Concomitant Inflammatory Bowel Disease Research Articles

Vancomycin may be an effective attempt in primary sclerosing cholangitis: antibiotic or immunomodulator

Primary Sclerosing Cholangitis(PSC) is a rare, chronic liver disease characterized by bile duct inflammation and concentric fibrogenesis. To date, there has been no evidence that any drug therapy can alter the natural course of this disease. PSC is often concomitant with inflammatory bowel disease(IBD), but the pathogenesis remains unclear. Oral antibiotics have been shown to improve PSC and concomitant IBD, and vancomycin is the most widely used. Therefore, this paper reviews literatures on the application of vancomycin in PSC, aiming to explore therapeutic approaches for PSC that target other pathophysiological pathways.

Anti-integrin αvβ6 autoantibodies are increased in PSC patients with concomitant IBD and correlate with liver disease severity

Anti-integrin αvβ6 autoantibodies (anti-αvβ6) are found in more than 50% of individuals with ulcerative colitis (UC). We aimed to determine the prevalence of anti-αvβ6 in patients with primary sclerosing cholangitis (PSC) and their association with liver disease severity. Four cohorts of pre-liver transplant PSC patients were recruited. Patients with inflammatory bowel disease (IBD) and healthy controls (HC) served as comparators. Total IgG and anti-αvβ6 levels were measured using enzyme-linked immunosorbent assay (ELISA). Olink® inflammation panel was run on a subset of samples. Multivariable linear regression analysis was performed to assess the association between anti-αvβ6 and indices of liver disease severity. A total of 137 PSC patients (including 76 with PSC-UC, 33 with PSC-Crohn's disease (CD) and 28 with PSC alone) and 160 controls (including 91 with IBD and 69 HC) were enrolled. Anti-αvβ6 levels were significantly higher in PSC-UC and PSC-CD compared to PSC alone (p<0.0001 and 0.003) and HC (p<0.0001 and p<0.0001). However, anti-αvβ6 levels in PSC alone were not increased compared to HC. In patients with PSC-IBD, anti-αvβ6 levels correlated with markers of liver disease severity including alkaline phosphatase level (r=0.32, p=0.004), the revised Mayo PSC risk score (r=0.25, p=0.02) and liver stiffness measurement (r=0.43, p=0.008) after adjusting for age, gender, race/ethnicity and IBD subtype. Additionally, anti-αvβ6 levels were associated with markers of systemic inflammation and tissue remodeling. Anti-αvβ6 autoantibodies identify a subset of PSC patients with concomitant IBD.

FAILURE OF THE FIRST BIOLOGIC TREATMENT IN PATIENTS WITH SPONDYLOARTHRITIS: DATA FROM THE MOROCCAN REGISTRY OF BIOLOGICAL THERAPIES IN RHEUMATIC DISEASES (RBSMR)

Introduction:Spondyloarthritis is a group of chronic inflammatory rheumatic diseases that commonly affect young adults. The advent of biological background treatments has revolutionized the management of these conditions, although some patients may not respond adequately to these interventions. Objectives: To assess the prevalence of first biological treatment failure in spondyloarthritis and identify the factors associated with this outcome. Methods: Our study included patients with spondyloarthritis retained according to the ASAS criteria, aged over 18 years, treated with biological treatment, and providing written informed consent. The participants were sourced from the ten rheumatology departments in Morocco, utilizing data from the RBSMR registry, a multicenter historical-prospective registry. Primary failure was characterized by treatment inefficacy within the initial six months, while secondary failure concerns cases of ineffectivenessbeyond six months of treatment. Patients were assessed every six months with a scheduled follow-up period of three years. Inclusion began in June 2017 and ended in January 2019, when the database was first frozen. Results: A total of 194 patients were included in the study. The mean age was 40.23 years with a standard deviation of 13.68. The gender ratio was 1.73 (M/F). The average disease duration was 615.9 weeks with a standard deviation of 349.12. HLA-B27 antigen was positive in 66% of patients. Peripheral involvement was observed in 70% of patients, axial involvement in 96.4%, and enthesic involvement in 61.5%. Radiographic sacroiliitis was identified in 87.6% of patients, radiographic coxitis in 40.7%, and sonographic coxitis in 19.8%. Regarding extra-articular manifestations, 14.5% of patients experienced anterior uveitis, 6.9% had cutaneous psoriasis, and 10.7% had concomitant chronic inflammatory bowel disease. The ASDAS CRP indicated high activity in 50.9% of patients, and the BASDAI (spondyloarthritis activity index) exceeded 4 in 79.2% of patients. During the initial visit, 22.5% of patients were undergoing corticosteroid therapy, and 53.8% were receiving csDMARDs. Etanercept was the most commonly prescribed biological, accounting for 33%. Over the three-year follow-up, five primary failures and 17 secondary failures to the first biological treatment were observed (eight failures at the 12th month, six at the 18th month, and three at the 24th month), resulting in a prevalence of 11,85% for the failure of the first biological. In bivariate analysis, no statistically significant factors were found to be associated with the failure of the first biological at the 6th, 12th, or 24th month visits. However, at the 18th-month visit, both the average BASDAI and C-reactive protein (CRP) levels were statistically higher in patients who experienced failure with the first biological. Conclusion: The failure of the first biologicaltreatment is a rather rare situation in our study. Specific factors were notably linked to this failure and should be considered in patient management, particularly elevated BASDAI and CRP values. These factors have also been reported in the literature to be associated with first biological treatment failure, along with additional factors.

Prevalence and clinical profiles of primary sclerosing cholangitis in China: Data from electronic medical records and systematic literature retrieval

Background & aimsEpidemiology of primary sclerosing cholangitis (PSC) is lacking in China. We aimed to estimate the period prevalence and depict the clinical features of PSC in China. MethodsWe identified and included PSC cases between 2000 and 2023 from two sources: electronic medical records (EMR) and systematical literature retrieval (SLR). The period prevalence of PSC was estimated by the multiplier method. Rate ratios (RRs) for PSC prevalence in relation to macroeconomic indicators were calculated by the negative binomial regression model. ResultsA total of 1358 PSC cases were retrieved from 299 hospitals (162 from EMR and 1196 from SLR). Males accounted for 55.7 % of the PSC cases and 25.7 % had concomitant inflammatory bowel disease (IBD). The estimated period prevalence of PSC from 2000 to 2023 was 2.36 (95 % CI: 1.82, 3.34) per 100,000. Males had a numerically higher PSC prevalence than females (2.56, 95 % CI: 1.97, 3.63 vs. 2.14, 95 % CI: 1.65, 3.04 per 100,000). The highest prevalence of PSC was in East China at 4.87 (95 % CI: 3.44, 7.18) per 100,000, followed by North China at 2.94 (95 % CI: 2.33, 3.74) per 100,000, and the lowest in South China at 0.92 (95 % CI: 0.66, 1.30) per 100,000. Regional per capita GDP (RR 1.65, 95 % CI: 1.03, 2.65) and healthcare expenditure (RR 1.94, 95 % CI: 1.13, 3.38) were identified to be associated with PSC prevalence. ConclusionOur study showed the estimated PSC prevalence varied within China, but was generally lower than that in Western countries.

Acute pancreatitis in children with inflammatory bowel disease: Risk factors, clinical course, and prognosis.

To characterize the clinical course of acute pancreatitis (AP) in pediatric inflammatory bowel disease (IBD) patients compared to children with AP without IBD and to identify risk factors associated with AP among IBD patients. This retrospective, single-center study compared clinical characteristics of children (<19 years) with AP with and without concomitant IBD who were hospitalized 2005-2019. We also conducted a risk factor analysis of AP development in pediatric IBD. Sixty-eight (54% males) patients with 120 episodes of AP were admitted at a median age of 15.3 years. Thirteen patients (14 episodes) had a co-diagnosis of IBD, representing 4% of our IBD patient population. The AP-IBD patients presented with lower amylase levels compared to the non-IBD patients (160 [interquartile range, IQR: 83-231] vs. 418 [IQR: 176-874] U/L, p > 0.01), all had a mild pancreatitis, and none required invasive intervention. The presumed etiology for AP in all IBD patients was IBD-related: IBD flare-up in five, side effects of medications in two, and undetermined in seven. The only risk factor for AP development among IBD patients was IBD-associated arthritis (23% vs. 3% for IBD-non-AP, p = 0.04), while extracolonic Crohn's disease and induction therapy with nutrition were negative risk factors (15% vs. 51%, p = 0.05, and 8% vs. 44%, p = 0.04, respectively). Other parameters, including disease type and medications, were nonsignificant. The clinical course of AP in pediatric IBD patients is mild. Only IBD-associated arthritis emerged as a risk factor for the development of AP, while, unexpectedly, IBD medication did not.

Inflammatory bowel disease-associated colorectal cancer negatively affects surgery outcomes and health care costs

BackgroundInflammatory bowel disease may affect the pathogenesis and clinicopathologic course of colorectal cancer. We sought to characterize the impact of inflammatory bowel disease on outcomes after colectomy and/or proctectomy for a malignant indication. MethodsPatients diagnosed with colorectal cancer as well as a pre-existing comorbid diagnosis of Crohn's disease or ulcerative colitis between 2018 and 2021 were identified from Medicare claims data. The postoperative textbook outcome was defined as the absence of complications, as well as no extended hospital stay, 90-day readmission, or mortality. Postdischarge disposition and expenditures were also examined. ResultsAmong 191,684 patients with colorectal cancer, 4,770 (2.5%) had a pre-existing diagnosis of inflammatory bowel disease. Patients with inflammatory bowel disease-associated colorectal cancer were less likely to undergo surgical resection (no inflammatory bowel disease: 47.6% vs inflammatory bowel disease: 42.1%; P < .001). Among patients who did undergo colorectal surgery, individuals with inflammatory bowel disease were less likely to achieve a textbook outcome (odds ratio 0.64 [95% confidence interval 0.58–0.70]). In particular, patients with inflammatory bowel disease had higher odds of postoperative complications (odds ratio 1.24 [1.12–1.38]), extended hospital stay (odds ratio 1.41 [1.27–1.58]), and readmission within 90 days (odds ratio 1.56 [1.42–1.72]) (all P < .05). Patients with inflammatory bowel disease-associated colorectal cancer were less likely to be discharged to their home under independent care (odds ratio 0.77 [0.68–0.87]) and had 12.2% higher expenditures, which correlated with whether the patient had a postoperative textbook outcome. ConclusionOne in 40 patients with colorectal cancer had concomitant inflammatory bowel disease. Inflammatory bowel disease was associated with a lower probability of achieving ideal postoperative outcomes, higher postdischarge expenditure, as well as worse long-term survival after colorectal cancer resection.

Use of dual biologic therapy targeting the Th2 and Th17 axes simultaneously to treat patients with atopic dermatitis and concomitant psoriasis, psoriatic arthritis, or inflammatory bowel disease

Use of dual biologic therapy targeting the Th2 and Th17 axes simultaneously to treat patients with atopic dermatitis and concomitant psoriasis, psoriatic arthritis, or inflammatory bowel disease

Risk of colorectal cancer in patients with primary sclerosing cholangitis and concomitant inflammatory bowel disease compared with primary sclerosing cholangitis only.

Primary sclerosing cholangitis (PSC) increases the risk of colorectal cancer (CRC) in inflammatory bowel disease (IBD) patients; however, there is a paucity of literature to suggest PSC alone as an independent risk factor for CRC. We aimed to determine if PSC is an independent risk factor for CRC in a large tertiary care medical center. Optimizing screening intervals is of great importance, given the burden and risks associated with a lifetime of colonoscopy screening. This retrospective cohort study consists of patients diagnosed with PSC preceding IBD (PSC-IBD) and PSC-only before January 6, 2023 from a large, tertiary, academic medical center. Patients diagnosed with IBD concurrently or before PSC were excluded to reduce IBD's impact on CRC risk. Demographic data and colonoscopy findings were collected and assessed. Overall, 140 patients from all NYU Langone Health clinical settings were included. Patients with PSC-IBD were more likely to be diagnosed with CRC (23.3% vs. 1.8%, p<0.01) and either low-grade or uncharacterized dysplasia (16.7% vs. 0.0%, p<0.01) compared with those with PSC-only. Among PSC-only patients, the estimated CRC risk was significantly elevated compared with that expected of the standard NYU Langone population (SIR 9.2, 95% CI 1.1, 33.2). Our study revealed a significantly heightened CRC risk in PSC-IBD patients compared with those with PSC-only. Importantly, individuals with PSC-only also face a greater CRC risk compared with the general population. Individuals with PSC-alone may require extended screening and surveillance colonoscopy intervals compared with those with PSC-IBD, yet still require more frequent monitoring than screening guidelines recommend for the general population.

A134 ENDOSCOPIC RESECTION IS EFFECTIVE FOR COMPLEX LARGE NON-PEDUNCULATED COLORECTAL POLYPS

Abstract Background Endoscopic resection is preferred for most large (≥20 mm) non-pedunculated colorectal polyps (LNPCPs) due to superior efficacy, safety, and cost-efficiency compared to surgery. However, endoscopic resection can be challenging due to anatomical location, lesion characteristics, and concomitant colonic disease; these complex LNPCPs (C-LNPCPs) historically have suboptimal outcomes compared to uncomplicated LNPCPs (UC-LNPCPs). Aims To compare the outcomes of C-LNPCPs to UC-LNPCPs following endoscopic resection. Methods Consecutive patients ampersand:003E 18 years of age who underwent endoscopic resection of a LNPCP were enrolled in a prospective single center observation cohort study (clinicaltrials.gov ID: NCT05402696). C-LNPCP were defined by at least one of the following criteria: involvement of the appendiceal orifice, ileocecal valve, or anorectal junction; previous resection attempt; ≥ 90% circumferential involvement; concomitant inflammatory bowel disease. All other lesions were classified as UC-LNPCPs. Performance was evaluated by technical success (all neoplastic tissue removed at index procedure), procedure-related adverse events (intra-procedural perforation, clinically significant post-endoscopic resection bleeding (CSPEB), delayed perforation, serositis), referral to surgery, and recurrence at first surveillance colonoscopy (SC1). Results From 06/2022-09/2023, 350 LNPCPs were referred for endoscopic resection and 335 were attempted (91 C-LNPCPs, 244 UC-LNPCPs). Median age was 68 years (IQR 62-74 years) and 144 (54.1%) were male. Median size was 30mm (IQR 20-40mm). Most lesions were adenomatous (63.7% C-LNPCPs, 64.8% UC-LNPCPs), with cancer identified in 3.3% and 4.9% of C-LNPCPs and UC-LNPCPs, respectively. EMR was the most common resection modality (62.6% C-LNPCPs vs. 64.8% UC-LNPCPs) with C-LNPCPs undergoing more ESD (17.6% vs. 7.0%) and less CSR (19.8% vs. 28.3%; p=0.011). Auxiliary modalities were more frequently used in C-LNPCPs (6.6% vs. 1.2% UC-LNPCPs; p=0.004). Technical success was 95.6% in C-LNPCPs compared to 99.2% in UC-LNPCPs (p=0.049). There was no significant difference between groups in the frequencies of adverse events. 17 LNPCPs (5.1%; 4 C-LNPCP, 13 UC-LNPCPs) underwent surgery (p=1.000). Of those LNPCPs assessed at SC1, there was 1 recurrence (1.0%) in the UC-LNPCP subgroup. Conclusions With site-specific technical modifications and mitigating strategies for procedural-related adverse events, endoscopic resection outcomes for C-LNPCPs are comparable to UC-LNPCPs. Funding Agencies None

CLINICAL OUTCOMES OF INFLAMMATORY BOWEL DISEASE AFTER ORTHOTOPIC HEART TRANSPLANT

Abstract BACKGROUND Limited data are available on outcomes of patients with pre-existing inflammatory bowel disease (IBD) who undergo orthotopic heart transplantation (OHT) or develop de novo IBD post-OHT. We aimed to assess the incidence and disease outcomes of pre-existing and de novo IBD in OHT patients while evaluating the effect of IBD on OHT outcomes. METHODS A retrospective review of records was performed from a tri-site tertiary care system between July 2000 and July 2022. A total of 83 OHT receipients were concomitantly diagnosed with colitis of infectious or inflammatory etiology. Only patients with a diagnosis of IBD were included. Sub-analyses of the outcomes and immunosuppressive regimens of OHT recepients were done relative to those with pre-existing or de novo IBD. RESULTS A total of 8 OHT patients with concomitant IBD were identified. The median patient age (IQR) was 54 (23) with OHT and IBD onset at 50 (21.2) and 32.5 (15.7), respectively. Six patients were diagnosed with ulcerative colitis (UC) and 2 were diagnosed with Crohn’s disease. Five of the patients were female. All patients developed IBD within 11.5 (8) years within OHT. Only 1 patient developed de novo IBD 15 years after the first OHT and 7 years prior to a second OHT. OHT immunosuppressive regimens included a combination of tacrolimus (TAC) and prednisone (n=2), TAC and mycophenolate mofetil (MMF) (n=2), TAC, MMF, and sirolimus (n=2), TAC and sirolimus (n=1), and MMF with sirolimus (n=1). Therapy for pre-existing IBD included maintenance of 5-aminosalicylic (5-ASA) (n=3), escalation to vedolizumab (VD) (n=2), and discontinuation of IBD therapy (5-ASA and azathioprine) (n=3). De novo IBD consistent with UC (15 years post-OHT) was managed with 5-ASA (n=1). Six patients (including de novo IBD case) maintained clinical and endoscopic remission of IBD with no flares post-OHT while 2 patients (1 UC and 1 CD) with active disease flares responded clinically and endoscopically to VD escalation from 5-ASA and azathioprine. Among two UC patients with ileal J-pouch pre-OHT, 1 developed refractory pouchitis requiring diverting ileostomy (while on TAC and prednisone) with no pouchitis in the other (maintained on TAC and MMF). Good graft tolerance limited to mild acute cellular rejection episodes was noted in 6 patients, while multiple or no rejection episodes were noted in the remaining two. None of the patients developed CMV or MMF-induced colitis. One patient died due to progressive functional decline unrelated to graft failure or IBD. DISCUSSION The clinical course and treatment of IBD preceding OHT or de novo (though rare) is not significantly worsened or altered post-OHT. The majority of patients achieve clinical and endoscopic remission while on heart transplant-related immunosuppression. Biologic therapy escalation to VD resulted in clinical remission with no effect on graft tolerance. Table 1 Clinical outcomes of OHT patients with concomitant IBD

DOP28 Yield of surveillance colonoscopy in patients with Primary Sclerosing Cholangitis

Abstract Background Patients with primary sclerosing cholangitis (PSC) have a higher risk of developing colorectal cancer (CRC), in particular in patients with concurrent diagnosis of inflammatory bowel disease (IBD). Therefore, strict surveillance colonoscopy in patients with PSC and PSC-IBD is recommended with consideration of random biopsies. The aim of this study was to assess the method and yield of surveillance colonoscopy in patients with PSC and PSC-IBD in routine practice in the Netherlands. Methods An observational cohort study was performed within the EpiPSC2 cohort in The Netherlands. Patients with a confirmed PSC diagnosis were included from January 2008 onwards. Data were collected retrospectively from the date of diagnosis until inclusion, and prospectively from that date forward. Patient demographics, PSC and IBD disease characteristics were collected at study inclusion and during annual follow-up. For this study, data collection was expanded retrospectively with colonoscopy and pathology reports. Outcomes were endoscopic surveillance technique, whether random or targeted biopsies were taken, if polypectomy was performed, dysplasia detection rate and type of dysplasia. Results The study population included 1,203 PSC patients, of whom 82.1% had large duct PSC, and 70.6% concomitant IBD (table 1). A total of 4,099 colonoscopies were performed in 759 individual patients, with a median of 4 colonoscopies per patient (IQR 2 – 8). The median follow-up duration was 11 years (IQR 12 – 17). In total, 11.5% (n=473) of colonoscopies were performed with chromo-endoscopy. Among the conducted colonoscopies, 2,543 included biopsies, 355 involved polypectomies, and 86 comprised both biopsies and polypectomies. Dysplasia was identified in 11.4% (341 out of 2,984) of the colonoscopies, including 14.1% indefinite for dysplasia (n=48), 75.1% low grade dysplasia (n=256), 7.6% high grade dysplasia (n=26), and 5.9% adenocarcinoma (n=20). The detection of dysplasia occurred through random biopsies in 89 colonoscopies (26.1%), targeted biopsies in 114 colonoscopies (33.4%) and polypectomy in 153 colonoscopies (44.9%) (figure 1). Dysplasia was observed in 195 (26%) individual patients, of whom 80.5% had PSC-IBD. Conclusion Our data highlights the importance of colonoscopic surveillance in PSC and PSC-IBD patients. Dysplasia was detected in over a quarter of patients undergoing surveillance colonoscopy. Notably, 26.1% of dysplasia cases were identified through random biopsies, emphasizing the importance of incorporating random biopsies into surveillance protocols for this specific patient population.

P715 Multiparametric assessment of IBD and SpA-IBD patients to explore disease biomarkers and response predictors

Abstract Background Immune-mediated inflammatory diseases (IMID) are an emerging problem in Western world. Despite being traditionally considered nosologically distinct entities, two or more IMID can coexist within the same patient and their pathogenesis overlap to a certain extent. Two IMID, inflammatory bowel disease (IBD) and spondylarthritis (SpA), often associate, but their pathogenesis remains unknown and disease biomarkers are not fully characterized. This project aims to investigate pathogenic and predictor markers of response Methods A collaborative study, enrolling IMID patients (pts) starting a target therapy, was performed. We focused on 2 cohorts: IBD and IBD-SpA. At baseline, serum (to measure CRP, IL17A, TNFα, and TREM1), intestinal biopsy and stools were collected. Clinical response was assessed at 4 months. The exploratory outcome of this preliminary analysis was to investigate whether serum, immunohistochemical and microbiological markers correlate with each other and with response to therapy Results We enrolled 60 pts (36 IBD, 24 IBD-SpA): 61.7% were female, median age was 46 years (IQR 30-57.3). At 4 months, 52.8% and 41.7% of the IBD and IBD-SpA cohorts showed clinical response. A nearly significant correlation between increased intestinal CD68+ cell infiltrate and higher baseline CRP levels (R=0.52, p=0.06), and between increased CD21+ cell infiltrate and CRP drop at 4 months (R=0.47, p=0.09) was observed. Lower baseline TNFα levels correlated with CRP drop at 4 months (R=0.35, p=0.02); higher baseline TNFα levels correlated with a reduced intestinal infiltrate of CD20+ and CD21+ cells (R=0.67, p=0.04; R=0.69, p=0.04). In the IBD-SpA cohort, a trend towards higher mean TREM1 levels was observed in non-responders vs responders (389.0 pg/mL vs 276.4 pg/mL, p=0.09); ROC curve identified a cut-off of 361.0 pg/mL to predict nonresponse (sensitivity 66.6%, specificity 75.0%, p=0.09). IBD patients had a reduced α-diversity compared to healthy controls (HC) and SpA patients; IBD and SpA patients had an increased β-diversity compared to HC. IBD pts had increased Proteobacteria and decreased Bacteroidetes compared to HC. Agathobacteria, Bacteroides, Faecalibacteria and Prevotella genera were significantly decreased in IBD vs HC, whereas Streptococci and Escherichia-Shigella were significantly increased Conclusion Baseline TNFα may correlate with specific immune signatures of the intestinal infiltrate. Baseline TREM1 may help predicting response in the specific setting of concomitant IBD and SpA. Gut microbiome composition is altered in IBD pts compared to HC, comprising more pathogenic and fewer protective bacteria. Further analyses will be needed to confirm such observations and explore additional features and predictive biomarkers

P427 Inflammatory bowel disease after liver transplantation: a retrospective cohort study from Latin America

Abstract Background The management of inflammatory bowel disease (IBD) in the setting of liver transplantation (LT) is a significant challenge. Previous data have described conflicting results on the incidence of relapses, risk of colectomy and post-transplant prognosis. In addition, there is no guidelines to recommend specific immunosuppressive regimens in this scenario. Our aim is to describe the IBD course in a cohort of liver transplanted patients in Latin America. Methods Medical records from two quaternary centers were reviewed using informatics tools to identify patients with Crohn’s Disease (CD) and Ulcerative Colitis (UC), associated with LT, from January 2010 and July 2023. Data on demographics, IBD phenotype, immunosuppressive therapy and infections were extracted. Results Among 1,683 patients that underwent LT, 45 had concomitant IBD diagnosis. Most for them (55%) were diagnosed with IBD prior to the LT. The median age at IBD diagnosis was 45 years and 57% were male. The majority had UC (80%). The causes of LT were primary sclerosing cholangitis in 24 (53.3%) patients, overlapping with autoimmune hepatitis (AIH) in 15 (33.3%), isolated AIH in 9 (20%), AIH with or without primary biliary cholangitis (PBC) in 4 (8.8%), viral hepatitis in 3 (6,6%) and other causes in 2 (4.4%) patients. Regarding immunosuppression, 19 (42.2%) patients were treated with tacrolimus, 10 (22.2%) with tacrolimus and mycophenolate mofetil, 8 (17.7%) with tacrolimus and azathioprine, 3 (6.6%) tacrolimus and everolimus, 3 (6.6%) with mycophenolate mofetil and cyclosporine, 2 (4.4%) patients with cyclosporine monotherapy. Before LT, 13 (28.8%) patients were treated with aminosalicylates and/or thiopurines, while 2 (4.4%) of them were on biologics. After LT, 20 (44.4%) patients required biological therapy, 11 (24.4%) were treated with anti-TNF (infliximab and adalimumab), 5 (11.1%) with vedolizumab, 3 (6.6%) with ustekinumab and 1 with tofacitinib. Seven (15.5%) patients required total colectomy for refractory disease, 75% after LT. Sixteen (35.5%) patients developed serious infections and the most frequent were cholangitis and cytomegalovirus (68.7%). Two patients developed adverse events, such as infliximab-induced autoimmune hepatitis and thrombocytopenic purpura related to the tacrolimus. Eight (17.7%) patients had malignancies, 3 of them related to the baseline conditions such as hepatocellular, gallbladder carcinoma, colorectal cancer, while 4 patients died during the follow-up. Conclusion In our experience, IBD patients undergoing LT exhibited an aggressive disease course and required concomitant biological therapy, despite the ongoing immunosuppressive regimens.

Elevated Liver Fibrosis Progression in Isolated PSC Patients and Increased Malignancy Risk in a PSC-IBD Cohort: A Retrospective Study.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease often associated with inflammatory bowel disease (IBD), particularly ulcerative colitis (CU), and rarely with Crohn's disease (CD). Various long-term analyses show different rates of cancer and the need for orthotopic liver transplantation (OLT) in patients with isolated PSC and with concomitant IBD, respectively. However, data on the detailed course of PSC with or without IBD are limited. We aimed to analyze the clinical disease course of PSC patients without IBD compared to PSC patients with UC and CD, respectively. A retrospective data analysis of patients with isolated PSC (n = 41) and of patients with concomitant IBD (n = 115) was performed. In detail, PSC disease characteristics including occurrence of dominant stenoses, liver cirrhosis, OLT and malignancy, as well as the temporal course of PSC activity and disease progression, were analyzed. A multivariable Cox regression model and a Fine-Gray competing risk model were further used for the independent risk factor analysis of cirrhosis development and OLT. Patients with isolated PSC were significantly older at first diagnosis than patients with PSC-IBD (39 vs. 28 years, p = 0.02). A detailed analysis of the course of PSC revealed a faster PSC progression after initial diagnosis in isolated PSC patients compared to PSC-IBD including significantly earlier diagnosis of dominant stenoses (29 vs. 74 months, p = 0.021) and faster progression to liver cirrhosis (38 vs. 103 months, p = 0.027). Patients with isolated PSC have a higher risk of developing cirrhosis than patients with PSC-IBD (Gray's test p = 0.03). OLT was more frequently performed in male patients with isolated PSC compared to males with coincident IBD (48% (n = 13) vs. 33% (n = 25), p = 0.003). Colorectal carcinoma was significantly more often diagnosed in patients with PSC-IBD than in isolated PSC (8.7% vs. 0%, p = 0.042). Patients with isolated PSC seem to have a different clinical course of disease than PSC patients with concomitant IBD characterized by a more pro-fibrotic disease course with earlier onset of liver cirrhosis and dominant stenosis but with less malignancy. These data may be interpreted as either a more progressive disease course of isolated PSC or a later diagnosis of the disease at an advanced disease stage. The different clinical courses of PSC and the underlying mechanisms of the gut-liver axis need further attention.

Primary Sclerosing Cholangitis-Associated Cholangiocarcinoma: From Pathogenesis to Diagnostic and Surveillance Strategies.

Cholangiocarcinoma (CCA) is the most common malignancy in patients with primary sclerosing cholangitis (PSC), accounting for 2-8% of cases and being the leading cause of death in these patients. The majority of PSC-associated CCAs (PSC-CCA) develop within the first few years after PSC diagnosis. Older age and male sex, as well as concomitant inflammatory bowel disease (IBD) or high-grade biliary stenosis, are some of the most relevant risk factors. A complex combination of molecular mechanisms involving inflammatory pathways, direct cytopathic damage, and epigenetic and genetic alterations are involved in cholangiocytes carcinogenesis. The insidious clinical presentation makes early detection difficult, and the integration of biochemical, radiological, and histological features does not always lead to a definitive diagnosis of PSC-CCA. Surveillance is mandatory, but current guideline strategies failed to improve early detection and consequently a higher patient survival rate. MicroRNAs (miRNAs), gene methylation, proteomic and metabolomic profile, and extracellular vesicle components are some of the novel biomarkers recently applied in PSC-CCA detection with promising results. The integration of these new molecular approaches in PSC diagnosis and monitoring could contribute to new diagnostic and surveillance strategies.

Current Evidence for Combined Targeted Therapy for the Treatment of Inflammatory Bowel Disease.

Biologicals and small molecules have revolutionized the medical management of inflammatory bowel diseases (IBD), yet they are only effective in a proportion of patients, and their impact on changing the natural history of the disease is still debatable. Recently, the concept of combining targeted biologics and small-molecule therapies has been introduced to the treatment of IBD. Dual-targeted therapy (sequential and combined), which is the combination of two targeted therapies, might be a reasonable choice for patients to break through the therapeutic ceiling. A recent randomized clinical trial (VEGA) provided the first controlled evidence that the short-term combination of two biological agents may lead to superior disease control than either of the agents alone in patients with ulcerative colitis (UC) without jeopardizing safety. Multiple studies are underway in both Crohn's disease and UC. Additionally, real-world evidence is accumulating in IBD patients receiving combination therapies with concomitant IBD and extraintestinal manifestations or in patients with medically refractory IBD. Of note, the majority of these patients were exposed to multiple biological agents earlier and lost response to at least one of the agents in the combination. This review summarizes current knowledge regarding this attractive novel therapeutic option in IBD. Clearly, more controlled data are needed to evaluate optimal timing, efficacy, and mitigation of safety concerns.

Hepatic safety and efficacy of immunomodulatory drugs used in patients with autoimmune hepatitis

Background and aimsThere is little data on the hepatic efficacy and safety of immunomodulatory drugs used in patients with autoimmune hepatitis (AIH), despite their established use in dermatology, rheumatology and inflammatory bowel diseases (IBD). Our aim was to collect real-life data on the experience of expert centres in treating AIH patients with these drugs, considered unconventional for AIH management. MethodsOnline survey among hepatology centres being part of the European Reference Network on Hepatological Diseases (ERN RARE-LIVER). Results25 AIH patients have been reported. Ten were female, median age at diagnosis was 28 years; median follow-up was 17 months. All had initially received AIH-standard treatment.AIH-unconventional treatment was initiated for concomitant autoimmune diseases in 15 cases: nine for IBD (five vedolizumab and four ustekinumab), and one each for following diseases: autoinflammatory syndrome (tocilizumab), chronic urticaria (omalizumab), rheumatoid arthritis (abatacept), psoriasis (guselkumab), psoriatric arthritis (secukinumab, followed by ustekinumab) and alopecia (ruxolitinib). Three patients were treated with immunomodulatory drugs for side effects of previous treatments, including two patients with IBD treated with vedolizumab and ustekinumab, respectively, and one treated with belimumab. At the end of follow-up, 13 patients were in complete biochemical response, the patient on omalizumab had a relapse, and four patients with concomitant IBD had insufficient response.Seven patients were treated for lack of biochemical remission, of whom six with belimumab, all initially reaching complete biochemical response, but five relapsing during follow-up; and one with secukinumab, having concomitant rheumatoid arthritis and ankylosing spondylitis, reaching complete biochemical response.Only the patient on abatacept received unconventional treatment as monotherapy. Side effects were reported in two patients on belimumab: one recurrent soft tissue infections, one fatigue and arthralgia. ConclusionAmong 25 AIH patients who were treated with immunomodulatory drugs for different reasons, the majority had a fovorable course, relapse was frequent in difficult-to-treat patients who received belimumab, and four with concomitant IBD had insufficient response.

A Gradient of Intestinal Inflammation in Primary Sclerosing Cholangitis.

Primary sclerosing cholangitis (PSC) is a progressive liver disease associated with inflammatory bowel disease (IBD). The percentage of PSC patients diagnosed with concomitant IBD varies considerably between studies. This raises the question whether all PSC patients would show intestinal inflammation if screened thoroughly, even in the absence of symptoms. To address this question, we collected intestinal biopsies of healthy controls (n = 34), PSC (n = 25), PSC-IBD (n = 41), and IBD (n = 51) patients in a cross-sectional study and carried out cytokine expression profiling, 16S sequencing, in-depth histology, and endoscopy scoring. We found that the vast majority of PSC patients even without clinically manifest IBD showed infiltration of immune cells and increased expression of IL17A and IFNG in intestinal biopsies. However, expression of IL10 and FOXP3 were likewise increased, which may explain why these PSC patients have intestinal inflammation only on a molecular level. This subclinical inflammation in PSC patients was focused in the distal colon, whereas PSC-IBD patients showed inflammation either at the distal colon or on the right side of the colon and the terminal ileum. Furthermore, we observed that PSC patients without IBD showed signs of dysbiosis and exhibited a distinct microbial profile compared with healthy controls. We found a gradient of intestinal inflammation in the vast majority of PSC patients even in the absence of IBD. Thus, further studies evaluating the effect of anti-inflammatory therapies in PSC patients and their impact on the emergence of clinically manifest IBD and colorectal cancer development are needed.

Colitis ameliorates cholestatic liver disease via suppression of bile acid synthesis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by chronic inflammation and progressive fibrosis of the biliary tree. The majority of PSC patients suffer from concomitant inflammatory bowel disease (IBD), which has been suggested to promote disease development and progression. However, the molecular mechanisms by which intestinal inflammation may aggravate cholestatic liver disease remain incompletely understood. Here, we employ an IBD-PSC mouse model to investigate the impact of colitis on bile acid metabolism and cholestatic liver injury. Unexpectedly, intestinal inflammation and barrier impairment improve acute cholestatic liver injury and result in reduced liver fibrosis in a chronic colitis model. This phenotype is independent of colitis-induced alterations of microbial bile acid metabolism but mediated via hepatocellular NF-κB activation by lipopolysaccharide (LPS), which suppresses bile acid metabolism in-vitro and in-vivo. This study identifies a colitis-triggered protective circuit suppressing cholestatic liver disease and encourages multi-organ treatment strategies for PSC.

Biliary microbial patterns in primary sclerosing cholangitis are linked to poorer transplant-free survival.

Factors that determine individual disease course of patients with primary sclerosing cholangitis (PSC) are poorly understood. Although an association between gut microbes and disease outcome has been suggested, little is known about the role of microbes in the biliary tract. We analyzed microbial cultures from bile specimens obtained during routine endoscopic retrograde cholangiopancreatography (ERCP) and intraoperatively before liver transplantation in 114 patients with PSC in our tertiary academic center. The presence of bacterial and fungal species was correlated with clinical characteristics and outcome data. A total of 87 patients (76%) had positive bile culture results. The presence of concomitant inflammatory bowel disease (IBD) was associated with positive bile culture results in multivariate analysis (OR, 4.707; 95% CI, 1.688-13.128; p=0.003). Enterococcus spp. in the bile was associated with a more frequent occurrence of liver transplantation and/or death (OR, 2.778; 95% CI, 1.147-6.728; p=0.021) and recurrent (≥3) cholangitis episodes (OR, 2.839; 95% CI, 1.037-7.768; p=0.037). Biliary candidiasis was linked to a higher frequency of recurrent (≥3) cholangitis episodes (OR, 5.677; 95% CI, 1.940-16.616; p=0.001). Proton pump inhibitor intake conferred a clinical feature associated with biliary candidiasis in multivariate analysis (OR, 3.559; 95% CI, 1.275-9.937; p=0.016). Our data indicate that in patients with PSC, presence of Enterococcus spp. and Candida spp. in bile is associated with an adverse outcome. Concomitant IBD is linked to presence of microbes in bile, and proton pump inhibitor intake is a feature associated with biliary candidiasis in patients with PSC.