Impact of Anti-CD20 therapies on the immune homeostasis of gastrointestinal mucosa and their relationship with de novo intestinal bowel disease in multiple sclerosis: a review.

Multiple sclerosis (MS) and inflammatory bowel disease (IBD) are autoimmune disorders characterized by inflammatory episodes affecting the brain and the gastrointestinal (GI) tract, respectively. The frequent association between MS and IBD suggests that both conditions may share common pathogenic mechanisms. However, different responses to biological therapies indicate differences in immune mechanisms of inflammation. Anti-CD20 therapies are high efficacy treatments increasingly used to control inflammatory bursts in MS, but they may alter GI homeostasis and promote the development of bowel inflammation in susceptible individuals. This review analyzes the mechanistic association between immunity in MS and IBD, the effect of anti-CD20 therapies on the gut microenvironment, and provides recommendations for early detection and management of GI toxicities in the context of B-cell depletion in MS patients.

Real-world short-term effectiveness of ustekinumab in 305 patients with Crohn's disease: results from the ENEIDA registry.

BACKGROUND: There are limited data of ustekinumab administered according to the doses recommended in the UNITI studies. AIM: To assess the real-world, short-term effectiveness of ustekinumab in refractory Crohn's disease (CD) METHODS: Multicentre study of CD patients starting ustekinumab after June 2017 at the recommend dose (260, 390 or 520 mg based on weight ~6 mg/kg IV week 0 and 90 mg subcutaneously week 8). Values for Harvey-Bradshaw Index (HBI), C-reactive protein (CRP) and faecal calprotectin (FC) were recorded at baseline and at weeks 8 and 14. Demographic and clinical data, previous treatments, AEs and hospitalisations were documented. Possible predictors of clinical remission were examined. RESULTS: Three hundred and five patients were analysed (≥2 previous anti-TNFα therapies 64% and vedolizumab 29%). At baseline, 217 (72%) had an HBI >4 points. Of these, 101 (47%) and 126 (58%) achieved clinical remission at weeks 8 and 14, respectively. FC levels returned to normal (<250 µg/g) in 46% and 54% of the patients at weeks 8 and 14 respectively. CRP returned to normal (<3 mg/L) in the 35% and 41% of the patients at week 8 and 14 respectively. AEs were recorded in 38, and 40 patients were hospitalised. Intolerance to the most recent anti-TNF agent and fewer previous anti-TNF agents were associated with clinical remission at week 14. Endoscopic severity was associated with poor response. CONCLUSION: This is the first study to show the real-world effectiveness and safety of ustekinumab administered according to the recommended induction regimen in a cohort of highly refractory CD patients.

Alpha-defensins (α-Defs) in Crohn's disease: decrease of ileal α-Def 5 via permanent methylation and increase in plasma α-Def 1-3 concentrations offering biomarker utility.

An impaired expression of α-defensins (α-Defs) in the ileal mucosa and, conversely, increased levels in plasma, have been reported in Crohn's disease (CD). However, the specificity and correlation of these findings with the degree of inflammation are unclear. We aimed to characterize the concentration and utility of ileal and plasma α-Defs in CD and to analyse a potential epigenetic mechanism of α-Def expression. Peripheral blood samples and ileal biopsies were obtained from patients at disease onset (aCD), from those who achieved remission (iCD) and from two control groups (healthy controls and non-CD-aetiology ileitis patients). Plasma α-Defs 1-3 and 4 were detected by enzyme-linked immunosorbent assay (ELISA); α-Def 5 by immunolocalization. Methylation analysis of the α-Def 5 gene was performed using the MassARRAY EpiTYPER system. Plasma α-Defs 1-3 concentrations were significantly higher in aCD with ileal involvement (L1, L3) versus iCD or the control groups. The α-Defs 1-3 concentrations were also similar to healthy controls in patients with non-CD ileitis. There was a significant positive correlation between plasma α-Defs 1-3 levels in aCD and the endoscopic index, as well as with C-reactive protein (CRP) levels. The immunopositivity scoring showed significantly reduced α-Def 5 expression in ileal inflamed (aCD) versus non-inflamed mucosa (iCD and healthy controls). The α-Def 5 gene showed a higher methylation status in CD patients than controls, regardless of the inflammation. Plasma α-Defs 1-3 concentrations correlate with the degree of inflammation and appear to be specific biomarkers of ileal-CD at diagnosis. Ileal α-Def 5 expression is down-regulated permanently by methylation.

Disease severity in familial cases of IBD.

BACKGROUND: Phenotypic traits of familial IBD relative to sporadic cases are controversial, probably related to limited statistical power of published evidence. AIM: To know if there are phenotype differences between familial and sporadic IBD, evaluating the prospective Spanish registry (ENEIDA) with 11,983 cases. METHODS: 5783 patients (48.3%) had ulcerative colitis (UC) and 6200 (51.7%) Crohn's disease (CD). Cases with one or more 1st, 2nd or 3rd degree relatives affected by UC/CD were defined as familial case. RESULTS: In UC and CD, familial cases compared with sporadic cases had an earlier disease onset (UC: 33 years [IQR 25-44] vs 37 years [IQR 27-49]; p<0.0001); (CD: 27 years [IQR 21-35] vs 29 years [IQR 22-40]; p<0.0001), higher prevalence of extraintestinal immune-related manifestations (EIMs) (UC: 17.2% vs 14%; p=0.04); (CD: 30.1% vs 23.6%; p<0.0001). Familial CD had higher percentage of ileocolic location (42.7% vs 51.8%; p=0.0001), penetrating behavior (21% vs 17.6%; p=0.01) and perianal disease (32% vs 27.1%; p=0.003). Differences are not influenced by degree of consanguinity. CONCLUSION: When a sufficiently powered cohort is evaluated, familial aggregation in IBD is associated to an earlier disease onset, more EIMs and more severe phenotype in CD. This feature should be taken into account at establishing predictors of disease course.

Smoking does influence disease behaviour and impacts the need for therapy in Crohn's disease in the biologic era.

BACKGROUND: Recently, the notion that smoking may adversely affect Crohn's disease (CD) outcomes has been challenged by the suggestion that the widespread use of immunosuppressants and anti-TNF drugs might offset the adverse effects of tobacco. AIM: To reassess the influence of tobacco smoking on disease phenotype and complications on a time-dependent analysis, taking into account the different therapeutic interventions. METHODS: We designed a retrospective cohort study of 3224 patients with Crohn's disease. The data were collected from the Spanish national inflammatory bowel disease registry (ENEIDA), including information regarding demographics, clinical characteristics, disease complications, therapeutic interventions and smoking status. Patients were classified as nonsmokers, smokers and former smokers, according to their present and past smoking habits. RESULTS: In the univariate analysis, smokers had more strictures (22.6% vs. 19.3%, P < 0.05) and less colonic involvement (7.2% vs. 10.9%, P < 0.05), and were more frequently under treatment with steroids (91.6% vs. 85.8%, P < 0.05), immunosuppressants (73.5% vs. 63.6% P < 0.05) or anti-TNF drugs (31.4% vs. 25.1%, P < 0.05) than nonsmokers. In the time-dependent multivariate analysis, smokers were found to have a significantly decreased survival free of stricturing disease (HR: 1.5, CI 95% 1.18-1.90) or perianal complications (HR: 1.50, CI 95% 1.01-1.46), and had a higher risk for requiring thiopurine therapy (HR: 1.20, CI 95% 1.05-1.30). CONCLUSION: These results suggest that, despite the widespread use of immunosuppressants and anti-TNF drugs, smokers with Crohn's disease still have a more severe disease course, with increased therapeutic requirements when compared with nonsmokers.

Identification of serum and tissue micro-RNA expression profiles in different stages of inflammatory bowel disease.

The altered expression of micro-RNA (miRNA) has been associated with Crohn's disease (CD) and ulcerative colitis (UC). The aim of this study was to establish specific miRNA expression patterns in the serum and mucosa of inflammatory bowel disease (IBD) patients (UC and CD with colonic involvement) at different stages of the disease. Serum and biopsies from nine active CD (aCD), nine inactive CD (iCD), nine active UC (aUC) and nine inactive UC (iUC) and serum from 33 healthy subjects were collected. Up to 700 miRNAs were evaluated by the TaqMan human miRNA array. The ΔCt values were obtained using the mean expression values of all expressed miRNAs in a given sample as a normalization factor for miRNA real-time quantitative polymerase chain reaction data. The levels of serum miRNAs in CD and UC patients were different to healthy subjects. Thirteen serum miRNAs were expressed commonly in CD and UC patients. Two miRNAs were higher and four miRNAs were lower in the serum of aCD than iCD. No serum miRNA was regulated exclusively in aUC compared with iUC patients. Four miRNAs were higher and three miRNAs were lower in the mucosa of aCD than iCD. Two miRNAs were higher and three miRNAs were lower in the mucosa of aUC than iUC. No serum miRNAs coincided with tissue miRNAs in aCD and aUC patients. Our results suggest the existence of specific miRNA expression patterns associated with IBD and their different stages and support the utility of miRNA as possible biomarkers. This pilot study needs to be validated in a large prospective cohort.

Long-term durability of response to adalimumab in Crohn's disease.

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-naïve and 72% anti-TNF-experienced. The loss of efficacy was 8% per patient-year of follow-up in the anti-TNF-naïve 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-naïve patients (22% vs. 8% per patient-year of treatment). Having extraintestinal manifestations seems to increase the risk of loss of efficacy.

Clinical outcome of newly diagnosed Crohn's disease: a comparative, retrospective study before and after infliximab availability.

BACKGROUND: Infliximab (IFX) could change the course of Crohn's disease (CD) by reducing steroid use, surgery or prompting earlier introduction of immunomodulators (IMM). AIM: To evaluate the impact of IFX availability on the course of early CD. METHODS: Two cohorts of newly diagnosed CD patients were identified: The first cohort included patients diagnosed from January 1994 to December 1997 and the second from January 2000 to December 2003. All patients were diagnosed, treated and followed up in the same centre until December 1999 (first cohort) or December 2005 (second cohort). Development of disease-related complications, steroid, IMM or IFX requirements and intestinal resections during follow-up were registered. RESULTS: A total of 328 patients were included (146 first cohort, 182 second cohort). A similar proportion of patients in both cohorts received steroids, but steroid exposure resulted significantly more intense in the first cohort (P = 0.001). In the second cohort, 14% of patients received IFX. Thiopurines were used more (P = 0.001) and earlier (P = 0.012) in the second cohort. No differences in surgical requirements or the development of disease-related complications were found. CONCLUSIONS: Following a step-up therapeutic algorithm, IFX availability did not reduce surgical requirements or the development of disease-related complications.

Healthcare seeking for constipation: a population-based survey in the Mediterranean area of Spain.

BACKGROUND: The use of healthcare resources for the management of constipation is not well-known. AIM: To analyse healthcare seeking for constipation, defined by three different criteria, and its related factors and to assess the frequency of use of laxatives, suppositories and enemas for the treatment of constipation. METHODS: A cross-sectional study in the general community. A questionnaire comprising 21-items was developed and delivered by mail to a random sample of 506 subjects aged 18-65 years, and belonging to a Spanish population. RESULTS: Seeking of health care was high in the sample (16%) and was similar for all definitions of constipation (over 40% of constipated subjects). It was associated with female gender, a higher educational level and two symptoms, such as prolonged defecation and abdominal pain. A 14% of the sample used laxatives, and about a 25% of constipated subjects used laxatives at least once a week. Utilization was more frequent in women, with no differences by age group. CONCLUSIONS: Chronic constipation is a problem that causes an important consumption of resources in our setting, derived from laxative use and the seeking of medical help to combat the problem. The use of these resources is higher in women.

Documento de consenso en el uso de la granulocitoaféresis en pacientes con enfermedad inflamatoria intestinal / Consensus document on the use of granulocytapheresis in patients with inflammatory bowel disease

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Ciclosporina en el brote grave de colitis ulcerosa / Cyclosporine in ulcerative colitis flares

No disponible

Clinical evolution of luminal and perianal Crohn's disease after inducing remission with infliximab: how long should patients be treated?

BACKGROUND: Few data are available regarding the evolution of Crohn's disease after discontinuing a successful course of infliximab. AIM: To evaluate clinical outcome of Crohn's disease after induction of remission with three infliximab infusions (luminal disease) and after maintenance of remission with 1-year course of infliximab every 8 weeks (luminal and perianal). METHODS: Twenty-three patients with active luminal Crohn's disease who responded to three infusions of infliximab (0, 2, and 6 weeks), and 23 patients with sustained response to infliximab every 8 weeks during 1 year, were included. Patients were followed-up until relapse or for at least 6 months after infliximab discontinuation. Clinical outcomes and factors associated to relapse were evaluated. RESULTS: In luminal Crohn's disease, a three-infusion infliximab regimen achieved a sustained response in most patients, especially if a complete response occurred at the time of the third infusion. In patients treated for 1-year, infliximab discontinuation was also successful, with a cumulative probability of being free of relapse of 69% at 12 months. In perianal disease, early relapse was the rule after stopping infliximab treatment, with only 34% of patient maintaining remission at 1 year. CONCLUSIONS: Short regimens of infliximab might be evaluated in patients with luminal Crohn's disease. However, infliximab discontinuation is not recommended in perianal Crohn's disease, because of a high rate of early relapse.

Incidence, risk factors and clinical course of thiopurine-induced liver injury in patients with inflammatory bowel disease.

BACKGROUND: The incidence of thiopurine-induced hepatotoxicity in patients with inflammatory bowel disease varies in different studies. AIMS: To assess the rate of thiopurine-induced liver toxicity in patients with inflammatory bowel disease; to determine the predictive factors and to characterize its clinical course and management. METHODS: A cohort of 161 patients was prospectively followed for a median of 271 days. Hepatotoxicity was established when alanine transaminase or alkaline phosphatase plasma levels were greater than twice the upper normal limit. RESULTS: Abnormal liver function was detected in 21 patients (13%; 95% CI: 7-18). Hepatotoxicity occurred in 16 patients (10%; 95% CI: 6-16) after a median of 85 days. In five cases, treatment was withdrawn due to hepatotoxicity. Use of corticosteroids was associated with hepatotoxicity (OR: 4.94; 95% CI: 1.01-23.98) with antitumour necrosis factor concomitant therapy showing a protective role (OR: 0.3; 95% CI: 0.1-3.1). gamma-Glutamyl transferase plasma levels at the onset of hepatotoxicity showed the best predictive value for treatment withdrawal (area under the receiver operating characteristic curve: 0.95). CONCLUSIONS: The incidence of hepatotoxicity in inflammatory bowel disease patients receiving thiopurines is relevant, mainly in patients co-treated with corticosteroids. gamma-Glutamyl transferase plasma level is a useful biomarker in therapy withdrawal prediction.

[Factors influencing the decision to administer systemic corticosteroids in Crohn's disease]. / Factores que influyen en la decisión de administrar corticoides sistémicos en la enfermedad de Crohn.

INTRODUCTION: Crohn's disease shows periods of exacerbation and remission. Corticosteroids are the most frequently used drugs in exacerbations of disease activity. The objective of this study is to determine which clinical and laboratory parameters are associated with the therapeutic decision to administer corticosteroids during the course of the disease. MATERIAL AND METHOD: Two-hundred seven consecutive visits made by 62 patients with Crohn's disease were selected from a database. Data from visits in which corticosteroid administration was initiated (n = 65) were compared with those from visits in which this decision was not made (n = 142). Univariate and multivariate (logistic regression) analyses were performed. The results are expressed as odds ratio (OR) with 95% confidence interval (95% CI). RESULTS: In the univariate analysis statistically significant differences were found between groups in localization, maintenance treatment, Crohn's Disease Activity Index (CDAI) score, the presence of abdominal pain, mass, perianal disease, extraintestinal manifestations and all laboratory parameters (leukocytes, platelets, fibrinogen, erythrocyte sedimentation rate, C-reactive protein). In the multivariate analysis (with corticosteroid administration as the dependent variable) a statistically significant positive association was found between the decision to administer corticosteroids and mild (OR = 31.9; 95% CI, 6.6-154.1), moderate or severe (OR = 49.7; 95% CI, 6.1-401.3) CDAI, ileocolic localization (OR = 4.8; 95% CI, 1-22.1) and the presence of perianal disease (OR = 7.4; 95% CI, 1.5-35.9), while a negative association was found with maintenance treatment with immunosuppressant drugs (OR = 0.05; 95% CI, 0.30-0.008). The laboratory variables positively associated with corticosteroid administration were C-reactive protein and leukocyte count. CONCLUSION: The variable with greatest predictive value for corticosteroid prescription is the CDAI score, although other clinical and laboratory variables not included in this index are also associated with corticosteroid administration. There is a negative association between the use of immunosuppressive drugs and corticosteroid prescription.

HLA antigens and anti-neutrophil cytoplasmic antibodies (ANCA) in inflammatory bowel disease.

HYPOTHESIS AND OBJECTIVES: the hypothesis of this study is that genes involved in the regulation of the immune system, expressed by HLA antigens and anti-neutrophil cytoplasmic antibodies (ANCA), could be determinants of disease susceptibility and behavior in inflammatory bowel disease (IBD). MATERIAL AND METHOD: seventy patients with a diagnosis of inflammatory bowel disease, 46 with ulcerative colitis and 24 with Crohn"s disease were included. HLA class I (A and B) and II (DR) antigens were studied by serological techniques. Detection of ANCA was carried out in all patients by an indirect immunofluorescence method. The relative frequencies of HLA antigens were compared with a control group made up of 156 blood donors. The control group for the ANCA study was made up of 100 individuals. RESULTS: we found a significant increased frequency of HLA-DR2 in patients with ulcerative colitis. No significant differences were found between patients with Crohn"s disease and controls regarding HLA typing. We detected a significant increase of HLA-DR3 in extensive forms of ulcerative colitis. Detection of ANCA was positive in 46% of the patients with ulcerative colitis and in 12% of the patients with Crohn"s disease (p <0.05). We observed an increased frequency of ANCA in patients with UC and HLA-DR2 (p = 0.15). CONCLUSIONS: the association found between HLA-DR3 and extensive forms of ulcerative colitis provides evidence of genetic heterogeneity. The relationship between ANCA and HLA phenotype (although not significant) supports this concept.