Peripheral inflammation increases the damage in animal models of nigrostriatal dopaminergic neurodegeneration: possible implication in Parkinson's disease incidence.

Inflammatory processes described in Parkinson’s disease (PD) and its animal models appear to be important in the progression of the pathogenesis, or even a triggering factor. Here we review that peripheral inflammation enhances the degeneration of the nigrostriatal dopaminergic system induced by different insults; different peripheral inflammations have been used, such as IL-1β and the ulcerative colitis model, as well as insults to the dopaminergic system such as 6-hydroxydopamine or lipopolysaccharide. In all cases, an increased loss of dopaminergic neurons was described; inflammation in the substantia nigra increased, displaying a great activation of microglia along with an increase in the production of cytokines such as IL-1β and TNF-α. Increased permeability or disruption of the BBB, with overexpression of the ICAM-1 adhesion molecule and infiltration of circulating monocytes into the substantia nigra, is also involved, since the depletion of circulating monocytes prevents the effects of peripheral inflammation. Data are reviewed in relation to epidemiological studies of PD.

Multiple sclerosis risk variant HLA-DRB1*1501 associates with high expression of DRB1 gene in different human populations.

The human leukocyte antigen (HLA) DRB1*1501 has been consistently associated with multiple sclerosis (MS) in nearly all populations tested. This points to a specific antigen presentation as the pathogenic mechanism though this does not fully explain the disease association. The identification of expression quantitative trait loci (eQTL) for genes in the HLA locus poses the question of the role of gene expression in MS susceptibility. We analyzed the eQTLs in the HLA region with respect to MS-associated HLA-variants obtained from genome-wide association studies (GWAS). We found that the Tag of DRB1*1501, rs3135388 A allele, correlated with high expression of DRB1, DRB5 and DQB1 genes in a Caucasian population. In quantitative terms, the MS-risk AA genotype carriers of rs3135388 were associated with 15.7-, 5.2- and 8.3-fold higher expression of DQB1, DRB5 and DRB1, respectively, than the non-risk GG carriers. The haplotype analysis of expression-associated variants in a Spanish MS cohort revealed that high expression of DRB1 and DQB1 alone did not contribute to the disease. However, in Caucasian, Asian and African American populations, the DRB1*1501 allele was always highly expressed. In other immune related diseases such as type 1 diabetes, inflammatory bowel disease, ulcerative colitis, asthma and IgA deficiency, the best GWAS-associated HLA SNPs were also eQTLs for different HLA Class II genes. Our data suggest that the DR/DQ expression levels, together with specific structural properties of alleles, seem to be the causal effect in MS and in other immunopathologies rather than specific antigen presentation alone.

CD40: Novel Association with Crohn's Disease and Replication in Multiple Sclerosis Susceptibility

Background: A functional polymorphism located at 21 from the start codon of the CD40 gene, rs1883832, was previously reported to disrupt a Kozak sequence essential for translation. It has been consistently associated with Graves’ disease risk in populations of different ethnicity and genetic proxies of this variant evaluated in genome-wide association studies have shown evidence of an effect in rheumatoid arthritis and multiple sclerosis (MS) susceptibility. However, the protective allele associated with Graves’ disease or rheumatoid arthritis has shown a risk role in MS, an effect that we aimed to replicate in the present work. We hypothesized that this functional polymorphism might also show an association with other complex autoimmune condition such as inflammatory bowel disease, given the CD40 overexpression previously observed in Crohn’s disease (CD) lesions. Methodology: Genotyping of rs1883832C.T was performed in 1564 MS, 1102 CD and 969 ulcerative colitis (UC) Spanish patients and in 2948 ethnically matched controls by TaqMan chemistry. Principal Findings: The observed effect of the minor allele rs1883832T was replicated in our independent Spanish MS cohort [p= 0.025; OR (95% CI)= 1.12 (1.01–1.23)]. The frequency of the minor allele was also significantly higher in CD patients than in controls [p= 0.002; OR (95% CI)= 1.19 (1.06–1.33)]. This increased predisposition was not detected in UC patients [p= 0.5; OR (95% CI)= 1.04 (0.93–1.17)]. Conclusion: The impact of CD40 rs1883832 on MS and CD risk points to a common signaling shared by these autoimmune conditions

CD209 in inflammatory bowel disease: a case-control study in the Spanish population

BACKGROUND The etiology of Ulcerative Colitis (UC) and Crohn's Disease (CD), considered together as Inflammatory Bowel Diseases (IBD), involves environmental and genetic factors. Although some genes are already known, the genetics underlying these diseases is complex and new candidates are continuously emerging. The CD209 gene is located in a region linked previously to IBD and a CD209 functional polymorphism (rs4804803) has been associated to other inflammatory conditions. Our aim was to study the potential involvement of this CD209 variant in IBD susceptibility. METHODS We performed a case-control study with 515 CD patients, 497 UC patients and 731 healthy controls, all of them white Spaniards. Samples were typed for the CD209 single nucleotide polymorphism (SNP) rs4804803 by TaqMan technology. Frequency comparisons were performed using chi2 tests. RESULTS No association between CD209 and UC or CD was observed initially. However, stratification of UC patients by HLA-DR3 status, a strong protective allele, showed that carriage of the CD209_G allele could increase susceptibility in the subgroup of HLA-DR3-positive individuals (p = 0.03 OR = 1.77 95% CI 1.04-3.02, vs. controls). CONCLUSION A functional variant in the CD209 gene, rs4804803, does not seem to be influencing Crohn's disease susceptibility. However, it could be involved in the etiology or pathology of Ulcerative Colitis in HLA-DR3-positive individuals but further studies are necessary.

Role of wireless capsule endoscopy in inflammatory bowel

Capsule endoscopy (CE) offers state-of-the-art imaging of the small bowel. In Crohn's disease its clinical role is still uncertain. This report analyses the usefulness of CE in patients with suspected Cronh's disease, in patients with established Crohn's disease (when assessing severity, occult gastrointestinal bleeding and/or as a guide to therapy), in patients with inflammatory bowel disease unclassified (IBDU), and in individuals with ulcerative colitis. The first item in this group is the most important although there is no strong evidence to establish the position of CE in the diagnostic workup. In patients with established Crohn's disease, recently developed activity scores are promising tools for an accurate assessment of severity. As a guide to therapy, CE should be focused on patients with unexplained symptoms when other investigations are inconclusive. In postoperative Crohn's Disease, international consensus recommended considering CE only if ileocolonoscopy is contraindicated or unsuccessful. In the case of IBDU, studies have shown a significant proportion of patients reclassified with Crohn's disease. In this setting, CE could have a role determining small bowel involvement. The role of CE in ulcerative colitis is limited. Some authors advocate CE before colectomy for refractory cases in order to exclude Crohn's disease. In summary, CE offers a new horizon in inflammatory bowel disease, and a better knowledge of mucosal abnormalities that could offer a paradigm shift: changing from symptom-based disease activity estimation to direct mucosal healing monitoring. Nevertheless, randomized controlled studies are still needed to provide stronger evidence in this setting.

Caspase-3 Protects Stressed Organs against Cell Death.

The ability to generate appropriate defense responses is crucial for the survival of an organism exposed to pathogenesis-inducing insults. However, the mechanisms that allow tissues and organs to cope with such stresses are poorly understood. Here we show that caspase-3-knockout mice or caspase inhibitor-treated mice were defective in activating the antiapoptotic Akt kinase in response to various chemical and environmental stresses causing sunburns, cardiomyopathy, or colitis. Defective Akt activation in caspase-3-knockout mice was accompanied by increased cell death and impaired survival in some cases. Mice homozygous for a mutation in RasGAP that prevents its cleavage by caspase-3 exhibited a similar defect in Akt activation, leading to increased apoptosis in stressed organs, marked deterioration of their physiological functions, and stronger disease development. Our results provide evidence for the relevance of caspase-3 as a stress intensity sensor that controls cell fate by either initiating a RasGAP cleavage-dependent cell resistance program or a cell suicide response.

Probióticos y prebióticos en la práctica clínica.

This article revises the concepts of prebiotics, probiotics and symbiotics, and their use in different situations of daily clinical practice. With a high level of evidence, it is concluded that the use of certain strains of probiotics significantly reduces the risk for antibiotic-induced diarrhea. Although further studies are needed, the use of probiotics, prebiotics, and symbiotics in people suffering from inflammatory bowel disease (particularly ulcerative colitis, and pouchitis) might improve the rates of remission induction/maintenance. The administration of probiotics and symbiotics to patients with liver transplant, severe acute pancreatitis, and intensive and surgical care patients, emerges as a promising therapeutic option that seems to reduce the number of infections; however, it is currently no possible to establish evidence-based recommendations, with a need for a higher number of better designed works. About safety of probiotics and symbiotics, the benefits/risks ratio clearly favors the former since the risk for infection is low, even in immunosuppressed patients. There are, however, selected groups of patients in which caution is advised.

High altitude journeys and flights are associated with the increased risk of flares in IBD patients

Background: There is increasing experimental evidence that hypoxia induces inflammation in the gastrointestinal tract. Hypoxia-inducible transcription factor (HIF)-1α influences adaptive immunity and has been shown to induce barrier-protective genes in the case of experimentally-induced colitis. The clinical impact of hypoxia in patients with inflammatory bowel disease (IBD) is so far poorly investigated. Aim: We wanted to evaluate if flights and journeys to regions ≥2000 meter above sea level are associated with the occurrence of flares in IBD patients in the following 4 weeks. Methods: A questionnaire was completed by inpatients and outpatients of the IBD clinics of three tertiary referral centers presenting with an IBD flare in the period from Sept 1st 2009 to August 31st 2010. Patients were inquired about their habits in the 4 weeks prior to the flare. Patients with flares were matched with an IBD group in remission during the observation period (according to age, gender, smoking habits, and medication). Results: A total of 103 IBD patients were included (43 Crohn's disease (CD), whereof 65% female, 60 ulcerative colitis, whereof 47% female, mean age 39.3±14.6 years for CD and 43.1±14.2 years for UC). Fifty-two patients with flares were matched to 51 patients without flare. Overall, IBD-patients with flares had significantly more frequently a flight and/or journey to regions ≥ 2000 meters above sea level in the observation period compared to the patients in remission (21/52 (40.4%) vs. 8/51 (15.7%), p=0.005). There was a statistically significant correlation between the occurrence of a flare and a flight and/or journey to regions ≥ 2000 meters above sea level among CD patients with flares as compared to CD patients in remission (8/21 (38.1%) vs. 2/22 (9.1%), p=0.024). A trend for more frequent flights and high-altitude journeys was observed in UC patients with flares (13/31 (41.9%) vs. 6/29 (20.7%), p=0.077). Mean flight duration was 5.8±4.3 hours. The groups were controlled for the following factors (always flare group cited first): age (39.6±13.4 vs. 43.5±14.6, p=0.102), smoking (16/52 vs. 10/51, p=0.120), regular sports activities (32/ 52 vs. 33/51, p=0.739), treatment with antibiotics in the 4 weeks before flare (8/52 vs. 7/ 51, p=0.811), NSAID intake (12/52 vs. 7/51, p=0.221), frequency of chronic obstructive pulmonary disease (both groups 0) and oxygen therapy (both groups 0). Conclusion: IBD patients with a flare had significantly more frequent flights and/or high-altitude journeys within four weeks prior to the IBD flare compared to the group that was in remission. We conclude that flights and stays in high altitude are a risk factor for IBD flares.

Serum ficolin-2 correlates worse than fecal calprotectin and CRP with endoscopic Crohn's disease activity.

BACKGROUND AND AIMS: Ficolin-2 is an acute phase reactant produced by the liver and targeted to recognize N-acetyl-glucosamine which is present in bacterial and fungal cell walls. We recently showed that ficolin-2 serum levels were significantly higher in CD patients compared to healthy controls. We aimed to evaluate serum ficolin-2 concentrations in CD patients regarding their correlation with endoscopic severity and to compare them with clinical activity, fecal calprotectin, and CRP. METHODS: Patients provided fecal and blood samples before undergoing ileo-colonoscopy. Disease activity was scored clinically according to the Harvey-Bradshaw Index (HBI) and endoscopically according to the simplified endoscopic score for CD (SES-CD). Ficolin-2 serum levels and fecal calprotectin levels were measured by ELISA. RESULTS: A total of 136 CD patients were prospectively included (mean age at inclusion 41.5±15.4 years, 37.5% females). Median HBI was 3 [2-6] points, median SES-CD was 5 [2-8], median fecal calprotectin was 301 [120-703] μg/g, and median serum ficolin-2 was 2.69 [2.02-3.83] μg/mL. SES-CD correlated significantly with calprotectin (R=0.676, P<0.001), CRP (R=0.458, P<0.001), HBI (R=0.385, P<0.001), and serum ficolin-2 levels (R=0.171, P=0.047). Ficolin-2 levels were higher in CD patients with mild endoscopic disease compared to patients in endoscopic remission (P=0.015) but no difference was found between patients with mild, moderate, and severe endoscopic disease. CONCLUSIONS: Ficolin-2 serum levels correlate worse with endoscopic CD activity when compared to fecal calprotectin or CRP.

Results of the 2nd scientific workshop of the ECCO (III): basic mechanisms of intestinal healing.

The second scientific workshop of the European Crohn's and Colitis Organization (ECCO) focused on the relevance of intestinal healing for the disease course of inflammatory bowel disease (IBD). The objective was to better understand basic mechanisms, markers for disease prediction, detection and monitoring of intestinal healing, impact of intestinal healing on the disease course of IBD as well as therapeutic strategies. The results of this workshop are presented in four separate manuscripts. This section describes basic mechanisms of intestinal healing, identifies open questions in the field and provides a framework for future studies.

When do we dare to stop biological or immunomodulatory therapy for Crohn's disease? Results of a multidisciplinary European expert panel.

BACKGROUND: Safety and economic issues have increasingly raised concerns about the long term use of immunomodulators or biologics as maintenance therapies for Crohn's disease (CD). Despite emerging evidence suggesting that stopping therapy might be an option for low risk patients, criteria identifying target groups for this strategy are missing, and there is a lack of recommendations regarding this question. METHODS: Multidisciplinary European expert panel (EPACT-II Update) rated the appropriateness of stopping therapy in CD patients in remission. We used the RAND/UCLA Appropriateness Method, and included the following variables: presence of clinical and/or endoscopic remission, CRP level, fecal calprotectin level, prior surgery for CD, and duration of remission (1, 2 or 4 years). RESULTS: Before considering withdrawing therapy, the prerequisites of a C-reactive protein (CRP) and fecal calprotectin measurement were rated as "appropriate" by the panellists, whereas a radiological evaluation was considered as being of "uncertain" appropriateness. Ileo-colonoscopy was considered appropriate 1 year after surgery or after 4 years in the absence of prior surgery. Stopping azathioprine, 6-mercaptopurine or methotrexate mono-therapy was judged appropriate after 4 years of clinical remission. Withdrawing anti-TNF mono-therapy was judged appropriate after 2 years in case of clinical and endoscopic remission, and after 4 years of clinical remission. In case of combined therapy, anti-TNF withdrawal, while continuing the immunomodulator, was considered appropriate after two years of clinical remission. CONCLUSION: A multidisciplinary European expert panel proposed for the first time treatment stopping rules for patients in clinical and/or endoscopic remission, with normal CRP and fecal calprotectin levels.

Chronology of extraintestinal manifestations relative to IBD diagnosis in the Swiss IBD Cohort

Background and Aims: Due to a p aucity of s uch data we aimed to a ssess the type and f requency o f extraintestinal manifestations ( EIM) in I BD p atients and to e valuate their chronologic behavior. Methods: A nalysis of d ata from t he Swiss Inflammatory Bowel Disease Cohort (SIBDCS) which c ollects data since 2 005 on a large sample o f IBD patients f rom hospitals and private practices across Switzerland. Results: A t total o f 1,143 patients were a nalyzed ( 572 (50%) female, mean age 42.1 ± 14.4 years), 629 with Crohn's disease (CD), 501 with ulcerative colitis (UC), and 13 with indeterminate colitis ( IC). Of t hese, 3 74 (32.7%) presented o ne to five E IM (65% w ith CD, 3 3% w ith UC, 2% w ith IC). O f those patients suffering from EIM, 4 1.7% p resented two, 1 2.4% t hree, 5 .3% four, and 3.2% f ive E IM d uring lifetime. T he initial EIM presented with the following frequencies: p eripheral a rthritis (PA) 6 3.4%, ankylosing spondylitis (AS) 8 .1%, primary sclerosing cholangitis (PSC) 6%, uveitis 5.7%, oral a phthosis 5.7%, erythema nodosum (EN) 5 %, other 3 .6%, pyoderma gangrenosum 1.8%, psoriasis 0.7%. In only 7.1% of cases, the EIM m anifested before IBD diagnosis was made (median time 28 months b efore IBD diagnosis, I QR 7 -60 months), in 9 2.9% EIM m anifested a fter e stablished IBD d iagnosis (median 72 months, IQR 9-147 months). Conclusions: EIM are a frequent problem in IBD patients. The vast m ajority of E IM m anifest a fter I BD d iagnosis has b een established. P eripheral a rthritis, a nkylosing spondylitis, a nd PSC represent the most frequent first manifestations of an EIM.

Prevalence of anaemia in inflammatory bowel disease in Switzerland: a cross-sectional study in patients from private practices and university hospitals.

BACKGROUND: Anaemia represents a common complication of inflammatory bowel disease (IBD). Most studies on anaemia in IBD patients have been performed in tertiary referral centres (RC) and data from gastroenterologic practices (GP) are lacking. We investigated the frequency and severity of anaemia in IBD patients from tertiary referral centres and gastroenterologic practices compared to the general population. METHODS: Data were acquired from patients included in the Swiss IBD Cohort Study. IBD activity was evaluated by CDAI and modified Truelove and Witts severity index (MTWSI). Anaemia was defined as haemoglobin ≤120g/L in women and ≤130g/L in men. RESULTS: 125 patients from RC (66 with Crohn's disease (CD) and 59 with ulcerative colitis (UC)) and 116 patients from GP (71 CD and 45 UC) were included and compared to 6074 blood donors. Anaemia was found in 21.2% (51/241) of the IBD patients and more frequently in patients from RC as compared to GP and healthy controls (28.8% vs. 12.9% vs. 3.4%; P<0.01). IBD patients from RC suffered more frequently from active disease compared to IBD patients in GP (36% vs. 23%, P=0.032). Supplementation therapy (iron, vitamin B12, folic acid) was performed in 40% of anaemic IBD patients in GP as compared to 43% in RC. CONCLUSIONS: Anaemia is a common complication in patients with IBD and significantly more prevalent in patients from referral centres as compared to patients from gastroenterologic practices. Physicians treating IBD patients should pay attention to the presence of anaemia and ensure sufficient supplementation therapy.

Thiopurines related malignancies in inflammatory bowel disease: Local experience in Granada, Spain.

AIM To investigate the incidence of neoplasms in inflammatory bowel disease (IBD) patients and the potential causative role of thiopurines. METHODS We performed an observational descriptive study comparing the incidence of malignancies in IBD patients treated with thiopurines and patients not treated with these drugs. We included 812 patients which were divided in two groups depending on whether they have received thiopurines or not. We have studied basal characteristics of both groups (age when the disease was diagnosed, sex, type of IBD, etc.) and treatments received (Azathioprine, mercaptopurine, infliximab, adalimumab or other immunomodulators), as well as neoplasms incidence. Univariate analysis was performed with the student t test, χ(2) test or Wilcoxon exact test as appropriate. A logistic regression analysis was performed as multivariate analysis. Statistical significance was establish at P values of less than 0.05, and 95%CI were used for the odds ratios. RESULTS Among 812 patients included, 429 (52.83%) have received thiopurines: 79.5% azathioprine, 14% mercaptopurine and 6.5% both drugs. 44.76% of patients treated with thiopurines and 46, 48% of patients who did not receive this treatment were women (P > 0.05). The proportion of ulcerative colitis patients treated with thiopurines was 30.3% compare to 66. 67% of patients not treated (P < 0.001). Mean azathioprine dose was 123.79 ± 36.5 mg/d (range: 50-250 mg/d), mean usage time was 72.16 ± 55.7 mo (range: 1-300 mo) and the accumulated dose along this time was 274.32 ± 233.5 g (1.5-1350 g). With respect to mercaptopurine, mean dose was 74.7 ± 23.9 mg/d (range: 25-150 mg/d), mean usage time of 23.37 ± 27.6 mo (range: 1-118 mo), and the accumulated dose along this time was 52.2 ± 63.5 g (range: 1.5-243 g). Thiopurine S-methyltransferase activity was tested in 66% of patients treated with thiopurines, among which 98.2% had an intermediate or high activity. Among the patients treated with thiopurines, 27.27% (112 patients) and 11.66% (50 patients) received treatment with Infliximab and Adalimumab respectively, but only 1.83% (7 patients) and 0.78% (3 patients) received these drugs in the group of patients who did not received thiopurines (P < 0.001 and P < 0.001 respectively). Finally, 6.8% (29 patients) among those treated with thiopurines have received other immunesupresants (Methotrexate, Tacrolimus, Cyclosporin), compare to 1% (4 patients) of patients not treated with thiopurines (P < 0.001). Among patients treated with thiopurines, 3.97% developed a malignancy, and among those not treated neoplasms presented in 8.1% (P = 0.013). The most frequent neoplasms were colorectal ones (12 cases in patients not treated with thiopurines but none in treated, P < 0.001) followed by non-melanoma skin cancer (8 patients in treated with thiopurines and 6 in not treated, P > 0.05). CONCLUSION In our experience, thiopurine therapy did not increase malignancies development in IBD patients, and was an efective and safe treatment for these diseases.

Vertebral fractures in patients with inflammatory bowel disease compared with a healthy population: a prospective case-control study.

BACKGROUND A prospective study was performed to compare the prevalence of morphometric vertebral fractures (MVF) between patients with inflammatory bowel disease (IBD) and healthy subjects and to identify predictive factors of fracture. METHODS A total of 107 patients with IBD (53 with Crohn's disease and 54 with ulcerative colitis) and 51 healthy subjects participated in the study. Information about anthropometric parameters, toxins, previous fractures, and parameters related to this disease were evaluated. The index of vertebral deformity, bone mass density (BMD), and biochemical parameters were calculated. RESULTS A total of 72 fractures were detected in 38.32% of patients with IBD, and 10 fractures were detected in 13.73% of healthy subjects; the risk of fracture in patients with IBD was higher than that in control subjects (OR, 4.03; 95% CI, 1.652-9.847; p < 0.002). We found no correlation between fracture and BMD in patients with IBD (lumbar spine, r = -0.103, p = 0.17 and femoral neck, r = -0.138, p = 0.07). Corticosteroid treatment was not associated with prevalent vertebral fractures nor with taking corticosteroids (r = 0.135, p = 0.14) or the duration for which they were taken (r = 0.08, p = 0.38), whereas this relationship was present in the controls (r = -0.365, p = 0.01). In the multivariate analysis, none of the measured parameters were significantly predictive of fracture, only to manifested IBD. Hypovitaminosis D was observed in 55.14% of patients with IBD. CONCLUSIONS The prevalence of morphometric vertebral fractures is higher in patients with IBD than in the healthy population, without association with BMD or corticoid treatment. Simply having IBD was proven to be a predictive factor of fracture. We observed a high incidence of hypovitaminosis D in patients with IBD.