Comprehensive Association Analyses of Extraintestinal Manifestations in Inflammatory Bowel Disease.

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) frequently develop extraintestinal manifestations (EIMs) that contribute substantially to morbidity. We assembled the largest multicohort data set to date to investigate the clinical, serologic, and genetic factors associated with EIM complications in IBD. METHODS: Data were available in 12,083 unrelated European ancestry IBD cases with presence or absence of EIMs (eg, ankylosing spondylitis [ankylosing spondylitis and sacroiliitis], primary sclerosing cholangitis [PSC], peripheral arthritis, and skin and ocular manifestations) across 4 cohorts (Cedars-Sinai Medical Center, National Institute for Diabetes and Digestive and Kidney Diseases IBD Genetics Consortium, Sinai Helmsley Alliance for Research Excellence Consortium, and Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn's Disease cohort). Clinical and serologic parameters were analyzed by means of univariable and multivariable regression analyses using a mixed-effects model. Within-case logistic regression was performed to assess genetic associations. RESULTS: Most EIMs occurred more commonly in female subjects (overall EIM: P = 9.0E-05, odds ratio [OR], 1.2; 95% CI, 1.1-1.4), with CD (especially colonic disease location; P = 9.8E-09, OR, 1.7; 95% CI, 1.4-2.0), and in subjects who required surgery (both CD and UC; P = 3.6E-19, OR, 1.7; 95% CI, 1.5-1.9). Smoking increased risk of EIMs except for PSC, where there was a "protective" effect. Multiple serologic associations were observed, including with PSC (anti-nuclear cytoplasmic antibody; IgG and IgA, anti-Saccharomyces cerevisiae antibodies; and anti-flagellin) and any EIM (anti-nuclear cytoplasmic antibody; IgG and IgA, anti-Saccharomyces cerevisiae antibodies; and anti-Pseudomonas fluorescens-associated sequence). We identified genome-wide significant associations within major histocompatibility complex (ankylosing spondylitis and sacroiliitis, P = 1.4E-15; OR, 2.5; 95% CI, 2.0-3.1; PSC, P = 2.7E-10; OR, 2.8; 95% CI, 2.0-3.8; ocular, P = 2E-08, OR, 3.6; 95% CI, 2.3-5.6; and overall EIM, P = 8.4E-09; OR, 2.2; 95% CI, 1.7-2.9) and CPEB4 (skin, P = 2.7E-08; OR, 1.5; 95% CI, 1.3-1.8). Genetic associations implicated tumor necrosis factor, JAK-STAT, and IL6 as potential targets for EIMs. Contrary to previous reports, only 2% of our subjects had multiple EIMs and most co-occurrences were negatively correlated. CONCLUSIONS: We have identified demographic, clinical, and genetic associations with EIMs that revealed underlying mechanisms and implicated novel and existing drug targets-important steps toward a more personalized approach to IBD management.

Can vulvar edema be the presenting sign of Crohn's disease? A case series.

Vulvar involvement as an extraintestinal manifestation of Crohn's disease (CD) is a challenging diagnosis considering that vaginal findings may precede gastrointestinal symptoms. The aim of this study is to describe the clinical presentation, radiological findings, and treatment of vulvar Crohn's disease (VCD). We reviewed the time from initial presentation to diagnosis, presenting symptoms, radiological findings, gastrointestinal Crohn's disease Paris classification, and treatment response of five female pediatric patients. All the patients had radiological findings of vulvar inflammation on magnetic resonance imaging. Vaginal symptoms preceded gastrointestinal disease in two of the patients, which correlated with a delay in diagnosis. All patients had active disease on colonoscopy, with three of them having significant colorectal inflammation. Four of the patients were treated with infliximab, while one patient received ustekinumab with a resolution of their symptoms. In conclusion, VCD can precede gastrointestinal symptoms and is easily miss-diagnosed, leading to a delayed Crohn's disease diagnosis and treatment.

Prevalence and clinical features of chronic uveitis in pediatric inflammatory bowel diseases: A nationwide study.

Inflammatory bowel diseases (IBD) encompass a group of chronic inflammatory disorders primarily affecting the gastrointestinal tract but capable of impacting various organs, including the eye, with uveitis being the most common ocular condition. We assessed uveitis prevalence and clinical features in a nationwide cohort of pediatric IBD. Among 4229 cases, six patients (four Crohn's disease, one ulcerative colitis, and one unclassified IBD) were identified, resulting in an overall prevalence rate of 141.8 per 100,000 patients. Uveitis onset varied: two before IBD, two after, and two concomitantly. Symptomatic uveitis occurred in 2/6 patients, with anterior involvement in all cases. Median follow-up was 3 years (interquartile range 2-4.75 years). At the last follow-up, 5/6 patients exhibited quiescent IBD, while 4/6 had inactive uveitis. One patient had ocular complications. Uveitis is a rare but potentially complicating manifestation of pediatric IBD.

The association between erythema nodosum and pyoderma gangrenosum and pediatric inflammatory bowel disease.

OBJECTIVES: The objectives of this study is to estimate rates and identify factors associated with erythema nodosum (EN) and pyoderma gangrenosum (PG) in pediatric patients with inflammatory bowel disease (IBD). METHODS: This cohort study examined longitudinal visits of patients aged ≤ 21 years from the ImproveCareNow (ICN) registry. We evaluated the association of factors at the patient-level (demographics and IBD diagnosis age) and visit-level (IBD severity scores, markers and phenotypes, comorbidities, and treatment) with the presence of EN and PG, using longitudinal logistic regression models adjusted for time and within-patient clustering. RESULTS: A total of 285,913 visits from 32,497 patients aged ≤ 21 years from the ICN registry were analyzed. The occurrence of EN was 1.57% (95% confidence interval [95% CI]: 1.43%-1.71%) and the occurrence of PG was 0.90% (95% CI: 0.80%-1.00%). Co-occurrence of EN and PG was reported in 0.30% (95% CI: 0.25%-0.37%) patients. Both EN and PG were associated (p < 0.0001) with worse intestinal disease, lower remission, higher inflammatory markers, and extraintestinal manifestations (EIMs) arthritis and uveitis. CONCLUSIONS: EN and PG were associated with increased disease severity and other noncutaneous EIMs (arthritis and uveitis). A small subset of patients had developed both EN and PG.

The impact of vedolizumab therapy on extraintestinal manifestations in patients with inflammatory bowel disease: A systematic review and meta-analysis.

BACKGROUND AND AIM: Extraintestinal manifestations (EIMs) pose a significant threat in inflammatory bowel disease (IBD) patients. Vedolizumab (VDZ) primarily affects the gastrointestinal tract. However, its impact on EIMs remains uncertain. Therefore, we conducted this meta-analysis to examine the effects of VDZ on EIMs during treatment. METHODS: Relevant studies were identified by conducting thorough searches across electronic databases, including PubMed, Ovid Embase, Medline, and Cochrane CENTRAL. Primary outcomes focused on the proportion of patients with resolution for pre-existing EIMs in IBD patients receiving VDZ. Secondary outcomes included the proportion of patients with EIM exacerbations and new onset EIMs during VDZ treatment. RESULTS: Our meta-analysis encompassed 21 studies. The proportion of patients with resolution of pre-existing EIMs in VDZ-treated IBD patients was 39% (150/386; 95% confidence interval [CI] 0.31-0.48). The proportion of patients with EIM exacerbations occurred at a rate of 28% (113/376; 95% CI 0.05-0.50), while new onset EIMs had a rate of 15% (397/2541; 95% CI 0.10-0.20). Subgroup analysis revealed a 40% (136/337) proportion of patients with resolution for articular-related EIMs and a 50% (9/18) rate for erythema nodosum. Exacerbation rates for arthritis/arthralgia, erythema nodosum/pyoderma gangrenosum, and aphthous stomatitis during VDZ use were 28% (102/328), 18% (7/38), and 11% (3/28), respectively. The incidence rate of newly developed EIMs during treatment was 11% (564/4839) for articular-related EIMs, with other EIMs below 2%. CONCLUSION: VDZ demonstrates efficacy in skin-related EIMs like erythema nodosum and joint-related EIMs including arthritis, arthralgia, spondyloarthritis, and peripheral joint diseases. Some joint and skin-related EIMs may experience exacerbation during VDZ therapy.

Managing metastatic Crohn's disease: a single center experience, review of the current evidence, and treatment algorithm.

BACKGROUND: Crohn's disease (CD) is an inflammatory bowel disease (IBD) that, besides gastrointestinal symptoms, may encompass extra-intestinal symptoms, such as dermatological manifestations. Of those, metastatic CD (MCD) is a rare extra-intestinal manifestation for which the management is uncertain. METHODS: We conducted a retrospective case series of patients with MCD seen at the University hospital Leuven, Belgium, combined with an overview of the recent literature. Electronic medical records were searched from January 2003 till April 2022. For the literature search, Medline, Embase, Trip Database, and The Cochrane Library were searched from inception to April 1, 2022. RESULTS: A total of 11 patients with MCD were retrieved. In all cases noncaseating granulomatous inflammation was found on skin biopsies. Two adults and one child were diagnosed with MCD prior to their diagnosis of CD. Seven patients were treated with steroids (intralesional, topical or systemic). Six patients needed a biological therapy to treat MCD. Surgical excision was performed in three patients. All patients reported a successful outcome and most cases achieved remission. The literature search yielded 53 articles, including three reviews, three systematic reviews, 30 case reports and six case series. A treatment algorithm was generated based on literature and multidisciplinary discussion. CONCLUSION: MCD remains a rare entity and diagnosis is often difficult. A multidisciplinary approach including skin biopsy is necessary to diagnose and treat MCD efficiently. Outcome is generally favorable, and lesions respond well to steroids and biologicals. We propose a treatment algorithm based on the available evidence and multidisciplinary discussion.

Is the microbiome the cause of irritable bowel syndrome and inflammatory bowel disease? Lessons to consider from odontology.

BACKGROUND: A substantial amount of research is pointing to the disrupted microbiome and dysfunctional host-microbiome interaction as potential causes of Irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). The true cause of the diseases is still not fully elucidated, and the various treatments used are not truly effective in the long run, especially for IBD, since a true cure is not known to exist. Treatment failure and surgery are common for IBD, many times leading to a perceived lower quality of life, not to mention the enormous cost for society for treatment up until that point and after. Although it is clear that the microbiome has a major role in the disease, it seems the majority of the research and treatments are still focused on treating and understanding the inflammation and not the primary cause of the inflammation in the first place. This was also the case for many decades in the search for the cause of periodontitis (PD) and gingivitis (GV), a destructive and non-destructive inflammatory disorder, respectively, the first resulting in loss of tissue supporting the teeth. There was much uncertainty and confusion until it was fully established that the microbiome was the cause. PD treatments primarily nowadays reflect the cause, i.e. the removal of microbes. There is no doubt, however, that the inflammatory pathways are important in both diseases and the purpose of this text is not to dispute this in respect to gastrointestinal disorders too. However, a different view on inflammation and associated disorders is explored to explain the nature of extraintestinal manifestations. PURPOSE: The aim of this report is not to systematically fully review the literature to try to strengthen causality, as there are many reviews that explore the microbial aspects of IBS and IBD. Instead, the objective is to above all reflect on what has been learned in the field of odontology/stomatology and discuss relevant gastrointestinal research in order to propose tentative hypotheses and questions regarding IBS and IBD aetiology. Perhaps it could help soften the confusion regarding the microbial aetiology and dysbiosis concept, while guiding future research and treatments, primarily regarding microbial transplants, antibiotics, and diet.

The risk of subsequent surgery following bowel resection for Crohn's disease in a national cohort of 19 207 patients.

AIM: Surgery is required for most patients with Crohn's disease (CD) and further surgery may be necessary if medical treatment fails to control disease activity. The aim of this study was to characterize the risk of, and factors associated with, further surgery following a first resection for Crohn's disease. METHODS: Hospital Episode Statistics from England were examined to identify patients with CD and a first recorded bowel resection between 2007 and 2016. Multivariable logistic regression was used to examine risk factors for further resectional surgery within 5 years. Prevalence-adjusted surgical rates for index CD surgery over the study period were calculated. RESULTS: In total, 19 207 patients (median age 39 years, interquartile range 27-53 years; 55% women) with CD underwent a first recorded resection during the study period. 3141 (16%) underwent a further operation during the study period. The median time to further surgery was 2.4 (interquartile range 1.2-4.6) years. 3% of CD patients had further surgery within 1 year, 14% by 5 years and 23% by 10 years. Older age (≥58), index laparoscopic surgery and index elective surgery (adjusted OR 0.65, 95% CI 0.54-0.77; 0.77, 0.67-0.88; and 0.77, 0.69-0.85; respectively) were associated with a reduced risk of further surgery by 5 years. Prior surgery for perianal disease (1.60, 1.37-1.87), an extraintestinal manifestation of CD (1.51, 1.22-1.86) and index surgery in a high-volume centre for CD surgery (1.20, 1.02-1.40) were associated with an increased risk of further surgery by 5 years. A 25% relative and 0.3% absolute reduction in prevalence-adjusted index surgery rates for CD was observed over the study period. CONCLUSIONS: Further surgery following an index operation is common in CD. This risk was particularly seen in patients with perianal disease, extraintestinal manifestations and those who underwent index surgery in a high-volume centre.

Clinical Features Focusing on Extraintestinal Manifestations in Japanese Patients with Inflammatory Bowel Diseases: Far East 1000.

BACKGROUND: Patients with inflammatory bowel diseases (IBD) can develop extraintestinal manifestations (EIMs) during the disease course, which sometimes impact their quality of life. OBJECTIVES: This study aimed to clarify the prevalence and types of EIMs using a hospital-based IBD cohort in Japan. METHODS: A patient cohort with IBD was established in 2019, as participated by 15 hospitals in Chiba Prefecture of Japan. Using this cohort, the prevalence and types of EIMs, which are defined based on previous reports and the Japanese guidelines, were investigated. RESULTS: This cohort enrolled 728 patients, including 542 ulcerative colitis (UC) and 186 Crohn's disease (CD). Of these patients with IBD, 10.0% were identified with one or more EIMs (57 (10.5%) with UC and 16 (8.6%) with CD). Arthropathy and arthritis were the most common EIM in 23 (4.2%) patients with UC, followed by primary sclerosing cholangitis (PSC) (2.6%). Arthropathy and arthritis were also the most common in patients with CD, but no cases of PSC were observed. EIMs were more frequently observed in patients with IBD treated by specialists than in those treated by non-specialists (12.7% vs. 5.5%, p = 0.011). The incidence of EIMs in patients with IBD was not significantly different over time. CONCLUSIONS: The prevalence and types of EIMs in our hospital-based cohort in Japan did not significantly differ from those reported in previous or Western studies. However, the incidence might be underestimated due to the limited ability of non-IBD specialists to discover and describe EIMs in patients with IBD.

Unraveling the Immunopathological Landscape of Celiac Disease: A Comprehensive Review.

Celiac disease (CD) presents a complex interplay of both innate and adaptive immune responses that drive a variety of pathological manifestations. Recent studies highlight the role of immune-mediated pathogenesis, pinpointing the involvement of antibodies against tissue transglutaminases (TG2, TG3, TG6), specific HLA molecules (DQ2/8), and the regulatory role of interleukin-15, among other cellular and molecular pathways. These aspects illuminate the systemic nature of CD, reflecting its wide-reaching impact that extends beyond gastrointestinal symptoms to affect other physiological systems and giving rise to a range of pathological landscapes, including refractory CD (RCD) and, in severe cases, enteropathy-associated T cell lymphoma. The existing primary therapeutic strategy, a gluten-free diet (GFD), poses significant challenges, such as low adherence rates, necessitating alternative treatments. Emerging therapies target various stages of the disease pathology, from preventing immunogenic gluten peptide absorption to enhancing intestinal epithelial integrity and modulating the immune response, heralding potential breakthroughs in CD management. As the understanding of CD deepens, novel therapeutic avenues are emerging, paving the way for more effective and sophisticated treatment strategies with the aim of enhancing the quality of life of CD patients. This review aims to delineate the immunopathology of CD and exploring its implications on other systems, its complications and the development of novel treatments.

[Drug therapy's new options in the treatment of the severe irritable bowel syndrome].

BACKGROUND: Stress, individual characteristics of each patient, visceral hypersensitivity and intestinal motility have the key importance in the pathogenesis of irritable bowel syndrome (IBS). In recent years, there has been growing interest in the use of selective serotonin and norepinephrine reuptake inhibitors (SNRIs) in the complex therapy of IBS patients with somatoform disorders. AIM: To examine the effectiveness of the SNRIs antidepressant therapy in the treatment of patients with IBS and diarrhea (IBS-D) with extraintestinal manifestations. MATERIALS AND METHODS: 42 patients with severe IBS and diarrhea (IBS-D) were examined, among them 22 female with a median age of 32 years old (22; 38), and 20 male with a median age of 31 years old (25; 35). Treatment with duloxetine 60 mg/day was prescribed. The effectiveness of the therapy was assessed after eight weeks. The IBS clinical symptoms dynamics were assessed by the intensity of pain syndrome and bloating, which were determined using Visual Analogue Pain Scale (VAS), stool frequency and shape based on the Bristol stool scale; Visceral sensitivity threshold was assessed according to the Balloon dilatation test. There was studied the effect of the duloxetine on the extraintestinal manifestations of IBS. The psycho-emotional state was assessed using the Beck scale of anxiety and depression and the Spielberger-Khanin scale by psychiatrist, neurologist-vegetol. RESULTS: All patients showed positive dynamics after eight weeks duloxetine treatment: the decrease of pain syndrome from 9 (9; 10) to 2 (2; 3) points, bloating from 8 (8; 9) points to 2,5 (1; 3) points according to VAS, and defecation frequency from 10 (9; 12) to 2 (1; 2) times a day; the change of stool consistency from 6th (6; 7) to 3rd (3; 4) type. The visceral sensitivity threshold increased: the time of appearance of the first urge to defecate increased from 56 (34; 74) ml to 95 (80; 98) ml. Significantly decreased extraintestinal manifestations of IBS. In reassessing each patient's individual characteristics there were the decrease of the depression level according to the Beck scale from 26 (23; 32) to 11.5 (10; 13) points and personal personal anxiety level according to the Spielberger-Khanin scale from 42.5 (35; 53) to 22 (20; 24) points, as well as the decrease of situational anxiety from 40 (37; 49) to 22 (21; 36) points. CONCLUSION: The severe course of IBS-D is mainly associated with the patients' individual characteristics and anxiety or anxiety-depressive syndromes. The positive impact of duloxetine therapy in severe IBS-D with extraintestinal manifestations is associated with the regulation of serotonergic and noradrenergic activity of the central.

[Inflammatory bowel diseases: Transformation of representations. A review].

The global burden of inflammatory bowel disease (IBD) is currently significant and continues to grow due to the increasing prevalence of ulcerative colitis (UC) and Crohn's disease (CD), the increasing costs of diagnosis and treatment, and the high level of disability in patients with this disease. Categories, which leads to the search for risk factors and predictors of aggressive course and extraintestinal manifestations. According to the latest data, the prevalence of UC in Russia is 16.6 per 100 000 population, the annual registered increase is 11.3%; the prevalence of CD is 5.6 per 100 000 population, and the increase is 13.7%. In the Russian population of patients with IBD, the average age of disease onset is 35.3 years for UC and 31.2 years for CD. Moreover, in 89.3% of patients with UC, it took at least 2 years to verify the diagnosis, and in CD, within 2 years from the onset of clinical symptoms, the diagnosis was established in only 72.6% of patients. One of the dominant characteristics of IBD is its multisystem nature, which leads to the development of extraintestinal manifestations (ECM), which can be observed in 50-60% of patients, while up to 25% of patients with IBD have several EMC and the most common variants are joint lesions. A higher frequency of extraintestinal manifestations is observed in CD (up to 45% of patients), in female patients, in smokers and with a longer duration of the disease. To predict clinical remission, the level of fecal calprotectin and CRP, the need for glucocorticosteroids are important, to predict endoscopic remission - the level of fecal calprotectin, and to predict histological remission, an endoscopic Schroeder index value of ≤1 is important. The absolute risk of developing colorectal cancer in IBD remains relatively low, ranging from 1.1 to 5.4% after 20 years of disease. The main risk factors for IBD are total intestinal damage, high inflammatory activity, the stricturing phenotype of CD and the presence of primary sclerosing cholangitis.

Prevalence of Primary Sclerosing Cholangitis in Patients With Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Although the association between inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC) is well recognized, uncertainties remain about the magnitude of this problem. We conducted a systematic review and meta-analysis assessing prevalence of PSC in IBD to investigate whether type of IBD, how presence of PSC was defined, sex, disease extent or location, time period, or geographic location influenced prevalence. METHODS: Medline, Embase, and Embase Classic were searched (from inception to April 10, 2021) to identify observational studies recruiting ≥50 adult patients with IBD and reporting prevalence of PSC. Data were extracted, and pooled prevalence, odds ratios (ORs), and 95% confidence intervals (CIs) calculated. RESULTS: Of 1204 citations, 64 studies were eligible, containing 776,700 patients. Overall, pooled prevalence of PSC in IBD was 2.16%; it was highest in South America and lowest in Southeast Asia. Pooled prevalences in patients with ulcerative colitis (UC), Crohn's disease (CD), and IBD-unclassified were 2.47%, 0.96%, and 5.01%, respectively. Pooled prevalence was significantly higher in UC versus CD (OR 1.69, 95% CI 1.24-2.29). In subgroup analyses according to method used to define presence of PSC, the highest prevalence was 2.88% in studies performing both liver biochemistry and endoscopic retrograde/magnetic resonance cholangiopancreatography and the lowest was 1.79% in studies using a clinical diagnosis. Prevalence was generally higher in men, patients with more extensive, compared with left-side, UC or ileocolonic or colonic, compared with ileal, CD. CONCLUSIONS: Our findings provide the first pooled estimates of the burden of PSC in IBD, as well as potential risk factors, which may be important in establishing a prompt diagnosis and initiating appropriate surveillance for relevant gastrointestinal malignancies.

Extraintestinal Manifestations of Inflammatory Bowel Disease: Current Concepts, Treatment, and Implications for Disease Management.

Inflammatory bowel diseases (IBDs) are systemic diseases that manifest not only in the gut and gastrointestinal tract, but also in the extraintestinal organs in many patients. The quality of life for patients with IBD can be substantially affected by these extraintestinal manifestations (EIMs). It is important to have knowledge of the prevalence, pathophysiology, and clinical presentation of EIMs in order to adapt therapeutic options to cover all aspects of IBD. EIMs can occur in up to 24% of patients with IBD before the onset of intestinal symptoms, and need to be recognized to initiate appropriate diagnostic procedures. EIMs most frequently affect joints, skin, or eyes, but can also affect other organs, such as the liver, lung, and pancreas. It is a frequent misconception that a successful therapy of the intestinal inflammation will be sufficient to treat EIMs satisfactorily in most patients with IBD. In general, peripheral arthritis, oral aphthous ulcers, episcleritis, or erythema nodosum can be associated with active intestinal inflammation and can improve on standard treatment of the intestinal inflammation. However, anterior uveitis, ankylosing spondylitis, and primary sclerosing cholangitis usually occur independent of disease flares. This review provides a comprehensive overview of epidemiology, pathophysiology, clinical presentation, and treatment of EIMs in IBD.

Pancreatic Disorders in Patients with Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) can involve multiple organ systems, and pancreatic manifestations of IBD are not uncommon. The incidence of several pancreatic diseases is more frequent in patients with Crohn's disease and ulcerative colitis than in the general population. Pancreatic manifestations in IBD include a heterogeneous group of disorders and abnormalities ranging from mild, self-limited disorders to severe diseases. Asymptomatic elevation of amylase and/or lipase is common. The risk of acute pancreatitis in patients with IBD is increased due to the higher incidence of cholelithiasis and drug-induced pancreatitis in this population. Patients with IBD commonly have altered pancreatic histology and chronic pancreatic exocrine dysfunction. Diagnosing acute pancreatitis in patients with IBD is challenging. In this review, we discuss the manifestations and possible causes of pancreatic abnormalities in patients with IBD.

MicroRNAs in Inflammatory Bowel Disease and Its Complications.

Inflammatory bowel disease (IBD), classified primarily between Crohn's disease and ulcerative colitis, is a collection of chronic gastrointestinal inflammatory conditions that cause multiple complications because of systemic alterations in the immune response. One major player is microRNA (miRNA), which is found to be associated with multiple pathways in mediating inflammation, especially those of a chronic nature in IBD, as well as irritable bowel syndrome. Although there have been studies linking miRNA alterations in IBD, even differentiating Crohn's disease and ulcerative colitis, this review focuses mainly on how miRNAs cause and mechanistically influence the pathologic complications of IBD. In addition to its role in the well-known progression towards colorectal cancer, we also emphasize how miRNA manifests the many extraintestinal complications in IBD such as cardiovascular diseases; neuropsychiatric conditions such as depression and anxiety disorders; and others, including various musculoskeletal, dermatologic, ocular, and hepatobiliary complications. We conclude through a description of its potential use in bettering diagnostics and the future treatment of IBD and its systemic symptoms.

[Calprotectin-a key for diagnosing chronic inflammatory bowel disease in inflammatory dermatoses? : Three case reports]. / Calprotectin ­ ein Schlüssel zur Diagnose einer chronisch entzündlichen Darmerkrankung bei entzündlichen Dermatosen? : Drei Kasuistiken.

We report on three patients with inflammatory dermatoses as a result of a chronic inflammatory bowel disease (IBD). The diagnosis of IBD was based on the initial determination of the fecal calprotectin value. Although the patients did not report any intestinal complaints, the increased calprotectin value in the stool was the reason for further gastroenterological evaluation. This article highlights the importance of determining the fecal calprotectin value as another parameter in the diagnosis of inflammatory dermatoses.

Platelet activating factor receptor acts to limit colitis-induced liver inflammation.

Liver inflammation is a common extraintestinal manifestation in inflammatory bowel disease (IBD), yet, the mechanisms driving gut-liver axis inflammation remain poorly understood. IBD leads to a breakdown in the integrity of the intestinal barrier causing an increase in portal and systemic gut-derived antigens, which challenge the liver. Here, we examined the role of platelet activating factor receptor (PAFR) in colitis-associated liver damage using dextran sulfate sodium (DSS) and anti-CD40-induced colitis models. Both DSS and anti-CD40 models exhibited liver inflammation associated with colitis. Colitis reduced global PAFR protein expression in mouse livers causing an exclusive re-localization of PAFR to the portal triad. The global decrease in liver PAFR was associated with increased sirtuin 1 while relocalized PAFR expression was limited to Kupffer cells (KCs) and co-localized with toll-like receptor 4. DSS activated the NLRP3-inflammasome and increased interleukin (IL)-1ß in the liver. Antagonism of PAFR amplified the inflammasome response by increasing NLRP3, caspase-1, and IL-1ß protein levels in the liver. LPS also increased NLRP3 response in human hepatocytes, however, overexpression of PAFR restored the levels of NLPR3 and caspase-1 proteins. Interestingly, KCs depletion also increased IL-1ß protein in mouse liver after DSS challenge. These data suggest a protective role for PAFR-expressing KCs during colitis and that regulation of PAFR is important for gut-liver axis homeostasis.

Different renal manifestations associated with very early onset pediatric inflammatory bowel disease: case report and review of literature.

BACKGROUND: Inflammatory bowel diseases are characterized by chronic inflammation of the gastrointestinal tract. In particular, Crohn disease and ulcerative colitis represent the two most common types of clinical manifestations. Extraintestinal manifestations of inflammatory bowel diseases represent a common complications, probably reflecting the systemic inflammation. Renal involvement is reported in 4-23% of cases. However, available data are limited to few case series and retrospective analysis, therefore the real impact of renal involvement is not well defined. CASE PRESENTATION: We report the case of a 10-years old male affected by very early onset unclassified-Inflammatory bowel diseases since he was 1-year old, presenting with a flare of inflammatory bowel diseases associated with acute kidney injury due to granulomatous interstitial nephritis. Of interest, at 7-year-old, he was treated for IgA nephropathy. To our knowledge, no previous reports have described a relapse of renal manifestation in inflammatory bowel diseases, characterized by two different clinical and histological phenotypes. CONCLUSIONS: The link between the onset of kidney injuries with flares of intestinal inflammation suggest that nephritis maybe considered an extra-intestinal manifestation correlated with active inflammatory bowel disease. However, if granulomatous interstitial nephritis represents a cell-mediated hypersensitivity reaction than a true extraintestinal manifestation of inflammatory bowel diseases is still not clarified. We suggest as these renal manifestations here described may be interpreted as extraintestinal disorder and also considered as systemic signal of under treatment of the intestinal disease.

Characterization and prevalence of extraintestinal manifestations in a cohort of patients with inflammatory intestinal disease in Medellin, Colombia. / Caracterización y prevalencia de manifestaciones extraintestinales en una cohorte de pacientes con enfermedad inflamatoria intestinal en Medellín (Colombia).

INTRODUCTION: Extraintestinal manifestations (EIMs) are frequent in patients with inflammatory bowel disease (IBD). Our objective is to characterize and determine the prevalence of MEIs in our cohort of patients with IBD. PATIENTS AND METHODS: A retrospective study was carried out in adult patients with IBD at the Pablo Tobón Uribe Hospital in Medellín. Colombia. Articular MEIs, primary sclerosing cholangitis (PSC), both ophthalmological and dermatological, were considered. Absolute and relative frequencies were used. The Chi square test of independence was used to compare 2proportions and the odds ratio (OR) was estimated. RESULTS: Our registry has 759 patients with IBD, 544 present UC (71.6%), 200 CD (26.3%) and 15 unclassifiable IBD (1.9%); 177 patients with IBD (23.3%) presented EIMs, 123 of 544 (22.6%) with UC and 53 of 200 (26.5%) with CD (OR: 0.81, 95% CI: 0.55-1.17, P=0.31). Regarding the type of EIMs, the articular ones were the most frequent (13.5%), more in CD than in UC (20.0 vs. 11.3%, OR 1.94, 95% CI: 1.25-3.00, P=0.0037). Patients with IBD and EIMs used more antibodies against tumor necrosis factor (anti-TNFs), compared to those without EIMs (43.5 vs. 18.5%, OR 3.38, 95% CI: 2.31-4.90, P=0.0001). CONCLUSIONS: The prevalence of EIMs in our cohort is high (23.3%) and the most frequent type is joint. Anti-TNFs are most used when IBD and EIMs coexist. Our study provides valuable information on the association of EIMs and IBD in Latin America.