Elderly-onset vs adult-onset ulcerative colitis: a different natural history?

BACKGROUND: Incidence of ulcerative colitis (UC) in elderly population is increasing because of ageing and because of its minimal impact on life span. Data on natural history, outcomes and therapeutic strategies are limited. Our aim is to characterize UC in elderly-onset patients followed at our Inflammatory Bowel Disease outpatient clinic and compare with adult-onset UC. METHODS: From January 2000 to June 2019, 94 patients with UC diagnosed after the age of 65 years (elderly group, E-O) were identified and matched 1-1 according to gender and calendar year of diagnosis with patients diagnosed with UC at age between 40 and 64 years (adult age, A-O). RESULTS: Comorbidity Index (3.8 vs 1.6, p < 0.0005) was higher for elderly UC patients. Symptoms at presentation were similar between the two groups, although abdominal pain was more common in adults, and weight loss was more common in the elderly. At diagnosis, left colitis (61% vs 39%) and proctitis (14% vs 26%) (p = 0.011) were more frequent in the elderly. Therapy and clinical behaviour were similar. Surgery was more frequently performed in the elderly (20% vs 9%, p = 0.02), while biological therapy was less used (2.1% vs 22%, p < 0.0005). Complications were more frequent in the elderly. Extraintestinal manifestations were lower in elderly patients (9.6% vs 19.2%, p = 0.061). Time to first relapse was similar between the two groups. Mortality (p < 0.0005) was higher in elderly patients. CONCLUSIONS: Ulcerative Colitis has similar presentation and behaviour in elderly and adults patients. However, the elderly are more fragile because of comorbidities, increased risk of infections and disease-related complications.

A novel monoallelic gain of function mutation in p110δ causing atypical activated phosphoinositide 3-kinase δ syndrome (APDS-1).

This study reports on a novel activating p110δ mutation causing adult-onset hypogammaglobulinemia with lymphopenia without the classical presentation of atypical Activated phosphoinositide 3-kinase δ syndrome (ADPS-1), underlining thus the heterogeneous clinical and immunological presentation of p110δ mutated individuals and offers additional data on the role of p110δ in early and late B cell development in humans.

Localization of TNF alpha in ileocolonic biopsies of patients with inflammatory bowel disease.

BACKGROUND: Although antitumor necrosis factor alfa (TNFα) agents are widely used to treat patients with inflammatory bowel diseases (IBD) - both Crohn's disease (CD) and ulcerative colitis (UC) - there is still some uncertainty in the cell type expressing TNFα in human ileo-colonic segments. AIMS: We investigated the immunohistochemical (IHC) expression of TNFα in the ileo-colonic segments of patients with both active CD and UC, to establish its anatomic and cellular localization in the inflamed sites. Our aim was to identify patients potentially resistant to anti TNFα agents. PATIENTS AND METHODS: Ileo-colonic slides of complete histological mapping of patients with CD and UC before any treatment was started were obtained, and serial sections assessed for TNFα expression, together with IHC markers for lymphocytes, macrophages, and plasma cells. RESULTS: TNFα was expressed in almost all inflamed segments of IBD patients, albeit with different strength, and was present, in addition to lymphocytes and, to a lesser extent, to macrophages, in plasma cells, where it had a strong positivity, as also demonstrated by colocalization of specific IHC staining. The expression of TNFα was mostly focal in CD patients and more diffuse in UC patients, likely due to the different patterns of inflammation (transmural and mucosal) of the two entities. CONCLUSIONS: In IBD, TNFα is strongly expressed also in plasma cells, and it is easily evidenced by conventional IHC techniques. It remains to be established whether this observation might be useful in future to establish in routine biopsy samples whether patients may be responsive to treatments toward this cytokine.

Ulcerative colitis and the aging-related development of colonic diverticula.

PURPOSE: Aim of this observational case-control study was to assess the prevalence, features, and risk factors of colonic diverticula in patients with ulcerative colitis (UC). METHODS: The data of 896 UC patients aged ≥ 30 years from Brescia IBD database were retrospectively analyzed. Individuals with colonic diverticula were identified and prevalence was compared with that of control patients undergoing screening colonoscopy after gender/age matching. A nested cohort study was then conducted among UC patients in order to define eventual association of diverticula with specific clinico-pathologic parameters. RESULTS: Prevalence of subjects with diverticula was 11.4% among 465 UC patients aged 49 years and older, significantly lower than 35.1% prevalence in control patients of same age and gender (p < 0.001). Advancing age was a significant risk factor for diverticula development in both groups. Among UC patients, a short duration and a late onset of UC were both significantly associated to the presence of diverticula. Moreover, UC patients with diverticula had a significantly lower frequency of flares per year, even if maximal flare severity and frequency of hospital admission were similar to those of subjects without diverticula. UC patients with diverticula had a trend toward more frequent extension of UC to the left colon, possibly because of their older age. The majority of those patients had few sigmoid diverticula without symptoms. CONCLUSIONS: Development of colonic diverticula is substantially reduced in patients with UC, markedly among those with an early onset, a long history of inflammatory disease, and a high flare frequency. This study reinforces the hypothesis sustaining a protective role of UC against colonic diverticula.

Autoimmune gastritis: relationships with anemia and Helicobacter pylori status.

BACKGROUND: Autoimmune gastritis (AIG) is a gastric pathologic condition affecting the mucosa of the fundus and the body and eventually leading to hypo-achlorhydria. AIMS: We report our clinical and pathological experience with AIG. METHODS: Data from patients with a diagnosis of AIG seen in the period January 2002-December 2012 were retrieved. Only patients with complete sets of biopsies were analyzed. RESULTS: Data from 138 patients were available for analysis. Pernicious anemia was present in 25% of patients, iron deficiency anemia was found in 29.7% of patients, hypothyroidism in 23% of patients, type 1 diabetes in 7.9% of patients, and vitiligo in 2.8% of patients. Parietal cell antibodies were positive in 65% of patients, and no patient had serology positive for celiac disease. All gastric biopsies showed glandular atrophy associated with enterochromaffin-like (ECL)-cells hyperplasia, features limited to the mucosa of the fundus and body, and focal glandular intestinal metaplasia. Helicobacter pylori was negative in all cases. CONCLUSIONS: AIG was strongly associated with anemia; atrophy, intestinal metaplasia and ECL hyperplasia in the gastric fundus and body are hallmarks of this condition.

Gastrointestinal Pathologic Abnormalities in Pediatric- and Adult-Onset Common Variable Immunodeficiency.

BACKGROUND: Common variable immunodeficiency is the most common form of primary symptomatic immunodeficiency. Gastrointestinal manifestations, such as gastritis, diarrhea, gastrointestinal infections, and malabsorption, may complicate the clinical history in almost 50 % of patients. AIM: To evaluate gastrointestinal histopathological findings in pediatric- and in adult-onset common variable immunodeficiency patients. METHODS: Twenty-two patients with common variable immunodeficiency (13 children, nine adults) were retrospectively studied from a clinical and histopathological point of view. RESULTS: Increased T lymphocyte infiltrate and the absence of plasma cells in duodenal lamina propria and submucosa were the most frequent findings, independently from onset age, whereas follicular lymphoid hyperplasia and polymorphonuclear infiltrate, as well as parasitic and viral infections, were only present in the adult group. Common variable immunodeficiency patients with minor gastrointestinal symptoms also presented pathological findings, mainly the absence of plasma cells, T cell infiltrate, and infections, independently of age. CONCLUSIONS: Gastrointestinal pathological abnormalities are common in both pediatric- and adult-onset common variable immunodeficiency patients. Histological alterations may vary depending upon the age of onset, possibly due to duration of disease. Minor gastrointestinal symptoms are also associated with pathological findings; therefore, these should be searched in all symptomatic patients.

Factors that contribute to hypertransaminasemia in patients with celiac disease or functional gastrointestinal syndromes.

BACKGROUND & AIMS: Transaminasemia develops via different pathways in patients with celiac disease; no information is available on risk factors specifically attributable to celiac disease. METHODS: We analyzed data collected from consecutive patients referred from January 1997 through December 2009 to the celiac disease clinic at the Spedali Civili of Brescia, Italy. We assessed the factors affecting hypertransaminasemia in 683 patients with celiac disease (based on serologic and biopsy analysis, cohort A; 34 ± 14 years of age) and 304 with functional syndromes (cohort B; 37 ± 13 years of age). RESULTS: Hypertransaminasemia was detected in 138 patients in cohort A (20%). It was associated with malabsorption (odds ratio [OR], 2.22; P = .004), diarrhea (OR, 1.72; P = .005), and increasing severity of mucosal lesion (Marsh-Oberhuber class; OR, 1.46; P = .001) but not with body mass index (BMI) or the serum level of tissue-transglutaminase antibodies (tTG). Hypertransaminasemia was detected in 22 patients in cohort B (7%) and was associated with the World Health Organization's BMI categories (OR, 7.9; P < .001). In subsets of patients studied with the same analytical method (313 of cohort A and 188 of cohort B), the level of tTG was significantly higher in cohort A at baseline (25.2 ± 16.9 U/L aspartate aminotransferase [AST]) than in cohort B (20.6 ± 9.9 U/L AST, P < .0001) and was related to BMI in cohort B (P = .0012) but not cohort A. When patients were placed on gluten-free diets, the levels of AST decreased from 25.2 ± 16.9 U/L to 19.9 ± 6.6 U/L (P < .0001), independently of the changes of duodenal histology and tTG and correlated with BMI (P = .0007); the prevalence of hypertransaminasemia decreased from 13% to 4%. CONCLUSIONS: Patients with celiac disease have a higher prevalence of hypertransaminasemia than controls (patients with functional syndromes). Hypertransaminasemia is related to the severity of the duodenal lesion and malabsorption but not BMI. By contrast, there was a positive correlation between the levels of AST and BMI in controls; this relationship was restored when patients with celiac disease were placed on gluten-free diets.

Clinical expression of lymphocytic duodenosis in "mild enteropathy" celiac disease and in functional gastrointestinal syndromes.

OBJECTIVE: Abnormally high number of duodenal intraepithelial lymphocytes is frequently found in many conditions including mild enteropathy celiac disease (CD) and functional gastrointestinal syndromes, but is unclear whether lymphocytosis affects the clinical phenotype particularly in functional syndromes. MATERIALS AND METHODS: We compared clinical characteristics of celiac patients with lymphocytic duodenosis and normal villous structure with those of patients with functional gastrointestinal syndromes with and without lymphocytic duodenosis. We retrospectively identified 3 cohorts among patients referred for suspected CD: (1) "CoelD", 135 patients (age 36 ± 14 years) with mild enteropathy CD; (2) "LymD", 245 patients (38 ± 12 years) with functional gastrointestinal syndromes and lymphocytic duodenosis; and (3) "NorD", 147 patients (37 ± 15 years) with functional syndromes and normal duodenal histology. RESULTS: Prevalence of gastrointestinal symptoms was similar in the three cohorts, but prevalence of extra-intestinal manifestations (42% vs. 27% vs. 18%, p < 0.003) and of associated diseases (35% vs. 15% vs. 14%, p < 0.0001) was higher in "CoelD" than in "LymD" and "NorD", respectively. Prevalence of Helicobacter pylori infection was similar in the three cohorts. The proportion of patients with final diagnosis of irritable bowel syndrome-diarrhea (38% vs. 37%), dyspepsia (31% vs. 27%), functional pain (14% vs. 19%), and functional diarrhoea (14% vs. 11%) was virtually the same in the cohorts with (LymD) and without (NorD) lymphocytic duodenosis. CONCLUSIONS: Lymphocytic duodenosis has different clinical presentation in patients with mild enteropathy CD than those with functional gastrointestinal syndromes, and is not specific for any particular functional syndrome.

Gluten-Free Diet and Other Celiac Disease Therapies: Current Understanding and Emerging Strategies.

A lifelong gluten-free diet (GFD) is the only treatment for celiac disease and other gluten-related disorders. Nevertheless, strict adherence to the GFD is often challenging due to concerns about social isolation, risk of gluten contaminations, high cost, poor quality and the taste of gluten-free products. Moreover, although the GFD is effective in achieving mucosal healing, it may lead to dietary imbalances due to nutrient deficiencies over a long period of time. To overcome these issues, several gluten-free wheat flours have been developed to create products that closely resemble their gluten-containing counterparts. Furthermore, given the critical importance of adhering to the GFD, it becomes essential to promote adherence and monitor possible voluntary or involuntary transgressions. Various methods, including clinical assessment, questionnaires, serology for celiac disease, duodenal biopsies and the detection of Gluten Immunogenic Peptides (GIPs) are employed for this purpose, but none are considered entirely satisfactory. Since adherence to the GFD poses challenges, alternative therapies should be implemented in the coming years to improve treatment efficacy and the quality of life of patients with celiac disease. The aim of this narrative review is to explore current knowledge of the GFD and investigate its future perspectives, focusing on technology advancements, follow-up strategies and insights into a rapidly changing future.

The development of artificial intelligence in the histological diagnosis of Inflammatory Bowel Disease (IBD-AI).

BACKGROUND: Inflammatory bowel disease (IBD) includes Crohn's Disease (CD) and Ulcerative Colitis (UC). Correct diagnosis requires the identification of precise morphological features such basal plasmacytosis. However, histopathological interpretation can be challenging, and it is subject to high variability. AIM: The IBD-Artificial Intelligence (AI) project aims at the development of an AI-based evaluation system to support the diagnosis of IBD, semi-automatically quantifying basal plasmacytosis. METHODS: A deep learning model was trained to detect and quantify plasma cells on a public dataset of 4981 annotated images. The model was then tested on an external validation cohort of 356 intestinal biopsies of CD, UC and healthy controls. AI diagnostic performance was calculated compared to human gold standard. RESULTS: The system correctly found that CD and UC samples had a greater prevalence of basal plasma cells with mean number of PCs within ROIs of 38.22 (95 % CI: 31.73, 49.04) for CD, 55.16 (46.57, 65.93) for UC, and 17.25 (CI: 12.17, 27.05) for controls. Overall, OR=4.968 (CI: 1.835, 14.638) was found for IBD compared to normal mucosa (CD: +59 %; UC: +129 %). Additionally, as expected, UC samples were found to have more plasma cells in colon than CD cases. CONCLUSION: Our model accurately replicated human assessment of basal plasmacytosis, underscoring the value of AI models as a potential aid IBD diagnosis.

Celiac disease with mild enteropathy is not mild disease.

BACKGROUND & AIMS: Patients with celiac disease have varying degrees of damage to the small intestinal mucosa, ranging from lymphocytic duodenosis with normal villous structure to severe villous atrophy. We assessed whether the severity of mucosal lesions was associated with clinical and laboratory features of celiac disease. METHODS: We compared demographic, clinical, and laboratory characteristics among patients with celiac disease who were classified based on the severity of duodenal lesions. We analyzed data from 1408 adult patients seen consecutively at a tertiary referral center since 1990. Patients were classified as having villous atrophy (n = 1249) or as having mild enteropathy (n = 159) in the presence or absence of villous atrophy. RESULTS: Similar percentages of patients with villous atrophy, vs mild enteropathy, experienced weight loss (17% vs 17%), gastrointestinal manifestations (70% vs 70%), extraintestinal manifestations (66% vs 57%), and other associated conditions (19% vs 23%). More patients with villous atrophy than patients with mild enteropathy developed osteopenia or osteoporosis (22% vs 5%; P = .0005). Greater percentages of patients with villous atrophy than those with mild enteropathy also had anemia (42% vs 29%; P = .002), folate deficiency (75% vs 64%; P = .02), hypocholesterolemia (7% vs 2%; P = .02), hypocalcemia (26% vs 13%; P = .004), or hyperparathyroidism (45% vs 29%; P = .004). CONCLUSIONS: Although osteopenia, osteoporosis, and alterations in laboratory parameters are prevalent among patients with celiac disease with mild enteropathy, they are more prevalent and severe in those with villous atrophy. The prevalence of associated conditions is similar between these groups. These results indicate that celiac disease with mild enteropathy is not mild disease, but requires treatment with a gluten-free diet.

Search for atoxic cereals: a single blind, cross-over study on the safety of a single dose of Triticum monococcum, in patients with celiac disease.

BACKGROUND: Cereals of baking quality with absent or reduced toxicity are actively sought as alternative therapy to a gluten-free diet (GFD) for patients with coeliac disease (CD). Triticum monococcum, an ancient wheat, is a potential candidate having no toxicity in in-vitro and ex-vivo studies. The aim of our study was to investigate on the safety of administration of a single dose of gluten of Tm in patients with CD on GFD. METHODS: We performed a single blind, cross-over study involving 12 CD patients who had been on a GFD for at least 12 months, challenged on day 0, 14 and 28 with a single fixed dose of 2.5 grams of the following (random order): Tm, rice (as reference atoxic protein) and Amygluten (as reference toxic protein) dispersed in a gluten-free pudding. The primary end-point of the study was the change in intestinal permeability, as assessed by changes in the urinary lactulose/rhamnose ratio (L/R ratio) measured by High Pressure Liquid Chromatography. We also assessed the occurrence of adverse gastrointestinal events, graded for intensity and duration according to the WHO scale. Variables were expressed as mean ± SD; paired t-test and χ² test were used as appropriate. RESULTS: The urinary L/R ratio did not change significantly upon challenge with the 3 cereals, and was 0.055 ± 0.026 for Tm Vs 0.058 ± 0.035 for rice (p = 0.6736) and Vs 0.063 ± 0.054 with Amygluten (p = 0.6071). Adverse gastrointestinal events were 8 for Tm, Vs 11 for rice (p = 0.6321) and Vs 31 for Amygluten p = 0.0016), and, in all cases events were graded as "mild" or "moderate" with TM and rice, and as "severe" or "disabling" in 4 cases during Amygluten. CONCLUSIONS: No definite conclusion can be drawn on the safety of Tm, based on no change in urinary L/R because even Amygluten, a toxic wheat protein, did not cause a significant change in urinary L/R indicating low sensitivity of this methodology in studies on acute toxicity. Tm was, however, well tolerated by all patients providing the rationale for further investigation on the safety of this cereal for CD patients. TRIAL REGISTRATION: EudraCT-AIFA n2008-000697-20.

Effectiveness of adalimumab for ulcerative colitis: A multicentre, retrospective study of clinical practice in Italy.

BACKGROUND: Adalimumab is used to treat ulcerative colitis, but additional effectiveness and safety data are needed. PATIENTS AND METHODS: This retrospective study considered adults with ulcerative colitis treated with adalimumab at 19 hospitals. Clinical data were collected from the start of treatment, after 2, 6 and 12 months, and at the last visit. Outcome measures of effectiveness were treatment duration, reasons for discontinuation and colectomy. RESULTS: We studied 381 patients treated with adalimumab for a median of 12.1 months. Disease activity at the start of treatment was moderate to severe in 262 cases (68.8%) and endoscopic activity was moderate to severe in 339 cases (89.0%). At week 8, clinical responses were observed in 177 cases (46.5%) and clinical remission in 136 cases (35.7%). At 12 months, remission was observed in 128 cases (33.6%). Overall, 44 patients required colectomy, and 170 patients (44.6%) were still taking adalimumab when data were collected. Variables associated with adalimumab discontinuation were concomitant steroid treatment, severe clinical-endoscopic activity at baseline, need for adalimumab intensification and drug-related adverse events. Variables associated with colectomy were concomitant steroid treatment and high baseline C-reactive protein. CONCLUSION: Adalimumab is safe and effective for the treatment of ulcerative colitis.

Bio-physical characteristics of gastrointestinal mucosa of celiac patients: comparison with control subjects and effect of gluten free diet-.

BACKGROUND: Intestinal mucosa is leaky in celiac disease (CD), and this alteration may involve changes in hydrophobicity of the mucus surface barrier in addition to alteration of the epithelial barrier. The aims of our study were i) to compare duodenal hydrophobicity as an index of mucus barrier integrity in CD patients studied before (n = 38) and during gluten- free diet (GFD, n = 68), and in control subjects (n = 90), and ii) to check for regional differences of hydrophobicity in the gastro-intestinal tract. METHODS: Hydrophobicity was assessed by measurement of contact angle (CA) (Rame Hart 100/10 goniometer) generated by a drop of water placed on intestinal mucosal biopsies. RESULTS: CA (mean ± SD) of distal duodenum was significantly lower in CD patients (56° ± 10°)) than in control subjects (69° ± 9°, p < 0.0001), and persisted abnormal in patients studied during gluten free diet (56° ± 9°; p < 0.005). CA was significantly higher (62° ± 9°) in histologically normal duodenal biopsies than in biopsies with Marsh 1-2 (58° ± 10°; p < 0.02) and Marsh 3 lesions (57° ± 10°; p < 0.02) in pooled results of all patients and controls studied. The order of hydrofobicity along the gastrointestinal tract in control subjects follows the pattern: gastric antrum > corpus > rectum > duodenum > oesophagus > ileum. CONCLUSIONS: We conclude that the hydrophobicity of duodenal mucous layer is reduced in CD patients, and that the resulting decreased capacity to repel luminal contents may contribute to the increased intestinal permeability of CD. This alteration mirrors the severity of the mucosal lesions and is not completely reverted by gluten-free diet. Intestinal hydrophobicity exhibits regional differences in the human intestinal tract.

Topographical distribution of microscopic colitis and the importance of orientation of paraffin-embedded biopsies.

The diagnosis of microscopic colitis (MC) relies on specific histopathological findings in colon biopsies. The number of biopsies needed to diagnose MC remains disputed. The aim of the study was to determine the number and site of biopsies necessary for the diagnosis and the effect of perpendicular orientation when embedding the biopsies. This retrospective multicenter European study included 42 patients with a consensus diagnosis of collagenous colitis (CC), 51 patients with lymphocytic colitis (LC), and three patients with incomplete LC (LCi). The number of individual diagnostic biopsies from each patient was determined. The diagnostic rate of 744 individual biopsies from 96 patients with MC was 69.5% for the specific MC subgroup, 79.4% for MC and 93.4% for MC plus incomplete MC (MCi). The risk of missing a diagnosis of the specific subgroup of MC when analyzing four biopsies was 0.87%, decreasing to 0.18% for MC and 0.0019% for MC plus MCi. More biopsies from the right colon were diagnostic of the specific MC subgroup (76.3% vs. 64.0%, p = 0.0014). Perpendicular orientation of biopsies increased the diagnostic rate of the specific MC subgroup (73.1% vs. 65.0%, p = 0.0201). Histological changes diagnostic of MC were present in almost all biopsies from the right colon, with orientated biopsies more often being diagnostic of the specific MC subgroup. The results of this study indicate that four biopsies from the colon, rectum excluded, are sufficient to diagnose MC.

[Extraintestinal manifestations in Crohn's disease: risk factors and influence of intestinal surgery]. / Manifestazioni extraintestinali della malattia di Crohn. Fattori di rischio e impatto della chirurgia digestiva.

BACKGROUND: Extraintestinal manifestations significantly affect the quality of life of patients with Crohn's disease. The aim of the present study is to define the risk factors for extraintestinal manifestations and the relative influence of intestinal surgery. PATIENTS AND METHODS: In a cohort of 223 patients with Crohn's disease we analyzed the association between demographic/clinico-pathological factors and extraintestinal manifestations. In addition, we evaluated their association with the timing of appearance of the extraintestinal manifestations with respect to the intestinal surgery. RESULTS: Fifty-seven patients (25.6%) developed 91 extraintestinal manifestations. Demographic and clinico-pathological variables significantly associated with extraintestinal manifestations were: female gender (OR 2.84, 95% CI: 1.37-5.90) and colonic involvement (OR 2.68, 95% CI: 1.06-6.76). In patients not undergoing surgery and in patients with extraintestinal manifestations present only before surgery, the latency period between the onset of Crohn'S disease and extraintestinal manifestations were 3.7 +/-8.2 and 2.1 +/- 6.3 years, respectively. In patients developed extraintestinal manifestations only after surgery, the latency between surgery and extraintestinal manifestations was 12.0 +/-10.0 years. In 5 patients with early onset of extraintestinal manifestations, these did not regress or recur after surgery. CONCLUSION: Female gender and colonic involvement are confirmed as risk factors for the development of extraintestinal manifestations in Crohn's disease. Surgical treatment of the intestinal disease represents a therapeutic option for patients with extraintestinal manifestations, as it seems to prevent or delay these manifestations in most cases.

Lack of association of coeliac disease with idiopathic and ischaemic dilated cardiomyopathies.

OBJECTIVE: A prevalence of coeliac disease higher than in the general population has been reported not only in patients with idiopathic dilated cardiomyopathy, a presumable autoimmune disease, but also in patients with ischaemic or valvular cardiomyopathy. The evidence is controversial, however, and the concept itself of an association unrelated to aetiology is intriguing and warrants further testing. The aim of our study was to assess the prevalence of coeliac disease in a cohort of patients with dilated cardiomyopathy screened for the presence of serum anti-transglutaminase antibodies. We provisionally assessed the sensitivity and specificity of two commercially available kits for tissue transglutaminase antibodies detection. MATERIAL AND METHODS: We screened for anti-transglutaminase antibodies in 350 consecutive patients with idiopathic (n = 182) and with ischaemic (n = 168) dilated cardiomyopathy using the previously validated method for anti-transglutaminase antibody assay. Coeliac disease diagnosis has been confirmed by duodenal histopathology in patients testing positive at serological screening. RESULTS: Two coeliac patients (0.6% prevalence) have been identified, one with idiopathic and one with ischaemic dilated cardiomyopathy. They presented with iron deficiency anaemia and with recurrent abdominal pain and diarrhoea, respectively, and both had villous atrophy at histopathology. After 1 year on a gluten-free diet, the echocardiographic parameters did not improve in either patient. CONCLUSIONS: Our results indicate that the prevalence of coeliac disease in patients with dilated cardiomyopathies is similar to that reported for the Italian general population. The confounding factor of conditions associated with both coeliac disease and dilated cardiomyopathies may explain the association unrelated to aetiology reported in previous studies mostly based on small sample size.

Usefulness of Different Pathological Scores to Assess Healing of the Mucosa in Inflammatory Bowel Diseases: A Real Life Study.

The concept of remission for patients with inflammatory bowel diseases has recently evolved, and should also include histological healing of the mucosa, difficult to evaluate since there is no agreement on pathological scores and those available are quite complex to use in the daily routine. We evaluated the possible usefulness of a simplified pathological score to assess histological healing of the mucosa in inflammatory bowel diseases patients compared with four commonly proposed pathological scores. Slides from 24 patients (12 Crohn's disease, 12 ulcerative colitis, age range 24-62 years), pre- and post-treatment with biological agents and displaying endoscopic remission were assessed by two pathologists. Pre- and post-treatment results and the time employed to calculate the various scores were obtained. All scores were useful to document highly significant post-treatment decreases of histological activity. However, the simplified score needed significant less time to be calculated for each slide, had high inter-rater agreement, and avoided subjectivity from the pathologists. The simplified score is easy to calculate and seems apt to document histological healing of the mucosa, in a manner similar to the more complex scores. It remains to be established whether this score could simplify the daily routinary practice in this context.

Novel treatment options for inflammatory bowel disease: targeting alpha 4 integrin.

The aetiology of inflammatory bowel disease (IBD) is complex and many aspects still remain unclear. However, significant progress has been made in understanding the pathogenesis of chronic inflammation in the intestine, and new insights have been gained recently. A better understanding of the immunopathology of IBD has led to the development of novel biological agents to target crucial molecules and processes in the inflammatory cascade. The development of novel therapies in the management of IBD has moved from empirical to scientific rational translation from bench to bedside. Lymphocyte infiltration into the intestinal tract in Crohn's disease (CD) is mediated by interaction between alpha4 integrin expressed on lymphocytes and its specific ligand mucosal vascular addressin cell adhesion molecule-1, expressed on the endothelial cells of the microvasculature in the inflamed intestinal tract. Development of monoclonal antibodies against alpha4 integrin permitted the targeting of lymphocyte trafficking into the intestine as a novel therapeutic intervention. Natalizumab, a recombinant humanised monoclonal antibody against alpha4 integrin, was effective in CD in a phase II randomised controlled trial. The highest response rate and remission rate were 71% and 44%, respectively, at 6 weeks after two infusions of natalizumab 3mg administered 4 weeks apart. Natalizumab was well tolerated in this trial. The phase III trial results are encouraging, although the primary efficacy endpoint of response at week 10 was not achieved. The maintenance of response and remission trial, ENACT (Evaluation of Natalizumab as Continuous Therapy)-2, has reported impressive efficacy in maintaining response and remission in those who responded in the initial induction of remission (ENACT-1) trial. This was associated with an improvement in quality-of-life parameters. A second humanised monoclonal antibody, MLN-02 (LDP-02), developed against alpha4beta7 has also shown evidence of efficacy in ulcerative colitis and CD. Although the clinical trials showed that inhibition of alpha4 integrin was well tolerated, use of natalizumab in multiple sclerosis and CD has raised serious concerns about the association with progressive multifocal leukoencephalopathy (PML) in a small number of patients, and the drug has been withdrawn from the market pending further safety evaluation. PML is caused by polyoma JC virus infection, is progressive and generally fatal, and is recognised to occur in patients with severe immunosuppression. Initial safety evaluation suggests that PML is very rare, despite its occurrence in one patient with CD receiving open-label natalizumab treatment.