI%: 57-75%) acknowledged some involuntary non-adherence: either forgetting to take their dose (63%) or being careless about having taken it (27%). A 16% (95 CI%: 9-22%) showed some voluntary non-adherence: interrupting the therapy when feeling better (13%) or when feeling worse (6%). A 25% forgot at least a dose a week in the last 12 months. Multivariate analysis identified as risk factors for a lower adherence the dosing in three or more takes a day (OR 3; 95%CI: 1.1-8.4; p=0.03) and feeling little informed about their disease (OR 4.9; 95%CI: 1.1-23.8; p=0.04). Immunomodulator therapy predicted better adherence (OR 0.29; 95%CI: 0.11-0.74; p=0.01). CONCLUSIONS: Adherence to therapy in inflammatory bowel disease patients is not satisfactory, and worse in patients treated with mesalazine. Optimizing the information on the disease and giving the medication in one or two daily doses could enhance therapeutic adherence.

Outcomes of pregnancies fathered by inflammatory bowel disease patients exposed to thiopurines.

OBJECTIVES: Immunomodulators are used as maintenance treatment of inflammatory bowel disease (IBD). Data regarding their possible effects in the course of pregnancy when the father is exposed at the time of conception are limited. METHODS: To evaluate the outcomes of pregnancies of which the fathers were exposed to thiopurines at the time of conception. A series of male patients followed in seven IBD clinics in Madrid, Spain, was studied. Any exposure to thiopurines during the 3 months preceding conception was considered significant. Controls were pregnancies fathered by patients who either had never been treated with thiopurines or had interrupted them >3 months before conception. Statistical comparisons and multivariate analysis were carried out with the generalized estimating equations model. RESULTS: There were 46 conceptions in the exposed group (mercaptopurine 9, azathioprine 37) and 84 in the control group. In the exposed group, there were more Crohn's patients (82.6% vs. 53.6%), the duration of the disease was longer (median: 8 vs. 5 years), fathers were slightly older (mean: 34.2 vs. 32.7 years), and there were fewer patients on mesalamine (15.2% vs. 47.6%). Otherwise, baseline characteristics were similar in both groups. There were no significant differences regarding unsuccessful pregnancies-namely, spontaneous abortions, ectopic pregnancies, anembryonic pregnancies, or fetal deaths (10.9% exposed group vs. 13.1% control group; odds ratio (OR): 0.79, confidence interval (CI): 0.22-2.85), preterm births (4.3% vs. 2.4%; OR: 1.3, CI: 0.22-7.61), low birth weight (6.5% vs. 6%; OR: 1.06, CI: 0.25-4.54), or congenital malformations (2.2% vs. 2.4%; OR: 0.82, CI: 0.08-9). No infant neoplasms were detected. The proportion of conceptions that needed >1 year to be achieved was higher in the exposed group, but this was not statistically significant (15.2% vs. 8.3%; OR: 1.92, CI: 0.54-6.88). Multivariate analysis was carried out for unsuccessful pregnancies and fertility impairment, and it showed that, although mesalamine exposure confounded the effect of the exposure to thiopurines on these outcomes, this effect was still nonsignificant (respectively, OR: 0.49, CI: 0.17-1.44; OR: 2.82, CI: 0.7-11.38). CONCLUSIONS: Our data do not support the practice of routinely recommending to male patients that they interrupt thiopurines when wanting to conceive.

[Lymphoproliferative disorders in an inflammatory bowel disease unit]. / Trastornos linfoproliferativos en una unidad de enfermedad inflamatoria intestinal.

INTRODUCTION: The relationship between inflammatory bowel disease (IBD) and lymphoproliferative disorders (LD) has been previously reported. AIMS: To establish the local incidence of LD in an IBD unit, and to describe the clinical characteristics of observed cases. MATERIAL AND METHODS: All the clinical records of patients with ulcerative colitis (UC) or Crohn's disease (CD) followed-up in a tertiary center were reviewed. In all cases, IBD had been diagnosed according to standard criteria. RESULTS: Of 911 patients with IBD, we identified seven with lymphoma. Five of the patients were men, four had been diagnosed with UC and three with Crohn's disease. The mean time from IBD to lymphoma diagnosis was 4.82 years (r: 0-20). The mean age at lymphoma diagnosis was 53 years (r: 33-76). Four were colorectal lymphomas. There was only one case of Hodgkin's disease. Five patients had been treated with thiopurines, and four of these had also been treated with biological agents. Three cases were associated with Epstein-Barr (EBV) virus infection. The estimated incidence of LD in these IBD patients was 81.74/100,000/year. After a mean follow-up of 32.3 months (r: 5-57) following the last treatment for LD, all patients except one are in remission. DISCUSSION: The incidence rate of LD was much higher than the expected rate for the general population (81.74 vs. 22). Chronic inflammation, immune-modifying drugs and Epstein Barr virus infection may be implicated in the pathogenesis of this disease.

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.

Infliximab maintenance therapy is associated with decreases in direct resource use in patients with luminal or fistulizing Crohn's disease.

GOALS: To estimate the impact of infliximab (IFX) maintenance therapy on the use of hospital resources in patients with Crohn's disease (CD). STUDY: Medical records of patients treated with IFX maintenance therapy (5 mg/kg body weight; intravenous infusion) for luminal (L) or fistulizing (F) CD at 13 hospitals were retrospectively reviewed. Patients were assessed as their own controls. Use of CD-related healthcare resources was recorded comparing 1-year periods before and after first IFX infusion (pre-IFX and post-IFX). RESULTS: One hundred fifty-three CD patients (n=84 L; 69 F) fulfilled the inclusion criteria. Mean number of IFX infusions was 7/y with an average of 335 mg/infusion dose/patient. During the pre-IFX period, 55% of patients needed hospitalization versus 31% in the post-IFX period (P<0.001). Mean inpatient stay was 11.3 d/y [11.2 (L), 11.5 (F)] for the pre-IFX period, and 6.3 d/y [6.2 (L), 6.3 (F)] in the post-IFX period (P<0.001). Surgery was required in 24% patients in the pre-IFX period and in 11% post-IFX (P<0.001). There were no significant changes in the incidence of outpatient visits although emergency room visits fell significantly. CONCLUSIONS: Maintenance IFX in CD patients is associated with decreases in the use and length of hospitalizations and the need for surgery in clinical practice.

Open-label infliximab therapy in Crohn's disease: a long-term multicenter study of efficacy, safety and predictors of response.

BACKGROUND: Efficacy of infliximab in Crohn's disease (CD) showed by randomized controlled trials must be confirmed in clinical practice. We aimed to evaluate efficacy and safety of infliximab in CD patients of the Madrid area, looking for clinical predictors of response. METHODS: Multicenter retrospective survey of all CD patients treated with infliximab in 8 University hospitals of the Madrid area (Spain) with a minimum follow up of 14 wks. RESULTS: 169 patients included (48%males, mean age 39 +/- 12 yrs). 64% of them had perianal disease. 82% were under immunosuppressants. 1,355 infliximab infusions administered (mean 8, range 1-30). 90% response rate and 48% remission rate were obtained with induction therapy. 73% followed maintenance treatment, and 78% of them maintained or improved the response after a mean follow up of 28 months (range 3.5-86). 24 patients lost response during the follow up, after a mean of 41 wks (range 6-248). Only the prescription of maintenance therapy was predictive factor for favourable response (p < 0.01). 17 infusion reactions were reported (10% of the patients, 1.2% of the infusions; only one case was severe) and were the cause of treatment withdrawal in 7 patients. Co-treatment with immunosuppressive drugs and maintenance infliximab therapy were protective factors for infusion reactions (p < 0.05). Other adverse events occurred in 26% of the patients, and were cause of treatment withdrawal in 7 patients. CONCLUSIONS: Infliximab is effective and safe for CD management but concomitant immunosuppressive drugs and maintenance treatment should be prescribed to obtain the best outcome. That confirms in a real life clinical setting the favourable results obtained in randomized clinical trials.

[Efficacy of premedication with intravenous corticosteroids and antihistaminics in preventing infusion reactions to infliximab]. / Eficacia de la premedicación con un esteroide y un antihistamínico en la prevención de reacciones infusionales por infliximab.

AIM: Infliximab can provoke acute or delayed infusion reactions (IR) leading to treatment withdrawal. Our aim was to determine the frequency of IR in patients with inflammatory bowel disease receiving intravenous infliximab and premedicated with steroids and antihistaminics. METHODS: We prospectively studied 100 consecutive patients (74 with Crohn's disease, 26 with ulcerative colitis) treated with infliximab induction therapy (3 doses: weeks 0-2-6), followed or not by maintenance every 8 weeks. All patients were premedicated with 100 mg i.v. hydrocortisone and 5 mg i.v. dexchlorpheniramine 30 min before each infusion. RESULTS: The mean age was 40.9+/-13 years (51% females, and 38% smokers). Ninety-two percent of the patients were under immunomodulator therapy (azathioprine/ mercaptopurine 85% or methotrexate 7%). A total of 560 infusions were administered, with a mean of 5.6 per patient (range, 1-21). Fifty-six percent of the patients received maintenance therapy. The mean length of follow-up was 17+/-16 months. IR occurred in 6 patients (6%) and in 1.4% of all infusions (8/560). All reactions were mild or moderate. Five IR were immediate, occurring in the second infusion. One IR was delayed (exanthema 5 days after the second infusion). Infliximab therapy was discontinued in only 3 patients (in the patient with the delayed IR and in 2 patients with immediate IR that reappeared during the third infusion). CONCLUSION: In patients with inflammatory bowel disease treated with infliximab and under immunomodulator therapy, premedication with steroids and antihistaminics was associated with a low prevalence of IR. Moreover, after close follow-up, infliximab had to be discontinued in only 3% of the patients.