[Show abstract][Hide abstract] ABSTRACT: Glucocorticosteroids are the first line therapy for moderate-severe flare-ups of ulcerative colitis. Despite that, up to 60% of patients do not respond adequately to steroid treatment. Previously, we reported that low IL-10 mRNA levels in intestine are associated with a poor response to glucocorticoids in active Crohn's disease. Here, we test whether IL-10 can favour the response to glucocorticoids by improving the TNFα-induced intestinal barrier damage (assessed by transepithelial electrical resistance) in Caco-2 monolayers, and their possible implications on glucocorticoid responsiveness in active ulcerative colitis. We show that the association of IL-10 and glucocorticoids improves the integrity of TNFα-treated Caco-2 cells and that p38 MAPK plays a key role. In vitro, IL-10 facilitates the nuclear translocation of p38 MAPK-phosphorylated thereby modulating glucocorticoids-receptor-α, IL-10-receptor-α and desmoglein-2 expression. In glucocorticoids-refractory patients, p38 MAPK phosphorylation and membrane desmoglein-2 expression are reduced in colonic epithelial cells. These results suggest that p38 MAPK-mediated synergism between IL-10 and glucocorticoids improves desmosome straightness contributing to the recovery of intestinal epithelium and reducing luminal antigens contact with lamina propria in ulcerative colitis. This study highlights the link between the intestinal epithelium in glucocorticoids-response in ulcerative colitis.
PLoS ONE 06/2015; 10(6):e0130921. DOI:10.1371/journal.pone.0130921 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fecal calprotectin (FC) is considered the best noninvasive way to assess disease activity in ulcerative colitis (UC). However, it is not known which is the more suitable moment for stool sampling in patients with increased stool frequency. The aims of this study were to assess the intraindividual variation of FC within day and to evaluate if the first bowel movement in the morning is the more suitable sample for FC measurement in patients with acute flares of UC.
Patients admitted because of active UC were invited to collect samples from several bowel movements (including the first in the morning) during the same day providing their ordinal chronology. FC was measured by means of a quantitative rapid point-of-care test based on lateral flow assay immunochromatography.
Eighteen patients were included for a total of 56 stool samples. Most patients had extensive UC and severe disease activity. Within-day FC values varied widely, and the median coefficient of variation was 40% (5%-114%) with a median range of variation of FC values of 3887 mg/kg (69-9946). The sample from the first stool in the morning obtained the highest individual FC within-day value in 33.3% of cases and the lowest in 38.9%.
FC values widely vary between motions in patients with active UC. Stool sample collection from the first bowel movement in the morning does not ensure the highest or lowest within-day FC value. In patients with overt active UC, a single FC determination should not be used as the basis for therapeutic strategies.
[Show abstract][Hide abstract] ABSTRACT: Background: Oral corticosteroids remain the mainstay of treatment for moderately active ulcerative colitis (UC). In patients who fail to respond to oral corticosteroids, attempting the intravenous route before starting rescue therapies is an alternative, although no evidence supports this strategy.
Aim: To evaluate clinical outcomes after a course of intravenous corticosteroids for moderate attacks of UC according to the failed oral corticosteroids or not.
Methods: All episodes of active UC admitted to three university hospitals between January 2005 and December 2011 were identified and retrospectively reviewed. Only moderately active episodes treated with intravenous corticosteroids were included. Treatment outcome was compared between episodes which failed to outpatient oral corticosteroids for the index flare and those directly treated by intravenous corticosteroids.
Results: 110 episodes were included, 45% of which failed to outpatient oral corticosteroids (median dose 60 mg/day [IQR 50–60], median length of course 10 days [IQR 7–17]). Initial response (defined as mild severity or inactive disease at day 7 after starting intravenous corticosteroids, without rescue therapy) was achieved in 75%, with no between-group differences (78% vs. 75%). After a median follow-up of 12 months (IQR 4–24), 35% of the initial responders developed steroid-dependency and up to 13% required colectomy. Unsuccessful response to oral corticosteroids was the only factor associated with steroid-dependency in the long term (P = 0.001).
Conclusions: Intravenous corticosteroids are efficient for inducing remission in moderately active UC unresponsive to oral corticosteroids, but almost half of these patients develop early steroid-dependency. Alternative therapeutic strategies should be assessed in this clinical setting.
Journal of Crohn s and Colitis 11/2014; 8(11). DOI:10.1016/j.crohns.2014.06.010 · 6.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
The short-term efficacy of infliximab (IFX) and cyclosporine A (CsA) in steroid-refractory ulcerative colitis (SRUC) has been recently shown to be similar, but long-term outcomes are still unclear. Moreover, the need for further rescue therapies in patients treated with IFX or CsA for SRUC has not been reported. The aims of our study were to compare short-term and long-term efficacy between 2 different strategies based on initial treatment with CsA or IFX for SRUC attacks.
Patients and methods:
Between January 2005 and December 2011, all patients admitted for SRUC who required medical rescue therapy were identified from the electronic databases of 3 referral centers and grouped according to whether they received CsA or IFX as first-line rescue therapy, and retrospectively reviewed.
Among 50 SRUC attacks, 20 were treated with CsA as first-line rescue therapy and 30 with IFX. The CsA group had a higher proportion of patients with severe UC activity immediately before rescue therapy (P = 0.03) and a shorter median time from intravenous corticosteroids to rescue therapy (P = 0.03). A higher proportion of patients in the CsA group received second-line drug therapy (switch) as compared with the IFX group (P = 0.04). Fifteen patients (30%) were colectomized during the study period, with no between-group differences. Previous thiopurine exposure (P = 0.004; odds ratio = 6.1 [1.7-20.9]) was the only independent predictor of colectomy.
CsA- and IFX-based strategies for SRUC seem similarly effective in preventing colectomy in the short and long term, although second-line drug therapy is more often required with CsA-based strategies.
[Show abstract][Hide abstract] ABSTRACT: 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.
Human Molecular Genetics 07/2014; 23(25). DOI:10.1093/hmg/ddu398 · 6.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite the availability of biological drugs and the widespread and earlier use of immunosuppressants, intestinal resection remains necessary in almost half of the patients with Crohn's disease. The development of new mucosal lesions in previously unaffected intestinal segments (a phenomenon known as post-operative recurrence, POR) occur within the first year in up to 80% if no preventive measure is started soon after resectional surgery, leading to clinical manifestations (clinical recurrence) and even needing new intestinal resection (surgical recurrence) in some patients. That is the reason why endoscopic monitoring has been recommended within 6 to 12 months after surgery. Active smoking is the only indisputable risk factor for early POR development. Among several evaluated drugs, only thiopurine and anti-tumor necrosis factor therapy seem to be effective and feasible in the long-term both for preventing or even treating recurrent lesions, at least in a proportion of patients. However, to date, it is not clear which patients should start with one or another drug right after surgery. It is also not well established how and how often POR should be assessed in patients with a normal ileocolonoscopy within the first 12 months.
Annals of Gastroenterology 06/2014; 27(4):313-319.
[Show abstract][Hide abstract] ABSTRACT: Background
Thiopurines prevent Crohn's disease (CD) endoscopic recurrence (ER) at least in 50% of patients one year after surgery.AimTo evaluate the value of adding mesalazine in patients with subclinical ER despite preventive thiopurine therapy.MethodsCD patients with ileocecal resection treated with thiopurines for post-surgical recurrence prevention in whom mesalazine was added (cases) to treat ER without clinical recurrence (CR) were identified and compared with those in whom no treatment was added to thiopurines (controls). All patients were followed up for at least one year from the index endoscopy. Development of CR as well as evolution of mucosal lesions was evaluated.ResultsThirty-seven patients were included (19 cases and 18 controls). Initial Rutgeerts’ score was i2 in 16 patients (9 cases and 7 controls), and i3 in 21 patients (10 cases and 11 controls). After a median clinical follow-up of 59 months (IQR 22 - 100) from the index endoscopy, 6 cases (32%) and 2 controls (11%) developed CR (P= 0.2). After a median time to last endoscopic follow-up of 23 months (IQR 17-71) 18 patients (49%) showed improvement in Rutgeerts’ score, 11 patients (30%) demonstrated progression of mucosal lesions and 8 (22%) had no changes, with no differences between study groups.Conclusions
The addition of mesalazine seems to be of no benefit in patients with subclinical endoscopic recurrence while on thiopurine prevention. Moderate endoscopic post-surgical recurrence while on thiopurines may even revert with no additional therapy in some patients.
Journal of Gastroenterology and Hepatology 03/2014; 29(7). DOI:10.1111/jgh.12579 · 3.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: No studies have specifically searched for predictors of a favourable outcome that would allow a conservative therapeutic approach in adult Crohn's disease (CD).
To identify predictors of a favourable disease course over time at CD diagnosis.
We identified and included all patients diagnosed with CD between January 1994 and December 2003, who had CD with an inflammatory pattern and no perianal disease at diagnosis, and who were followed up for at least 5 years. Clinical and therapeutic features until December 2008 and losses to follow-up were identified. We defined a favourable outcome as the absence of stricturing and penetrating complications of the disease (including perianal disease), together with the absence of need for anti-TNF therapy or resectional surgery during follow up.
One hundred and forty-five patients were included and followed up for a median of 96 months (IQR, 79-140). At diagnosis, location was ileal in 39%, colonic in 28%, and ileocolonic in 32%; 50% of the patients were active smokers, and 41% used immunomodulators. Eighty-two patients (57%) met the criteria for a favourable outcome at the end of follow-up. The only factor associated with a favourable outcome was isolated colonic involvement (P=0.022), with 73% of these patients meeting the criteria for a favourable outcome.
A favourable outcome of initially uncomplicated CD is not easily predicted at disease diagnosis by means of clinical or epidemiologic factors. Nevertheless, patients with isolated colonic disease are less likely to have an aggressive course.
Gastroenterología y Hepatología 09/2013; 36(10). DOI:10.1016/j.gastrohep.2013.07.004 · 0.84 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.
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%.
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.
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: BACKGROUND: The association between inflammatory bowel disease (IBD) and synovitis, acne, pustulosis, hyperostosis, osteitis syndrome (SAPHO syndrome) was first reported in 1992. To date, only case reports and short series have been published. AIMS: The purpose of this study was to report new cases and systematically review the literature on this association. MATERIALS AND METHODS: All patients with concomitant diagnosis of SAPHO syndrome and IBD were identified from the databases of the rheumatology and gastroenterology departments of our institution. In addition, we systematically searched for published full articles in Medlars Online International Literature via PubMed. Relevant information of each positive match was collected and all authors were contacted for additional clinical data. RESULTS: Three patients sharing both SAPHO syndrome and IBD were identified among the 62 patients with SAPHO syndrome (4.8 % of the SAPHO cohort) and the 1,309 patients with IBD (0.2 % of the IBD cohort) from our hospital database. After a systematic review, a total of 39 reported patients with concomitant diagnosis of SAPHO syndrome and IBD were identified. There was a female predominance and most had Crohn's disease with colonic involvement. CONCLUSIONS: The association of SAPHO syndrome and IBD seems to be rare among IBD patients but not so among SAPHO patients. SAPHO could be underdiagnosed because of the similarity of its clinical manifestations and some more common extraintestinal manifestations or drug-related side effects in IBD.
[Show abstract][Hide abstract] ABSTRACT: Aim:
The aim was to assess the impact of inflammatory bowel disease (IBD) and its treatment on fertility, pregnancy outcomes, and breastfeeding. IBD is a chronic inflammatory condition that is usually diagnosed in young adulthood. Patients are often concerned about fertility and pregnancy outcomes.
A structured questionnaire was posted to 850 adults with IBD followed-up on in a single center.
A total of 503 patients (59%) with a median age of 40 years and equally distributed for gender and type of IBD returned the questionnaire. Overall, 71% of the patients had a total of 659 children, 36% of whom were born after the diagnosis. A total of 132 miscarriages were registered, 46% after the diagnosis of IBD. Most childless patients stated that having no children was a personal decision, and only 6% of them were evaluated and diagnosed with infertility. Pregnancies after diagnosis of IBD had a higher probability of caesarean section and preterm delivery. IBD-related drug therapy was discontinued in 16% of the pregnancies, mainly as a result of medical advice. Babies born after the diagnosis of IBD were less often breastfed.
The infertility rate among IBD patients seems to be similar to that seen in the general population. However, a large proportion of patients chose to remain childless. Vaginal delivery and breastfeeding are less likely to occur in babies born after the diagnosis. Suitable information for patients to avoid unwarranted concerns about adverse reproductive outcomes, as well as improved obstetrical and perinatal management, still seems to be necessary.
[Show abstract][Hide abstract] ABSTRACT: Objectives:
The safety of thiopurines and anti-tumor necrosis factor-α (TNF-α) drugs during pregnancy remains controversial, as the experience with these drugs in this situation is limited. Our aim is to assess the safety of thiopurines and anti-TNF-α drugs for the treatment of inflammatory bowel disease (IBD) during pregnancy.
Retrospective, multicenter study in IBD patients. Pregnancies were classified according to the therapeutic regimens during pregnancy or during the 3 months before the conception: non-exposed group, pregnancies exposed to thiopurines alone (group A), and pregnancies exposed to anti-TNF-α drugs (group B). An unfavorable Global Pregnancy Outcome (GPO) was considered if pregnancy developed with obstetric complications in the mother and in the newborn.
A total of 187 pregnancies in the group A, 66 pregnancies in the group B, and 318 pregnancies in the non-exposed group were included. The rate of unfavorable GPO was different among the three groups (31.8% in non-exposed group, 21.9% in group A, and 34.8% in group B), being lower in pregnancies under thiopurines than among non-exposed (P = 0.01). The rate of pregnancy complications was similar among the three groups (27.7% in non-exposed, 20.9% in group A, and 30.3% in group B). The rate of neonatal complications was different among the three groups (23.3% in non-exposed group, 13.9% in group A, and 21.2% in group B), being lower in pregnancies under thiopurines than among non-exposed (P = 0.01). In the multivariate analysis, the treatment with thiopurines (odds ratio = 0.6; 95% confidence interval = 0.4-0.9, P = 0.02) was the only predictor of favorable GPO, whereas maternal age >35 years at conception was the only predictor of unfavorable GPO. The treatment with anti-TNF-α drugs was not associated with an unfavorable GPO.
The treatment with thiopurines and anti-TNF-α drugs does not seem to increase the risk of complications during pregnancy and does seem to be safe for the newborn.
The American Journal of Gastroenterology 01/2013; 108(3). DOI:10.1038/ajg.2012.430 · 10.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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 (κ 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.
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 (κ = 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.
Familial IBD is associated with diagnostic anticipation in younger individuals. Familial history does not allow predicting any phenotypic feature other than IBD type.
Journal of Crohn s and Colitis 01/2013; 8(7). DOI:10.1016/j.crohns.2013.12.005 · 6.23 Impact Factor