Guillermo Bastida

Mitochondrial dysfunction, persistent oxidative damage, and catalase inhibition in immune cells of naïve and treated Crohn's disease

Background: Oxidative stress is considered a potential etiological factor for Crohns disease (CD). We characterized the reactive oxygen species (ROS) generated in immune peripheral cells of CD patients, as well as their antioxidant enzyme status and the presence of oxidative damage. In addition, mitochondrial function (&Dgr;&ggr;m) was analyzed to detect the possible origin of ROS. Methods: Cells were obtained from patients at the onset of disease, prior to any treatment. Experiments were repeated when patients were in clinical remission. A set of experiments was carried out in a group of CD patients in persistent morphological remission. Controls were healthy volunteers who were not receiving any treatment at the time. The generation of superoxide, hydrogen peroxide (H2O2) and nitric oxide, &Dgr;&ggr;m, superoxide dismutase (SOD) and catalase (CAT) activities, and concentrations of malondyaldehyde (MDA) and 8‐oxo‐deoxyguanosine (8‐oxo‐dG) were measured. Results: SOD activity and H2O2 production were significantly higher during active CD but returned to control levels in remission. &Dgr;&ggr;m was inhibited during active CD and, although it returned to control levels, its recovery took longer than clinical remission. CAT activity was permanently inhibited during CD, independent of the disease activity. MDA and 8‐oxo‐dG were permanently elevated. Conclusions: Oxidative stress during active CD depends on H2O2 production. The inhibition of &Dgr;&ggr;m suggests that this organelle is a source of ROS. CAT is permanently inhibited in CD, the biological significance of which is under study. The persistent oxidative damage detected may have implications for the evolution of the disease. Inflamm Bowel Dis 2010

Adalimumab in prevention of postoperative recurrence of Crohn's disease in high-risk patients

AIM To evaluate the effectiveness of adalimumab in preventing recurrence after intestinal resection for Crohns disease in high-risk patients. METHODS A multicenter, prospective, observational study was conducted from June 2009 until June 2010. We consecutively included high-risk Crohns 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, r(s) = 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.

Ulcerative colitis in smokers, non-smokers and ex-smokers

Smoking is a major environmental factor that interferes in the establishment and clinical course of ulcerative colitis (UC). Firstly, the risk of smoking status impact in the development of UC is reviewed, showing that current smoking has a protective association with UC. Similarly, being a former smoker is associated with an increased risk of UC. The concept that smoking could have a role in determining the inflammatory bowel disease phenotype is also discussed. Gender may also be considered, as current smoking delays disease onset in men but not in women. No clear conclusions can be driven from the studies trying to clarify whether childhood passive smoking or prenatal smoke exposure have an influence on the development of UC, mainly due to methodology flaws. The influence of smoking on disease course is the second aspect analysed. Some studies show a disease course more benign in smokers that in non-smokers, with lower hospitalizations rates, less flare-ups, lower use of oral steroids and even less risk of proximal extension. This is not verified by some other studies. Similarly, the rate of colectomy does not seem to be determined by the smoking status of the patient. The third issue reviewed is the use of nicotine as a therapeutic agent. The place of nicotine in the treatment of UC is unclear, although it could be useful in selected cases, particularly in recent ex-smokers with moderate but refractory attacks of UC. Finally, the effect of smoking cessation in UC patients is summarised. Given that smoking represents a major worldwide cause of death, for inpatients with UC the risks of smoking far outweigh any possible benefit. Thus, physicians should advise, encourage and assist UC patients who smoke to quit.

Role of oxidative stress and antioxidant enzymes in Crohn's disease.

There is increasing interest in oxidative stress being a potential aetiological factor and/or a triggering factor in Crohns disease, rather than a concomitant occurrence during the pathogenesis of the disease. Recent research has shown that the immune mononuclear cells of Crohns 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 Crohns disease and their possible implications in regulating cellular processes are reviewed in the present paper.

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

Aliment Pharmacol Ther 2011; 33: 340–348

Infliximab and adalimumab-induced psoriasis in Crohn's disease: a paradoxical side effect.

Treatment with antitumor necrosis factor-alpha (anti-TNF-α) offers a significant improvement in several immune-based diseases, including Crohns 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.

On-Demand Therapy with Rabeprazole in Nonerosive and Erosive Gastroesophageal Reflux Disease in Clinical Practice: Effectiveness, Health-Related Quality of Life, and Patient Satisfaction

On-demand therapy is effective for maintaining symptoms control in nonerosive gastroesophagealreflux disease (GERD). Our aim was to assess the clinical effectiveness of on-demand therapy witha proton pump inhibitor (PPI) in mild GERD (nonerosive and low-grade esophagitis), its impact onhealth-related quality of life (HRQoL), and the degree of patient satisfaction. Fifty-five patients (17with nonerosive GERDand 38 with low-grade esophagitis) were treated with rabeprazole, 20 mg/day.The healed patients started on-demand therapy. We evaluated symptoms (clinical questionnaire),HRQoL (SF-36 questionnaire), and patient satisfaction (visual analogue scale). Of the 55 patientsincluded, 51 started on-demand therapy for 6 months. Symptom control (heartburn <twice a week)was achieved in over 85% of the patients. The mean (SD) amount of PPI used was 0.3 (0.19)tablet/day. The patient satisfaction score at the end of the acute phase was 98 (range, 0-100) andremained high (90; range, 10-100) and stable during on-demand therapy. Short-term treatmentnormalized the HRQoL scores, which were subsequently maintained during on-demand therapy.On-demand therapy is useful for the clinical management of patients with mild GERD, allowingadequate symptoms control, limiting PPI consumption, and affording important patient satisfactionwith normalization of HRQoL.

Manifestations of Gastroesophageal Reflux and Response to Omeprazole Therapy in Patients with Chronic Posterior Laryngitis: An Evaluation Based on Clinical Practice

Our aims were to describe clinical characteristics of patients with chronic posterior laryngitis and to predict the response to omeprazole therapy. Ninety-one patients with posterior laryngitis were evaluated by a questionnaire, esophageal manometry and pH recording, and endoscopy. Patients were treated with omeprazole, 20 mg twice daily for 3 months. Therapy was continued another 3 months if necessary. Clinical manifestations of reflux occurred in 84 (92%) patients, abnormal acid reflux in 53 (65%) cases, and esophagitis in 6 of 50 (12%). After 3 months of therapy significant improvement occurred in 30 of 70 patients (41%). Continuing therapy for 3 more months increased the response to 65% (45 of 69 cases). Response to therapy was associated with lower age and lower duration of laryngeal symptoms, but a consistent prediction of the response could not be made. In conclusion, patients with posterior laryngitis frequently present with manifestations of gastroesophageal reflux. Response to therapy can not be predicted with certainty.

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.

Septic thrombophlebitis of the superior mesenteric vein and multiple liver abscesses in a patient with Crohn's disease at onset

BackgroundPortal-mesenteric vein thrombosis, pylephlebitis and liver abscesses are rare complications of inflammatory bowel disease (IBD). The purpose of this case report is to relate an unusual presentation of CD in order to show how conservative treatment could be an appropriate option as a bridge to the surgery, in patients with septic thrombophlebitis and multiple liver abscesses with CD.Case presentationWe report a case of a 25-year-old man with Crohns disease (CD) who developed a superior mesenteric venous thrombosis, multiple liver abscesses and pylephlebitis, diagnosed through abdominal ultrasound and an abdominal computed tomography (CT) scan. The patient was successfully treated with conservative treatment consisting of intravenous antibiotics, subcutaneous anticoagulation and percutaneous catheter drainage of liver abscesses.ConclusionWe reported an unnusual case of pylephlebitis in CD. Until now this association has not been reported in adult patients at onset. We hypothesise that the infection developed as a result of mucosal disease and predisposed by corticoid therapy. Adequated management was discussed.