Exposure of Colon-Derived Epithelial Monolayers to Fecal Luminal Factors from Patients with Colon Cancer and Ulcerative Colitis Results in Distinct Gene Expression Patterns.

Microbiota and luminal components may affect epithelial integrity and thus participate in the pathophysiology of colon cancer (CC) and inflammatory bowel disease (IBD). Therefore, we aimed to determine the effects of fecal luminal factors derived from patients with CC and ulcerative colitis (UC) on the colonic epithelium using a standardized colon-derived two-dimensional epithelial monolayer. The complex primary human stem cell-derived intestinal epithelium model, termed RepliGut® Planar, was expanded and passaged in a two-dimensional culture which underwent stimulation for 48 h with fecal supernatants (FS) from CC patients (n = 6), UC patients with active disease (n = 6), and healthy subjects (HS) (n = 6). mRNA sequencing of monolayers was performed and cytokine secretion in the basolateral cell culture compartment was measured. The addition of fecal supernatants did not impair the integrity of the colon-derived epithelial monolayer. However, monolayers stimulated with fecal supernatants from CC patients and UC patients presented distinct gene expression patterns. Comparing UC vs. CC, 29 genes were downregulated and 33 genes were upregulated, for CC vs. HS, 17 genes were downregulated and five genes were upregulated, and for UC vs. HS, three genes were downregulated and one gene was upregulated. The addition of FS increased secretion of IL8 with no difference between the study groups. Fecal luminal factors from CC patients and UC patients induce distinct colonic epithelial gene expression patterns, potentially reflecting the disease pathophysiology. The culture of colonic epithelial monolayers with fecal supernatants derived from patients may facilitate the exploration of IBD- and CC-related intestinal microenvironmental and barrier interactions.

Ustekinumab Is Associated with Real-World Long-Term Effectiveness and Improved Health-Related Quality of Life in Crohn's Disease.

BACKGROUND: Prospectively and systematically collected long-term real-world clinical data on ustekinumab (anti-interleukin-12/23) are still scarce. AIMS: To assess the long-term effectiveness of ustekinumab in patients with active Crohn's disease (CD). METHODS: This is a prospective multicenter study of adult patients with CD initiating ustekinumab according to recommended doses at 20 Swedish hospitals. The primary outcome was clinical remission (Harvey-Bradshaw Index (HBI) ≤ 4 points) at weeks 52 and 104. Secondary outcomes included clinical response (≥ 3-point-decrease in HBI among patients with initial HBI ≥ 5 points), treatment retention, and biomarkers (C-reactive protein (CRP), hemoglobin, fecal-calprotectin) at weeks 52 and 104 compared to baseline. We also reported Health-related Quality of Life (HRQoL) measures. RESULTS: Of 114 included patients, 107 (94%) had previously failed ≥ 1 and 58 (51%) ≥ 2 anti-tumor necrosis factor agents. Forty (35%) had failed anti-integrin agents. Ustekinumab retention rates at weeks 52 and 104 were 70% (n = 80/114) and 61% (n = 69/114), respectively. Clinical response was seen in 36% (n = 25/69) and 29% (n = 20/69) of the patients, and remission was achieved in 32% (n = 31/96) and 29% (n = 28/96) at weeks 52 and 104, respectively. Median HBI and CRP levels decreased significantly at both timepoints as compared to baseline. Significant improvements were also observed in HRQoL. Adverse events were reported in 11% (n = 13/114) of the patients, including five cases of severe adverse events. No malignancies were observed. CONCLUSIONS: In this nationwide prospective real-world 104-week-follow-up study of adult patients with active CD, ustekinumab was associated with long-term clinical effectiveness and improvement in HRQoL measures when used in routine clinical care.

Fecal Luminal Factors from Patients with Gastrointestinal Diseases Alter Gene Expression Profiles in Caco-2 Cells and Colonoids.

Previous in vitro studies have shown that the intestinal luminal content, including metabolites, possibly regulates epithelial layer responses to harmful stimuli and promotes disease. Therefore, we aimed to test the hypothesis that fecal supernatants from patients with colon cancer (CC), ulcerative colitis (UC) and irritable bowel syndrome (IBS) contain distinct metabolite profiles and establish their effects on Caco-2 cells and human-derived colon organoids (colonoids). The metabolite profiles of fecal supernatants were analyzed by liquid chromatography-mass spectrometry and distinguished patients with CC (n = 6), UC (n = 6), IBS (n = 6) and healthy subjects (n = 6). Caco-2 monolayers and human apical-out colonoids underwent stimulation with fecal supernatants from different patient groups and healthy subjects. Their addition did not impair monolayer integrity, as measured by transepithelial electrical resistance; however, fecal supernatants from different patient groups and healthy subjects altered the gene expression of Caco-2 monolayers, as well as colonoid cultures. In conclusion, the stimulation of Caco-2 cells and colonoids with fecal supernatants derived from CC, UC and IBS patients altered gene expression profiles, potentially reflecting the luminal microenvironment of the fecal sample donor. This experimental approach allows for investigating the crosstalk at the gut barrier and the effects of the gut microenvironment in the pathogenesis of intestinal diseases.

Prospective observational study on Stelara (ustekinumab) assessing effectiveness in Crohn's disease (PROSE): a 16-week follow-up.

BACKGROUND: Prospectively and systematically collected real-world data on the effectiveness of ustekinumab (anti-interleukin-12/23) for treating Crohn's disease (CD) are still limited. AIM: To assess the short-term real-world effectiveness of ustekinumab in Swedish patients with active CD. METHODS: Prospective multicentre study of adult CD patients initiating ustekinumab according to recommended doses at 20 hospitals, between January 2017 and November 2018. Data were collected through an electronic case report form (eCRF) linked to the Swedish Inflammatory Bowel Disease Registry (SWIBREG). The primary outcomes were clinical response (≥3-point-decrease of Harvey-Bradshaw index (HBI)) and remission (HBI ≤4 points) at week 16. Secondary outcomes included C-reactive protein (CRP) and haemoglobin (Hb) at baseline compared to week 16. RESULTS: Of 114 included patients, 107 (94%) had failed ≥ 1 and 58 (51%) ≥ 2 biological agents (anti-tumour necrosis factor [aTNF] agents or vedolizumab). The 16-week ustekinumab retention rate was 105 (92%). Data on HBI at baseline were available for 96 patients. At week 16, response or remission was achieved in 38/96 (40%) patients (25/96 (26%) achieving clinical remission and 23/96 (24%) showing a clinical response). The median CRP concentration (N = 65) decreased from 6 to 4 mg/l (p = .006). No significant changes in Hb were observed. No incident malignancies or infections, requiring antibiotic treatment, were reported. CONCLUSIONS: In this nation-wide prospective real-world study of adult patients with CD, ustekinumab was associated with clinical effectiveness when administered according to clinical practice and seemed to represent a safe treatment option.

Clinical effectiveness of golimumab in ulcerative colitis: a prospective multicentre study based on the Swedish IBD Quality Register, SWIBREG.

OBJECTIVES: Clinical trials demonstrated that golimumab is effective in anti-TNF naïve patients with ulcerative colitis. We aimed to assess the clinical effectiveness of golimumab in a real-world setting. MATERIALS AND METHODS: This was a prospective cohort study, conducted at 16 Swedish hospitals. Data were collected using an electronic case report form. Patients with active ulcerative colitis, defined as Mayo endoscopic subscore ≥2 were eligible for inclusion. The primary outcomes were clinical effectiveness at 12 weeks and 52 weeks, i.e. response (defined as a decrease in Mayo score by ≥3 points or 30% from baseline) and remission (defined as a Mayo score of ≤2 with no individual subscores >1). RESULTS: Fifty patients were included. At study entry, 70% were previously exposed to anti-TNF, 16% to vedolizumab, and 96% to immunomodulators. The 12 and 52-week drug continuation rates were 37/50 (74%) and 23/50 (46%), respectively. The 12-week response rate was 14/50 (28%), the remission rate, 8/50 (16%) and the corresponding figures at week 52 were 13/50 (26%) and 10/50 (20%). Among patients who continued golimumab, the median Mayo score decreased from 7 (6-9) at baseline to 1 (0-5) at 52 weeks (p < .01) and the faecal calprotectin decreased from 862 (335-1759) µg/g to 90 (34-169) µg/g (p < .01). Clinical response at week 12 was highly predictive of clinical remission at week 52 (adjusted OR: 73.1; 95% CI: 4.5‒1188.9). CONCLUSIONS: The majority of golimumab treated patients represented a treatment refractory patient-group. Despite this, our results confirm that golimumab is an effective therapy in ulcerative colitis.

The use of ICD codes to identify IBD subtypes and phenotypes of the Montreal classification in the Swedish National Patient Register.

Introduction: Whether data on International Classification of Diseases (ICD)-codes from the Swedish National Patient Register (NPR) correctly correspond to subtypes of inflammatory bowel disease (IBD) and phenotypes of the Montreal classification scheme among patients with prevalent disease is unknown.Materials and methods: We obtained information on IBD subtypes and phenotypes from the medical records of 1403 patients with known IBD who underwent biological treatment at ten Swedish hospitals and retrieved information on their IBD-associated diagnostic codes from the NPR. We used previously described algorithms to define IBD subtypes and phenotypes. Finally, we compared these register-generated subtypes and phenotypes with the corresponding information from the medical records and calculated positive predictive values (PPV) with 95% confidence intervals.Results: Among patients with clinically confirmed disease and diagnostic listings of IBD in the NPR (N = 1401), the PPV was 97 (96-99)% for Crohn's disease, 98 (97-100)% for ulcerative colitis, and 8 (4-11)% for IBD-unclassified. The overall accuracy for age at diagnosis was 95% (when defined as A1, A2, or A3). Examining the validity of codes representing disease phenotype, the PPV was 36 (32-40)% for colonic Crohn's disease (L2), 61 (56-65)% for non-stricturing/non-penetrating Crohn's disease behaviour (B1) and 83 (78-87)% for perianal disease. Correspondingly, the PPV was 80 (71-89)% for proctitis (E1)/left-sided colitis (E2) in ulcerative colitis.Conclusions: Among people with known IBD, the NPR is a reliable source of data to classify most subtypes of prevalent IBD, even though misclassification commonly occurred in Crohn's disease location and behaviour and also among IBD-unclassified patients.

Fecal microbiota composition is linked to the postoperative disease course in patients with Crohn's disease.

BACKGROUND: The role of the fecal microbiota composition for the postoperative disease course of patients with Crohn's disease (CD) who have undergone ileocecal resection remains to be established. In this study, we investigated if the fecal microbiota composition, determined by a high throughput test quantifying a pre-selected set of bacteria, is associated with the postoperative disease course of CD patients. METHODS: Fecal samples were obtained from healthy subjects as well as from CD patients, 3-10 weeks and 1 year after ileocaecal resection. The fecal microbial composition was analyzed by Genetic Analysis GA-map Dysbiosis test, targeting ≥300 bacteria on different taxonomic levels. Postoperative disease status was assessed endoscopically according to Rutgeerts scoring system 1 year after surgery. Differences in fecal microbiota composition between groups were analyzed by multivariate factor analyses and cluster analysis. Microbial stability over time was determined using Bray-Curtis dissimilarity. RESULTS: One year after surgery, the fecal microbiota composition differed between CD patients (n = 21) and healthy subjects (n = 7). At this time point, the microbiota composition of CD patients was associated with disease course, clearly separating patients with disease relapse (n = 8) and patients in remission (n = 13). Further, the microbial within-patient stability was high during the first year after surgery, irrespective of disease course. CONCLUSION: The fecal microbiota composition of CD patients, analyzed by GA-map Dysbiosis test, is subject to little variation over time, and may potentially be used as a non-invasive diagnostic tool for the postoperative disease course.

Swedish Inflammatory Bowel Disease Register (SWIBREG) - a nationwide quality register.

Background: Inflammatory bowel disease (IBD) is a chronic, inflammatory relapsing disease with increasing incidence. IBD research and long-term follow-up of patients have, however, been hampered by lack of detailed data on disease phenotype, patient-reported outcome measures, Physician Global Assessment, disease activity, and hospital-administered drugs. Aim: To review the Swedish IBD quality register (SWIBREG). Methods: Review of SWIBREG including questionnaire data from users and patients. Results: SWIBREG was launched in 2005, and as of April 2019, contains 46,400 patients with IBD (Crohn's disease: n = 15,705, ulcerative colitis: n = 21,540, IBD unclassified and other colitis (including e.g., microscopic colitis): n = 9155). Of these IBD patients, 7778 had been diagnosed in childhood (16.8%). Earlier research has shown that combining SWIBREG and the Swedish National Patient Register (NPR) yields a positive predictive value of 100% (95%CI = 95-100%) for having a diagnosis of IBD. Moreover, out of all patients in the NPR with a diagnosis of IBD plus either IBD-related surgery or immunomodulatory/biological treatment during the past 18 months, SWIBREG covers 59.0%. SWIBREG records not only information on conventional therapies but also on biological treatment, surgery, smoking, disease activity, patient-reported outcome measures (PROMs), and patient-experienced measures (PREMs). Data are presented through a graphical decision support system. Conclusion: SWIBREG benefits patients with IBD, and offers an ideal opportunity for healthcare personnel and researchers to examine disease phenotype and activity, PROMs/PREMs, and hospital-administered drugs in patients with IBD.

Clinical effectiveness of golimumab in Crohn's disease: an observational study based on the Swedish National Quality Registry for Inflammatory Bowel Disease (SWIBREG).

OBJECTIVE: The effectiveness of golimumab in Crohn's disease (CD) is largely unknown as it is not approved for the treatment of the disease. We aimed to identify the population of CD patients treated with golimumab in Sweden, to assess the effectiveness of golimumab (defined as the drug retention rate), and to identify predictors of drug discontinuation. METHODS: Patients with CD who received at least one injection of golimumab were identified through the Swedish National Quality Registry for Inflammatory Bowel Disease, which includes prospectively collected clinical information. Cox regression models were used to identify predictors of golimumab discontinuation. RESULTS: The study cohort involved 94 patients of whom the majority (96.8%) had previously discontinued at least one anti-tumour necrosis factor (anti-TNF) agent. The drug retention rate at 12 weeks was 85.1%. Predictors of golimumab discontinuation at 12 weeks were previous surgery (adjusted HR = 7.52, 95% CI: 1.12-50.36), concomitant corticosteroid use at baseline (adjusted HR = 5.70, 95% CI: 1.13-28.68) and female sex (adjusted HR = 6.59; 95% CI: 1.04-41.62). The median duration of follow-up was 89 (IQR: 32-158) weeks. The drug retention at the most recent follow-up was 35.1%. Predictors of golimumab discontinuation at the most recent follow-up were corticosteroid use at baseline (adjusted HR = 2.60, 95% CI: 1.17-5.79) and female sex (adjusted HR = 2.24; 95% CI: 1.19-4.23). CONCLUSION: Patients with CD treated with golimumab were a treatment-refractory group. Despite this, more than one-third of the patients appeared to have had clinical benefit after a median follow-up of more than 1.5 years.

Validating inflammatory bowel disease (IBD) in the Swedish National Patient Register and the Swedish Quality Register for IBD (SWIBREG).

BACKGROUND: Both the Swedish National Patient Register (NPR) and the Swedish Quality Register for inflammatory bowel disease (IBD, SWIBREG) are important sources of research data and information. However, the validity of a diagnosis of IBD in these registers is unknown. METHODS: Medical charts of 129 randomly selected patients from the NPR and 165 patients registered both in SWIBREG and the NPR were reviewed. Patients were classified according to standardized criteria for ulcerative colitis (UC), Crohn's disease (CD), or IBD unclassified (IBD-U). Positive predictive values (PPVs) for UC, CD, IBD-U (only SWIBREG), or having any form of IBD were then calculated. RESULTS: For cases with ≥2 diagnoses of IBD in the NPR (hospitalizations or non-primary care outpatient visits), the PPV was 93% (95% CI: 87-97) for any IBD, 79% (66-88) for UC and 72% (60-82) for CD. In UC patients with ≥2 UC diagnoses but never a CD diagnosis, the PPV increased to 90% (77-97). The PPV for CD in patients with ≥2 CD diagnoses but never a UC diagnosis was 81% (67-91)). Combining data from SWIBREG (≥1 record) and the NPR (≥1 record), the PPV was 99% for any IBD (97-100), 96% (89-99) for UC, and 90% (82-96) for CD. CONCLUSION: The validity of the UC, CD, and IBD diagnoses is high in the NPR but even higher when cases were identified both in SWIBREG and the NPR. These results underline the need for a well-functioning Swedish Quality Register for IBD as a complement to the NPR.

Long-term effectiveness of vedolizumab in inflammatory bowel disease: a national study based on the Swedish National Quality Registry for Inflammatory Bowel Disease (SWIBREG).

OBJECTIVES: Clinical trials have demonstrated the efficacy of vedolizumab in inflammatory bowel disease (IBD). However, these findings may not reflect the clinical practice. Therefore, we aimed to describe a vedolizumab-treated patient population and assess long-term effectiveness. MATERIALS AND METHODS: Patients initiating vedolizumab between 1 June 2014 and 30 May 2015 were identified through the Swedish National Quality Registry for IBD. Prospectively collected data on treatment and disease activity were extracted. Clinical remission was defined as Patient Harvey Bradshaw index <5 in Crohn's disease (CD) and Patient Simple Clinical Colitis Activity index <3 in ulcerative colitis (UC). RESULTS: Two-hundred forty-six patients (147 CD, 92 UC and 7 IBD-Unclassified) were included. On study entry, 86% had failed TNF-antagonist and 48% of the CD patients had undergone ≥1 surgical resection. After a median follow-up of 17 (IQR: 14-20) months, 142 (58%) patients remained on vedolizumab. In total, 54% of the CD- and 64% of the UC patients were in clinical remission at the end of follow-up, with the clinical activity decreasing (p < .0001 in both groups). Faecal-calprotectin decreased in CD (p < .0001) and in UC (p = .001), whereas CRP decreased in CD (p = .002) but not in UC (p = .11). Previous anti-TNF exposure (adjusted HR: 4.03; 95% CI: 0.96-16.75) and elevated CRP at baseline (adjusted HR: 2.22; 95% CI: 1.10-4.35) seemed to be associated with discontinuation because of lack of response. Female sex was associated with termination because of intolerance (adjusted HR: 2.75; 95% CI: 1.16-6.48). CONCLUSION: Vedolizumab-treated patients represent a treatment-refractory group. A long-term effect can be achieved, even beyond 1 year of treatment.

Global mucosal and serum cytokine profile in patients with ulcerative colitis undergoing anti-TNF therapy.

BACKGROUND AND OBJECTIVE: The knowledge of the effects of anti-tumour necrosis factor (TNF) treatment on the global cytokine profile in patients with ulcerative colitis (UC) is limited. A better understanding of these mechanisms could improve the ability to select patients that should undergo the therapy. Therefore, the aim was to determine the global mucosal and serum cytokine profile before and during induction therapy with anti-TNF in UC patients. MATERIALS AND METHODS: In total, mucosal biopsies (n = 28) and serum samples (n = 42) were collected from UC patients (total n = 48) before anti-TNF therapy. At week 14 response to the therapy was evaluated and again mucosal biopsies (n = 14) and serum samples (n = 42) were collected. Quantitative real-time PCR was used to determine mucosal cytokine mRNA expression and the MSD MULTI-ARRAY assay system platform was used for analysis of cytokines in serum. The global cytokine profile was evaluated by multivariate factor analysis. RESULTS: At baseline, the global profile of mucosal cytokine mRNA expression and serum cytokines discriminated therapy responders from non-responders. Responders had lower mucosal mRNA expression of interleukin 1ß (IL-1ß), IL-17A, IL-6 and interferon γ (IFN-γ) than non-responders. Fourteen weeks after therapy start mucosal IL-1ß and IL-6 were down-regulated in therapy responders but not in non-responders. At week 14, serum levels of IL-6 were decreased in therapy responders whereas IFN-γ and IL-12p70 were increased in non-responders. CONCLUSIONS: Our data suggest that patients with a therapy failure have a more severe pro-inflammatory cytokine profile before start of anti-TNF treatment, which is less well suppressed by the treatment as compared to therapy responders.

Factors Associated With Abdominal Pain in Patients With Active and Quiescent Ulcerative Colitis: A Multicohort Study.

BACKGROUND: Abdominal pain can be an overlooked symptom in patients with ulcerative colitis (UC). AIMS: The aim of this study was to investigate the prevalence and factors associated with abdominal pain in active and quiescent UC. METHODS: Three study cohorts of adult UC patients were used. Cross-sectional cohorts I and II included 130 (46 active) and 288 (156 active) patients. Longitudinal cohort III included 83 patients with active disease at diagnosis that reached deep remission during follow-up. The Gastrointestinal Symptom Rating Scale was used to assess abdominal pain and other validated questionnaires to assess psychological distress, fatigue and quality of life (QoL). RESULTS: In the two cross-sectional cohorts, 63% and 58% of the active vs. 54% and 33% of the quiescent UC patients reported abdominal pain (both p ≤ 0.02). In the longitudinal cohort, 71% had abdominal pain at diagnosis vs. 46% when in remission (p < 0.001). In multivariable models, symptoms of anxiety were associated with higher abdominal pain levels in both cross-sectional cohorts (OR 1.75 [IQR 1.11-2.76] and OR 1.99 [1.45-2.73]), whereas in cohort II, active disease (OR 2.68 [1.61-4.45]) and female sex (OR 2.03 [1.21-3.41]) were also associated with pain. QoL was negatively correlated with higher levels of abdominal pain, both in active and quiescent disease. CONCLUSIONS: Abdominal pain in UC is prevalent and associated with lower QoL in both active and quiescent disease. Associated factors are active disease, female sex and psychological symptoms, especially anxiety. We suggest considering a holistic approach when treating UC patients with abdominal pain.

[Health-related quality of life for patients with inflammatory bowel disease requires more than anti-inflammatory treatment]. / Hälsorelaterad livskvalitet vid inflammatorisk tarmsjukdom.

The care of IBD patients aims to achieve the best possible health. The treatment goals in IBD should therefore, in addition to stable control of intestinal inflammation, also consider health-related quality of life (HRQL) and extraintestinal complications. Fatigue is an underrecognized array of symptoms that need more attention and, if possible, treatment. Iron deficiency is very common in IBD patients and should be monitored at regular intervals and treated. Deficiencies in vitamin D, calcium and phosphate are probably common and can be related to both the disease and the treatments, with a risk of reduced HRQL.

Predictors of Symptoms Trajectories in Newly Diagnosed Ulcerative Colitis: A 3-Year Follow-up Cohort Study.

BACKGROUND AND AIMS: Psychological symptoms are associated with poorer ulcerative colitis [UC]-related outcomes. However, the majority of research is cross-sectional. We aimed to identify subgroups based on the longitudinal evolution of GI symptom levels and health-related quality of life [HRQoL], and to disentangle the directionality of effects between GI symptom levels and psychological distress. METHODS: Self-reported gastrointestinal [GI] symptom severity, HRQoL, inflammatory biomarkers, and psychological distress were assessed in 98 newly diagnosed UC patients at disease onset and yearly for 3 consecutive years. Latent class growth analysis was used to determine subgroups based on longitudinal trajectories of symptom severity and HRQoL, and baseline predictors of trajectory group membership were determined. Cross-lagged structural equation models were used to disentangle temporal relationships between psychological functioning and symptom severity. RESULTS: Patients with higher initial psychological distress had increased probability of maintaining higher levels of diarrhoea and abdominal pain. Conversely, patients with lower initial levels of diarrhoea and abdominal pain had higher chances of maintaining lower levels of psychological distress. Higher levels of C-reactive protein at baseline predicted greater improvements in mental health after anti-inflammatory treatment. Reductions in diarrhoea and abdominal pain preceded reductions in psychological symptoms over time. CONCLUSIONS: Baseline psychological distress is predictive of increased GI symptom severity and reduced mental HRQoL over time, suggesting early assessment of psychological symptoms may identify patients who may have worse disease trajectories. Abdominal pain predicted increased psychological distress, but not the other way around. Intervening on abdominal pain may help prevent or reduce future psychological distress.

Faecal biomarkers for diagnosis and prediction of disease course in treatment-naïve patients with IBD.

BACKGROUND: Faecal biomarkers can be used to assess inflammatory bowel disease (IBD). AIM: To explore the performance of some promising biomarkers in diagnosing and predicting disease course in IBD. METHODS: We included 65 patients with treatment-naïve, new-onset Crohn's disease (CD), 90 with ulcerative colitis (UC), 67 symptomatic controls (SC) and 41 healthy controls (HC) in this prospective observational study. We analysed faecal samples for calprotectin (FC), myeloperoxidase (MPO), human neutrophil lipocalin (HNL), eosinophil cationic protein ECP and eosinophil-derived neurotoxin (EDN) and compared markers among groups. We assessed the diagnostic capability of biomarkers with receiver operating characteristic curves. Clinical disease course was determined for each patient with IBD and analysed the association with biomarkers by logistic regression. RESULTS: All markers were elevated at inclusion in patients with IBD compared with HC (p < 0.001) and SC (p < 0.001). FC (AUC 0.85, 95% CI: 0.79-0.89) and MPO (AUC 0.85, 95% CI: 0.80-0.89) showed the highest diagnostic accuracy in distinguishing IBD from SC. The diagnostic ability of biomarkers differed between IBD subtypes with the highest performance for FC and MPO in CD. The diagnostic accuracy was further improved by combining FC and MPO (p = 0.02). Levels of FC, MPO and HNL at inclusion were predictive of an aggressive disease course with MPO showing the strongest association (p = 0.006). CONCLUSIONS: This study provides new insight into the diagnostic and prognostic capability of neutrophil and eosinophil biomarkers in IBD and suggests that MPO, alone or in combination with FC, may add to the diagnostic power of faecal biomarkers.

Long-term outcomes of vedolizumab in inflammatory bowel disease: the Swedish prospective multicentre SVEAH extension study.

Background: Real-world data on long-term outcomes of vedolizumab (VDZ) are scarce. Objective: To assess long-term outcomes (up to 3 years) of VDZ in treating inflammatory bowel disease (IBD). Design: A nationwide, prospective multicentre extension of a Swedish observational study on VDZ assessing Effectiveness And Healthcare resource utilization in patients with IBD (SVEAH). Methods: After re-consent, data of patients with Crohn's disease (CD) (n = 68) and ulcerative colitis (UC) (n = 46) treated with VDZ were prospectively recorded using an electronic case report form integrated with the Swedish IBD Register (SWIBREG). The primary outcome was clinical remission (defined as Harvey-Bradshaw Index ⩽4 in CD and partial Mayo score ⩽2 in UC) at 104 and 156 weeks in patients with a response and/or remission 12 weeks after starting VDZ. Secondary outcomes included health-related quality of life (HRQoL) and biochemical outcomes. Results: VDZ continuation rates were high at weeks 104 and 156, 88% and 84%, respectively, for CD and 87% and 78%, respectively, for UC. Of the 53 CD patients with a response/remission at 12 weeks, 40 (75%) patients were in remission at 104 weeks and 42 (79%) patients at 156 weeks. For UC, these numbers were 25/31 (81%) and 22/31 (71%), respectively. Improvements were seen in the Short Health Scale (p < 0.01 for each dimension; CD, n = 51; UC, n = 33) and the EuroQol 5-Dimensions, 5-levels index value (p < 0.01; CD, n = 39; UC, n = 30). Median plasma-C-reactive protein concentrations (mg/L) decreased from 5 at baseline to 4 in CD (p = 0.01, n = 53) and from 5 to 4 in UC (p = 0.03, n = 34) at 156 weeks. Correspondingly, median faecal-calprotectin (µg/g) decreased from 641 to 114 in CD patients (p < 0.01, n = 26) and from 387 to 37 in UC patients (p = 0.02, n = 17). Conclusion: VDZ demonstrated high continuation rates and was associated with improvements in clinical outcomes, HRQoL measures and inflammatory markers at 2 and 3 years after treatment initiation in this prospective national SVEAH extension study. Registration: ENCePP registration number: EUPAS22735.

Fecal Biomarkers of Neutrophil and Eosinophil Origin Reflect the Response to Biological Therapy and Corticosteroids in Patients With Inflammatory Bowel Disease.

INTRODUCTION: Fecal calprotectin (FC) is a noninvasive tool for examining response to biologics in inflammatory bowel disease (IBD), but its performance in relation to other novel fecal markers of various cellular origins is unknown. METHODS: We performed a prospective multicenter cohort study and included patients with active IBD who provided a fecal sample at initiation of biological therapy. Levels of FC, myeloperoxidase (MPO), human neutrophil lipocalin (HNL), and eosinophil-derived neurotoxin (EDN) were analyzed and related to clinical remission status at 3 months. Changes in levels of markers at 3 months were calculated, and the impact of concomitant use of corticosteroids at baseline was estimated. RESULTS: In patients achieving clinical remission (n = 27), a decrease in levels of FC ( P = 0.005), MPO ( P < 0.001), HNL ( P < 0.001), and EDN ( P < 0.001) was observed, whereas no significant decrease was seen in patients not achieving remission (n = 39). There was a significant difference in the change in the level of MPO ( P = 0.01) and HNL ( P = 0.02) between patients achieving clinical remission and those who did not, but changes in FC and EDN could not differentiate between these groups. Patients with concomitant systemic corticosteroids at inclusion had lower levels of HNL ( P = 0.01) and EDN ( P < 0.001) at baseline, compared with patients without corticosteroids. DISCUSSION: Fecal MPO, HNL, and EDN are all promising biomarkers for assessing the treatment outcome of biologics in patients with IBD. Fecal levels of EDN and HNL are significantly affected by corticosteroids indicating a greater sensitivity to the effects of corticosteroids compared with levels of FC and MPO.

Health-related quality of life in patients with long-standing ulcerative colitis in remission.

INTRODUCTION: Ulcerative colitis (UC) contributes to impaired health-related quality of life (HRQoL). Although disease activity is the most important factor, reduced HRQoL has been reported even in quiescent UC. We aimed to determine HRQoL, and identify predictors thereof, in patients with long-standing UC in remission. METHODS: In total, 66 patients with inactive UC were included 10 years after the disease onset. Clinical assessment including rigid sigmoidoscopy was performed to ensure remission. Data on demographic, clinical, treatment-related, and psychological determinants of HRQoL were obtained with a structured interview and self-assessment questionnaires measuring gastrointestinal (GI) and psychological symptoms and fatigue. HRQoL was measured with the Short Form Health Survey (SF-36). RESULTS: The SF-36 domains were comparable to the general Swedish population, except for Vitality, where UC patients scored lower. Gender, smoking, comorbidity, or disease phenotype had no impact on HRQoL. In contrast, corticosteroid use and sick leave during the previous year were independently associated with Physical Functioning and Bodily Pain domains of SF-36; persisting GI symptoms during remission with Bodily Pain; and fatigue with Role Physical, General Health and Vitality. For all other SF-36 domains reflecting mental HRQoL (Social Function, Role Emotional, Mental Health), only psychological distress contributed uniquely. CONCLUSIONS: Although overall HRQoL in long-standing UC in remission is comparable to the general population, previous disease activity as well as persisting GI symptoms, fatigue, and psychological distress are associated with a lower HRQoL among these patients. Improved HRQoL may allow for better UC patient health and reduced costs for health care.

Ustekinumab treatment in ulcerative colitis: Real-world data from the Swedish inflammatory bowel disease quality register.

BACKGROUND: Real-world data on clinical outcomes of ustekinumab in ulcerative colitis are lacking. OBJECTIVE: To assess short- and long-term clinical outcomes of ustekinumab in ulcerative colitis. METHODS: Adult ulcerative colitis patients without previous colectomy starting ustekinumab treatment up until 11 December 2020 were identified through the Swedish Inflammatory Bowel Disease Register (SWIBREG). Prospectively recorded data were extracted from the SWIBREG. The primary outcome was persistence to ustekinumab 16 weeks after treatment initiation. Secondary outcomes included drug persistence beyond week 16, clinical remission (defined as a patient-reported Mayo rectal bleeding subscore = 0 and stool frequency subscore ≤1), biochemical remission (defined as faecal-calprotectin <250 µg/g) and changes in health-related quality of life (HRQoL), as measured by the Short Health Scale (SHS). Logistic regression was used to identify potential predictors of ustekinumab persistence at 16 weeks. RESULTS: Of the 133 patients with ulcerative colitis, only three were naïve to biologics and tofacitinib. The persistence rates of ustekinumab were 115/133 (86%) at 16 weeks and 89/133 (67%) at last follow-up, that is, after a median follow-up of 32 (interquartile range 19-56) weeks. The clinical remission rates were 17% at 16 weeks and 32% at the last follow-up. The corresponding rates for biochemical remission were 14% and 23%. The median faecal-calprotectin concentration decreased from 740 µg/g at baseline to 98 µg/g at the last follow-up (p < 0.01, n = 37). Improvement was seen in each dimension of the SHS between baseline and last follow-up (p < 0.01 for each dimension, n = 46). Male sex was associated with ustekinumab persistence at 16 weeks (adjusted odds ratio = 4.00, 95% confidence interval: 1.35-11.83). CONCLUSION: In this nationwide real-world cohort of ulcerative colitis patients with prior drug failures, including other biologics and tofacitinib, ustekinumab was associated with high drug persistence rates and improvements in clinical, biochemical and HRQoL measures.