[Show abstract][Hide abstract] ABSTRACT: To investigate a possible genetic influence of claudin (CLDN)1, CLDN2 and CLDN4 in the etiology of inflammatory bowel disease.
Allelic association between genetic regions of CLDN1, CLDN2 or CLDN4 and patients with inflammatory bowel disease, Crohn's disease (CD) or ulcerative colitis were investigated using both a case-control study approach (one case randomly selected from each of 191 Swedish inflammatory bowel disease families and 333 controls) and a family-based study (463 non-Swedish European inflammatory bowel disease -families). A nonsynonymous coding single nucleotide polymorphism in MORC4, located on the same linkage block as CLDN2, was investigated for association, as were two novel CLDN2 single nucleotide polymorphism markers, identified by resequencing.
A single nucleotide polymorphism marker (rs12014762) located in the genetic region of CLDN2 was significantly associated to CD (case-control allelic OR = 1.98, 95%CI: 1.17-3.35, P = 0.007). MORC4 was present on the same linkage block as this CD marker. Using the case-control approach, a significant association (case control allelic OR = 1.61, 95%CI: 1.08-2.41, P = 0.018) was found between CD and a nonsynonymous coding single nucleotide polymorphism (rs6622126) in MORC4. The association between the CLDN2 marker and CD was not replicated in the family-based study. Ulcerative colitis was not associated to any of the single nucleotide polymorphism markers.
These findings suggest that a variant of the CLDN2-MORC4 region predisposes to CD in a Swedish population.
World Journal of Gastroenterology 08/2013; 19(30):4935-43. · 2.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: Despite their well known anti-inflammatory actions, the clinical usefulness of omega-3 PUFA in inflammatory bowel disease is controversial. We aimed to systematically review the available data on the performance of omega-3 PUFA as therapeutic agents in these patients.
Electronic databases were systematically searched for RCT of fish oil or omega-3 PUFA therapy in both active and inactive ulcerative colitis or Crohn's disease, without limitation on either the length of therapy or the form it was given, including nutritional supplements and enteral formula diets. Eligible articles were assessed for methodological quality on the basis of the adequacy of the randomisation process, concealment of allocation, blinding of intervention and outcome, possible biases, and completeness of follow-up. The five-point Oxford quality score was calculated.
A total of 19 RCT were finally selected for this review. Overall, available data do not allow to support the use of omega-3 PUFA supplementation for the treatment of both active and inactive inflammatory bowel disease. Negative results are quite consistent in trials assessing the use of omega-3 PUFA to maintain disease remission, particularly ulcerative colitis, and to a lesser extent Crohn's disease. Trials on their use in active disease do not allow to draw firm conclusions mainly because the heterogeneity of design (ulcerative colitis) or their short number (Crohn's disease). In most trials, the appropriateness of the selected placebo is questionable.
The present systematic review does not allow to make firm recommendations about the usefulness of omega-3 PUFA in inflammatory bowel disease.
The British journal of nutrition 06/2012; 107 Suppl 2:S240-52. · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Intestinal commensal flora seems to be a requisite for both human and experimental intestinal inflammation. Our aim was to assess the immunological changes in the colon of IL-10(-/-) mice depending on the environmental conditions.
Twelve wild-type (WT) and 24 IL-10(-/-) 4-week-old mice were kept under specific pathogen-free (SPF) conditions for 4 weeks. Half of them were transferred to a conventional environment. Mice were sacrificed at 12 weeks of age, and the incidence and severity of colitis was assessed. Intraepithelial (IEL) and lamina propria (LPL) lymphocytes were assessed for phenotype and apoptosis by flow cytometry. Toll-like receptors 2 (TLR2) and TLR9 expression was assessed by real-time PCR. Immunohistochemical analyses for cell apoptosis, TLR2 and MyD88 were also performed.
IL-10(-/-) mice shifted to conventional conditions showed a greater incidence (66% vs. 50%) and severity of colitis than animals kept under SPF conditions (P = 0·009). The number of CD3+ IEL was higher and their apoptosis rate lower in IL-10(-/-) than in their WT counterparts, regardless of the environment. In LPL, however, these differences were only observed in mice shifted to conventional conditions. TLR2 expression was significantly increased in SPF-housed IL-10(-/-) mice when compared to WT controls. Immunohistochemistry demonstrated the loss of TLR2 and MyD88 in damaged areas.
In SPF conditions, IL-10 deficiency appears to be compensated by an increased epithelial TLR2 expression, thus resulting in a milder colonic damage. However, in conventional conditions, this compensatory mechanism would be exceeded inducing a more severe colonic damage with activation of LPL immune cells.
European Journal of Clinical Investigation 10/2011; 41(10):1047-53. · 3.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Apoptosis resistance of T-cells is considered an abnormality of immune pathways in Crohn's disease (CD). It has been previously shown that corticosteroids induce apoptosis of cells involved in inflammation. Thus, our aim was to assess the apoptosis of mononuclear cells and pro/antiinflammatory cytokines in the intestinal mucosa of patients with active CD, related to steroid response, and identify cellular and molecular factors that may predict this response to therapy.
Patients with CD (n = 26), ulcerative colitis (UC) (n = 32), and controls (n = 10) were prospectively studied with mucosal biopsies before and 7-10 days after corticosteroid treatment. Immunophenotype and apoptosis of T and B lymphocytes, plasma cells, and macrophages were assessed by flow cytometry, immunohistochemistry, and immunofluorescence. The cytokine expression pattern was evaluated by quantitative polymerase chain reaction (PCR).
Apoptosis resistance of T and B lymphocytes was observed only in steroid-refractory and -dependent CD patients as compared to responsive patients (P = 0.032; P = 0.004, respectively), being evident after steroid treatment. Interleukin (IL)-10 was markedly increased at baseline in steroid-responsive patients compared to the nonresponders (P = 0.006; sensitivity: 88.8%; specificity: 66.6% to predict steroid response).
Apoptosis resistance of mucosal T and B cells in steroid-refractory and -dependent CD patients appears during the evolution of the acute phase, limiting its clinical application as a predictor marker. In contrast, increased expression of IL-10 at an early stage of active steroid-sensitive CD patients supports its usefulness at predicting a good steroid response. Steroid-dependent and -refractory CD patients share similar molecular and cellular pathophysiological mechanisms.
[Show abstract][Hide abstract] ABSTRACT: Antisecretory factor (AF) is expressed in all tissues of mammals, inhibits intestinal hypersecretion and has anti-inflammatory properties as well. Endogenous AF synthesis may be stimulated by feeding hydrothermally processed cereals. Alternatively, freeze-dried egg yolk can be used as a source of exogenous AF. Several reports have suggested that AF from freeze-dried egg yolk may be useful in inflammatory bowel disease. We assessed the effect of freeze-dried, AF-rich egg yolk intake on 2,4,6-trinitrobenzenesulphonic acid (TNBS) colitis. Balb/c mice were randomised to receive (1) AF in sterile drinking-water (4 g/l, n 38) and (2) sterile drinking-water alone (vehicle, n 38) from TNBS or saline administration onwards. Different subsets of mice were killed at weeks 1-3 after TNBS or saline administration. Macroscopic and microscopic damage was assessed in colonic specimens. Eicosanoid and cytokine production was evaluated in supernatants of 24 h-incubated colonic explants. Myeloperoxidase activity was measured in frozen colonic samples, while apoptosis was assessed in paraffined samples by the in situ oligoligation method. AF-treated mice showed a milder colonic damage compared with the vehicle group, which became statistically significant at week 3. This was accompanied by decreased IL-2, IL-1 and leukotriene B4 production at weeks 2 and 3, as well as increased interferon-γ at week 1, in AF-treated mice compared with vehicle-treated mice. AF-treated mice had significantly increased counts of apoptotic cells in the lamina propria at weeks 1 and 2 post-TNBS. In conclusion, the administration of AF-rich egg yolk has a therapeutic effect in the late phases of TNBS colitis in Balb/c mice.
The British journal of nutrition 07/2011; 106(10):1522-8. · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Corticosteroids are the treatment of choice for moderate-to-severe active ulcerative colitis (UC) but up to 30%-40% of patients fail to respond. It has been reported that early clinical-biological parameters may identify those patients at high risk of colectomy. The aim was to identify predictors of rapid response to systemic steroids in moderate-to-severe attacks of UC.
Consecutive patients treated with prednisone 1 mg/kg/day for moderate-to-severe attacks of UC were prospectively included. Clinical and biological parameters at 3 and 7 days after starting steroids were recorded. Response was defined as mild or inactive UC activity at day 7 (as assessed by the Montreal Classification of severity) together with no need for rescue therapies (cyclosporin, infliximab, or colectomy). A logistic regression analysis was performed to identify those independent predictors of response. In addition, a decision-tree analysis was also performed.
Sixty-eight percent of patients (64 out of 94) responded to steroids. In the univariate analysis the number of bowel movements, rectal bleeding, platelet count, and C-reactive protein (CRP) levels at day 3 were associated with response at day 7, but only rectal bleeding was found to be an independent predictor in the logistic regression analysis. Conversely, the classification and regression tree (CART) model included these four variables. The decision-tree model showed a higher sensitivity in predicting a rapid response to steroids than the logistic regression one.
Rapid response to steroids in active UC attacks can be predicted after 3 days of treatment by simple clinical and biological parameters. A decision-tree model for early introduction of rescue therapies is provided.
[Show abstract][Hide abstract] ABSTRACT: Background & aim: Immunosenescence can increase morbi-mortality. Lactic acid producing bacteria may improve immunity and reduce morbidity and mortality in the elderly. We aimed to investigate the effects of a mixture of two new probiotic strains of Lactobacillus plantarum-CECT 7315 and 7316- on systemic immunity in elderly. Methods: 50 institutionalized elderly subjects were randomized, in a double-blind fashion, to receive for 12 weeks 1) 5·108 cfu/day of L. plantarum CECT7315/7316 ("low probiotic dose") (n = 13), 2) 5·109 cfu/day of the probiotic mixture ("high probiotic dose") (n = 19), or 3) placebo (n = 15). Leukocyte subpopulations, and cytokine levels (IL-1 , IL-10, TGF-β1) were measured in venous blood at baseline, end of treatment (week 12), and end of follow-up (week 24). Infection and survival rates were recorded. Results: After treatment, high probiotic dose resulted in significant increases in the percentages of activated potentially T-suppressor (CD8+CD25+) and NK (CD56+ CD16+) cells, while low probiotic dose increased activated T-helper lymphocytes (CD4+CD25+), B lymphocytes (CD19+), and antigen presenting cells (HLA-DR+). Also, plasma TGF-β1 concentration significantly decreased after treatment with both probiotic doses. Most of these changes remained 12 weeks after probiotic discontinuation. Incidence of infections during treatment showed a significant trend to be lower in the high probiotic dose group. In addition, there was a significant trend for mortality to be greater in the placebo group vs. both probiotic groups. Conclusions: Depending on the dose, L. plantarum CECT7315/7316 have different immune-enhancing effects in elderly subjects. These effects might result in a better clinical outcome.
Nutricion hospitalaria: organo oficial de la Sociedad Espanola de Nutricion Parenteral y Enteral 02/2011; 26(1):228-235. · 1.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease. However, common disease-associated SNPs explain at most ∼20% of the genetic variance for Crohn's disease. Several factors may account for this unexplained heritability, including rare risk variants not adequately tagged thus far in GWAS. That rare susceptibility variants indeed contribute to variation in multifactorial phenotypes has been demonstrated for colorectal cancer, plasma high-density lipoprotein cholesterol levels, blood pressure, type 1 diabetes, hypertriglyceridemia and, in the case of Crohn's disease, for NOD2 (refs. 14,15). Here we describe the use of high-throughput resequencing of DNA pools to search for rare coding variants influencing susceptibility to Crohn's disease in 63 GWAS-identified positional candidate genes. We identify low frequency coding variants conferring protection against inflammatory bowel disease in IL23R, but we conclude that rare coding variants in positional candidates do not make a large contribution to inherited predisposition to Crohn's disease.
[Show abstract][Hide abstract] ABSTRACT: The advent of biological therapy has revolutionized inflammatory bowel disease (IBD) care. Nonetheless, not all patients require biological therapy. Selection of patients depends on clinical characteristics, previous response to other medical therapy, and comorbid conditions. Availability, reimbursement guidelines, and patient preferences guide the choice of first-line biological therapy for luminal Crohn's disease (CD). Infliximab (IFX) has the most extensive clinical trial data, but other biological agents (adalimumab (ADA), certolizumab pegol (CZP), and natalizumab (NAT)) appear to have similar benefits in CD. Steroid-refractory, steroid-dependent, or complex fistulizing CD are indications for starting biological therapy, after surgical drainage of any sepsis. For fistulizing CD, the efficacy of IFX for inducing fistula closure is best documented. Unique risks of NAT account for its labeling as a second-line biological agent in some countries. Patients who respond to induction therapy benefit from systematic re-treatment. The combination of IFX with azathioprine is better than monotherapy for induction of remission and mucosal healing up to 1 year in patients who are naïve to both agents. Whether this applies to other agents remains unknown. IFX is also effective for treatment-refractory, moderate, or severely active ulcerative colitis. Patients who have a diminished or loss of response to anti-tumor necrosis factor (TNF) therapy may respond to dose adjustment of the same agent or switching to another agent. Careful consideration should be given to the reasons for loss of response. There are insufficient data to make recommendations on when to stop anti-TNF therapy. Preliminary evidence suggests that a substantial proportion of patients in clinical remission for >1 year, without signs of active inflammation can remain in remission after stopping treatment.
The American Journal of Gastroenterology 11/2010; 106(2):199-212; quiz 213. · 9.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The increasing number of trials testing management strategies for luminal Crohn's disease (CD) has not filled all the gaps in our knowledge and thus, in clinical practice, many decisions for CD patients have to be taken without the benefit of high-quality evidence.
A multidisciplinary European expert panel used the RAND Appropriateness Method to develop and rate explicit criteria for the management of individual patients with active, steroid-dependent (ST-D) and steroid-refractory (ST-R) CD.
Overall, 296 indications pertaining to mild-to-moderate, severe, ST-D, and ST-R CD were rated. In anti-TNF naïve patients, budesonide and prednisone were found to be appropriate for mild-moderate CD, and infliximab (IFX) was appropriate when these had previously failed or had not been tolerated. In patients with a prior successful treatment by IFX, this drug, with or without co-administration of a thiopurine analog, was favoured. Other anti-TNFs were appropriate in the presence of intolerance or resistance to IFX. High-dose steroids, IFX or adalimumab were appropriate in severe active CD. For the 105 indications for ST-D or ST-R disease, the panel considered the thiopurine analogs, methotrexate, IFX, adalimumab, and surgery for limited resection, to be appropriate, depending on the outcome of prior therapies. Anti-TNFs were generally considered appropriate in ST-R.
Steroids, including budesonide for mild-to-moderate CD, remain the first-line therapy for active luminal CD. Anti-TNFs, in particular IFX as shown by the amount of available evidence, remain the second-line therapy for most indications. Thiopurine analogs, methotrexate and anti-TNFs are favoured in ST-D patients and ST-R patients.
Journal of Crohn s and Colitis 12/2009; 3(4):232-40. · 3.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Most available data on infliximab therapy come from large, short-term, pivotal RCTs and concerns about long-term safety profile still remain.
To evaluate the long-term safety profile of infliximab in inflammatory bowel disease (IBD) in a clinical practice setting.
Since 1999, all IBD patients treated with infliximab were registered and clinical outcomes prospectively recorded up to March 2008, loss of follow-up or patient's death. Infliximab regimens and preventive measures were in accordance with the prevalent guidelines or with the manufacturer's recommendations.
One hundred fifty-two patients were included (121 Crohn's disease, 24 ulcerative colitis, 7 indeterminate colitis), with a median of 5 infliximab infusions (IQR 3-8) and 87% of patients received at least three infusions. Seventy-nine per cent of them received concomitant immunomodulators and 70% were pre-medicated with hydrocortisone from the first infusion. After a median follow-up of 142 weeks, 13% presented infusion reactions, 13% viral or bacterial infections and two patients developed neoplasia. The mortality rate was 2.6% (four patients).
Infliximab therapy is safe when the recommended preventive measures are implemented, with a rate of serious adverse events less than 10%. No new safety signals were found.
[Show abstract][Hide abstract] ABSTRACT: Infliximab (IFX) could change the course of Crohn's disease (CD) by reducing steroid use, surgery or prompting earlier introduction of immunomodulators (IMM).
To evaluate the impact of IFX availability on the course of early CD.
Two cohorts of newly diagnosed CD patients were identified: The first cohort included patients diagnosed from January 1994 to December 1997 and the second from January 2000 to December 2003. All patients were diagnosed, treated and followed up in the same centre until December 1999 (first cohort) or December 2005 (second cohort). Development of disease-related complications, steroid, IMM or IFX requirements and intestinal resections during follow-up were registered.
A total of 328 patients were included (146 first cohort, 182 second cohort). A similar proportion of patients in both cohorts received steroids, but steroid exposure resulted significantly more intense in the first cohort (P = 0.001). In the second cohort, 14% of patients received IFX. Thiopurines were used more (P = 0.001) and earlier (P = 0.012) in the second cohort. No differences in surgical requirements or the development of disease-related complications were found.
Following a step-up therapeutic algorithm, IFX availability did not reduce surgical requirements or the development of disease-related complications.