Search

Background and Aims Several characteristic features of the fecal microbiota have been described in primary sclerosing cholangitis (PSC), whereas data on mucosal microbiota are less consistent. We aimed to use a large colonoscopy cohort to investigate key knowledge gaps, including the role of gut microbiota in PSC with inflammatory bowel disease (IBD), the effect of liver transplantation (LT), and whether recurrent PSC (rPSC) may be used to define consistent microbiota features in PSC irrespective of LT. Approach and Results We included 84 PSC and 51 liver transplanted PSC patients (PSC-LT) and 40 healthy controls (HCs) and performed sequencing of the 16S ribosomal RNA gene (V3–V4) from ileocolonic biopsies. Intraindividual microbial diversity was reduced in both PSC and PSC-LT versus HCs. An expansion of Proteobacteria was more pronounced in PSC-LT (up to 19% relative abundance) than in PSC (up to 11%) and HCs (up to 8%; QFDR

Immune responses following SARS-CoV-2 vaccination in patients with inflammatory bowel disease (IBD) are not well characterized. The aims of this study were to explore the serological response associated with IBD, and immunosuppressive medications including serum concentrations of biologics and thiopurine metabolites. This prospective, observational study included adult patients with ulcerative colitis (UC) and Crohn’s disease (CD), and healthy controls. Antibodies to the receptor-binding domain of SARS-CoV-2 spike proteins, and serum concentrations of ongoing biologic and immunomodulatory medications were assessed prior to, and 2-5 weeks after the second vaccine dose. Serologic response was defined as anti-Spike antibodies ≥70 AU/ml. In 958 IBD patients (380 UC, 578 CD) and 323 healthy controls, the median (Q1; Q3) anti-Spike antibody level (AU/ml) was lower in patients (618 (192; 4370)) compared to controls (3355 (896; 7849)) (p < 0.001). The antibody levels were lower in CD (439 (174; 3304)) compared to UC (1088 (251; 5975)) (p < 0.001). No associations were demonstrated between antibody levels and serum drug concentrations for TNF inhibitor (TNFi), vedolizumab and ustekinumab. Patients receiving TNFi + thiopurines with a subtherapeutic 6-thioguanine nucleotide (6-TGN) level had higher response rate (93%) compared to patients with 6-TGN within the therapeutic range (53%) (p = 0.003). A diagnosis of UC, mRNA-1273 vaccine, and other treatments than TNFi + thiopurines were associated with humoral response. Patients with CD had an attenuated humoral response to SARS-COV-2 vaccination as compared to patients with UC. The lack of association between serum levels of biologics and serologic response indicates vaccination regardless of proximity to drug administration.

Data on response and safety of repeated vaccinations and hybrid immunity in patients with immune-mediated inflammatory diseases on immunosuppressive therapy is needed to further develop vaccination strategies in this vulnerable population. This study aimed to evaluate hybrid immunity and humoral immune response and safety of four SARS-CoV-2 vaccine doses in patients with immune-mediated inflammatory diseases on immunosuppressive therapy.This prospective observational Norwegian study of vaccine response to COVID-19 (Nor-vaC) included adult patients aged 18 years and older with immune-mediated inflammatory diseases (rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, Crohn's disease, or ulcerative colitis) on immunosuppressive therapy, who had received four SARS-CoV-2 vaccine doses (vaccine group) or three vaccine doses followed by COVID-19 (hybrid group), and healthy controls receiving three vaccine doses (control group). Patients were recruited from the Division of Rheumatology at Diakonhjemmet Hospital, Oslo, and the Department of Gastroenterology at Akershus University Hospital, Lørenskog. Patients who had COVID-19 before the third vaccine dose, and patients with allergies or intolerances to elements of the vaccine were excluded. Antibodies to the receptor-binding domain of SARS-CoV-2 spike protein (anti-RBD antibodies) were assessed 2-4 weeks following vaccination or COVID-19. This study is registered at Clinialtrials.gov, NCT04798625.Between Nov 12, 2021, and April 19, 2022, 1458 participants with immune-mediated inflammatory diseases provided post-vaccination samples at 2-4 weeks following a third vaccine dose. After 544 participants were excluded, 715 (78%) of the remaining 914 participants received the fourth dose of the vaccine, and of these, 536 (75%) provided post-vaccination samples 2-4 weeks after their fourth vaccination (vaccine group). 199 (22%) of the 914 had COVID-19 after their third dose of the vaccine and of these, 167 (84%) provided samples (hybrid group). 256 of the eligible 703 patients had rheumatoid arthritis, 107 had spondyloarthritis, 115 had psoriatic arthritis, 130 had Crohn's disease, and 95 had ulcerative colitis). Median age was 56 years [IQR 45-65], 398 (57%) were women, and 305 (43%) were men. Patients in the vaccine group had higher anti-RBD antibody concentrations following the fourth vaccine dose (median 6192 BAU/ml [IQR 2878-11 243]) than after the third dose (median 5087 BAU/ml [1250-9081]; p0·0001), but lower antibody concentrations than the control group following the third dose (median 7595 BAU/ml [5916-12 001]; p0·0001). Antibody concentrations were higher in the patients in the hybrid group (23 548 BAU/ml [IQR 11 440-35 935]) than in the vaccine group (p0·0001). No difference was found in antibody concentrations between the fourth dose of BNT162b2 (full-dose) and mRNA-1273 (half-dose). Patients and controls had a comparable safety profile after both three and four vaccine doses.Vaccine boosters improve humoral immune responses and are safe in patients with immune-mediated inflammatory diseases on immunosuppressive therapy, and administration should be considered regularly in this patient group. Hybrid immunity with omicron induces a strong humoral response suggesting longer intervals between booster doses in this patient group.The South-Eastern Norway Regional Health Authority, The Coalition for Epidemic Preparedness Innovations, Akershus University Hospital.

Background & Aims: Identifying patients at high risk of immunogenicity is important when selecting tumor necrosis factor (TNF)-α antagonists in patients with immune-mediated inflammatory diseases (IMIDs). We evaluated the association HLA-DQA1∗05 genotype and risk of immunogenicity with TNF-α antagonists. Methods: Through a systematic review through July 14, 2022, we identified studies in patients with IMIDs treated with TNF-α antagonists, which reported the risk of immunogenicity and/or secondary loss of response in patients with HLA-DQA1∗05 variants. Primary outcome was risk of immunogenicity. We performed random effects meta-analysis and used GRADE to appraise certainty of evidence. Results: On meta-analysis of 13 studies (3756 patients; median follow-up, 12 months; 41% with variants), HLA-DQA1∗05 variants were associated with 75% higher risk of immunogenicity compared with non-carriers (relative risk, 1.75; 95% confidence interval, 1.37-2.25) with considerable heterogeneity (I2 = 62%) (low certainty evidence). Positive and negative predictive values of HLA-DQA1∗05 variants for predicting immunogenicity were 30% and 80%, respectively. Proactive therapeutic drug monitoring, but not concomitant use of IMMs, IMIDs, and TNF-α antagonist-type, modified this association. Patients with HLA-DQA1∗05 variants experienced 2.2-fold higher risk of secondary loss of response (6 cohorts; relative risk, 2.24; 95% confidence interval, 1.67-3.00; I2 = 0%) (moderate certainty evidence). Conclusion: Variants in HLA-DQA1∗05 are associated with an increased risk in immunogenicity and secondary loss of response in patients with IMIDs treated with TNF-α antagonists. However, the positive and negative predictive value is moderate, and decisions on concomitant use of IMMs to prevent immunogenicity should be individualized based on all factors that influence drug clearance.

Immune responses in people with multiple sclerosis (pwMS) on disease-modifying therapies (DMTs) have been of significant interest throughout the COVID-19 pandemic. Lymphocyte-targeting immunotherapies including anti-CD20 treatments and sphingosine-1-phosphate receptor (S1PR) modulators attenuate antibody responses after vaccination. Evaluation of cellular responses after vaccination is therefore of particular importance in these populations. In this study, we analysed CD4 and CD8 T cell functional responses to SARS-CoV-2 spike peptides in healthy controls and pwMS on five different DMTs by flow cytometry. Although pwMS on anti-CD20 and S1PR therapies had low antibody responses after both 2 and 3 vaccine doses, T cell responses in pwMS on anti-CD20 therapies were preserved after a third vaccination, even when additional anti-CD20 treatment was administered between vaccine doses 2 and 3. PwMS taking S1PR modulators had low detectable T cell responses in peripheral blood. CD4 and CD8 T cell responses to SARS-CoV-2 variants of concern Delta and Omicron were lower than to the ancestral Wuhan-Hu-1 variant. Our results indicate the importance of assessing both cellular and humoral responses after vaccination and suggest that even in the absence of robust antibody responses vaccination can generate immune responses in pwMS.

Proactive therapeutic drug monitoring (TDM) has been proposed to improve outcomes in patients with inflammatory bowel disease (IBD) treated with tumor necrosis factor (TNF)α antagonists. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing proactive TDM with conventional management in patients with IBD.We identified RCTs in patients with IBD treated with TNFα antagonists comparing proactive TDM (routine assessments of trough concentration with dose adjustments to maintain predetermined trough concentration, regardless of disease activity) with conventional management (clinically driven dose adjustments). The primary outcome was failure to maintain clinical remission. Certainty of evidence was appraised using Grading of Recommendations, Assessment, Development and Evaluations.On meta-analysis of 9 RCTs (8 RCTs in adults, and focusing on maintenance phase), there was no significant difference in the risk of failing to maintain clinical remission in patients who underwent proactive TDM (267/709; 38%) vs conventional management (292/696; 42%) (relative risk [RR], 0.96; 95% confidence interval [CI], 0.81-1.13) with moderate heterogeneity (inconsistency index = 36%) (Grading of Recommendations, Assessment, Development and Evaluations; low certainty evidence), with no differences in patients with Crohn's disease (RR, 0.87 ; 95% CI, 0.66-1.15) and ulcerative colitis (RR, 0.88; 95% CI, 0.72-1.07). Disease duration, concomitant immunomodulators, disease activity at baseline, and optimization of therapy before randomization did not modify this association. No differences were observed in risk of developing antidrug antibodies or serious adverse events. Patients in the proactive TDM arm were more likely to undergo dose escalation (RR, 1.56; 95% CI, 1.25-1.94).Routine proactive TDM to target biologic concentration to specific thresholds, regardless of disease activity, did not offer clinical benefit in patients with IBD treated with TNFα antagonists in RCTs conducted to date. We cannot exclude the possibility of benefit in disease subtypes and phases of therapy (induction) not represented in these RCT populations.

Background Anti-drug antibodies (ADAb) frequently form early in the treatment course of infliximab and other tumour necrosis factor (TNF) inhibitors, leading to treatment failure and adverse events. Objective To identify risk factors for ADAb in the early phase of infliximab treatment. Methods Patients (n = 410) with immune-mediated inflammatory diseases who initiated infliximab treatment were included in the 38-week Norwegian Drug Monitoring Trial (NOR-DRUM) A and randomised 1:1 to therapeutic drug monitoring (TDM) or standard therapy. Serum levels of infliximab and ADAb were measured at each infusion. Possible risk factors for ADAb formation were assessed using logistic regression, adjusting for potential confounders. Results ADAb were detected in 78 (19%) patients. A diagnosis of rheumatoid arthritis (RA) (odds ratio [OR], 1.9 [95% confidence interval [CI] 1.0–3.6]) and lifetime smoking (OR, 2.0 [CI 1.1–3.6]) were baseline risk factors, while baseline use of concomitant immunosuppressors (OR, 0.4 [CI 0.2–0.8]) and a diagnosis of spondyloarthritis (SpA) (OR, 0.4 [CI 0.2–0.8]) reduced the risk of ADAb. Higher disease activity during follow-up (OR, 1.1 [CI 1.0–1.1]) and “drug holidays” of more than 11 weeks (OR, 4.1 [CI 1.2–13.8]) increased the risk of ADAb, whereas higher infliximab doses (OR, 0.1 [CI 0.0–0.3) and higher serum infliximab concentrations (OR, 0.7 [CI 0.6–0.8]) reduced the risk of immunogenicity. Conclusion Several risk factors for ADAb formation during early-phase infliximab treatment were identified. This knowledge provides a basis for treatment strategies to mitigate the formation of ADAb and identify patients in whom these measures are of particular importance.

IMPORTANCE: Proactive therapeutic drug monitoring (TDM), consisting of individualized treatment based on scheduled assessments of serum drug levels, has been proposed as an alternative to standard therapy to optimize efficacy and safety of infliximab and other biologic drugs. However, it remains unclear whether proactive TDM improves clinical outcomes during maintenance therapy. OBJECTIVE: To assess whether proactive TDM during maintenance therapy with infliximab improves treatment efficacy by preventing disease worsening compared with standard infliximab therapy without TDM. DESIGN, SETTING, AND PARTICIPANTS: Randomized, parallel-group, open-label clinical trial including 458 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis undergoing maintenance therapy with infliximab in 20 Norwegian hospitals. Patients were recruited from June 7, 2017, to December 12, 2019. Final follow-up took place on December 14, 2020. INTERVENTIONS: Patients were randomized 1:1 to proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 228) or to standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 230). MAIN OUTCOME AND MEASURES: The primary outcome was sustained disease control without disease worsening, defined by disease-specific composite scores or consensus about disease worsening between patient and physician leading to a major change in treatment (switching to another biologic drug, adding an immunosuppressive drug including glucocorticoids, or increasing the infliximab dose), during the 52-week study period. RESULTS: Among 458 randomized patients (mean age, 44.8 [SD, 14.3] years; 216 women [49.8%]), 454 received their randomly allocated intervention and were included in the full analysis set. The primary outcome of sustained disease control without disease worsening was observed in 167 patients (73.6%) in the TDM group and 127 patients (55.9%) in the standard therapy group. The estimated adjusted difference was 17.6% (95% CI, 9.0%-26.2%; P

Autoimmune hepatitis is a chronic liver disease which, if untreated, can lead to cirrhosis of the liver and liver failure. The majority of patients respond well to standard immunosuppressive therapy, but some experience adverse effects, or lack of treatment efficacy. Diagnosis, assessment of therapeutic response and choice of second-line therapy may be challenging. This article provides a summary of updated knowledge concerning diagnosis and treatment of patients with complex autoimmune hepatitis.

Autoimmune hepatitis is a chronic liver disease which, if untreated, can lead to cirrhosis of the liver and liver failure. The majority of patients respond well to standard immunosuppressive therapy, but some experience adverse effects, or lack of treatment efficacy. Diagnosis, assessment of therapeutic response and choice of second-line therapy may be challenging. This article provides a summary of updated knowledge concerning diagnosis and treatment of patients with complex autoimmune hepatitis.

Background: TNF-alpha inhibitors have improved treatment of chronic immune-mediated inflammatory disorders. The NOR-SWITCH main and extension trial addressed switching from infliximab originator (IFX) to CT-P13 across six diseases. Here we present the exploratory post-hoc analyses in Crohn's disease (CD) and ulcerative colitis (UC). Methods: The 52-week, randomized, non-inferiority, double blind, multicenter, phase 4 NOR-SWITCH study was followed by a 26-week open extension trial where all patients received treatment with CT-P13. Treatment efficacy, safety and immunogenicity were assessed throughout the 78-week study period. The primary endpoint was disease worsening. Findings: The main and extension trials included 155 and 93 patients with CD and 93 and 80 patients with UC, respectively. The baseline characteristics were comparable between treatment arms in both diseases. Disease worsening in the main trial occurred in 14 (21%) of CD patients in the IFX group and 23 (37%) in the CT-P13 group (risk difference -14⋅3%, CI -29⋅3 to 0⋅7). In the extension study, disease worsening occurred in 13 (21%) patients in the CT-P13 maintenance group and 8 (13%) in the IFX/CT-P13 switch group (risk difference 7⋅9%, CI -5⋅2 to 21). The corresponding results in UC were 3 (9%) and 5 (12%) patients (risk difference -2⋅6%, CI -15⋅2 to 10⋅0) in the main trial, and 6 (15%) and 1 (3%) patients (risk difference 12⋅4%, CI -0⋅1 to 25⋅0) in the extension trial. In both diseases, the treatment groups were similar across disease activity measures, drug levels and immunogenicity. Interpretation: The subgroup analyses of IBD in the NOR-SWITCH main and extension trials support switching from originator infliximab to CT-P13 for non-medical reasons. Trial Registration: ClinicalTrials.gov NCT-02148640, EudraCT Number: 2014-002056-40. Funding Statement: This work was supported by the Norwegian Ministry of Health and Care Services. Declaration of Interests: KKJ reports personal fees from Intercept, Norgine and Celltrion. GLG reports personal fees from AbbVie, Biogen, Eli Lilly, MSD, Novartis, Pfizer, Roche, Sandoz, Orion Pharma, Celltrion and Boehringer Ingelheim. NB reports personal fees received from Orion Pharma, Roche, Napp Pharmaceuticals, Pfizer, and Takeda. ICO reports grants from Norwegian Ministry of Health and Care Services during the conduct of the study, and personal fees from Pfizer. EAH reports grants from AbbVie, Pfizer, UCB, Roche, and MSD. IPB reports personal fees from AbbVie, MSD, Takeda, Hospira, and Ferring. KEAL reports grants from MSD, personal fees from Takeda, Orion, Abbvie, Pfizer, and MSD. JJ reports personal fees from MSD, AbbVie, Celltrion, Orion Pharma, Takeda, Napp Pharm, AstroPharma, Hikma and Pfizer. TKK reports reports grants from Norwegian Ministry of Health and Care Services during the conduct of the study and personal fees from AbbVie, Biogen, BMS, Boehringer Ingelheim, Celltrion, Eli Lilly, Epirus, Janssen, Merck-Serono, MSD, Mundipharma, Novartis, Oktal, Orion Pharma, Hospira/Pfizer, Roche, Sandoz, and UCB Pharma. SOF reports personal fees from Takeda, Pharmacosmos, Tillotts, Janssen, Intercept and Pfizer. Ethics Approval Statement: The study was conducted in compliance with the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. The study protocol and consent documents were approved by an independent ethics committee (Regional Committees for Medical and Health Research Ethics South East; reference number 2014/848), by appropriate institutional review boards and by the Norwegian Medicines Agency (reference number 14/07192-11).

Background: The first monoclonal antibody biosimilar to be used in clinical practice is the tumour necrosis factor-alpha inhibitor Remsima® (CT-P13). The drug is approved for all indications as the originator infliximab (Remicade®) although clinical efficacy has been demonstrated only in rheumatic diseases. Since the fall of 2013, Remsima® has been available in Norway and from January 2014, it has been the drug of choice when initiating biological treatment in biologics naïve patients with inflammatory bowel disease (IBD). However, many gastroenterologists have been greatly concerned about the extrapolation of indication. Switching between Remsima® and the innovator product is another issue that has been discussed. Key Messages: Good efficacy, tolerability and safety were demonstrated in a prospective observational study of IBD patients with moderate to severe disease activity. After 14 weeks of treatment there was a significant reduction in the Harvey Bradshaw index in patients with Crohns disease (CD) and reduction in the partial Mayo score and simple clinical colitis activity index in patients with ulcerative colitis. In both patient groups, there was also a significant reduction in fecal calprotectin and C-reactive protein (CRP). In another observational study, IBD patients on maintenance treatment with Remicade® were switched to Remsima®. By comparing values before and after switch, no changes in activity indices, CRP or calprotectin were observed. However, a significant increase in infliximab trough levels was shown in the CD group. No unexpected adverse events occurred after switching. Conclusions: Based on our experience in Norway, Remsima® seems to be efficacious and well tolerated in IBD. The increasing use of Remsima® in clinical practice has also contributed to significant cost savings on the health budget. Results from the NOR-SWITCH study will be available during 2016 and will hopefully contribute to answer some of the important questions that have been raised following the introduction of biosimilars as a treatment option for IBD and other immune-mediated inflammatory diseases.

Background and Aims: There is an unexplained association between ulcerative colitis (UC) and primary sclerosing cholangitis (PSC) with the intestinal microbiota implicated as an important factor. The study aim was to compare the structure of the intestinal microbiota of patients with UC with and without PSC. Methods: UC patients with PSC (PSC-UC) and without PSC (UC) were identified from biobanks at Oslo University Hospital, Foothills Hospital Calgary and Mount Sinai Hospital Toronto. Microbial DNA was extracted from colonic tissue and sequencing performed of the V4 region of the 16S rRNA gene on Illumina MiSeq. Sequences were assigned to operational taxonomic units (OTUs) using QIIME. Microbial alpha-diversity, beta-diversity and relative abundance were compared between PSC-UC and UC phenotypes. Results: 31 PSC-UC patients and 56 UC patients were included. Principal coordinate analysis (PCoA) demonstrated that city of sample collection was the strongest determinant of taxonomic profile. In the Oslo cohort Chao 1 index was modestly decreased in PSC-UC compared with UC (p=0.04) however did not differ significantly in the Calgary cohort. No clustering by PSC phenotype was observed using beta-diversity measures. For multiple microbial genera there were nominally significant differences between UC and PSC-UC, however results were not robust to false discovery rate correction. Conclusions: No strong PSC specific microbial associations in UC patients consistent across different cohorts were identified. Recruitment center had a strong effect on microbial composition. Future studies should include larger cohorts to increase power and the ability to control for confounding factors.

The risk for recurrent primary sclerosing cholangitis (rPSC) after liver transplantation is associated with inflammatory bowel disease (IBD). We assessed the frequency of rPSC and studied risk factors for recurrent disease with special focus on IBD. We also evaluated the importance of rPSC for prognosis.All liver transplanted PSC patients in the Nordic countries between 1984 and 2007 (n = 440), identified by the Nordic Liver Transplant Registry, were studied. Data were retrieved from patients' chart reviews. Multivariable Cox regression models were used to calculate risk factors for rPSC and death.Of the 440 patients with a follow-up time after liver transplantation of 3743 patient years, rPSC was diagnosed in 19% (n = 85). Colectomy before liver transplantation was associated with a reduced risk of rPSC (HR 0.49; 95% CI, 0.26-0.94, p = 0.033). Neither high IBD activity nor presence of IBD flares before or after liver transplantation was associated with rPSC. Treatment with tacrolimus was an independent risk factor associated with increased risk for rPSC (HR, 1.81; 95% CI, 1.15-2.86, p = 0.010). The risk of dying or needing a re-transplantation after rPSC was increased in all age groups, but highest in patients transplanted before 40 years of age (HR 7.3; 95% CI, 4.1-12.8, p = 0.0001).This study confirms that colectomy before liver transplantation is associated with a decreased risk of rPSC. Inflammatory activity of IBD was not associated with the risk of rPSC. Tacrolimus was an independent risk factor for PSC recurrence and its use as first line immunosuppression in PSC needs further study.

Background & Aims Recruitment of gut-derived memory T-cells to the liver is believed to drive hepatic inflammation in primary sclerosing cholangitis (PSC). However, whether gut-infiltrating and liver-infiltrating T-cells share T cell receptors (TCRs) and antigenic specificities is unknown. We used paired gut and liver samples from PSC patients with concurrent inflammatory bowel disease (PSC-IBD), and normal tissue samples from colon cancer controls, to assess potential T cell clonotype overlap between the two compartments. Methods High-throughput sequencing of TCRβ repertoires was applied on matched colon, liver and blood samples from patients with PSC-IBD (n=10), and on paired tumor-adjacent normal gut and liver tissue samples from colon cancer patients (n=10). Results An average of 9.7% (range: 4.7–19.9%) memory T cell clonotypes overlapped in paired PSC-IBD affected gut and liver samples, after excluding clonotypes present at similar frequencies in blood. Shared clonotypes constituted on average 16.0% (range: 8.7–32.6%) and 15.0% (range: 5.9–26.3%) of the liver and gut memory T-cells, respectively. A significantly higher overlap was observed between paired PSC-IBD affected samples (8.7%, p =0.0007) compared to paired normal gut and liver samples (3.6%), after downsampling to equal number of reads. Conclusion Memory T-cells of common clonal origin were detected in paired gut and liver samples of patients with PSC-IBD. Our data indicate that this is related to PSC-IBD pathogenesis, suggesting that memory T-cells driven by shared antigens are present in the gut and liver of PSC-IBD patients. Our findings support efforts to therapeutically target memory T cell recruitment in PSC-IBD. Lay summary Primary sclerosing cholangitis (PSC) is a devastating liver disease strongly associated with inflammatory bowel disease (IBD). The cause of PSC is unknown, but it has been suggested that the immune reactions in the gut and the liver are connected. Our data demonstrate for the first time that a proportion of the T-cells in the gut and the liver react to similar triggers, and that this proportion is particularly high in patients with PSC and IBD.

The objective of this study was to study the prevalence of gastrointestinal (GI) symptoms and histopathology in patients with common variable immunodeficiency (CVID) as well as linking the findings to GI infections and markers of systemic immune activation.In this cross-sectional study, we addressed GI symptoms in 103 patients and GI histopathological findings in 53 patients who underwent upper and lower endoscopic examination. The most frequent histopathological findings were linked to GI symptoms, B-cell phenotype, and markers of systemic immune activation (soluble (s)CD14, sCD25, and sCD163). Microarray analysis compared "celiac-like disease" in CVID to celiac disease. Screening for selected bacterial and viral infections in fecal samples and gut mucosal biopsies was performed.The main findings of this study were as follows: most common GI symptoms were bloating (34%), pain (30%), and diarrhea (26%). The most frequent histopathological findings were increased intraepithelial lymphocytes in the descending part of the duodenum, i.e., "celiac-like disease" (46% of patients), decreased numbers of plasma cells in GI tract mucosa (62%), and lymphoid hyperplasia (38%), none of which were associated with GI symptoms. Reduced plasma cells in GI mucosa were associated with B-cell phenotypic characteristics of CVID, and increased serum levels of sCD14 (P=0.025), sCD25 (P=0.01), and sCD163 (P=0.04). Microarray analyses distinguished between CVID patients with "celiac-like disease" and celiac disease. Positive tests for bacterial and viral infections were scarce both in fecal samples and gut mucosal biopsies, including PCR test for norovirus in biopsy specimens (0 positive tests).In conclusion, GI pathology is common in CVID, but does not necessarily cause symptoms. However, reduced plasma cells in GI mucosa were linked to systemic immune activation, "celiac-like disease" in CVID and true celiac disease appear to be different disease entities, as assessed by gene expression, and infections (including norovirus) are rarely a cause of the CVID enteropathy.

Several studies have implicated primary sclerosing cholangitis (PSC) as an additional risk factor for colorectal neoplasia in inflammatory bowel disease (IBD). Some reports have indicated that the risk is even higher in PSC-IBD patients after liver transplantation (Ltx), but this issue is controversial. We aimed to compare the risk of colorectal neoplasia in PSC-IBD patients before and after Ltx and to identify risk factors for colorectal neoplasia post-transplant.In a multicenter study within the Nordic Liver Transplant Group, we assessed the risk of colorectal neoplasia by using the competing risk regression analysis.Among the 439 PSC patients included, 353 (80%) had IBD at the time of Ltx and 15 (3%) patients developed de novo IBD post-Ltx. The median duration of IBD was 15 (0-50) years at the time of Ltx and follow-up after Ltx was 5 (0-20) years. Ninety-one (25%) PSC-IBD patients developed colorectal neoplasia. The cumulative risk of colorectal neoplasia was higher after than before Ltx (HR: 1.9, 95% CI: 1.3-2.9, p = 0.002). A multivariate analysis demonstrated aminosalicylates and ursodeoxycholic acid as significantly associated with an increased risk of colorectal neoplasia post-Ltx. Duration and activity of IBD did not significantly affect the risk of neoplasia.The even higher risk of colorectal neoplasia in PSC-IBD patients after when compared with that of before Ltx underscores the importance of regular surveillance colonoscopies post-Ltx. The association of aminosalicylates and ursodeoxycholic acid to the development of colorectal neoplasia after Ltx should be further investigated.

The presence of Mycobacterium avium subspecies paratuberculosis (MAP) has previously been inferred in the genesis of Crohn's disease (CD), and a higher incidence of MAP PCR positivity has been demonstrated in the gut and peripheral blood of CD patients than in healthy individuals. The objective of this prospective study was to assess the potential etiological role of MAP in the pathogenesis of CD.The presence of mycobacteria was assessed in bowel biopsies from newly diagnosed, treatment naïve Norwegian patients with IBD, including CD and ulcerative colitis (UC), as compared to a hospital-based cohort of CD and UC patients. Biopsies were collected from the small and large bowel in 354 individuals with suspected IBD. Detection of mycobacteria was performed by long-term cultivation in combination with direct detection by MAP IS900-specific PCR.Among the specimens included from the patients with early IBD, samples from only two of the patients with CD (2.7%) and two of the non-IBD controls (1.5%) exhibited a positive growth signal. None of the CD patients and only one of the non-IBD controls was MAP PCR positive. Only the single PCR positive non-IBD control was also mycobacterial culture positive with Mycobacterium avium subsp. hominissuis. In the referral patients with long-term IBD, the prevalence of growth signal and MAP PCR positivity was higher (52 and 9%, respectively).These findings demonstrate the paucity of MAP in the gut of treatment naïve CD patients. This study does not provide evidence for a role of MAP in early IBD.

Background and aims Primary sclerosing cholangitis (PSC) occurs in 2%–8% of patients who suffer from ulcerative colitis (UC). For patients who require colectomy, ileal pouch-anal anastomosis (IPAA) or ileorectal anastomosis (IRA) is employed to preserve continence.We evaluated the outcomes after IPAA and IRA for patients with UC–PSC, using patients with UC but without PSC as controls (UC-only group). Patients In a case–control study conducted at Sahlgrenska University Hospital, Sweden, patients with UC–PSC (N = 48; 31 IPAA and 17 IRA) were compared to patients with UC only (N = 113; 62 IPAA and 51 IRA). Functional outcomes (Oresland score), pouchitis, surgical complications, and failure were evaluated. Results For patients with IPAA, the median Oresland scores were similar for the two groups: 5 (range, 0–13) for the UC-PSC group and 5 for the UC-only group (range, 0–12; p > 0.05). However, the IRA scores were significantly different at 7 (range, 2–11) and 3 (range, 0–11) for the respective groups (p = 0.005). Pouchitis was more frequent in patients with UC–PSC. Complication rates did not differ. For patients with IPAA, the failure rate was 16% for those in the UC-PSC group versus 6% for those in the UC-only group (p > 0.05); the corresponding results for IRA were 53% versus 22% (p = 0.03). Conclusions For cases of IPAA, pouchitis seems to be more common in patients with UC–PSC. However, the functional outcomes and failure rates are unaffected by concurrent PSC. For patients with UC–PSC, functional outcome is poor and the failure rate is high after IRA.

Previous studies have shown conflicting results regarding the course of inflammatory bowel disease (IBD) after liver transplantation in patients with primary sclerosing cholangitis (PSC). We studied the progression of IBD in patients with PSC who have undergone liver transplantation. We also studied risk factors, including medical therapy, that could influence on IBD disease activity.In a longitudinal multicenter study, we analyzed data from the Nordic Liver Transplant Group on 439 patients with PSC who underwent liver transplantation from November 1984 through December 2006; 353 had IBD at the time of transplantation. We compared IBD activity before and after liver transplantation. Two hundred eighteen patients who had an intact colon and had undergone pretransplant and post-transplant colonoscopies were characterized further.Macroscopic colonic inflammation was more frequent after liver transplantation than before liver transplantation (153 vs 124 patients; P.001). The degree of inflammation decreased in 37 patients (17%), was unchanged in 93 patients (43%), and increased in 88 patients (40%) (P.001). The rate of relapse after transplantation was higher than that before transplantation (P.001), and overall clinical IBD activity also increased (P.001). Young age at diagnosis of IBD and dual treatment with tacrolimus and mycophenolate mofetil were significant risk factors for increased IBD activity after transplantation, whereas combination treatment with cyclosporin A and azathioprine had protective effects.Immunosuppression affects IBD activity after liver transplantation in patients with PSC; a shift from present standard maintenance treatment of tacrolimus and mycophenolate mofetil to cyclosporin A and azathioprine should be considered for these patients.

Background: Inflammatory bowel disease (IBD) in patients with primary sclerosing cholangitis (PSC) seems to differ from IBD without PSC, but a systematic, prospective study of IBD in PSC has until now not been reported. We aimed to describe the clinical, endoscopic, and histopathologic features of PSC-IBD in liver-transplanted and nontransplanted patients. Methods: PSC patients (n = 184) were included and underwent ileocolonoscopy with assessment of segmental histopathology. Results: A total of 155 (84%) patients had IBD, of whom 39 (25%) had undergone colectomy. The patients with an intact colon and complete tissue samples (n = 110) were further investigated. Forty-two (38%) patients had undergone liver transplantation. The median IBD duration was 11 (range, 0–50) years. The majority (65%) had no or sparse IBD symptoms. Inflammatory findings were more frequent by histology than by endoscopy (89% versus 47%, P < 0.001). Histopathological signs of inflammation involved the right colon in 86% of patients and were purely right-sided in 23%. The findings of inflammation were higher in the right compared to the left colon (P < 0.001), but the general inflammatory activity was low. Backwash ileitis was demonstrated in 20% (17/87) of patients and rectal sparing in 65% (70/107). The liver-transplanted patients had lower clinical (P = 0.035) and histological (P = 0.013) IBD activity than the nontransplanted group. Conclusions: PSC-IBD may represent a distinct entity of colitis in which low endoscopic activity may mask an active histologic inflammation that possibly contributes to an increased risk of malignancy. Circumstances related to liver transplantation seem to act favorably on colonic inflammation in PSC. (Inflamm Bowel Dis 2012;)