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Background Therapeutic drug monitoring (TDM) is used in inflammatory bowel disease to guide dosing of biologics to individualise drug exposure and optimise outcomes. In case of undetectable levels of Adalimumab (levels Methods Since October 13 to August 19, 758 TDM were performed in 260 patients treated with ADA. We selected the patients who had at least a level Results We identified 46 patients with undetectable levels; 12 were excluded. Thirty-four patients were included, 29 (85.3%) with Crohn’s disease and 5 (14.7%) with ulcerative colitis. Ten (29.4%) patients had combined treatment and 17 (50%) had previously received another anti-TNF. In 24 (70.6%) TDM was performed proactively. After detection of levels 5 μg/ml), 12 (60%) in the intensified-patient group and 2 (14.3%) in the group in whom the treatment was not modified. ADA was withdrawn in 13 patients (32.8%) after a mean time of 358 days (SD 258). The ADA maintenance rate (HR=3.88; 95% CI 1.2–12.4; p = 0.02) and the recovery ratio of ADA levels (HR = 6.75; 95% CI 1.1–39, 8; p = 0.03) was higher in the intensified group. Hypoalbuminemia was associated with an earlier withdrawal of ADA (p = 0.03) Conclusion The intensification of ADA in patients with IBD and undetectable plasma concentrations allows recovery of levels and maintenance of the drug in a high percentage of patients. The decision to withdraw treatment in patients with undetectable levels should be individualised.

Background & aims: Disease outcome has been found to be poorer in familial inflammatory bowel disease (IBD) than in sporadic forms, but assessment of phenotypic concordance in familial IBD provided controversial results. We assessed the concordance for disease type and phenotypic features in IBD families. Methods: Patients with familial IBD were identified from the IBD Spanish database ENEIDA. Families in whom at least two members were in the database were selected for concordance analysis (K index). Concordance for type of IBD [Crohn's disease (CD) vs. ulcerative colitis (UC)], as well as for disease extent, localization and behaviour, perianal disease, extraintestinal manifestations, and indicators of severe disease (i.e., need for immunosuppressors, biological agents, and surgery) for those pairs concordant for IBD type, were analyzed. Results: 798 out of 11,905 IBD patients (7%) in ENEIDA had familial history of IBD. Complete data of 107 families (231 patients and 144 consanguineous pairs) were available for concordance analyses. The youngest members of the pairs were diagnosed with IBD at a significantly younger age (p < 0.001) than the oldest ones. Seventy-six percent of pairs matched up for the IBD type (kappa = 0.58; 95%CI: 0.42-0.73, moderate concordance). There was no relevant concordance for any of the phenotypic items assessed in both diseases. Conclusions: Familial IBD is associated with diagnostic anticipation in younger individuals. Familial history does not allow predicting any phenotypic feature other than IBD type. (C) 2013 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

OBJECTIVES: To determine the efficacy and safety of cyclosporine (CyA) in a large national registry-based population of patients with steroid-refractory (SR) acute severe ulcerative colitis (ASUC) and to establish predictors of efficacy and adverse events. METHODS: Multicenter study of SR-ASUC treated with CyA, based on data from the ENEIDA registry. SR-ASUC patients treated with infliximab (IFX) or sequential rescue therapy (CyA-IFX or IFX-CyA) were used as comparators. RESULTS: Of 740 SR-ASUC patients, 377 received CyA, 131 IFX and 63 sequential rescue therapy. The cumulative colectomy rate was higher in the CyA (24.1%) and sequential therapy (32.7%) than in the IFX group (14.5%; P = 0.01) at 3 months and 5 years. There were no differences in early and late colectomy between CyA and IFX in patients treated after 2005. 62% of patients receiving CyA remained colectomy-free in the long term (median 71 months). There were no differences in mortality between CyA (2.4%), IFX (1.5%) and sequential therapy (0%; P = 0.771). The proportion of patients with serious adverse events (SAEs) was lower in CyA (15.4%) than in IFX treated patients (26.5%) or sequential therapy (33.4%; P < 0.001). This difference in favor of CyA was maintained when only patients treated after 2005 were analyzed. CONCLUSIONS: Treatment with CyA showed a lower rate of SAE and a similar effi cacy to that of IFX thereby supporting the use of either CyA or IFX in SR-ASUC. In addition, the risk-benefi t of sequential CyA-IFX for CyA non-responders is acceptable.

Resumen Introduccion Los fenomenos tromboembolicos venosos y arteriales son una complicacion extraintestinal infrecuente de la enfermedad inflamatoria intestinal (EII) potencialmente prevenible. Caso clinico Varon de 62 anos, con diagnostico de enfermedad de Crohn (EC) (A3, L1 + L4, B3) que durante su ingreso para drenaje percutaneo de absceso retroperitoneal presenta episodio de tromboembolia arterial periferica de miembro superior derecho, que requirio embolectomia urgente. Tras anticoagulacion con heparina de bajo peso molecular (HBPM), se realiza estudio etiologico con hallazgo en la resonancia magnetica vascular de un trombo arterial de gran tamano en la aorta descendente, por lo que se realizo cirugia aortica y se pauto anticoagulacion indefinida con acenocumarol. Conclusion La trombosis arterial periferica es una complicacion poco comun de la EII que debe ser considerada en pacientes con enfermedad activa y prevenida adecuadamente con HBPM. El tratamiento habitual es la cirugia combinada con anticoagulacion y optimizacion de la terapia farmacologica.

Resumen La enfermedad inflamatoria intestinal (EII) es una patologia cronica y recidivante con un importante impacto sanitario, social y economico. Los pacientes con EII precisan de un seguimiento continuo y personalizado, y el uso de los recursos sanitarios en este contexto esta aumentando progresivamente. En la ultima decada, el uso de las tecnologias de la informacion y la comunicacion (TIC) han transformado el manejo de las enfermedades cronicas, como la EII. La telemedicina consiste en la aplicacion de las TIC para proporcionar atencion sanitaria a distancia sin necesidad de contacto directo con el paciente. La telemedicina y sus diferentes aplicaciones (telemonitorizacion, teleconsulta y teleeducacion) permiten un seguimiento mas estrecho, ademas de promover la autonomia del paciente y mejorar el conocimiento de su enfermedad. Estos recursos favorecen a su vez la optimizacion del tratamiento en cada momento evolutivo de la enfermedad. En esta revision se describe el impacto de las aplicaciones de la telemedicina sobre los resultados en salud de los pacientes con EII, asi como las limitaciones para la implantacion de estos sistemas en la vida real.

Despite controversy regarding the use of granulocyte/monocyte adsorption (GMA) in inflammatory bowel disease, some studies have shown favorable outcomes when it is used in steroid-dependent patients with ulcerative colitis (UC). The mechanisms responsible for such outcomes are not well characterized, but changes in immune cell populations and cytokine levels have been suggested to play an important role. We report the cases of 3 patients with chronically active severe UC who underwent GMA due to an inadequate response to standard and rescue therapy, as well as changes to their plasma cytokine profile. All the patients presented severe UC that was only partially responsive to various immunosuppressive drugs, and they were, therefore, referred for colectomy; however, all 3 refused this option, which led to the compassionate use of GMA as a last therapeutic resort. Following GMA treatment, rapid normalization of the clinical, endoscopic and laboratory parameters was observed in all the patients. Despite having achieved a good response, most cytokines remained at high concentrations after GMA, and only two, IL-6 and IL-8, showed a clear decrease throughout the GMA sessions. In view of this outcome, we hypothesize that GMA can help to lower the inflammatory load, thereby enhancing the effect of biologic drugs. To confirm this hypothesis and explore further indications for GMA, we propose the need for research directed toward the characterization of immune cell populations and their specific cytokine production rather than global cytokine assessment.

Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic and relapsing disorder characterized by inflammation of the gastrointestinal tract. The natural progression includes periods of flares and remission, requiring continuous and personalized follow-up to achieve long remission and minimize short and long term damage. In fact, IBD patients show significantly higher rates of utilization of healthcare resources than patients with other conditions [1]. It is important to emphasize that 30-45% of adults are nonadherents [2], making these patients five times more likely to suffer relapses and consequently increasing health care costs [3]. The high percentage of nonadherence may be due to the difficulty in accessing specialized IBD care and behavioral factors. Furthermore, IBD is associated with high levels of school and work disability [4], interference with social activities and impairment of quality of life [5]. For these reasons, IBD generates a signi...

A substantial percentage of patients fail to follow health professionals' recommendations, which affects the management of chronic diseases, reducing the effectiveness of therapeutic interventions and increasing the costs of the disease. Lack of adherence is a multidimensional phenomenon and is influenced by numerous factors that should be identified. A multiplicity of measures is available to improve adherence, such as simplifying treatment administration, but none of these measures is effective when used alone. One way of tackling lack of adherence is by identifying patients' barriers to medication and involving them in decision making. Ulcerative colitis (UC) poses a risk for lack of treatment adherence. In this disease, poor adherence correlates with poor disease control (drug effectiveness) and with higher costs. As in other chronic diseases, the causes associated with poor adherence are multiple, including psychosocial factors, the physician-patient relationship and patients' prejudices toward medication. A single dose of aminosalycylates (5-ASA) should be recommended, as this dose is as safe and effective as other regimens. However, by itself, this recommendation does not seem to improve adherence. Identifying the scale of the problem and developing strategies to involve the patient in decision making is crucial to improve treatment adherence.

Background Few data are available on the efficacy of methotrexate (MTX) in ulcerative colitis (UC). Aim To evaluate the efficacy and safety of MTX in UC patients. Patients and methods UC patients who had been treated with MTX were identified from the databases of 8 Spanish IBD referral hospitals. Patients were included in the study if they received MTX for steroid dependency or steroid refractoriness. Therapeutic success was defined as the absence of UC-related symptoms, complete steroid withdrawal and no requirement of rescue therapies within the first 6months after starting MTX. Results Forty patients were included, 70% treated for steroid dependency and 27% for steroid refractoriness. Thiopurines had been previously attempted in 87.5% of patients. The median dose of MTX used for induction was 25mg (IIQ 17.5–25) weekly given parenterally in 82.5% of cases. Eighty-five percent of patients were on steroids when MTX was started. Forty-five percent of patients met criteria for therapeutic success. Initial treatment failures were mainly due to inefficacy (50%) or intolerance (36%). After a median follow-up of 28months (IQR 22–47), 38% of patients with initial therapeutic success required new steroid courses, 22% started biological therapy, and only 1 patient required colectomy. The cumulative probability of maintaining steroid-free clinical remission was 60%, 48%, and 35% at 6, 12, and 24months after starting MTX, respectively. Eleven patients (27.5%) experienced adverse events, leading to MTX discontinuation in only 8 of them. Conclusions MTX appears to be effective to maintain clinical remission in UC, at least in the short-term, with an acceptable safety profile.

Background Epidemiological studies have shown a greater prevalence of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) among first-degree relatives of patients diagnosed of these diseases. However, it is not known whether relatives of patients with IBD have a greater prevalence of IBS than the general population. Aims To analyse the prevalence of IBS among first-degree relatives by consanguinity (parents, siblings and offspring) and affinity (spouses) of patients with IBD. Materials and methods A prevalence study was conducted identifying 490 relatives of 91 patients with IBD. Of these, 404 met inclusion criteria; and 360 (response rate: 89.1%) answered the questionnaires. Subjects were invited to participate in the study through index cases (patients with IBD). The following variables were collected: age, sex, history of digestive diseases, kinship and cohabitation with the index case. The relatives completed a questionnaire to identify those who met Rome I and Rome II criteria for IBS. Results The overall prevalence of IBS among the first-degree relatives of patients with IBD was 49.4% and 10% according to Rome I and Rome II criteria respectively. IBS prevalence was higher in first-degree blood relatives than in spouses of patients (Rome I: 53.1% vs 29.1%, p=0.001; Rome II: 10.8% vs 5.4%, NS). No differences were found in IBS prevalence depending on whether relatives were living with the index case or not. Conclusion IBS prevalence in first-degree relatives of patients with IBD is elevated. It is significantly greater in blood relatives, which suggests involvement of genetic and psychological factors rather than environmental factors.

Treatment with antitumor necrosis factor-alpha (anti-TNF-α) offers a significant improvement in several immune-based diseases, including Crohn's disease (CD) and psoriasis. Different cutaneous side effects have been described for anti-TNF-α therapy such as psoriasis. Previous reports showed that inhibition of TNF-α can induce over expression of cutaneous IFN-α, which in turn caused a predisposition to psoriasis. We report a 31-year-old woman with extensive CD and perianal lesions, without response to conventional treatment. She paradoxically developed a cutaneous eruption with psoriasiform morphology and distribution during treatment with both anti-TNF-α approved in Europe for CD, infliximab and adalimumab. These lesions cleared after topical application of corticosteroids and cessation of the anti-TNF-α treatment. Due to uneffectiveness of pharmacological treatment on disease, the patient had to undergo surgery. TNF-induced psoriasis in patients with CD is rare and has been previously documented with infliximab or adalimumab. The reason for this apparently paradoxical effect of the therapy is still unclear. This is the first case of psoriasis induced first by infliximab and later by adalimumab in the same CD patient. We would like to review and to draw attention about psoriasis as a cutaneous side effect with anti-TNF-α treatments.

Background Ustekinumab is a fully human monoclonal antibody against IL-12/23. Ustekinumab induced clinical response and maintained higher rate of response than placebo in patients with Crohn's disease (CD). This study aims to assess the effectiveness and safety of ustekinumab in refractory patients with CD in real-life practice. Methods Consecutive patients with CD who were treated with subcutaneous ustekinumab between March 2010 and December 2014 were retrospectively included in a multicenter open-label study. Clinical response was defined by Harvey-Bradshaw index score and assessed after the loading doses, 6, 12 months, and last follow-up. Results One hundred sixteen patients were included, with a median follow-up of 10 months (interquartile range: 5-21). Clinical response after loading ustekinumab was achieved in 97/116 (84%) patients. The clinical benefit at 6, 12 months, and at the end of the follow-up was 76%, 64%, and 58%, respectively. Dose escalation was effective in 8 of 11 (73%) patients. Perianal disease also improved in 11 of 18 (61%) patients with active perianal fistulae. The initial response to ustekinumab and previous use of more than 2 immunosuppressant drugs were associated with a clinical response to ustekinumab maintenance therapy. In contrast, previous bowel resection predicted a long-term failure with ustekinumab. Adverse events were reported in 11 (9.5%) patients, but none required ustekinumab withdrawal. Conclusions Subcutaneous ustekinumab is effective and safe in a high proportion of patients with CD that were resistant to conventional immunosuppressant and antitumor necrosis factor drugs.

Resumen Antecedentes Hay una informacion limitada respecto al uso optimo de los inmunosupresores tiopurinicos en la enfermedad inflamatoria intestinal, sin que este completamente clarificada su posologia, eficacia y toxicidad. Objetivo Evaluar la evolucion clinica y los efectos adversos de los inmunosupresores tiopurinicos en condiciones de practica clinica (efectividad) y las posibles variables asociadas. Metodos Los datos se obtuvieron de una base de datos de pacientes con enfermedad de Crohn y colitis ulcerosa que iniciaban tratamiento inmunosupresor con azatioprina o mercaptopurina con un identico seguimiento preestablecido. Se definieron los conceptos de remision para cada indicacion, recidiva y toxicidad, y se analizaron las posibles variables clinicas, biologicas y demograficas (analisis multivariante) relacionadas. Resultados Un total de 150 cursos de tratamiento se evaluaron en 126 pacientes. En 118 cursos en los que la indicacion fue la induccion de la remision clinica, esta se alcanzo en el 62% de los pacientes y se mantuvo durante una media de 52 meses. La enfermedad perianal fue la unica variable que se asocio con una peor respuesta. En el 34% de los cursos se detectaron efectos adversos y estos fueron la principal causa de retirada del farmaco. La dosis plena de inicio (odds ratio [OR] = 4,26; intervalo de confianza [IC] del 95%, 1,12-16,32) y el cotratamiento con infliximab (OR = 5,6; IC del 95%, 1,17-27,1) se asociaron significativamente con una mayor retirada del farmaco por efectos adversos. Conclusiones Algunas variables fenotipicas y farmacologicas (posologia y cotratamientos) pueden tener una notable influencia en el perfil de efectos secundarios y, por tanto, en la efectividad de los inmunusupresores tiopurinicos en la enfermedad inflamatoria intestinal.

Background Recurrence after surgery to treat Crohn's disease is frequent and unpredictable. The efficacy of postsurgery capsule endoscopy in detecting recurrence in patients with Crohn's disease is yet to be confirmed. Objective To assess the safety, accuracy, and therapeutic impact of capsule endoscopy in these patients. Design Crohn's disease recurrence at the neoileum (Rutgeers score) was assessed in the patients by colonoscopy and capsule endoscopy. The M2A Patency Capsule (Given Imaging, Yoqneam, Israel) was administered 1 week before capsule endoscopy. Capsule endoscopy was performed within 2 weeks of colonoscopy. Investigators were blinded to the results of each technique. Patient comfort during the procedures was recorded. Patients Twenty-four patients with Crohn's disease with ileocolonic anastomosis were prospectively included. All patients were asymptomatic and did not receive any prophylactic treatment. Main Outcome Measurements Neoileum recurrence. Results A colonoscopy was performed in all patients, although the neoileum could not be reached in 3 of them. M2A Patency Capsule excretion was delayed in 2 patients; thus capsule endoscopy was given only to 22 patients. Recurrence was visualized with colonoscopy in 6 patients and with capsule endoscopy in 5. Ten additional recurrences were visualized only with capsule endoscopy. Moreover, proximal involvement was detected in 13 patients. Therapeutic management was modified in 16 patients. All patients preferred capsule endoscopy. Conclusions Capsule endoscopy is more effective in the evaluation of recurrence after surgery for Crohn's disease and is better tolerated than colonoscopy. This is of significant therapeutic relevance.

A substantial percentage of patients fail to follow health professionals' recommendations, which affects the management of chronic diseases, reducing the effectiveness of therapeutic interventions and increasing the costs of the disease. Lack of adherence is a multidimensional phenomenon and is influenced by numerous factors that should be identified. A multiplicity of measures is available to improve adherence, such as simplifying treatment administration, but none of these measures is effective when used alone. One way of tackling lack of adherence is by identifying patients' barriers to medication and involving them in decision making. Ulcerative colitis (UC) poses a risk for lack of treatment adherence. In this disease, poor adherence correlates with poor disease control (drug effectiveness) and with higher costs. As in other chronic diseases, the causes associated with poor adherence are multiple, including psychosocial factors, the physician-patient relationship and patients' prejudices toward medication. A single dose of aminosalycylates (5-ASA) should be recommended, as this dose is as safe and effective as other regimens. However, by itself, this recommendation does not seem to improve adherence. Identifying the scale of the problem and developing strategies to involve the patient in decision making is crucial to improve treatment adherence.

To investigate the influence of thiopurines and biological drugs on the presence of small intestinal bacterial overgrowth (SIBO) in patients with inactive Crohn's disease (CD).This was a prospective study in patients with CD in remission and without corticosteroid treatment, included consecutively from 2004 to 2010. SIBO was investigated using the hydrogen glucose breath test.One hundred and seven patients with CD in remission were included. Almost 58% of patients used maintenance immunosuppressant therapy and 19.6% used biological therapy. The prevalence of SIBO was 16.8%. No association was observed between SIBO and the use of thiopurine Immunosuppressant (12/62 patients), administration of biological drugs (2/21 patients), or with double treatment with an anti-tumor necrosis factor drugs plus thiopurine (1/13 patients). Half of the patients had symptoms that were suggestive of SIBO, though meteorism was the only symptom that was significantly associated with the presence of SIBO on univariate analysis (P0.05). Multivariate analysis revealed that the presence of meteorism and a fistulizing pattern were associated with the presence of SIBO (P0.05).Immunosuppressants and/or biological drugs do not induce SIBO in inactive CD. Fistulizing disease pattern and meteorism are associated with SIBO.

The genetic analysis of ulcerative colitis (UC) has provided new insights into the etiology of this prevalent inflammatory bowel disease. However, most of the heritability of UC (>70%) has still not been characterized. To identify new risk loci for UC we have performed the first genome-wide association study (GWAS) in a Southern European population and undertaken a meta-analysis study combining the newly genotyped 825 UC patients and 1525 healthy controls from Spain with the six previously published GWAS comprising 6687 cases and 19 718 controls from Northern-European ancestry. We identified a novel locus with genome-wide significance at 6q22.1 [rs2858829, P = 8.97 × 10(-9), odds ratio (OR) (95% confidence interval, CI] = 1.12 (1.08-1.16)] that was validated with genotype data from a replication cohort of the same Southern European ancestry consisting in 1073 cases and 1279 controls [combined P = 7.59 × 10(-10), OR (95% CI) = 1.12 (1.08-1.16)]. Furthermore, we confirmed the association of 33 reported associations with UC and we nominally validated the GWAS results of nine new risk loci (P < 0.05, same direction of effect). SNP rs2858829 lies in an intergenic region and is a strong cis-eQTL for FAM26F gene, a gene that is shown to be selectively upregulated in UC colonic mucosa with active inflammation. Our results provide new insight into the genetic risk background of UC, confirming that there is a genetic risk component that differentiates from Crohn's Disease, the other major form of inflammatory bowel disease.

AIM: To evaluate the effectiveness of adalimumab in preventing recurrence after intestinal resection for Crohn’s disease in high-risk patients. METHODS: A multicenter, prospective, observational study was conducted from June 2009 until June 2010. We consecutively included high-risk Crohn’s disease patients who had undergone an ileal/ileocolonic resection. High-risk patients were defined as two or more criteria: smokers, penetrating pattern, one or more previous surgical resections or prior extensive resection. Subcutaneous adalimumab was administered 2 wk (± 5 d) after surgery at a dose of 40 mg eow, with an initial induction dose of 160/80 mg at weeks 0 and 2. Demographic data, previous and concomitant treatments (antibiotics, 5-aminosalicylates, corticosteroids, immunomodulators or biologic therapies), smoking status at the time of diagnosis and after the index operation and number of previous resections (type and reason for surgery) were all recorded. Biological status was assessed with C-reactive protein, erythrocyte sedimentation rate and fecal calprotectin. One year (± 3 mo) after surgery, an ileocolonoscopy and/or magnetic resonance enterography was performed. Endoscopic recurrence was defined as Rutgeerts score ≥ i2. Morphological recurrence was based on magnetic resonance (MR) score ≥ MR1. RESULTS: Twenty-nine patients (55.2% males, 48.3% smokers at diagnosis and 13.8% after the index operation), mean age 42.3 years and mean duration of the disease 13.8 years were included in the study. A mean of 1.76 (range: 1-4) resections previous to adalimumab administration and in 37.9% was considered extensive resection. 51.7% had previously received infliximab. Immunomodulators were given concomitantly to 17.2% of patients. Four of the 29 (13.7%) developed clinical recurrence, 6/29 (20.7%) endoscopic recurrence and 7/19 (36.8%) morphological recurrence after 1-year. All patients with clinical recurrence showed endoscopic and morphological recurrence. A high degree of concordance was found between clinical-endoscopic recurrence (κ = 0.76, P < 0.001) and clinical-morphological recurrence (κ = 0.63, P = 0.003). Correlation between endoscopic and radiological findings was good (comparing the 5-point Rutgeerts score with the 4-point MR score, a score of i4 was classified as MR3, i3 as MR2, and i2-i1 as MR1) (P < 0.001, rs = 0.825). During follow-up, five (17.2%) patients needed adalimumab dose intensification (40 mg/wk); Mean time to intensification after the introduction of adalimumab treatment was 8 mo (range: 5 to 11 mo). In three cases (10.3%), a biological change was needed due to a worsening of the disease after the dose intensification to 40 mg/wk. One patient suffered an adverse event. CONCLUSION: Adalimumab seems to be effective and safe in preventing postoperative recurrence in a selected group of patients who had undergone an intestinal resection for their CD.

Inflammatory bowel disease (IBD) is a debilitating immune disorder that impairs function and health-related quality of life (HRQOL). A goal of IBD treatment is mucosal healing, but it is not known whether it achieves normalization of the patients' perception of health. This can be assessed by using a cut-off scoring threshold of the Inflammatory Bowel Disease Questonnaire-36 (IBDQ-36).To determine whether patients with Crohn's disease (CD) and ulcerative colitis (UC) in clinical remission and with mucosal healing normalize their HRQOL.This is a multicentric, prospective, observational, cross-sectional study of patients who are in stable clinical remission and having mucosal healing. Patients completed the IBDQ-36, the EuroQol-5D, and the Daily Fatigue Impact Scale fatigue questionnaires. Complete restoration of health was believed to have occurred when the global score in the IBDQ-36 was at least 209 points.A total of 115 patients (48 with CD, 67 with UC) were included. The median activity index (the Harvey-Bradshaw or the colitis activity index) was 1.0 and the median endoscopic index (Simple Endoscopic Score for Crohn's disease or Mayo) was 0. Eighty percent of the patients (79% in CD and 82% in UC patients, P=NS) normalized their HRQOL. Type of treatment was not related to normalization of HRQOL. The lack of restoration of health was significantly related to fatigue and anxiety/depression.Mucosal healing is associated with a normalization of the perception of health by most IBD patients independently of treatment. However, a significant group of patients do not achieve restoration of HRQOL, which reinforces the necessity of a global care addressed to all patient concerns to achieve patients' complete health restoration.

Inflammatory Bowel Disease (IBD) usually affects the gastrointestinal tract, although some patients can also develop extraintestinal manifestations, such as vascular symptoms both venous and arterial ones. The former being more frequent than the latter.We report the case of a 62-year-old male, diagnosed of Crohńs disease (CD) (A3,L1+L4,B3), admitted to hospital for treatment of a retroperitoneal abscess. He presented a peripheral arterial thromboembolism during his stay, which required urgent embolectomy. After anticoagulation with low-molecular-weight heparin (LMWH), vascular magnetic resonance imaging revealed a large thrombus involving the descent aorta, which was solved with surgery and long-term anticoagulation.Peripheral arterial thrombosis is a rare extraintestinal manifestation of IBD. Nevertheless it is always important to consider it in patients with IBD. Prophylactic treatment should be made with low-molecular-weight heparin (LMWH) and definitive treatment with a combination of LMWH and surgery.

There is increasing interest in oxidative stress being a potential aetiological factor and/or a triggering factor in Crohn's disease, rather than a concomitant occurrence during the pathogenesis of the disease. Recent research has shown that the immune mononuclear cells of Crohn's disease patients are induced to produce hydrogen peroxide (H2O2). Similarly, the regulation of antioxidant enzymes during disease in these cells has been unravelled, showing that SOD (superoxide dismutase) activity and GPx (glutathione peroxidase) activity is increased during active disease and returns to normal in remission phases. However, catalase remains constantly inhibited which supports the idea that catalase is not a redox-sensitive enzyme, but a regulator of cellular processes. ROS (reactive oxygen species) can be produced under the stimulus of different cytokines such as TNFα (tumour necrosis factor α). It has been shown in different experimental models that they are also able to regulate apoptosis and other cellular processes. The status of oxidative stress elements in Crohn's disease and their possible implications in regulating cellular processes are reviewed in the present paper.

There is limited information on the optimal use of thiopurinic immunomodulators in inflammatory bowel disease (IBD) and the dosage, efficacy and toxicity of these drugs has not been clearly established.To evaluate clinical outcomes and the toxicity of thiopurinic immunomodulators in clinical practice (effectiveness), as well as possible associated variables.Data were obtained from a database of patients with ulcerative colitis and Crohn's disease who started treatment with azathioprine or 6-mercaptopurine with an identical predetermined schedule and follow-up. Remission, relapse and toxicity were defined and analyzed and their relationship with clinical, biologic and demographic variables was evaluated with multivariate analysis.We evaluated 150 courses of treatment in 126 patients. Treatment was given to induce clinical remission in 118 courses and 62% of the patients reached this outcome, which was maintained for a mean of 52 months. The only variable associated with poor response was perianal disease. Adverse events were detected in 34% of the courses and were the main cause of treatment withdrawal. Factors significantly associated with withdrawal due to adverse events were starting with full doses of thiopurinic drugs (OR, 4.26; 95% CI, 1.12-16.32) and cotreatment with infliximab (OR, 5.6; 95% CI, 1.17-27.1).Some clinical variables such as disease phenotype, the use of full doses of thiopurinic drugs from the start of treatment, and co-treatments can have a notable influence on adverse effects and thus on the effectiveness of this therapy in IBD.

Summary Background : The incidence of thiopurine-induced hepatotoxicity in patients with inflammatory bowel disease varies in different studies. Aims : To assess the rate of thiopurine-induced liver toxicity in patients with inflammatory bowel disease; to determine the predictive factors and to characterize its clinical course and management. Methods : A cohort of 161 patients was prospectively followed for a median of 271 days. Hepatotoxicity was established when alanine transaminase or alkaline phosphatase plasma levels were greater than twice the upper normal limit. Results : Abnormal liver function was detected in 21 patients (13%; 95% CI: 7–18). Hepatotoxicity occurred in 16 patients (10%; 95% CI: 6–16) after a median of 85 days. In five cases, treatment was withdrawn due to hepatotoxicity. Use of corticosteroids was associated with hepatotoxicity (OR: 4.94; 95% CI: 1.01–23.98) with antitumour necrosis factor concomitant therapy showing a protective role (OR: 0.3; 95% CI: 0.1–3.1). γ-Glutamyl transferase plasma levels at the onset of hepatotoxicity showed the best predictive value for treatment withdrawal (area under the receiver operating characteristic curve: 0.95). Conclusions : The incidence of hepatotoxicity in inflammatory bowel disease patients receiving thiopurines is relevant, mainly in patients co-treated with corticosteroids. γ-Glutamyl transferase plasma level is a useful biomarker in therapy withdrawal prediction.

Introduccion Azatioprina (AZA) y 6-mercaptopurina (6MP) son efectivas en el tratamiento de la enfermedad inflamatoria intestinal (EII). Su mayor inconveniente es el desarrollo de efectos adversos que obligan a su retirada. Uno de los efectos secundarios mas frecuentes es el desarrollo de intolerancia gastrointestinal. Objetivos Valorar la incidencia de intolerancia gastrointestinal en pacientes tratados con AZA, valorar variables clinicas asociadas a su aparicion y evaluar prospectivamente la utilidad de la 6MP en esta situacion. Material y metodos Se incluyeron prospectiva y consecutivamente todos los pacientes con EII que iniciaron tratamiento con AZA y se siguieron durante 12 meses. Se determino la actividad de la tiopurina metiltransferasa (TPMT) antes del inicio. Todos recibieron AZA segun el mismo protocolo: inicio con 50 mg/dia y a los 15 dias en caso de tolerancia aumento a dosis plenas (2.5 mg/Kg). En caso de intolerancia gastrointestinal se intento una reintroduccion de AZA mas lenta. En caso de nueva toxicidad gastrointestinal se retiro la AZA y se inicio 6MP (1,5 mg/Kg). Se recogio el motivo de retirada de AZA, el tiempo de aparicion, la medicacion concomitante en ese momento y la tolerancia a 6MP. Resultados Se incluyeron 92 pacientes (68 enfermedad de Crohn y 24 Colitis Ulcerosa), edad media 36,8 (DE 10,97) anos. Valor medio de TPMT 19,65 (DE 4,6) U/mL (rango 6,6–35,7). Se dieron efectos secundarios en 58 pacientes (63%) tras 3,42 meses de media, los mas frecuentes fueron la intolerancia gastrointestinal 30 (33%) y la leucopenia 8 (9%). Abandonaron el tratamiento por efectos secundarios 25 (27%) pacientes tras 1,5 meses de media, rango 0,36 a 6,51. La intolerancia gastrointestinal aparecio tras 2,1 meses de media, rango 0,4–12. Los factores asociados a su aparicion fueron el sexo femenino, OR 2,83, IC95% (1,29–6,2), valores de TPMT (P=0,04) y el tratamiento con infliximab OR 5,8, IC95% (1,1–32). Quince (50%) de los 30 pacientes toleraron la reintroduccion de AZA mas lentamente, en el resto de suspendio la AZA. Las variables asociadas a la retirada de AZA fueron los niveles de TPMT (P=0,04) y el tratamiento concomitante con 5-ASA, OR 1,4, IC95% (1,01–1,9). El area bajo la curva para predecir la retirada de AZA en funcion de los niveles de TPMT fue de 0,7 CI95% (0,5–0,9) con una sensibilidad del 73% y una especificidad del 67%. Se le ofrecio cambio a 6MP a todos los pacientes intolerantes a AZA, aceptaron 14 de 15. Cinco, (38%) por protocolo y 36% por intencion de tratar toleraron el tratamiento con 6MP. La tolerancia a 6MP no se asocio a ninguna de las variables estudiadas. Conclusiones La incidencia de intolerancia gastrointestinal es un hecho relevante durante el tratamiento con AZA. En caso de intolerancia se debe contemplar el tratamiento con 6MP. La asociacion con los niveles de TPMT podria reflejar el papel de los nucleotidos de 6-metilmercaptoprurina en su patogenesis.

Introduccion El tratamiento precoz con inmunomoduladores podria modificar la historia natural de la enfermedad de Crohn (EC). Es importante definir el subgrupo de pacientes con una enfermedad mas agresiva. Un estudio publicado en una cohorte francesa se ha realizado con este objetivo (Beaugerie L. Gastroenterology 2006;130(3):650–6). Objetivo Validar los marcadores predictivos identificados en la serie francesa en una cohorte espanola y valorar un mayor numero de variables asociadas con el desarrollo de enfermedad de EC grave con un seguimiento mayor. Metodos Se incluyeron pacientes con EC y un seguimiento minimo de 5 anos. Se excluyeron aquellos pacientes tratados con inmunomoduladores o que requirieron cirugia en el mes inmediato al diagnostico. Se definio EC grave segun los criterios previamente propuestos: mas de dos tantas de esteroides, desarrollo de corticodependencia, hospitalizaciones tras el diagnostico por brote o complicaciones de la enfermedad, necesidad de tratamiento con inmunomoduladores, necesidad de reseccion intestinal o de cirugia de enfermedad perianal (EPA). Resultados Se incluyeron 511 pacientes, media de edad 29,6 (DE 11,6) anos, mediana de seguimiento 109 meses, rango 60–438. El porcentaje de EC grave en los cinco anos siguientes al diagnostico fue de 70,2%. La edad menor de 40 anos al diagnostico (OR: 1,95 (95% CI: 1,1–3,42)), la necesidad de esteroides para tratar el primer brote (OR: 1,6 (95% CI: 1,05–2,3)), la localizacion ileo-colica (OR: 1,84 (95% CI: 1,1–2,9)), y la presencia de EPA al diagnostico (OR: 1,8 (95% CI: 1,01–3,5)) se confirmaron como marcadores predictivos independientes de desarrollar EC grave en los 5 anos tras el diagnostico. El valor predictivo positivo (VPP) fue de 0,82 y 0,89 respectivamente en los pacientes que tenian 3 o 4 factores de riesgo. Durante toda la evolucion de la enfermedad el porcentaje de pacientes con EC grave fue de 84,5%. Por regresion logistica se identificaron 6 factores independientes predictivos de EC grave: patron estenosante o fistulizante al diagnostico (OR: 2,3 (95% CI: 1,2–4,2)), fumador activo (OR: 1,7 (95% CI: 1,1–2,9)), edad menor de 40 anos (OR: 2,3 (95% CI: 1,2–4,2)), la necesidad de esteroides para tratar el primer brote (OR: 1,8 (95% CI: 1,1–2,9)), la localizacion ileo-colica (OR: 2,3 (95% CI: 1,2–4,3)), y EPA en el momento del diagnostico (OR: 5,8 (95% CI: 1,8–19.2)). El VPP de estos factores fue de 0,91 en aquellos pacientes que tenian 4 factores, todos los que presentaban 5 o 6 en el momento del diagnostico desarrollaron una EC grave. Conclusiones Se confirman y se validan en poblacion espanola la edad menor de 40 anos, la presencia de EPA al diagnostico y la necesidad de esteroides para el tratamiento inicial de la enfermedad como predictivos de desarrollo de EC grave. Este subgrupo de pacientes es subsidiario de ser tratado de una manera mas agresiva. El resto de factores identificados necesitan ser corroborados por otros estudios. Enfermedad celiaca

Crohn's Disease in Common Variable Immunodeficiency: Treatment with Antitumor Necrosis Factor Alpha

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.

at least one additional ICR. Therefore a group of patients with repeatedly performed ICR (ICR > 1) and a group with only one ICR (ICR = 1) were defined. Mean time until first ICR significantly varied between the groups, being 6.58 years in the ICR = 1 group and 4.80 years in the ICR > 1 group (Figure 1). Mean time to second ICR was 6.1 years. RFs for a second ICR determined in univariate analysis are shown in Figure 2. Non stricturing, non penetrating disease and IMT within 1 year after ICR were significant protective factors, while penetrating behaviour and ileal location were significant risk factors. In the multivariate logistic regression, only ileal disease (OR 3.07 [1.22;7.72], p = 0.02) was a significant RF. IMT at time of or within one year after first ICR (OR 0.23 [0.07;0.79], p < 0.01) presented as significant protective factors in the logistic regression.

surgery was 40.4% at one year and 59.3% at two years with a median time to surgery of 22 months (range 0.5 84 months). Patients who were steroid refractory, or dependent, prior to starting tacrolimus were more likely to have surgery (P= 0.006), while patients who were able to achieve or maintain a clinical response with tacrolimus by 90-days were less likely (P= 0.004). Conclusions: Tacrolimus is able to induce a clinical response in a third and remission in a fifth of medically refractory IBD patients at one year. A 90 day therapeutic trial is worthwhile in difficult to treat patients.

Results: Chronic DSS colitis induced persistent thickening of the muscularis propria (MP) with infiltration of vimentin+ cells in the chronic phase but not in acute colitis. Moreover, a mucosal healing response was associated with more cycles and recovery. Myofibroblasts (vimentin+ a-SMA+) were present in the submucosa (SM) in the chronic phase and not in the acute model. Differential deposition of collagen I and III was observed: collagen I was present in the SM around vimentin+ cells. Collagen III deposition in the SM started in the acute phase, further increased in chronic colitis with infiltration of collagen III between smooth muscle cells of the MP, to intestinal stricture formation in CD. During prolonged recovery there was a decrease in collagen III. Tenascin expression was scant in control colon but was clearly present in the mucosa and SM in the acute phase in individual cells. A linear deposition of tenascin around the crypts was also seen as expected in acute colitis. The linear deposition in the mucosa and submucosal spots persisted after 2 cycles of DSS, correlating with persisting tissue damage. The expression of tenascin decreased after 3 cycles and more so after additional recovery, in association with the disappearance of tissue damage. Conclusions: The connective tissue changes observed in chronic murine colitis induced by repeated cycles of DSS reflects tissue remodeling as seen in CD. The technical ease and reproducibility of the DSS model and ability to induce it in mice of a common inbred strain makes it an attractive model to study the connective tissue changes occurring in IBD.