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.

Induction and maintenance of mucosal healing in Crohn's disease with ustekinumab in clinical practice across all care levels in Germany (MUCUS).

The impact of ustekinumab (UST) on mucosal- and fistula healing and extraintestinal manifestations (EIM) in Crohn's disease (CD) were not fully elucidated in the registration trials. In this prospective, multicenter study (EudraCT number: 2017-005151-83) we evaluated the German label real-world-effectiveness of UST to achieve the primary endpoint of combined clinical and endoscopic response at week 52 and several secondary endpoints. Of 79 screened we enrolled 52 patients (female n = 28, bionaïve n = 13, biologic n = 39). At week 52 (per protocol analysis), 52% (n = 13/25) of patients achieved the primary endpoint [50% (n = 3/6) in the bionaïve, 45.5% (n = 5/11) biologic, 62.5% (n = 5/8 ) multiple biologics cohorts, respectively with age as independent predictor [OR 95% CI 0.933 (0.873, 0.998) p = 0.043], 60% (n = 15/25) achieved endoscopic response [50% (n = 3/6) in the bionaïve, 54.5% (n = 6/11) biologic, 75% (n = 6/8) multiple biologics cohorts, respectively], 36% (n = 9/25) achieved endoscopic remission [50% (n = 3/6) in the bionaïve, 27.3% (n = 3/11) biologic, 37.5% (n = 3/8) multiple biologics cohorts, respectively], 48% (n = 12/25) achieved mucosal healing [50% (n = 3/6) in the bionaïve, 36.4% (n = 4/11) biologic, 62.5% (n = 5/8) multiple biologics cohorts, respectively]. All achieved a fistula response and 33.3% (n = 1/3) in the multiple biologics group fistula remission at week 52. EIM decreased (week 0 28.2% vs. week 52 8%). CRP, FCP, PRO-2, EQ-5D-5L improved throughout. 36 patients (69.2%) experienced ≥ 1 treatment emergent adverse event, in 8 (15.4%) cases rated as severe and in 5 (9.6%) leading to UST discontinuation, but no very severe events or deaths. The effectiveness of UST was better than in the registration trials.

Enthesitis in IBD Patients.

Inflammatory bowel disease (IBD) is marked by chronic inflammation of the gastrointestinal tract and encompasses two major subtypes, Crohn's disease (CD) and ulcerative colitis (UC). IBD is frequently accompanied by extraintestinal manifestations (EIMs), with axial and peripheral spondyloarthritis (SpA) being the most common. Enthesitis, an inflammation of the bone insertions of capsules, ligaments, and tendons, represents an initial lesion in SpA. However, enthesitis remains an underestimated and often obscured EIM. The early detection of subclinical entheseal involvement in IBD patients using ultrasound (US) could provide an opportunity for timely intervention. US is a more feasible and affordable approach than magnetic resonance imaging (MRI). While previous meta-analyses have reported on the incidence and prevalence of SpA in IBD, specific attention to enthesitis has been lacking. Therefore, this narrative review aims to assess the current knowledge on existing IBD-SpA cohorts, focusing specifically on enthesitis.

Rare extraintestinal manifestations of ulcerative colitis treated with dual biologic therapy: A case report.

BACKGROUND: Ulcerative colitis (UC) is an idiopathic, chronic inflammatory bowel disease (IBD) most often located in the rectum, but may involve the entire colon. Extra intestinal manifestations (EIMs) occur with varying frequency depending on the affected organ. The most common ones are musculoskeletal EIMs, affecting up to 33%-40% of IBD patients. These include, among others, inflammatory back pain, tendinitis, plantar fasciitis and arthritis. Only a few case reports in literature discuss Achilles tendinitis. CASE SUMMARY: This report describes a patient with UC and Achilles tendinitis in whom after many unsuccessful attempts of treatment with sulfasalazine, mesalazine, glucocorticosteroids, infliximab and tofacitinib, a complete UC remission and resolution of Achilles tendinitis were achieved with the use of dual biologic therapy (DBT)-ustekinumab and adalimumab (ADA). CONCLUSION: This case mentions rare EIMs of UC and suggests that DBT may be an alternative for patient with ulcerative colitis and EIMs.

Specific Oral Manifestations in Adults with Crohn's Disease.

Background: Oral manifestations of Crohn's disease (CD) include non-specific lesions and specific lesions directly related to intestinal inflammation. Oral lesions that can be overlooked in CD are sometimes challenging to treat. Methods: In this retrospective single-center study, patients with CD aged over 18 years who complied with follow-up and treatment were included. Clinical definitions of specific oral lesions included pyostomatitis vegetans, glossitis with fissuring, lip swelling with fissuring, cobblestoning, and orofacial granulomatosis. Experienced dentists confirmed the specific lesions in each case. Three groups of patients were identified: those without oral lesions, those with non-specific oral lesions, and those with specific oral lesions. The groups were compared based on demographics, disease extent and behavior (based on the Montreal classification), extraintestinal involvement, biologic and steroid treatment, and the requirement of resective surgery. Results: A total of 96 patients (14.2%) with oral lesions were found among the 676 patients with CD (59.7% male, median age 38 years) who were followed for 6.83 years (IQR 0.5-29.87 years). Eight patients (1.2%, 9 lesions) had specific oral lesions, while eighty-eight patients (13%) had non-specific lesions. Orofacial granulomatosis (n = 3), cobblestoning (n = 2), glossitis with fissuring (n = 2), and lip swelling with fissuring (n = 2) were among the specific lesions. The majority of patients (75%) with specific lesions were male, and their median age was 46.5 years (range: 23-68 years). Disease localization was commonly ileocolonic (50%), and perianal disease was present in 25% of patients. Three patients were active smokers. Extraintestinal manifestations were peripheral arthritis/arthralgia (n = 7) and sacroiliitis (n = 1). All specific lesions were associated with moderate-to-severe disease. Five patients improved with biologic therapy, and two patients with immunomodulatory therapy. Conclusions: Specific oral lesions in CD were associated with active disease and improved with immunomodulators or biologic therapy. Close cooperation between gastroenterologists and dentists is essential for early diagnosis and optimal management of CD.

Biologic therapy for ulcerative colitis associated with immune thrombocytopenia.

Ulcerative colitis (UC), a subtype of inflammatory bowel disease, occasionally manifests with extraintestinal manifestations. We present a 51-year-old male with refractory UC and immune thrombocytopenia (ITP) resistant to conventional treatments. The introduction of biologics, ustekinumab or adalimumab, resulted in clinical remission of colitis and improvements in platelet count. This case underscores the efficacy of biologics in managing refractory UC associated with ITP, emphasizing their potential to control intestinal inflammation and address concurrent thrombocytopenia, potentially avoiding surgical intervention.

Going Outside the Gut: Immune Thrombocytopenia Presenting as a Rare Extraintestinal Manifestation of Ulcerative Colitis.

A 26-year-old male with no significant medical history presented with hematochezia and was diagnosed with ulcerative colitis (UC) accompanied by immune thrombocytopenia (ITP) as an extraintestinal manifestation (EIM) of UC. This case report delves into the uncommon overlap between UC, a subtype of inflammatory bowel disease primarily affecting the colon and rectum, and ITP, an autoimmune condition leading to platelet destruction. The patient's atypical presentation and subsequent positive response to a treatment regimen targeting both UC and ITP underscores the necessity for a thorough and multifaceted diagnostic approach in individuals with UC, especially when faced with non-gastrointestinal symptoms like unexplained thrombocytopenia. The findings from this study enhance the understanding of UC's diverse manifestations and highlight its potential intersection with other autoimmune diseases, advocating for integrated care strategies in managing such intricate clinical cases.

Associations between Celiac Disease, Extra-Gastrointestinal Manifestations, and Gluten-Free Diet: A Narrative Overview.

Millions of children and adults worldwide suffer from undiagnosed and untreated celiac disease (CeD). The clinical picture of CeD is highly heterogeneous and comprises manifestations that can affect almost the whole body. This narrative overview is aimed at characterizing diseases and complaints that are associated with unrecognized CeD and that frequently involve sites other than the gastrointestinal (G.I.) tract, i.e., dental, otorhinolaryngological, and ocular complications; skin and hair abnormalities; afflictions of the bones, joints, and muscles; cardiovascular affectations; kidney diseases; neuro-psychiatric disorders; and gynecological-obstetrical manifestations. The association between CeD and extra-GI manifestations is frequently overlooked, which leads to a delay in diagnosis. Most CeD-mediated disorders can be treated with a strict gluten-free diet (GFD), but some of them are irreversible unless CeD is diagnosed in time. Some manifestations can be classified as risk factors for CeD, and CeD screening tests for affected patients should be selectively considered. Apart from gastroenterologists, specialists in other medical disciplines can play an important role in identifying people with unrecognized CeD and may help prevent its progress and long-term complications. Further comprehensive investigations are necessary to clarify the pathogenesis of extra-GI manifestations and the effect of a GFD.

A case of ulcerative colitis with a variety of autoimmune diseases including ankylosing spondylitis, type 2 autoimmune pancreatitis, and primary sclerosing cholangitis.

Ankylosing spondylitis (AS), primary sclerosing cholangitis (PSC), and autoimmune pancreatitis (AIP) are known as extraintestinal manifestations (EIMs) of ulcerative colitis (UC). A 74-year-old Japanese man visited our hospital because of white stool. He had been diagnosed with AS when he was 30 years old, and he was HLA-B27-positive. Based on various examination results, it was suspected that AIP had caused bile duct stricture. During the clinical course, he was diagnosed with UC and PSC. Then, AIP was diagnosed because he had localized pancreatic enlargement, irregular stenosis of the main pancreatic duct, PSC, and no tumor cells of pancreas. A patient with all four of these diseases, AS, AIP, PSC, and UC, is very rare. Therefore, we report a quite rare case with three EIMs (AS, PSC, and AIP) of UC.

Challenges in IBD Research 2024: Preclinical Human IBD Mechanisms.

Preclinical human inflammatory bowel disease (IBD) mechanisms is one of 5 focus areas of the Challenges in IBD Research 2024 document, which also includes environmental triggers, novel technologies, precision medicine, and pragmatic clinical research. Herein, we provide a comprehensive overview of current gaps in inflammatory bowel diseases research that relate to preclinical research and deliver actionable approaches to address them with a focus on how these gaps can lead to advancements in IBD interception, remission, and restoration. The document is the result of multidisciplinary input from scientists, clinicians, patients, and funders and represents a valuable resource for patient-centric research prioritization. This preclinical human IBD mechanisms section identifies major research gaps whose investigation will elucidate pathways and mechanisms that can be targeted to address unmet medical needs in IBD. Research gaps were identified in the following areas: genetics, risk alleles, and epigenetics; the microbiome; cell states and interactions; barrier function; IBD complications (specifically fibrosis and stricturing); and extraintestinal manifestations. To address these gaps, we share specific opportunities for investigation for basic and translational scientists and identify priority actions.

To address the unmet medical needs of patients with inflammatory bowel diseases (IBD) and move toward cures, preclinical human-relevant research must center on mechanistic questions pertinent to patients with IBD in the 3 areas of disease interception, remission, and restoration.

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.

Prevalence of Classical Extraintestinal Manifestations among Inflammatory Bowel Disease Patients in Saudi Arabia: A Single Tertiary Center Experience.

Background: Patients with inflammatory bowel disease (IBD) may also experience extraintestinal manifestations (EIMs), which can affect various organ systems, and their occurrence is based on disease activity. Objectives: To determine the prevalence of EIMs and their most common types among IBD patients from Saudi Arabia. Materials and Methods: This retrospective study included all IBD patients aged 14-80 years who visited the Gastroenterology and Hepatology clinics at King Fahad Medical City, Riyadh, between February 2017 and December 2022. The collected data included demographic characteristics, disease characteristics, EIMs, and treatment. Results: The study included 578 IBD patients, of which 65 (11.2%) had at least one EIM, with primary sclerosing cholangitis (46.2%) and sacroiliitis (16.9%) being the most common. Patients with ulcerative colitis were more likely to have EIMs than those with Crohn's disease (15.1% vs. 9%; P = 0.026). Patients with ileocolonic (L3) Crohn's disease reported a higher prevalence of EIMs (7.5%) than those with other disease locations (P = 0.012), while in patients with ulcerative colitis, those with extensive colitis (E3) reported higher prevalence of EIMs (19.2%) (P = 0.001). Patients receiving 6 MP had a significantly high prevalence of EIMs (P = 0.014). Conclusion: The prevalence of extraintestinal manifestations among IBD patients in Saudi Arabia is 11.2%. These findings suggest the need for clinicians to screen for EIMs and manage them early. Further research is needed to understand the mechanisms underlying EIMs for the development of more effective treatments.

Portal vein thrombosis as extraintestinal complications of Crohn's disease: a case report and review of literature.

INTRODUCTION: Thrombotic events are more than twice as common in inflammatory bowel disease patients as in the general population. We report an interesting and rare case of portal vein thrombosis as a venous thromboembolic event in the context of extraintestinal manifestations of Crohn's disease. We also conducted a literature review on portal vein thrombosis associated with inflammatory bowel disease, with the following concepts: inflammatory bowel diseases, ulcerative colitis, Crohn's disease, portal vein, and thrombosis. CASE PRESENTATION: A 24-year-old Syrian female with active chronic Crohn's disease was diagnosed 11 years ago and classified as A1L3B1P according to the Montreal classification. She had no prior surgical history. Her previous medications included azathioprine and prednisolone. Her Crohn's disease activity index was 390 points. Gastroduodenoscopy revealed grade I esophageal varices, a complication of portal hypertension. Meanwhile, a colonoscopy revealed several deep ulcers in the sigmoid, rectum, and descending colon. An investigation of portal vein hypertension revealed portal vein thrombosis. We used corticosteroids to induce remission, followed by tapering; additionally she received ustekinumab to induce and maintain remission. She began on low-molecular-weight heparin for 1 week, warfarin for 3 months, and then apixaban, a novel oral anticoagulant, after excluding antiphospholipid syndrome. Primary prophylaxis for esophageal varices was not required. After 1 year, she achieved clinical, biochemical, and endoscopic remission. Despite 1 year of treatment, a computed tomography scan revealed no improvement in portal vein recanalization. CONCLUSION: Portal vein thrombosis is a rare and poorly defined complication of inflammatory bowel disease. It is usually exacerbated by inflammatory bowel disease. The symptoms are nonspecific and may mimic a flare-up of inflammatory bowel disease, making the diagnosis difficult. Portal vein Doppler ultrasound for hospital-admitted inflammatory bowel disease patients may contribute to the diagnosis and management of this complication.

Proportion of inflammatory bowel diseases patients with suboptimal disease control in daily clinical practice-Real-world evidence from the inflammatory bowel diseases-podcast study.

BACKGROUND: Crohn's disease and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) characterized by a progressive nature of the disease resulting in subsequent intestinal damage, limited efficacy of current treatments and suboptimal disease management and a significant burden for patients. OBJECTIVES: The IBD-PODCAST study aims to estimate the proportion of Crohn's disease and UC patients with suboptimal disease control (SDC) in a real-world setting. METHODS: A non-interventional and cross-sectional study was conducted across 103 sites in 10 countries (Austria, Belgium, Canada, Germany, Greece, Italy, Portugal, Spain, Turkey, and UK). Criteria for SDC were based on STRIDE-II criteria and adapted by an expert panel. RESULTS: 2185 patients (Crohn's disease: n = 1,108, UC: n = 1077) with a mean (SD) age of 44.0 (14.8) years and mean (SD) disease duration of 12.4 (9.2) years were included (52.2% male). Ileal involvement was present in 39.1% of Crohn's disease patients, 35.3% of UC patients had extensive colitis. 77.3% of Crohn's disease and 65.3% of UC patients were on targeted immunomodulators and, according to STRIDE-II-based treatment phases, 85.6% of Crohn's disease and 85.4% of UC patients were assigned to the long-term treatment phase. SDC was detected in 52.2% of Crohn's disease and 44.3% of UC patients predominantly due to impaired quality of life (QoL), clinically significant extraintestinal manifestations, steroid overuse, signs of active inflammation in UC and Crohn's disease, and active fistulas in Crohn's disease. More than one criterion was seen in 37% of patients with SDC. Opportunities for on-label treatment optimization were observed in 49% of Crohn's disease and 61% of UC patients on advanced therapy. CONCLUSION: The high percentage of SDC in this global, real-world cohort suggests a large disease burden and high unmet medical need in IBD patients. Future analysis should focus on monitoring and responding to SDC in this cohort and on patients' QoL.

Clinical characteristics of ulcerative colitis patients with different types of Helicobacter pylori infection.

There has been a suggestion of a potential protective effect of Helicobacter pylori (H. pylori) in the development of ulcerative colitis (UC). Virulence factor is an important factor in H. pylori, but little is known about the clinical characteristics of ulcerative colitis. In this retrospective study, a total of 322 patients with UC were analyzed. They were divided into three groups based on H. pylori antibody typing classification: type I H. pylori infection group, type II H. pylori infection group, and H. pylori-negative group. The study aimed to analyze the clinical characteristics of different types of H. pylori infection groups. The proportions of disease course, nationality, clinical type, and disease severity among UC patients in different types of H. pylori infection groups exhibited statistically significant differences (P < 0.05). However, no significant differences were observed in terms of sex, age, smoking status, alcohol consumption, body mass index (BMI), or lesion range (P > 0.05). Among the extraintestinal manifestations, the incidence of joint lesions in the type I H. pylori infection group was significantly lower compared with H. pylori-negative group (P < 0.05). The levels of red blood cell, hemoglobin, packed cell volume, albumin, A/G, and alanine aminotransferase were significantly higher in the type I H. pylori infection group compared with both the type II H. pylori infection group and H. pylori-negative group in the hematology index. Conversely, the levels of D-Dimer, C-reactive protein, and erythrocyte sedimentation rate were significantly lower in the type II H. pylori infection group (P < 0.05). In patients with UC, infections with the highly virulent type I H. pylori exhibit a negative correlation with both the severity of the disease and extraintestinal manifestations. While infections with the less virulent type II H. pylori are negatively correlated only with the disease severity. Therefore, the virulence factors of H. pylori play an important role in the regulation of UC. IMPORTANCE: The number of patients with ulcerative colitis (UC) has increased dramatically worldwide, posing a global public health challenge, There has been a suggestion of a potential protective effect of Helicobacter pylori in the development of UC. Virulence factor is an important factor in H. pylori, but high-quality clinical evidence is lacking. This study comprehensively analyzed the clinical characteristics of UC patients with different types of H. pylori infection. Infections with the highly virulent type I H. pylori are found to be negatively correlated with the severity of the disease as well as extraintestinal manifestations, whereas infections with the less virulent type II H. pylori demonstrate a negative correlation solely with disease severity. These results suggest that the virulence factors of H. pylori play a pivotal role in UC. Consequently, virulence factors should be taken into consideration when targeting H. pylori eradication in clinical practice, particularly in UC patients. It is crucial to evaluate the individual benefits to optimize personalized eradication therapies.

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.

Growth differentiation factor-15 serum concentrations reflect disease severity and anemia in patients with inflammatory bowel disease.

BACKGROUND: Population of patients with inflammatory bowel disease (IBD) is burdened by various extraintestinal manifestations which substantially contribute to greater morbidity and mortality. Growth-differentiation factor-15 (GDF-15) is often over-expressed under stress conditions, such as inflammation, malignancies, heart failure, myocardial ischemia, and many others. AIM: To explore the association between GDF-15 and IBD as serum concentrations of GDF-15 were shown to be an independent predictor of poor outcomes in multiple diseases. An additional aim was to determine possible associations between GDF-15 and multiple clinical, anthropometric and laboratory parameters in patients with IBD. METHODS: This cross-sectional study included 90 adult patients diagnosed with IBD, encompassing both Crohn's disease (CD) and ulcerative colitis (UC), and 67 healthy age- and sex-matched controls. All patients underwent an extensive workup, including colonoscopy with subsequent histopathological analysis. Disease activity was assessed by two independent gastroenterology consultants specialized in IBD, employing well-established clinical and endoscopic scoring systems. GDF-15 serum concentrations were determined following an overnight fasting, using electrochemiluminescence immunoassay. RESULTS: In patients with IBD, serum GDF-15 concentrations were significantly higher in comparison to the healthy controls [800 (512-1154) pg/mL vs 412 (407-424) pg/mL, P < 0.001], whereas no difference in GDF-15 was found between patients with CD and UC [807 (554-1451) pg/mL vs 790 (509-956) pg/mL, P = 0.324]. Moreover, multiple linear regression analysis showed that GDF-15 levels predict CD and UC severity independent of age, sex, and C-reactive protein levels (P = 0.016 and P = 0.049, respectively). Finally, an association between GDF-15 and indices of anemia was established. Specifically, negative correlations were found between GDF-15 and serum iron levels (r = -0.248, P = 0.021), as well as GDF-15 and hemoglobin (r = -0.351, P = 0.021). Accordingly, in comparison to IBD patients with normal hemoglobin levels, GDF-15 serum levels were higher in patients with anemia (1256 (502-2100) pg/mL vs 444 (412-795) pg/mL, P < 0.001). CONCLUSION: For the first time, we demonstrated that serum concentrations of GDF-15 are elevated in patients with IBD in comparison to healthy controls, and the results imply that GDF-15 might be involved in IBD pathophysiology. Yet, it remains elusive whether GDF-15 could serve as a prognostic indicator in these patients.

Fecal microbiota is associated with extraintestinal manifestations in inflammatory bowel disease.

INTRODUCTION: A large proportion of patients with inflammatory bowel disease (IBD) experience IBD-related inflammatory conditions outside of the gastrointestinal tract, termed extraintestinal manifestations (EIMs) which further decreases quality of life and, in extreme cases, can be life threatening. The pathogenesis of EIMs remains unknown, and although gut microbiota alterations are a well-known characteristic of patients with IBD, its relationship with EIMs remains sparsely investigated. This study aimed to compare the gut microbiota of patients with IBD with and without EIMs. METHODS: A total of 131 Danish patients with IBD were included in the study, of whom 86 had a history of EIMs (IBD-EIM) and 45 did not (IBD-C). Stool samples underwent 16S rRNA sequencing. Amplicon sequence variants (ASVs) were mapped to the Silva database. Diversity indices and distance matrices were compared between IBD-EIM and IBD-C. Differentially abundant ASVs were identified using a custom multiple model statistical analysis approach, and modules of co-associated bacteria were identified using sparse correlations for compositional data (SparCC) and related to patient EIM status. RESULTS: Patients with IBD and EIMs exhibited increased disease activity, body mass index, increased fecal calprotectin levels and circulating monocytes and neutrophils. Microbiologically, IBD-EIM exhibited lower fecal microbial diversity than IBD-C (Mann-Whitney's test, p = .01) and distinct fecal microbiota composition (permutational multivariate analysis of variance; weighted UniFrac, R2 = 0.018, p = .01). A total of 26 ASVs exhibited differential relative abundances between IBD-EIM and IBD-C, including decreased Agathobacter and Blautia and increased Eggerthella lenta in the IBD-EIM group. SparCC analysis identified 27 bacterial co-association modules, three of which were negatively related to EIM (logistic regression, p < .05) and included important health-associated bacteria, such as Agathobacter and Faecalibacterium. CONCLUSIONS: The fecal microbiota in IBD patients with EIMs is distinct from that in IBD patients without EIM and could be important for EIM pathogenesis.