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BACKGROUND/OBJECTIVES Immune-mediated inflammatory diseases (IMIDs) are prevalent diseases. There is, however, a lack of understanding of the link between diet and IMIDs, how much dietary patterns vary between them and if there are food groups associated with a worsening of the disease. SUBJECTS/METHODS To answer these questions we analyzed a nation-wide cohort of n = 11,308 patients from six prevalent IMIDs and 2050 healthy controls. We compared their weekly intake of the major food categories, and used a Mendelian randomization approach to determine which dietary changes are caused by disease. Within each IMID, we analyzed the association between food frequency and disease severity. RESULTS After quality control, n = 11,230 recruited individuals were used in this study. We found that diet is profoundly altered in all IMIDs: at least three food categories are significantly altered in each disease (P

The production of antibodies to anti-tumor necrosis factor alpha (TNF) agents is one of the main causes of treatment failure in Crohn’s disease (CD). To date, however, the contribution of genetics to anti-TNF immunogenicity in CD is still unknown. The objective of the present study was to identify genetic variation associated with anti-TNF immunogenicity in CD. We performed a two-stage genome-wide association study in a cohort of 96 and 123 adalimumab-treated patients, respectively. In the discovery stage, we identified a genome-wide significant association between the CD96 locus and the production of antibodies to anti-TNF treatment (P = 1.88e–09). This association was validated in the replication stage (P

Background and aims: The aims of this study were to evaluate the frequency of entero-urinary fistulas in a cohort of Crohn’s disease (CD) patients and to analyse the outcomes of medical and surgical therapy. Methods: This multicentre retrospective study included all CD patients with entero-urinary fistulas diagnosed by the presence of clinical symptoms and confirmed at surgery or by radiological or endoscopic techniques. We evaluated outcomes of medical and surgical therapy. We defined remission as absence of clinical symptoms with a radiological confirmation of fistula closure. Cox regression analysis was performed to evaluate factors predictive of achieving remission without need for surgery. Results: Of 6081 CD patients screened, 97 had entero-urinary fistulas (frequency 1.6%). Seventy-five percent of fistulas occurred in men. After a median follow-up of 91 months, 96% of patients were in sustained remission. Thirty-three patients (35%) received anti-tumour necrosis factor (TNF) therapy. Of these, 45% achieved sustained remission (median follow-up 35 months) without needing surgery. More than 80% of patients required surgery, which induced remission (median follow-up 101 months) in 99% of them. Only the use of anti-TNF agents was associated with an increased rate of remission without need for surgery (hazard ratio 0.23, 95% confidence interval 0.12–0.44; p < 0.001). Conclusion: In this large cohort of CD patients, the frequency of entero-urinary fistulas was lower than previously described. More than 80% of patients required surgery, and in all but one of them surgery induced sustained remission. In a selected subgroup of patients, anti-TNF may induce long-term fistula remission and radiographic closure, making it possible to avoid surgery.

Autoimmune diseases like celiac disease (CeD) and ulcerative colitis (UC) show a common genetic background defined by the existence of shared susceptibility loci. We aimed to go deeper into this common genetic background through performing a cross-disease study based on gene expression. We measured the expression of 21 genes located in 13 CeD-UC susceptibility regions, and 10 genes in five CeD risk regions. Determinations were carried out in colon/rectum samples from 13 UC patients (inflamed and uninflamed tissue) and four colon samples from controls. Duodenal samples from 19 CeD patients and 12 controls were used for comparisons. Differences were analyzed using the Bayesian method. The shared chromosomal regions containing TNFAIP3, PTPN2, ICOSLG, C1orf106, and IL21 showed similar results in both diseases. FASLG, PLEK, CCR4, and TAGAP, all located in CeD risk loci, were up-regulated in both CeD and UC patients. Finally, ZFP36L1, ZMIZ1, PUS10, UBE2L3, and BACH2 showed opposite results in CeD and UC. A high complexity underlies autoimmune common susceptibility loci, as the expression pattern of the studied genes does not always correlate with the one expected attending to the apparent genetic background. Differentially expressed genes such as ZFP36L1, ZMIZ1, PUS10, and BACH2 deserve further research in autoimmune diseases.

Background & Aims Crohn's disease is a highly heterogeneous inflammatory bowel disease comprising multiple clinical phenotypes. Genome-wide association studies (GWASs) have associated a large number of loci with disease risk but have not associated any specific genetic variants with clinical phenotypes. We performed a GWAS of clinical phenotypes in Crohn's disease. Methods We genotyped 576,818 single-nucleotide polymorphisms in a well-characterized cohort of 1090 Crohn's disease patients of European ancestry. We assessed their association with 17 phenotypes of Crohn's disease (based on disease location, disease behavior, disease course, age at onset, and extraintestinal manifestations). A total of 57 markers with strong associations to Crohn's disease phenotypes ( P -4 ) were subsequently analyzed in an independent replication cohort of 1296 patients of European ancestry. Results We replicated the association of 4 loci with different Crohn's disease phenotypes. Variants in MAGI1 , CLCA2 , 2q24.1 , and LY75 loci were associated with a complicated stricturing disease course ( P combined = 2.01 × 10 -8 ), disease location ( P combined = 1.3 × 10 -6 ), mild disease course ( P combined = 5.94 × 10 -7 ), and erythema nodosum ( P combined = 2.27 × 10 -6 ), respectively. Conclusions In a GWAS, we associated 4 loci with clinical phenotypes of Crohn's disease. These findings indicate a genetic basis for the clinical heterogeneity observed for this inflammatory bowel disease.

Substantial proportion of Crohn’s disease (CD) patients shows no response or a limited response to treatment with infliximab (IFX) and to identify biomarkers of response would be of great clinical and economic benefit. The expression profile of five genes (S100A8-S100A9, G0S2, TNFAIP6, andIL11) reportedly predicted response to IFX and we aimed at investigating their etiologic role through genetic association analysis. Patients with active CD (350) who received at least three induction doses of IFX were included and classified according to IFX response. A tagging strategy was used to select genetic polymorphisms that cover the variability present in the chromosomal regions encoding the identified genes with altered expression. Following genotyping, differences between responders and nonresponders to IFX were observed in haplotypes of the studied regions:S100A8-S100A9(rs11205276*G/rs3014866*C/rs724781*C/rs3006488*A;P=0.05);G0S2(rs4844486*A/rs1473683*T;P=0.15);TNFAIP6(rs11677200*C/rs2342910*A/rs3755480*G/rs10432475*A;P=0.10); andIL11(rs1126760*C/rs1042506*G;P=0.07). These differences were amplified in patients with colonic and ileocolonic location for all but theTNFAIP6haplotype, which evidenced significant difference in ileal CD patients. Our results support the role of the reported expression signature as predictive of anti-TNF outcome in CD patients and suggest an etiological role of those top-five genes in the IFX response pathway.

Infliximab (IFX) is a valid treatment for Crohn’s disease (CD), but a relevant percentage of patients do not benefit from this therapy. In the Japanese population, the response to IFX was associated with markers in the TNF receptor superfamily 1A ( TNFRSF1A ) and 1B ( TNFRSF1B ) genes. We aimed to replicate the association previously described in the Japanese population and to ascertain the role of TNF receptors as modulators of the response to IFX. We studied 297 white Spanish CD patients with a known response to IFX: 238 responders and 59 primary nonresponders. Four single nucleotide polymorphisms (SNPs) were analyzed: rs767455 in TNFRSF1A and rs1061622 , rs1061624 , and rs3397 in TNFRSF1B . Comparisons between groups were performed with chi-square tests or the Fisher’s exact test. Different features (sex, age, disease duration, smoking among others) were evaluated as possible confounding factors. No significant association was found between the studied TNFRSF1A polymorphisms and response to IFX. In the TNFRSF1B gene, the haplotype rs1061624_A-rs3397_T was significantly increased in nonresponders: p = 0.015, OR = 1.78, 95% CI 1.09–2.90; and an increased frequency of rs1061622_G carriers was observed in patients with remission: p = 0.033 vs nonresponders and p = 0.023 vs patients with a partial response. Our results support a role of TNFRSF1B gene variants in the response to IFX in CD patients.

Objective: to describe the experience at two tertiary centres during the first year of use of magnetic resonance enterography (MRE) for the management of Crohn's disease (CD): indications and influence of the technique in clinical decision making. Material and method: retrospective descriptive study in which patients who underwent MRE were included consecutively. Epidemiological and clinical data were collected from the patients, as well as the indication for the study and how it influenced clinical decision making in the 10 days following the radiological study. Results: 24 MREs were performed in suspected CD and 126 known CD; partial bowel obstruction in 53 patients (42%), monitoring of medical treatment in 34 (27%), due to incomplete ileocolonoscopy in 16 (13%), extension study of the small intestine in 15 (12%) and suspected complicated CD in 8 patients (6%). The MRE influenced in a change in treatment in 83 (55.3%) patients: 16 (10.7%) started with immunosuppressants, 41 (27.3%) with anti-TNFα were started on or switched, 15 (10%) were ordered surgery and in 3 (2%) changed from combined therapy to monotherapy. The MRE had less influence on clinical decision making in the group in which the indication was suspected CD (p < 0.05). Conclusions: the use of MRE helped on decision making in more than half of patients, especially with regards to decisions related to the use of biological therapies and the indication for surgery. MRE was less useful in suspected CD patients.

Objective Genome-wide association studies (GWAS) have identified multiple risk loci for Crohn9s disease (CD). However, the cumulative risk exerted by these loci is low, and the likelihood that additional, as-yet undiscovered loci contribute to the risk of CD is very high. We performed a GWAS on a southern European population to identify new CD risk loci. Design We genotyped 620 901 genome markers on 1341 CD patients and 1518 controls from Spain. The top association signals representing new candidate risk loci were subsequently analysed in an independent replication cohort of 1365 CD patients and 1396 controls. Results We identified a genome-wide significant association on chromosome 22q13.2 in the intergenic region between the RBX1 and EP300 genes (single nucleotide polymorphism rs4820425, OR 1.27, 95% CI 1.17 to 1.38, p=3.42E-8). We also found suggestive evidence for the association of the IFNGR2 (21q22.11), FOXP2 (7q31), MACROD2 (20p12.1) and AIF1 (6p21.3) loci with CD risk. Conclusions In this GWAS performed on a southern European cohort, we have identified a new risk locus for CD between RBX1 and EP300 . This study demonstrates that using populations of different ancestry is a useful strategy to identify new risk loci for CD.

Methotrexate is an effective treatment for inflammatory bowel disease (IBD). However, long-term treatments have been associated with the development of liver fibrosis. FibroScan® is a noninvasive, safe, and effective technique to evaluate liver fibrosis.To evaluate the presence of significant liver fibrosis by transient elastography (FibroScan®) in IBD patients treated with methotrexate.Cross-sectional study including IBD patients treated with methotrexate from different hospitals. Clinical and analytical data, duration of treatment, and cumulative dose of methotrexate were obtained. Liver stiffness was assessed by FibroScan®. The cutoff value for significant liver fibrosis (according to METAVIR) was F ≥ 2: 7.1 kPa. Results. In the study, 46 patients were included, 30 women (65%), with a mean age of 43 ± 10 years. 31 patients had Crohn's disease (67.4%), 13 ulcerative colitis (28.3%), and 2 indeterminate colitis (4.3%). The mean cumulative dose of methotrexate was 1242 ± 1349 mg, with a mean treatment duration of 21 ± 24 months. The mean value of liver stiffness was 4.7 ± 6.9 kPa. There were 35 patients (76.1%) with F01, 8 patients (17.4%) with F = 2, and 3 patients with F ≥ 3 (6.5%). There were no differences in liver stiffness depending on sex, age, type of IBD, or cumulative dose of methotrexate.(1) Development of advanced liver fibrosis in IBD patients treated with methotrexate is exceptional. (2) There were no differences in liver stiffness depending on the type of IBD or the cumulative dose of methotrexate. (3) FibroScan® may be potentially useful for evaluation and follow-up of liver fibrosis in methotrexate-treated patients.

Aliment Pharmacol Ther 2012; 35: 275–283 Summary Background Ciclosporin has proven to be effective in patients with corticosteroid-refractory ulcerative colitis (UC). When therapy with this drug fails, infliximab can be considered to avoid colectomy. The efficacy and safety of this sequential approach remain unknown. Aim To assess the efficacy and safety profile of treatment with infliximab after failure of ciclosporin in patients with a corticosteroid-refractory flare of UC. Methods Retrospective review of medical records of patients with a corticosteroid-refractory flare of UC who did not respond to ciclosporin and received salvage therapy with infliximab within a month of discontinuing ciclosporin. The severity of the flare and response to the treatment were graded using the Lichtiger index. Cumulative rates of colectomy were calculated using Kaplan–Meier analysis. Cox regression analysis was performed to identify predictors of colectomy. To evaluate the safety profile of this treatment strategy, any adverse event occurring after the first infusion of infliximab was considered. Results The study population comprised 47 patients with corticosteroid-refractory UC treated with infliximab after failure of ciclosporin. The median baseline Lichtiger index was 13. The mean time from the last ciclosporin dose to the first infliximab infusion was 6 days. After the first infliximab infusion, 13% of patients achieved remission, and 74% partial response. Of the 35 patients who received the third infliximab infusion, 60% achieved remission, and 37% partial response. Fourteen patients (30%) underwent colectomy. The rate of adverse events was 23%. One death occurred in a 40-year-old man who failed ciclosporin and infliximab and underwent surgery 10 days after the first infliximab infusion; he died of nosocomial pneumonia. Conclusions Treatment with infliximab makes it possible to avoid colectomy in two-thirds of corticosteroid-refractory UC patients in whom ciclosporin fails. However, the rates of adverse events and mortality mean that the decision to administer sequential therapy (ciclosporin–infliximab) should be taken on an individual basis.

Background Mucosal healing (MH) has emerged as a desirable treatment goal for patients with ulcerative colitis (UC). Currently little is known about the efficacy of using thiopurine immunosuppressants in monotherapy to achieve and maintain long-term MH in UC. This study analyzes the efficacy and the clinical impact of MH in patients with UC responded to thiopurine immunosuppressants in the long term. Methods An open, observational, cohort study in 20 patients with UC had been in clinical remission in monotherapy with thiopurine immunosuppressants for at least 1 year. MH was assessed by endoscopy. The patients according to the Mayo Endoscopic Score (0 vs 1 and 2), were followed until the end of the study or patient relapse. (according to Truelove and Witts criteria). Results Mean treatment time was 5.4 years. Twelve (60%) patients presented a Mayo Endoscopic Score of 0. A total of 18 patients were followed up for a median of 27.1 months. After endoscopy, 4 patients (22.2%) presented relapse, with a mean time of 27.5 months for a score ≥ 1 (95% CI; 18.2–36.8) versus 54.3 months for a score = 0 (95% CI 47.2–61.3) (p = 0.032). Conclusions This study shows the efficacy of thiopurine immunosuppressants in achieving mucosal healing in patients who respond to thiopurine immunosuppressants in the long term. We also observe the presence of endoscopy activity is not a rare event in this group of patients and is a predictor of early relapse.

Aliment Pharmacol Ther 2011; 34: 125–145 Summary Background Cross-sectional imaging techniques, including ultrasonography (US), computed tomography (CT) and magnetic resonance imaging (MRI), are increasingly used for evaluation of Crohn’s disease (CD). Aim To perform an assessment of the diagnostic accuracy of cross-sectional imaging techniques for diagnosis of CD, evaluation of disease extension and activity and diagnosis of complications, and to provide recommendations for their optimal use. Methods Relevant publications were identified by literature search and selected based on predefined quality parameters, including a prospective design, sample size and reference standard. A total of 68 publications were chosen. Results Ultrasonography is an accurate technique for diagnosis of suspected CD and for evaluation of disease activity (sensitivity 0.84, specificity 0.92), is widely available and non-invasive, but its accuracy is lower for disease proximal to the terminal ileum. MRI has a high diagnostic accuracy for the diagnosis of suspected CD and for evaluation of disease extension and activity (sensitivity 0.93, specificity 0.90), and is less dependent on the examiner and disease location compared with US. CT has a similar accuracy to MRI for assessment of disease extension and activity. The three techniques have a high accuracy for identification of fistulas, abscesses and stenosis (sensitivities and specificities >0.80), although US has false positive results for abscesses. As a result of the lack of radiation, US or MRI should be preferred over CT, particularly in young patients. Conclusions Cross-sectional imaging techniques have a high accuracy for evaluation of suspected and established CD, reliably measure disease severity and complications; they may offer the possibility to monitor disease progression.

Background: Thr300Ala polymorphism in ATG16L1 was reported as a susceptibility factor to Crohn's disease (CD). Inconsistently replicated associations with ulcerative colitis (UC) and specifically with ileal CD were also reported. Our aims were: to replicate the ATG16L1 Thr300Ala association with inflammatory bowel disease (IBD) in the Spanish population, to perform a meta-analysis to determine the risk conferred to the different IBD subgroups, and to test for the interaction with CARD15 or IL23R risk loci. Methods: Thr300Ala (rs2241880) single nucleotide polymorphism (SNP) was genotyped in 712 IBD patients and 745 controls by TaqMan technology. Genetic frequencies were compared with chi-square tests. Our findings were pooled in a meta-analysis. Results: In Spain, we observed an association of rs2241880 with CD (P = 0.008; odds ratio [OR, 95% confidence interval, CI] = 1.28 [1.06–1.54]), but not with UC. No significant differences emerged when patients were stratified by clinical features. Similarly, the meta-analysis demonstrated a significant association only with CD (P < 10−4; OR [95% CI] = 1.33 [1.28–1.38]). A significant difference between ileal CD patients and controls was observed, but heterogeneity was found in comparisons involving colonic CD patients and definite conclusions cannot be drawn. No interaction between rs2241880 and the established CARD15 or IL23R susceptibility variants was observed. Conclusions: The Thr300Ala polymorphism is associated with CD, regardless of the CARD15 or IL23R status, but not with UC. Stratification by clinical phenotypes did not show definitive results because of the existing heterogeneity among studies. (Inflamm Bowel Dis 2009;)

Genome-wide association studies have reported the role of the interleukin (IL) 2-IL21 chromosomal region at 4q27 in several autoimmune conditions. Mice deficient in IL-2 develop a disease with clinical and histological similarity to ulcerative colitis (UC) in humans. Modest evidence of linkage with UC was tentatively proposed for the IL2 gene more than a decade ago. Therefore, we decide to investigate the association of polymorphisms in the IL-2 axis (IL2, IL2RA, and IL2RB genes) with inflammatory bowel diseases (IBDs).Seven hundred and twenty-eight white Spanish unrelated IBD patients (356 Crohn's disease (CD) and 372 UC) and 549 ethnically matched controls were included in a case-control study. In addition, a Spanish replication cohort with 562 CD and 430 UC patients and 1,310 controls were analyzed. Eight single-nucleotide polymorphisms previously associated with different autoimmune diseases were analyzed using TaqMan chemistry.The IL2-rs6822844 polymorphism modified CD predisposition (P=0.002; odds ratio, OR (95% confidence interval, CI)=0.61 (0.44-0.84)); this was replicated in the other Spanish cohort, resulting in a strong protective effect of the minor allele in the merged samples (P=0.0002; OR (95% CI)=0.70 (0.58-0.85)). A similar effect of rs6822844 was detected for UC. Another marker, rs11938795, also showed evidence of an association with CD (P=0.006; OR (95% CI)=0.73 (0.58-0.92)).Polymorphisms within the IL2-IL21 linkage disequilibrium (LD) block show a novel association with IBD, this is concordant with suggestive previous results of whole genome analyses in CD and type 1 diabetes. Our data agree with the effect previously observed for other conditions and delineate a shared underlying mechanism.

Independent genome-wide association studies highlighted the function of CLEC16A/KIAA0350 polymorphisms modifying the risk to either multiple sclerosis (rs6498169) or type 1 diabetes (rs2903692). This C-type lectin gene maps to a linkage disequilibrium block at 16p13 and a functional role of this gene could be envisaged for other immune-related conditions, such as inflammatory bowel disease (IBD). The present study, aimed at investigating the association of those two polymorphisms with IBD, included 720 IBD patients and 550 ethnically matched healthy controls. The effect of rs2903692 previously described in diabetes was observed specifically for Crohn's disease (CD) patients lacking the main susceptibility factor described to date, that is, three polymorphisms within another pattern recognition gene, NOD2/CARD15 (NOD2(-) vs NOD2(+) CD patients, G vs A: P=0.008; OR (95% CI)=1.54 (1.10-2.15); NOD2(-) CD patients vs controls: P=0.008; OR (95% CI)=1.37 (1.08-1.73)). Replication of these findings was performed in independent Spanish cohorts of 544 IBD patients and 340 controls and the combined data yielded significant differences (405 NOD2(-) vs 204 NOD2(+) CD patients, G vs A: P=0.0012; OR(M-H) (95% CI)=1.49 (1.17-1.90); NOD2(-) CD patients vs controls: P=0.0007; OR(M-H) (95% CI)=1.35 (1.13-1.60)). The pooled analysis of the ulcerative colitis patients vs controls also yielded a significant risk (P=0.0005; OR (95% CI)=1.52 (1.19-1.93)). These data would suggest that microbial recognition through different pathways seems to converge in the development of these polygenic bowel diseases.

Neuropathic pain of various etiologies is a frequent symptom in HIV-infected patients that is underdiagnosed and inadequately treated. It requires a multidisciplinary pain approach based on psychosocial factors, diet and exercise, etiologic treatment whenever possible, symptomatic medical treatment, and sometimes, interventional techniques. Medical treatment should be individualized and introduced gradually, with a mind to potential drug interactions. Neuropathic pain responds poorly to conventional analgesics, such as nonsteroidal antiinflammatory drugs and opiates; tricyclic antidepressants and anticonvulsants are the drugs of choice. Before establishing an analgesic treatment, possible drug interactions should be ruled out, mainly those occurring with antiretroviral agents.

Efficacy of infliximab in Crohn's disease (CD) showed by randomized controlled trials must be confirmed in clinical practice. We aimed to evaluate efficacy and safety of infliximab in CD patients of the Madrid area, looking for clinical predictors of response.Multicenter retrospective survey of all CD patients treated with infliximab in 8 University hospitals of the Madrid area (Spain) with a minimum follow up of 14 wks.169 patients included (48%males, mean age 39 +/- 12 yrs). 64% of them had perianal disease. 82% were under immunosuppressants. 1,355 infliximab infusions administered (mean 8, range 1-30). 90% response rate and 48% remission rate were obtained with induction therapy. 73% followed maintenance treatment, and 78% of them maintained or improved the response after a mean follow up of 28 months (range 3.5-86). 24 patients lost response during the follow up, after a mean of 41 wks (range 6-248). Only the prescription of maintenance therapy was predictive factor for favourable response (p0.01). 17 infusion reactions were reported (10% of the patients, 1.2% of the infusions; only one case was severe) and were the cause of treatment withdrawal in 7 patients. Co-treatment with immunosuppressive drugs and maintenance infliximab therapy were protective factors for infusion reactions (p0.05). Other adverse events occurred in 26% of the patients, and were cause of treatment withdrawal in 7 patients.Infliximab is effective and safe for CD management but concomitant immunosuppressive drugs and maintenance treatment should be prescribed to obtain the best outcome. That confirms in a real life clinical setting the favourable results obtained in randomized clinical trials.

The protein tyrosine phosphatase N22 (PTPN22) gene encodes a lymphoid-specific phosphatase (LYP), a downregulator of T-cell activation. Because a functional PTPN22 polymorphism, C1858T, has been found to be associated with different autoimmune diseases, we aimed to elucidate the role of this variant in predisposition to achalasia. We performed a case-control study with 231 nonrelated Spanish patients of white ethnicity diagnosed with achalasia and in 554 healthy control subjects, all genotyped for PTPN22 C1858T using TaqMan chemistry. The frequency of the 1858T allele was higher in the achalasia patients than in the healthy controls (carriers of allele T vs CC: OR = 1.38, 95% confidence interval [95% CI] 0.88-2.16, p = 0.13). Moreover a different genotype distribution was found between female and male patients (carriers of allele T vs CC: OR = 2.06, 95% CI 0.96-4.42, p = 0.04) and also between female patients and controls (OR = 1.94, 95% CI 1.12-3.36, p = 0.01), but not between male patients and controls (OR = 0.94, 95% CI 0.50-1.77, p = 0.85). We conclude that the PTPN22 1858T allele is a susceptibility factor for Spanish women with achalasia.

Background: To investigate the contribution of multidrug resistance 1 (MDR1) gene pharmacogenetics (G2677T/A and C3435T) to the efficacy of azathioprine in inducing remission in patients with Crohn's disease (CD). Methods: A cohort of 327 unrelated Spanish patients with CD recruited from a single center was studied. All patients were rigorously followed up for at least 2 years (mean time, 11.5 years). A case-control analysis of MDR1 G2677T/A and C3435T SNPs and 2 loci haplotypes in 112 steroid-dependent CD patients treated with azathioprine was performed. Patients were classified on the basis of response to azathioprine. Results: A total 76 patients treated with azathioprine for longer than 3 months were included. Remission was achieved in 42 CD patients (55.3%). A higher frequency of the 2677TT genotype was found in nonresponders than in responders (17.65% versus 7.14%; OR = 2.8; 95% CI; 0.6–12.1; P = 0.11). Nonresponders to azathioprine were found to have a higher frequency of the 3435TT genotype than did CD patients who had achieved clinical remission (17.64% versus 4.76%; OR = 4.3; 95% CI, 0.8–22.8; P = 0.06). The 2677T/3435T haplotype was also more abundant in nonresponders (29.4% versus 20.2%), whereas the 2677G/3435C haplotype was more frequent in responders (58.3% versus 47.1%). Lack of response to azathioprine therapy in CD patients was 1.8-fold greater in carriers of the 2677T/3435T haplotype than in carriers of the 2677G/3435C haplotype (OR = 1.8; 95% CI, 0.82–3.9; P = 0.14). Conclusions: The results of our study indicate higher frequencies of the 2677TT and 3435TT genotypes and the 2677T/3435T haplotype in CD patients who did not respond to azathioprine. Additional replications in independent populations would confirm the real impact of these polymorphisms in response to azathioprine therapy. (Inflamm Bowel Dis 2007)

The outcomes of infliximab dose escalation in ulcerative colitis (UC) have not been well evaluated. To assess the short- and long-term outcomes of infliximab dose escalation in a cohort of patients with UC. This was a multicenter, retrospective, cohort study. All consecutive UC patients who had lost response to infliximab maintenance infusions and who underwent infliximab dose escalation were included. Post-escalation short-term clinical response and remission were evaluated. In the long term, the cumulative probabilities of infliximab failure-free survival and colectomy-free survival were calculated. Predictors of short-term response and event-free survival were estimated using logistic regression analysis and Cox proportional hazard regression analysis. Seventy-nine patients were included. Fifty-four patients (68.4 %) achieved short-term clinical response and 41 patients (51.9 %) entered in clinical remission. After a median follow-up of 15 months [interquartile range (IQR) 8–26], 33 patients (41.8 %) had infliximab failure. Patients with short-term response had a significantly lower adjusted rate of infliximab failure [hazard ratio (HR) 0.24, 95 % confidence interval (CI) 0.12–0.49; p

Background: The most consistently described associations in ulcerative colitis (UC) have been with human leukocyte antigen (HLA) class II alleles. Our aim was to look for associations among distinct genetic polymorphisms in the major histocompatibility complex (MHC) that might play a role in determining the susceptibility to UC and especially to the extensive form of the disease. Methods: A case-control study was performed with a total of 253 patients with UC and 315 healthy controls recruited from a single Spanish center. All the samples and 4 cell lines carrying DRB1*0103 or DRB1*1501 alleles were typed for the HLA-DRB1 class II gene and for a panel of HLA class III markers (D6S273, BAT_2, TNFa, b, c, d, e, IKBL+738, MICA). Results: The frequency of the alleles DRB1*0103, IKBL+738(C) (extending our previous results) and BAT_2-8 (newly typed) was increased in patients compared with controls (P = 0.00001, odds ratio [OR] = 5.90; P = 0.002, OR = 2.42; and P = 0.0001, OR = 3.04, respectively), and these associations were greatest in patients with extensive disease compared with patients with distal disease (P = 0.02, OR = 2.53; P = 0.002, OR = 3.06; and P = 0.03, OR = 2.08, respectively). The allelic combination DRB1*0103/D6S273-5/BAT_2-8/TNFa11b4c1d3e3/IKBL+738(C)/MICA5.1 that includes the telomeric class III markers of the 7.1 ancestral haplotype is highly increased in patients with UC (P = 0.0001, OR = 10.57), especially in those with the extensive form of the disease (P = 0.02, OR = 3.41 extensive versus distal). Conclusions: The above-mentioned pattern, most likely formed by recombination of the telomeric fragment of the MHC 7.1 ancestral haplotype, seems to be the most important genetic determinant of susceptibility to the extensive form of UC in our population.

Fundamento y objetivo La prevalencia de las manifestaciones extraintestinales (MEI) en la enfermedad inflamatoria intestinal (EII) varia en funcion de las areas geograficas, el tipo de EII, la localizacion, la duracion de la enfermedad y el tratamiento y la rapidez en el diagnostico. El objetivo de este trabajo ha sido determinar la prevalencia de las principales MEI en la EII y las diferencias existentes entre la enfermedad de Crohn (EC) y la colitis ulcerosa (CU). Pacientes y metodo Estudio prospectivo en el que se incluyo a 566 pacientes con EII (295 con EC y seguimiento medio de 11,6 anos [extremos: 2-32 anos] y 271 con CU y seguimiento medio de 10,4 anos [extremos: 2-36 anos]. Los datos referidos a las MEI y tests de laboratorio se obtuvieron en el momento del diagnostico y durante las visitas posteriores. Resultados La aparicion de al menos una MEI se observo en el 46,6% de los pacientes. Las MEI fueron frecuentes tanto en la CU (51,5%) como en la EC (42,2%). Las manifestaciones hepatobiliares (odds ratio [OR] = 1,91; intervalo de confianza [IC] del 95%, 1,15-3,16), la enfermedad tromboembolica venosa (OR = 4,26; IC del 95%, 1,3-15,4) y las artralgias (OR = 1,59; IC del 95%, 1,01-2,5) fueron mas frecuentes en la CU que en la EC. El eritema nodoso (OR = 2,35; IC del 95%, 1,13-5,0) y las artritis perifericas (OR = 1,95; IC del 95%, 1,02- 3,74) fueron mas frecuentes en la EC. La prevalencia de las manifestaciones oculares y del resto de manifestaciones articulares no difirio entre la CU y la EC. Conclusiones La prevalencia de las MEI en los pacientes con EII espanoles es una de las mas altas publicadas. La frecuencia del tipo de MEI es diferente entre los pacientes con EC y CU, un aspecto que es importante conocer para realizar un diagnostico adecuado de la EII y de sus complicaciones.

Background: Inflammatory bowel disease (IBD) is considered a heterogeneous, complex polygenic disease where both genetic and environmental factors are involved in the development of the disease. Interleukin-10 (IL-10) is a regulatory cytokine that might play an important role in disease pathogenesis. IL-10 contains single nucleotide polymorphisms and 2 polymorphic microsatellites in the 5′-flanking region. Our aim was to ascertain if any of these polymorphic markers is associated with IBD among Spanish patients. Methods: We genotyped 470 patients with IBD, 242 with ulcerative colitis and 228 with Crohn's disease (CD), and 572 ethnically matched controls for microsatellites IL-10R and IL-10G and 2 single nucleotide polymorphisms at positions -1082 and -819 in the proximal promoter of the gene. Results: IL-10G14 microsatellite allele as well as -1082G allele were significantly increased in patients with CD. The combined presence of both alleles in 1 individual notably increased the risk to develop CD (P = 0.00006, odds ratio = 3.18). Conclusion: IL-10 polymorphisms contribute to susceptibility to CD in Spanish population.

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.

Magnetic resonance enterography in Crohn disease management has been rapidly growing in importance during recent years. Being familiar to this technique is essential for radiologists and also, to some extent, for gastroenterologists. Our aim is to study and describe the imaging findings in magnetic resonance enterography in Crohn disease to develop a comprehensive and useful review article and imaging atlas.

Objectives Treatment of HIV infection with highly antiretroviral therapy (HAART) may be limited by liver toxicity. Its incidence and risk factors are not well known. Patients and methods Retrospective chart review. Naive patients beginning HAART between January 1997 and January 2000. Severe transaminase elevation was defined as fivefold or higher rise over upper normal limits, or as > or =3.5-fold rise above abnormal baseline values. Results Of 222 study subjects, 38%, 5%, and 2% were coinfected with hepatitis C virus (HCV), hepatitis B virus, and hepatitis D virus, respectively. Besides two nucleoside reverse transcriptase inhibitors (NRTIs), 96 patients received protease inhibitors (PIs), 90 received nonnucleoside reverse transcriptase inhibitors (NNRTIs), and 35 received a PI + NNRTI combination. Severe hepatic injury developed in 21 (9%): 10% PI, 9%, and 9% PI + NNRTI. Both univariate and multivariate analyses identified alcohol abuse, HCV coinfection, and older age as independent risk factors. Predictor variables in the final multivariate model were: alcohol abuse (risk ratio [RR], 5.87; 95% confidence interval [CI], 1.49-23.15; p =.01], positive HCV serology (RR, 3.99; 95% CI, 1.32-12.10; p =.01], and older age (RR, 1.11; 95% CI, 1.04-1.18; p = 0.001). Conclusions Nearly 10% of study subjects who start HAART experience severe transaminase elevation, irrespective of the treatment. Avoidance of alcohol abuse, especially in study subjects coinfected with HCV, will reduce the risk of hepatic injury after HAART. When possible, prior treatment for chronic HCV infection should be considered.

Fundamento El beneficio de la terapia antirretroviral de gran actividad (TARGA) puede verse limitado por la aparicion de hepatotoxicidad. La frecuencia de esta complicacion con las distintas combinaciones de farmacos y los factores que propician su aparicion no se conocen bien. Pacientes y metodo Estudio retrospectivo de todos los pacientes sin experiencia previa a los antirretrovirales que iniciaron TARGA entre enero de 1997 y enero de 2000 en un hospital de Madrid. La hepatotoxicidad se definio por una elevacion de la cifra de transaminasas. Resultados Se incluyo a un total de 91 pacientes. De ellos, 36 (40%) eran ex-adictos a drogas por via parenteral, 35 (38%) homosexuales y 20 (22%) heterosexuales. Un total de 43 (47%) estaban coinfectados por algun virus hepatotropo (42% virus de la hepatitis C [VHC], 8% virus de la hepatitis B [VHB]). El tratamiento consistio en dos nucleosidos mas un inhibidor de la proteasa (IP) en 48 sujetos o bien un no nucleosido en 50. Tres pacientes recibieron dos nucleosidos, un IP y un no nucleosido. Las caracteristicas basales de los pacientes eran similares en los diferentes grupos de tratamiento. En 30 individuos (31%) se produjo hepatotoxicidad. Aunque fue transitoria en el 80%, ocurrieron formas graves en 10 (11%). La hepatotoxicidad grave fue mas frecuente en las personas coinfectadas por VHC y/o VHB (riesgo relativo [RR], 10,36; intervalo de confianza [IC] del 95%, 1,38–77,56; p = 0,03). La ingestion elevada de alcohol tambien se asocio con una mayor frecuencia de hepatotoxicidad (RR, 3,35; IC del 95%, 2,43–4,62; p = 0,01). No se objetivaron diferencias en cuanto al tipo de medicacion antirretroviral. La hiperbilirrubinemia aislada (27%) se asocio al uso de indinavir (RR, 3,61; IC del 95%, 1,81–7,21; p Conclusiones Un tercio de los pacientes que inician TARGA desarrollan hepatotoxicidad, sin diferencias apreciables en frecuencia o gravedad al comparar las distintas combinaciones de antirretrovirales. La coinfeccion por VHB y/o VHC, asi como la ingestion elevada de alcohol representan los principales factores predictivos de hepatotoxicidad.

Idiopathic achalasia is a motility disorder of the esophagus whose etiology is unknown. An association between HLA genes and susceptibility to achalasia which suggests a possible immunogenetic mechanism has been reported recently. This study was designed to examine the HLA class II association in a large group of achalasia patients further and to investigate the distribution of TNFa and TNFb microsatellites in these patients. The study population, all Spanish, white and unrelated, consisted of 115 consecutive patients and 339 healthy controls. All of the patients had been diagnosed with primary achalasia of the esophagus with manometric, radiographic and endoscopic studies. All studies were performed on DNA samples after locus-specific amplification with the polymerase chain reaction: HLA-DRB1, DQA1 and DQB1 were typed by dot-blot hybridization and the size of the TNFa and TNFb microsatellites was measured using a semiautomatic method. The broad allele HLA-DQ1 was seen to be weakly associated with achalasia. The TNFa11 allele and the DRB1*1501-DQA1*0102-DQB1*0602 haplotype were reduced in achalasia patients but the stratified analyses showed that this was true only when both were present in the same individual. These results confirm the association between achalasia and HLA-DQ1 allele and suggest that TNFa11 is a marker for a protective allele for the disease, present on the B7-DRB1*1501 (7.1) ancestral haplotype in our population.

Fundamento La promocion y el fomento de la investigacion es actualmente una de las estrategias fundamentales sobre la que se asienta el desarrollo de nuestra sociedad moderna. Los parses estan invirtiendo grandes recursos destinados a este fin, y por ello se hace necesario un proceso serio y riguroso de evaluacion de la investigacion, asi como el analisis de los resultados obtenidos en los numerosos proyectos de investigacion subvencionados tanto en convocatorias publicas como privadas, para asegurar el buen fin de las inversiones realizadas. Material y metodo Se ha analizado una muestra de 431 proyectos pertenecientes a la convocatoria FIS de 1998. Las evaluaciones FIS y ANEP (Agencia Nacional de Evaluacion y Prospectiva) fueron analizadas y puntuadas (calidad de evaluacion) en sus principales contenidos por tres evaluadores independientes; asimismo, los resultados fueron sometidos a comparaciones intraagencia e interagencia Resultados En la evaluacion FIS intervinieron 20 comisiones, y el analisis intraFIS detecto que la calidad de la evaluacion era dependiente de la comision correspondiente responsable de la evaluacion (F = 3,71; p Conclusiones Los resultados obtenidos aconsejan una modificacion de la estructura evaluativa y de la composicion de las comisiones cientifico-tecnicas del FIS que tenga como finalidad una mejora del proceso de evaluacion de los proyectos de investigacion presentados en convocatoria publica al FIS.

Fundamento y objetivo: La enfermedad inflamatoria intestinal (EII) es una enfermedad poligenica compleja. Tanto la expresion de PAR1 y PAR2 como su presencia en biopsias de pacientes con EII apuntan a un posible papel de estos genes en la susceptibilidad genetica a presentar EII. Este es el primer estudio de asociacion genetica que se realiza con estos genes en la EII. Pacientes y metodo: Se analizaron mediante sondas TaqMan dos polimorfismos en el gen F2R/PAR1 y otro mas en el gen F2RL1/PAR2 en 778 controles sanos y 943 afectados de EII (pacientes con enfermedad de Crohn y colitis ulcerosa de Madrid y Granada). Resultados: No se encontraron diferencias significativas en la distribucion de alelos entre pacientes y controles. Conclusiones: No hay evidencia de asociacion de los polimorfismos analizados en F2R/PAR1 y F2RL1/PAR2 con modificaciones del riesgo de presentar EII.

Achalasia is a motor disorder of the esophagus resulting in functional obstruction. The cause of the lesion is unknown although genetic and immunologic factors have been suggested. An association with serological HLA epitopes has been previously reported. In this study, we have further examined this HLA class II association with susceptibility to achalasia by DNA based methods. Achalasia patients (n=40) and healthy controls (n=275), all Caucasians and unrelated, were included in the analysis. The strongest associations were with HLA-DQA1*0101 and two HLA-DQ alphabeta heterodimers having their alpha chain encoded by this allele. Moreover, relative risk was significantly higher in DQA1*0101 homozygotes as compared to heterozygotes and results suggested that DQB1*02 may have a protective role.

Background: Adalimumab is an effective treatment for Crohn's disease (CD), but may also be associated with loss of response. Few reports provide insight into the durability of treatment of CD with adalimumab for periods longer than 12 months in clinical practice. Aims: To evaluate the long-term durability of adalimumab maintenance treatment and to identify predictive factors associated with loss of response. Methods: CD patients who initially responded to adalimumab were evaluated in a historical cohort study. Maintenance of long-term response was estimated using Kaplan–Meier analysis. Cox regression analysis was performed to identify potential predictive factors for loss of efficacy. Results: In all, 380 CD patients were included (mean age, 38 years; 52% female). Of these, 43% had ileocolic CD, 50% inflammatory CD, and 41% perianal CD. Median follow-up with adalimumab was 8 months (range, 4–75 months). The annual risk of loss of response to adalimumab was 18% per patient-year of follow-up. Twenty-eight percent of patients were anti-TNF-naive and 72% anti-TNF-experienced. The loss of efficacy was 8% per patient-year of follow-up in the anti-TNF-naive patients and 22% in the anti-TNF-experienced group (P < 0.01). In the multivariate analysis, the presence of extraintestinal manifestations (hazard ratio [HR] = 1.7; 95% confidence interval [CI] = 1.02–2.9) and previous experience with other anti-TNF agents (HR = 2.5,95% CI = 1.2–5.3) were associated with higher risk of loss of efficacy. Conclusions: A relevant proportion of CD patients on long-term adalimumab lost response. The risk of loss of response was higher (more than 2-fold) in anti-TNF-experienced than in anti-TNF-naive patients (22% vs. 8% per patient-year of treatment). Having extraintestinal manifestations seems to increase the risk of loss of efficacy. (Inflamm Bowel Dis 2011;)

The efficacy of infliximab therapy in patients with Crohn's disease (CD) is unknown beyond 12 months. For patients who lose their initial response, consideration can be given to dose "escalation" to regain therapeutic benefit.Our primary goal was to evaluate the long-term durability of maintenance infliximab treatment. The secondary goals were to identify potential predictors of loss of infliximab efficacy, to evaluate the response to infliximab escalation, and the safety of the treatment with infliximab with and without escalation of dose.CD patients treated with infliximab with response to an induction regimen were evaluated. Maintenance of long-term response was estimated using Kaplan-Meier analysis. The effect of specific variables was calculated using logistic regression analysis. Efficacy of dose escalation in patients who lose response to infliximab was analyzed.Three hundred and nine CD patients were included. The mean follow-up time with infliximab treatment was 41 months, and the majority (95%) were on concomitant immunosuppressive therapy. The annual risk of loss of response to infliximab was 12% per patient-year of treatment. After loss of response, 41% of patients were managed with infliximab therapy escalation. After the first intensified dose, 56% of patients achieved remission and 40% partial response. Concurrent immunomodulators enhanced and smoking decreased the proportion of patients who maintained response (P0.05).A relevant proportion of CD patients on long-term infliximab treatment loss response. After loss of response, a high proportion of these patients initially respond to infliximab dose escalation. Concurrent immunomodulators may increase and smoking may decrease maintenance of response.

The aim of this study was to evaluate the possible implication of CD24 gene in the genetic predisposition to inflammatory bowel disease (IBD). Our study population consisted of 1321 female Spanish individuals (369 Crohn's disease [CD] patients, 323 ulcerative colitis [UC] patients, and 629 healthy matched controls). Two putative functional polymorphisms, a C to T coding polymorphism (rs8734) and a TG deletion in the 3' untranslated region (rs3838646), were used as CD24 genetic markers and genotyped using a Taqman 5' allelic discrimination assay. The >del> allele of the dinucleotide deletion was associated with an increased risk of CD (odds ratio = 1.61, 95% confidence interval = 1.17-2.21, pFDR = 6.4E-03) but not with UC. Moreover, this allele was significant associated with the age of CD diagnosis between 17 and 40 years, the ileocolonic location, and the inflammatory behavior of CD. We observed no significant differences between the allelic or genotypic frequencies of the A57V polymorphism in our studied IBD cohort. Our results suggest that the rs3838646 CD24 polymorphism is part of the genetic background of CD. © 2011 American Society for Histocompatibility and Immunogenetics.

2 páginas.-- Póster presentado al 5º European Workshop on Immune-Mediated Inflammatory Diseases celebrado en Sitges (Barcelona) dxel 1 al 3 de Diciembre de 2010.-- et al., The PTPN22 gene is an important risk factor for human autoimmunity. Two PTPN22 missense-SNPs, both with functional influence, the R620W (1858C>T, rs2476601) in exon 14 and the R263Q (788G>A, rs33996649) in exon 10 have been associated with autoimmune diseases [1-4].

The Faculty of Management, at the Rosario University (Colombia) has been developing since 2004 studies aimed at understanding the dynamics of different sectors of the Colombian economy, with the aim of identifying elements contribute to achieving the sustainability of enterprises. One of the methodologies implemented for this purpose, structural analysis is called strategic sectors, which to identify levels of market consolidation, structural analysis market forces and an assessment of competitors. The information obtained in tests, allows decision makers to take steps to achieve business improvement. On this occasion, an analysis of the sector passenger and freight transport. Unlike previous studies, the analysis seeks to place a focus on improvement track.

To analyse the possible influence of a non-synonymous single nucleotide polymorphism (SNP) of the histamine-degrading enzyme diamine oxidase (DAO) on genetic susceptibility to Crohn's disease (CD).In this prospective, case-control study, 210 unrelated Caucasian consecutive CD patients were recruited at the Inflammatory Bowel Disease Unit of a single tertiary centre (Hospital Clínico San Carlos) in Madrid, Spain. A total of 261 healthy volunteers from the same geographic area were also recruited and matched with patients. Both cases and controls were analysed for the presence of a non-synonymous SNP (rs1049793) of DAO using amplification-restriction procedures of the genotype obtained in a blood sample.No significant differences were found in the distribution of carriers of the non-synonymous SNP of DAO between CD patients and controls (OR 1.2 (95% CI 0.9-1.6; p=0.3)). Nor were any differences found between carriers and non-carriers of the non-synonymous SNP in demographic characteristics, phenotypes, complications or treatment of CD.The study of a non-synonymous SNP (rs1049793) of DAO does not seem to be of use in assessing susceptibility to CD, either as a marker of disease activity or as a marker of clinical behaviour in patients with the disease.

Background: The mechanisms responsible for the pathogenesis of peripheral arthropathies (PA) in Crohn's disease (CD) are largely unknown, although many studies indicate that genetic and environmental factors are likely to contribute to risk. Methods: Because variants in the Fc receptor-like 3 (FcRL3) gene have recently been associated with rheumatoid arthritis and several other autoimmune diseases, we tested 2 FcRL3 promoter variants (−169 C>T and −110 G>A) for association with PA in Spanish CD patients that were recruited from a single center and followed for at least 4 years (mean follow-up time, 11 years). Results: Among the 342 CD patients evaluated, there were 88 cases of peripheral arthropathy; 31 were classified as arthritis and 57 were classified as arthralgia. We used contingency tables and logistic regression to test for association between PA or either subtype and FcRL3 and other factors that have previously been associated with extraintestinal manifestations in CD. Conclusions: We found that female sex, colonic involvement, and the AA genotype at −110 G>A were associated with increased risk of both subtypes of PA, although the association appears to be stronger for arthritis than for arthralgia. (Inflamm Bowel Dis 2009)

Results of randomized controlled trials showing efficacy of infliximab in ulcerative colitis (UC) should be confirmed in clinical practice. We aimed to evaluate the efficacy and safety of infliximab in UC patients of the Madrid area, looking for clinical predictors of response.Multicenter retrospective survey of all UC patients treated with infliximab in the region of Madrid (Spain).47 UC patients were included (45% males, mean age 44 +/- 15 yrs), mean follow up of 4.7 months (range 0.5-21), and a total number of 211 infliximab infusions. Clinical response and steroid-free remission rates were, respectively, 97/42% in the 2nd week, 93/69% in the 6th week, and 80/65% at the long-term follow up (mean 8.2 months, range 3.5-21). Colectomy rate was 10.6% (five patients). Age, gender, disease duration, indication (steroid-resistance/dependence), disease severity, C-reactive protein, concomitant thiopurinic therapy or smoking habit did not influence on efficacy. Extent of the disease was the only predictive factor (p=0.02). Only 4 cases of mild adverse events were reported.Infliximab is effective and safe for UC. Real life clinical practice may have better outcome than showed in randomized controlled trials. Extent of the disease was the only predictive factor for clinical response in our experience.

Inflammatory bowel disease (IBD) is a polygenic complex trait. The expression and presence in biopsiae from IBD patients points to a putative role of these genes in genetic susceptibility to IBD. This is the first association study on these genes in relation with IBD.Two polymorphisms were analyzed within F2R/PAR1 and another one mapping to F2RL1/PAR2 in 778 healthy controls and 943 IBD cases (Crohn's disease and ulcerative colitis patients from 2 cohorts from Madrid and Granada).No significant differences in the distribution of the PARs' polymorphisms were found.There is no evidence of association of the analyzed polymorphisms with IBD risk.

Objective The STAT4 gene encodes a transcription factor involved in the signaling pathways of several cytokines, including interleukin-12 (IL-12), the type I interferons, and IL-23. Recently, the association of a STAT4 haplotype marked by rs7574865 with rheumatoid arthritis (RA) and systemic lupus erythematosus was reported. The aim of this study was to investigate the role of this STAT4 tagging polymorphism in other immune-mediated diseases. Methods The study group comprised 2,776 consecutively recruited Spanish individuals: 575 with RA, 440 with multiple sclerosis, 700 with inflammatory bowel disease, 311 with type 1 diabetes, and 723 ethnically matched healthy control subjects. The STAT4 polymorphism rs7574865 was genotyped using a predesigned TaqMan assay. Allele and genotype frequencies in patients and control subjects were compared by chi-square test. Results The association of STAT4 polymorphism rs7574865 with RA was validated in patients of Spanish origin (for T versus G, P = 1.2 × 10−6, odds ratio [OR] 1.59, 95% confidence interval [95% CI] 1.31–1.92), and the association was described for the first time in both clinical forms of inflammatory bowel disease, Crohn's disease and ulcerative colitis (for T versus G, P = 0.006, OR 1.29, 95% CI 1.07–1.55), and in type 1 diabetes mellitus (for T versus G, P = 0.008, OR 1.36, 95% CI 1.07–1.71). In contrast, the genotypic distribution of this polymorphism showed no difference between patients with multiple sclerosis and healthy control subjects (for T versus G, P = 0.83, OR 1.02, 95% CI 0.82–1.28). Conclusion The STAT4 gene is emerging as a novel common risk factor for diverse complex diseases.

Background Selenoprotein S (SelS) protects the functional integrity of the endoplasmic reticulum against the deleterious effects of metabolic stress. SEPS1/SelS polymorphisms have been involved in the increased release of pro-inflammatory cytokines interleukin (IL)-1β, tumor necrosis factor (TNF)-α and IL-6 in macrophages. We aimed at investigating the role of the SEPS1 variants previously associated with higher plasma levels of these cytokines and of the SEPS1 haplotypes in the susceptibility to develop immune-mediated diseases characterized by an inflammatory component. Results Six polymorphisms distributed through the SEPS1 gene (rs11327127, rs28665122, rs4965814, rs12917258, rs4965373 and rs2101171) were genotyped in more than two thousand patients suffering from type 1 diabetes, rheumatoid arthritis or inflammatory bowel diseases and 550 healthy controls included in the case-control study. Conclusion Lack of association of SEPS1 polymorphisms or haplotypes precludes a major role of this gene increasing predisposition to these inflammatory diseases.