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Mechanisms of extraintestinal manifestations (EIMs). (a) Activation and expansion of effector memory T cells can lead to induction of mucosal vascular addressin cell adhesion molecule 1 and C-C motif chemokine ligand 25 (CCL25) expression in the liver. (b) Intercellular adhesion molecule-1, vascular adhesion protein-1, and vascular cell adhesion molecule 1 are associated with T cell trafficking. (c) Microbial antigens and materials translocate to extraintestinal sites and drive EIMs. (d) Circulating antibodies can provoke an autoimmune response and peptide(s) expressing common epitopes shared by colon and extra-colonic organs. (e) Neutrophil priming and alteration of circulating monocytes and macrophages can induce intestinal inflammation and are associated with innate immune responses. (f) Gut dysbiosis drives non-intestinal inflammation and increases mucosal permeability and lipopolysaccharides.
Source publication
A considerable number of patients with inflammatory bowel disease (IBD) experience extraintestinal manifestations (EIMs), which can present either before or after IBD diagnosis. Unraveling the pathogenic pathways of EIMs in IBD is challenging because of the lack of reliable criteria for diagnosis and difficulty in distinguishing EIMs from external...
Context in source publication
Context 1
... an EIM from extraintestinal complications or a secondary EIM caused by drugs. EIMs are considered to be the result of an antigen-specific immune response from the intestine to an extraintestinal site or an independent inflammatory event that is initiated or persisting from covalent genetic or environmental risk factors in the host, or from IBD ( Fig. ...
Citations
... 4. Происходят изменения в кроветворении, вызванные воспалением кишечника, микробными продуктами, воспалительными цитокинами, повышением проницаемости кишечника и др. [11,12]. ...
This review presents the main extraintestinal manifestations (EIMs) in patients with inflammatory bowel diseases (IBD), in particular ulcerative colitis (UC) and Crohn’s disease (CD), describes the modern potential mechanisms, classification, characteristics and frequency of the main EIMs (rheumatological, skin, ophthalmological and orofacial manifestations). The issues of the mechanism of action, indications for prescribing ustekinumab are also covered in detail, the place of ustekinumab in the treatment of IBD is highlighted, the effectiveness of this drug in relation to the treatment of IBD is assessed – summarizes the results of a retrospective analysis of data from the UNITI-1, UNITI-2, IM-UNITI clinical trial program, prospective cohort studies, retrospective cohort studies and a registry study on the effect of ustekinumab on the course of various EIMs and the outcomes of immune-mediated diseases (IMDs) in patients with CD and UC. Ustekinumab is a fully monoclonal human immunoglobulin G1k that binds to the common p40 subunit of interleukin (IL)-12 and IL-23, which are actively involved not only in the development of intestinal symptoms, but are also triggers in the development of various EIMs. A review of the literature showed that ustekinumab may be effective for the treatment of EIMs in patients with UC and CD, especially in relation to dermatological and rheumatological manifestations, and is effective against psoriasis and psoriatic arthritis. A literature search of MEDLINE®, EMBASE®, BIOSIS Previews® and DERWENT® and/or other resources, including internal/external databases was conducted on April 15, 2024.
... Although the epidemiology of IBD is not well studied in Iran, one could say that IBD was a rare disorder in Iranian populations until 1985 and has started to rise since then (3). A large number of patients experience extraintestinal symptoms, including hepatobiliary disorders as the most common extraintestinal manifestation of IBD and NAFLD as the most important complication (13,14). Considering that both intestinal inflammation and metabolic factors are effective in the pathogenesis of IBD-related NAFLD, a study showed that the risk factors for NAFLD in the IBD population are not different from those in the general population (15). ...
Background
According to the significance of extraintestinal symptoms in inflammatory bowel disease (IBD) patients and their connection with obesity, we aimed to investigate the prevalence of fatty liver in IBD patients of Sayyad Shirazi Hospital in Gorgan, Iran, in relation to obesity, anthropometric indicators and body image in these patients.
Methods
Forty patients with IBD were recruited from all registered patients at the Golestan Research Center of Gastroenterology and Hepatology, following the specified inclusion and exclusion criteria. After obtaining written informed consent and filling in the questionnaire, the demographic and anthropometric indicators, and variables related to the disease were measured. The liver sonography was performed on all patients and graded by an expert radiologist. Data were analyzed using SPSS Version 16.0 statistical software at the significance level of 0.05.
Results
We showed no significant difference between the distribution of demographic and anthropometric indicators in different groups of IBD patients. However, we demonstrated that the inappropriate values of HDL (0.004) and high values of LDL (0.015) were associated with fatty liver in IBD patients. Our findings also showed that NAFLD was significantly associated with overweight and obesity among IBD patients (P = 0.003).
Conclusion
Our findings showed the epidemiological burden of NAFLD in IBD patients. Since fatty liver was associated with obesity, it is recommended that IBD patients be screened for risk factors associated with NAFLD to prevent liver disease.
... IBD affects the gastrointestinal tract and extra-intestinal organs of many patients. EIMs have the potential to impact diverse organ systems, emerging at any stage of IBD, possibly preceding gastrointestinal symptoms (1,12,13). In 1976, Greenstein et al. (14) summarized the characteristics and prevalence of EIMs in IBD by analyzing several patients with IBD. ...
... IBD-related musculoskeletal symptoms can impact both the axial and peripheral skeletal systems (16)(17)(18). The classification of peripheral musculoskeletal manifestations includes two types: Type I (oligoarticular), affecting fewer than five large joints and presenting as acute, asymmetrical, and migratory, and Type II, characterized by symmetrical arthritis impacting more than five facet joints, irrespective of intestinal disease activity (13,19,20). ...
... Diagnosis of IBD-associated arthritis relies primarily on clinical assessments, patient history, and exclusion of other arthritis forms (1,22,23). Treatment is primarily based on studies of SpA, and emphasizes addressing the underlying gut inflammation (13). ...
Most host-microbiota interactions occur within the intestinal barrier, which is essential for separating the intestinal epithelium from toxins, microorganisms, and antigens in the gut lumen. Gut inflammation allows pathogenic bacteria to enter the blood stream, forming immune complexes which may deposit on organs. Despite increased circulating immune complexes (CICs) in patients with inflammatory bowel disease (IBD) and discussions among IBD experts regarding their potential pathogenic role in extra-intestinal manifestations, this phenomenon is overlooked because definitive evidence demonstrating CIC-induced extra-intestinal manifestations in IBD animal models is lacking. However, clinical observations of elevated CICs in newly diagnosed, untreated patients with IBD have reignited research into their potential pathogenic implications. Musculoskeletal symptoms are the most prevalent extra-intestinal IBD manifestations. CICs are pivotal in various arthritis forms, including reactive, rheumatoid, and Lyme arthritis and systemic lupus erythematosus. Research indicates that intestinal barrier restoration during the pre-phase of arthritis could inhibit arthritis development. In the absence of animal models supporting extra-intestinal IBD manifestations, this paper aims to comprehensively explore the relationship between CICs and arthritis onset via a multifaceted analysis to offer a fresh perspective for further investigation and provide novel insights into the interplay between CICs and arthritis development in IBD.
... That's why large proportions of patients are classified as undetermined IBD [6]. Extra intestinal manifestations are frequent with IBD [7] and consist of eye inflammation, rheumatologic, mucocutaneous, hepatic and biliary symptoms [8,9]. Silent IBD may be found just as clinically significant cases [10]. ...
... Additionally, serum CRP level was higher (3.91 ± 4.93 mg/dL) than in the previous study [21]. Intestinal BD is an intestinal manifestation of systemic BD, and careful evaluation and management of extra-intestinal disease symptoms such as skin lesions, uveitis, oral and genital ulcers are required when managing intestinal BD [34]. We also investigated extra-intestinal symptoms during every visit and followed the status of extra-intestinal symptom changes to integrate extraintestinal symptoms into the systematic effect of adalimumab in intestinal BD. ...
Background
Intestinal Behçet’s disease (BD) is characterized by typical gastrointestinal ulcers in patients with BD followed by complications such as bleeding, perforation and fistula. Biologic agents are currently under active investigation to delay the disease course. Various data regarding infliximab are available, but there is relatively lack of data regarding adalimumab.
Methods
This was a multicenter, real-world prospective observational study to evaluate the effectiveness and safety of adalimumab in intestinal BD. The primary endpoint was disease activity at each follow up, including disease activity index for intestinal Behçet’s disease (DAIBD), serum C-reactive protein (CRP) level, and endoscopic findings. The secondary endpoint was the incidence of adverse drug reactions (ADRs).
Results
A total of 58 patients were enrolled and 8 of them were excluded. Adverse events were reported in 72.0% of patients with 122 events. ADRs were reported in 24.0% with 28 events. For adverse events, arthralgia was most commonly reported (13.1%: 16/122) and only one experienced critical adverse event (0.82%, 1/122: death due to stroke). On multivariable regression analysis, a longer disease duration was significantly associated with decreased ADRs [Odds ratio 0.976 (0.953–0.999, 95% CI); p = 0.042]. Clinical response rates as assessed by DAIBD were 90.9% at Week 12 and 89.7% at Week 56, respectively. The mean serum CRP level at baseline was significantly decreased after 12 weeks (3.91 ± 4.93 to 1.26 ± 2.03 mg/dL; p = 0.0002).
Conclusion
Adalimumab was found to be safe and effective in Korean patients with intestinal BD. A longer disease duration was significantly associated with decreased ADRs.
... 3 One of the pathologic characteristics of IBD is presenting various extraintestinal manifestations. 4 Primary sclerosing cholangitis (PSC) is a chronic, biliary tract disease which causes progressive inflammation in the bile duct, resulting in obstruction and dilatation. The annual incidence of PSC in Western countries is 0.5-1.3 per 100,000 people. ...
... Los antígenos derivados de la microbiota intestinal alterada son transportados al hígado por la circulación portal, activando las células T hepáticas a través de interacciones de la integrina α4β7 y la molécula de adhesión MAdCAM-1 (que en un principio son específicas del intestino, pero se expresan también en la circulación portal) [17,18], lo que sugiere un tropismo compartido entre el intestino y el hígado [19]. Asimismo, el proceso inflamatorio independiente pero sostenido por la presencia de EII o de factores de riesgo genéticos o ambientales, que son comunes para las manifestaciones hepatobiliares y para la EII, produce sobreexpresión de mediadores inflamatorios como la interleuquina 6 (IL-6), el factor de necrosis tumoral alfa (TNF-α), el interferón gamma (IFN-γ) y el factor de crecimiento endotelial vascular (VEGF), permitiendo la captura de las células T efectoras generadas a nivel intestinal y su reclutamiento en otras localizaciones extraintestinales [16,19,20]. ...
... Existen factores genéticos de susceptibilidad, como genes del antígeno leucocitario humano (HLA) y loci independientes de HLA, tanto para la EII como para las manifestaciones hepatobiliares, que se solapan ampliamente; por ejemplo, el HLA-B8/DR3 [18,26], HLA-DRB3*0101 (DRw52a), HLA-DRB1*0301 (DR3) y el HLA-DRB1*0401 (DR4) [11,14,27] se asocian con un riesgo aumentado de CEP en pacientes con CU. Entre los genes de riesgo para CEP y para EII, se han reportado UBASH3A, BCL2L11, FOXO1, IRF8, SOCS1, JAK2, STAT3 y TYK2 [20], y otros genes que pueden participar en una vía fisiopatológica común para colangitis biliar primaria (CBP) y EII, tales como TNFSF15 y ICOSLG-CXCR5 [28]. ...
... Se estima que del 70 % al 80 % de los pacientes con CEP presentan concomitantemente EII, siendo la CU la más frecuente (>75 %) [1,10,11,22,32,[34][35][36][37]. La CEP puede preceder al diagnóstico de la EII o diagnosticarse después de la EII, inclusive muchos años después con un promedio de 10 años [20,27,28,[38][39][40]; por otra parte, debido a que la CEP progresa independientemente de la actividad de la EII intestinal, el tratamiento de la EII no mejora la afección por CEP [16]. Es importante destacar que la CEP se asocia con un riesgo 10 veces mayor de desarrollar carcinoma colorrectal en EII, y 15 % de los pacientes pueden desarrollar cáncer de las vías biliares [11,16], entre estos, colangiocarcinoma (HR=28,46), carcinoma hepatocelular (HR=21,00), cáncer de páncreas (HR=5,26) y cáncer de vesícula biliar (HR=9,19) [10]. ...
La enfermedad inflamatoria intestinal (EII) engloba dos entidades, la enfermedad de Crohn (EC) y la colitis ulcerativa (CU), las cuales son enfermedades inmunomediadas, crónicas y recurrentes que, aunque afectan al intestino, pueden ir acompañadas de manifestaciones extraintestinales de tipo hepatobiliar en el 5 % de los casos. Entre ellas, las más frecuentes son la enfermedad por hígado graso no alcohólico (EHGNA), la colelitiasis, la colangitis esclerosante primaria (CEP), la colangitis relacionada con IgG4, la hepatitis autoinmune (HAI), el síndrome de superposición HAI/CEP, así como la lesión hepática inducida por fármacos (DILI); y otras menos frecuentes como la colangitis biliar primaria (CBP), la trombosis de la vena porta, los abscesos hepáticos, la hepatitis granulomatosa, las hepatitis B y C, la reactivación de la hepatitis B por terapia inmunosupresora, y la amiloidosis. Estas manifestaciones hepatobiliares cursan con una fisiopatología similar o inclusive la misma de la EII, en la que participan el sistema inmune innato y adaptativo, alteración de la microbiota (disbiosis), permeabilidad intestinal, factores de riesgo genéticos (comunes para EII y manifestaciones hepatobiliares) y desencadenantes ambientales. La primera manifestación de un trastorno hepatobiliar es la alteración del perfil de función hepática, por lo que el abordaje diagnóstico se debe dirigir a evaluar y monitorizar las enzimas hepáticas y su asociación a algún patrón diferencial de alteración hepatocelular o colestásico, con el fin de tomar decisiones oportunas con respecto a la suspensión, indicación o modificación de algún medicamento, o cualquier otro abordaje que impida o retrase la evolución de la enfermedad hepatobiliar, y al mismo tiempo garantice el control de la EII, mejorando potencialmente el pronóstico de estos pacientes.
... 5 IBD patients require life-long treatment and may experience diverse extraintestinal manifestations throughout their lifetime. [6][7][8] Primary sclerosing cholangitis (PSC) is the most trouble-2 www.irjournal.org by reduced use of steroids, decreased hospitalizations and a less frequent need for immunosuppression. 10,19,20 However, the risk of malignancy, such as colorectal cancer and cholangiocarcinoma, is remarkably increased in PSC-IBD patients. ...
Primary sclerosing cholangitis (PSC) is a progressive cholestatic, inflammatory, and fibrotic disease that is strongly associated with inflammatory bowel disease (IBD). PSC-IBD represents a unique disease entity and patients with this disease have an increased risk of malignancy development, such as colorectal cancer and cholangiocarcinoma. The pathogenesis of PSC-IBD involves genetic and environmental factors such as gut dysbiosis and bile acids alteration. However, despite the advancement of disease characteristics, no effective medical therapy has proven to have a significant impact on the prognosis of PSC. The treatment options for patients with PSC-IBD do not differ from those for patients with PSC alone. Potential candidate drugs have been developed based on the pathogenesis of PSC-IBD, such as those that target modulation of bile acids, inflammation, fibrosis, and gut dysbiosis. In this review, we summarize the current medical treatments for PSC-IBD and the status of new emerging therapeutic agents.
... Patients with IBD can experience abdominal pain, diarrhea, hematochezia, and fever. In addition, pat ients with IBD can have cutaneous manifestations, such as erythema nodosum, pyoderma gangrenosum, and Sweet's syndrome [11][12][13]. ...
Introduction:
Rosacea and inflammatory bowel disease (IBD) are chronic inflammatory disorders of the skin and the gut, which are interfaces between the environment and the human body. Although growing evidence has implicated a possible link between rosacea and IBD, it remains unclear whether IBD increases the risk of rosacea and vice versa. Therefore, we investigated the association between rosacea and IBD in this study.
Methods:
We performed a systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines.
Results:
Eight eligible studies were included in this meta-analysis. Overall, the prevalence of rosacea was higher in the IBD group than in the control group, with a pooled odds ratio (OR) of 1.86 (95% confidence interval [CI](1), 1.52-2.26). Both the Crohn's disease and the ulcerative colitis groups had higher prevalences of rosacea than the control group, with ORs of 1.74 (95% CI 1.34-2.28) and 2.00 (95% CI 1.63-2.45), respectively. Compared with those in the control group, the risks of IBD, Crohn's disease, and ulcerative colitis were significantly higher in the rosacea group, with incidence rate ratios of 1.37 (95% CI 1.22-1.53), 1.60 (95% CI 1.33-1.92), and 1.26 (95% CI 1.09-1.45), respectively.
Conclusion:
Our meta-analysis suggests that IBD is bidirectionally associated with rosacea. Future interdisciplinary studies are needed to better understand the mechanism of interaction between rosacea and IBD .
... Ulcerative colitis (UC), a chronic and inflammatory disease, mainly affects the colon, rarely accompanied by primary sclerosing cholangitis (PSC). 1 PSC is a chronic cholestatic disease of liver in which bile ducts are progressively destroyed by repeated inflammation and fibrosis leading to liver cirrhosis. 2 Previous studies have reported an increased risk of colorectal cancer (CRC) in patients with UC, and a further increased risk has been reported in patients with UC and PSC. 3 In addition, the risk of cholangiocarcinoma in PSC patients is reported to be 1,560 times higher than in the general population, with a lifetime prevalence of 5% to 10%. 4 However, because the number of PSC and cholangiocarcinoma cases in UC patients is limited, reports on cholangiocarcinoma risk and follow-up recommendations are limited. ...
