Need for therapeutic escalation in patients with refractory ulcerative proctitis: Results from the PROCU study of the ENEIDA registry.

BACKGROUND: Ulcerative proctitis (UP) can have a milder, less aggressive course than left-sided colitis or extensive colitis. Therefore, immunosuppressants tend to be used less in patients with this condition. Evidence, however, is scarce because these patients are excluded from randomised controlled clinical trials. Our aim was to describe the characteristics of patients with refractory UP and their disease-related complications, and to identify the need for immunosuppressive therapies. METHODS: We identified patients with UP from the prospective ENEIDA registry sponsored by the GETECCU. We evaluated socio-demographic data and complications associated with immunosuppression. We defined immunosuppression as the use of immunomodulators, biologics and/or small molecules. We used logistic regression to identify factors associated with immunosuppressive therapy. RESULTS: From a total of 34,716 patients with ulcerative colitis, we identified 6281 (18.1%) with UP; mean ± SD age 53 ± 15 years, average disease duration of 12 ± 9 years. Immunosuppression was prescribed in 11% of patients, 4.2% needed one biologic agent and 1% needed two; 2% of patients required hospitalisation, and 0.5% underwent panproctocolectomy or subtotal colectomy. We identified 0.2% colorectal tumours and 5% extracolonic tumours. Patients with polyarthritis (OR 3.56, 95% CI 1.86-6.69; p < 0.001) required immunosuppressants. CONCLUSIONS: Among patients with refractory UP, 11% required immunosuppressant therapy, and 4.2% required at least one biologic agent.

Persistence, effectiveness and safety of ustekinumab and vedolizumab therapy for complex perianal fistula in Crohn's disease: The HEAL study from GETECCU.

BACKGROUND: The efficacy of ustekinumab and vedolizumab for treating complex perianal fistula in Crohn's disease has been barely studied. We aimed to assess treatment persistence, clinical remission, and safety of these drugs in this context. METHODS: Crohn's disease patients who had received ustekinumab or vedolizumab for the indication of active complex perianal fistula, were included. Clinical remission was defined according to Fistula Drainage Assessment Index (no drainage through the fistula upon gentle pressure) based on physicians' assessment. RESULTS: Of 155 patients, 136 received ustekinumab, and 35 vedolizumab (16 received both). Median follow-up for ustekinumab was 27 months. Among those on ustekinumab, 54 % achieved remission, and within this group, 27 % relapsed during follow-up. The incidence rate of relapse was 11 % per patient-year. Multivariate analysis found no variables associated with treatment discontinuation or relapse. Median follow-up time for patients receiving vedolizumab was 19 months. Remission was achieved in 46 % of the patients receiving vedolizumab, and among them, 20 % relapsed during follow-up. The incidence rate of relapse was 7 % per patient-year. Adverse events were mild in 6 % on ustekinumab and 8 % on vedolizumab. CONCLUSION: Ustekinumab and vedolizumab appear effective, achieving remission in around half of complex perianal fistula patients, with favorable safety profiles.

Economic impact of inflammatory bowel disease in Catalonia: a population-based analysis.

Background: Inflammatory bowel disease (IBD) has a major economic impact on healthcare costs. Objectives: The aim of this study was to evaluate the current healthcare expenditure associated with IBD in a population-wide study in Catalonia. Design: Retrospective observational study. Methods: All patients with IBD included in the Catalan Health Surveillance System (CHSS) were considered eligible. The CHSS compiles data on more than 7 million individuals in 2020 (34,823 with IBD). Data on the use of healthcare resources and its economic impact were extracted applying the International Classification of Diseases, 10th revision, Clinical Modification codes (ICD-10-CM codes). Health expenditure, comorbidities, and hospitalization were calculated according to the standard costs of each service provided by the Department of Health of the Catalan government. The data on the IBD population were compared with non-IBD population adjusted for age, sex, and income level. IBD costs were recorded separately for Crohn's disease (CD) and ulcerative colitis (UC). Results: Prevalence of comorbidities was higher in patients with IBD than in those without. The risk of hospitalization was twice as high in the IBD population. The overall healthcare expenditure on IBD patients amounted to 164M€. The pharmacy cost represents the 60%. The average annual per capita expenditure on IBD patients was more than 3.4-fold higher (IBD 4200€, non-IBD 1200€). Average costs of UC were 3400€ and 5700€ for CD. Conclusion: The risk of comorbidities was twice as high in patients with IBD and their use of healthcare resources was also higher than that of their non-IBD counterparts. Per capita healthcare expenditure was approximately 3.4 times higher in the population with IBD. Trial registration: The study was not previously registered.

Economic impact of inflammatory bowel disease in Catalonia The manuscript includes data of the most recent epidemiologic data about the high economic impact of IBD in Catalonia.

The NUTRIENT Trial (NUTRitional Intervention among myEloproliferative Neoplasms): Results from a Randomized Phase I Pilot Study for Feasibility and Adherence.

PURPOSE: Chronic inflammation is integral to myeloproliferative neoplasm (MPN) pathogenesis. JAK inhibitors reduce cytokine levels, but not without significant side effects. Nutrition is a low-risk approach to reduce inflammation and ameliorate symptoms in MPN. We performed a randomized, parallel-arm study to determine the feasibility of an education-focused Mediterranean diet intervention among patients with MPN. EXPERIMENTAL DESIGN: We randomly assigned patients with MPN to either a Mediterranean diet or standard U.S. Dietary Guidelines for Americans (USDA). Groups received equal but separate education with registered dietician counseling and written dietary resources. Patients were prospectively followed for feasibility, adherence, and symptom burden assessments. Biological samples were collected at four timepoints during the 15-week study to explore changes in inflammatory biomarkers and gut microbiome. RESULTS: The Mediterranean diet was as easy to follow for patients with MPN as the standard USDA diet. Approximately 80% of the patients in the Mediterranean diet group achieved a Mediterranean Diet Adherence Score of ≥8 throughout the entire active intervention period, whereas less than 50% of the USDA group achieved a score of ≥8 at any timepoint. Improvement in symptom burden was observed in both diet groups. No significant changes were observed in inflammatory cytokines. The diversity and composition of the gut microbiome remained stable throughout the duration of the intervention. CONCLUSIONS: With dietician counseling and written education, patients with MPN can adhere to a Mediterranean eating pattern. Diet interventions may be further developed as a component of MPN care, and potentially incorporated into the management of other hematologic conditions. SIGNIFICANCE: Diet is a central tenant of management of chronic conditions characterized by subclinical inflammation, such as cardiovascular disease, but has not entered the treatment algorithm for clonal hematologic disorders. Here, we establish that a Mediterranean diet intervention is feasible in the MPN patient population and can improve symptom burden. These findings warrant large dietary interventions in patients with hematologic disorders to test the impact of diet on clinical outcomes.

Incidence of Myelotoxicity and Other Adverse Effects Related to Thiopurine Starting in Patients with Inflammatory Bowel Disease: Retrospective Observational Study in a Third-Level Hospital.

BACKGROUND AND OBJECTIVES: Thiopurines are an effective treatment for the maintenance of remission in inflammatory bowel disease (IBD). They can present adverse effects (AEs), with myelotoxicity being the most relevant. This study aims to determine the incidence of AEs related to the starting of thiopurines in our centre. METHODOLOGY: Retrospective study. The AEs in patients that were started on thiopurines between January 2016 and June 2020 were registered, with a two-year follow-up. The mean and standard deviation were used to describe the quantitative variables, and percentages and confidence intervals were used for the qualitative variables. The statistical significance was set at a p-value < 0.05. RESULTS: 98 patients were included, with 64 AEs detected in 48 patients (49%). Most of the AEs appeared in the first 6 months. The most relevant were: 21 neutropenia (21.4%), 19 hypertransaminasemia (19.4%), 13 digestive intolerances (13.2%), 6 acute pancreatitis (6.12%), 3 phototoxicity (3%), and 2 unknown origin fevers (2%). In 29 patients (29.4%) the treatment had to be suspended due to AEs. In 11 cases (11.2%), azathioprine (AZA) was switched to 6-mercaptopurine (6 MP) as 5 showed tolerance and 6 patients needed suspension due to AEs. Eight patients required hospital admission, but none of them needed intensive care unit admission. There were no fatal adverse effects. CONCLUSIONS: Thiopurines are a safe drug with few AEs, especially after the first months of treatment. These results suggest that periodic analytic follow-up may not be necessary after the initial period of treatment.

Cigarette smoke stimulates clonal expansion of Jak2V617F and Tet2-/- cells.

Introduction: Somatic mutations in myeloid growth factor pathway genes, such as JAK2, and genes involved in epigenetic regulation, such as TET2, in hematopoietic stem cells (HSCs) leads to clonal hematopoiesis of indeterminate potential (CHIP) which presents a risk factor for hematologic malignancy and cardiovascular disease. Smoking behavior has been repeatedly associated with the occurrence of CHIP but whether smoking is an environmental inflammatory stressor in promoting clonal expansion has not been investigated. Methods: We performed in vivo smoke exposures in both wildtype (WT) mice and transplanted mice carrying Jak2V617F mutant and Tet2 knockout (Tet-/-) cells to determine the impact of cigarette smoke (CS) in the HSC compartment as well as favoring mutant cell expansion. Results: WT mice exposed to smoke displayed increased oxidative stress in long-term HSCs and suppression of the hematopoietic stem and progenitor compartment but smoke exposure did not translate to impaired hematopoietic reconstitution in primary bone marrow transplants. Gene expression analysis of hematopoietic cells in the bone marrow identified an imbalance between Th17 and Treg immune cells suggesting a local inflammatory environment. We also observed enhanced survival of Jak2V617F cells exposed to CS in vivo and cigarette smoke extract (CSE) in vitro. WT bone marrow hematopoietic cells from WT/Jak2V617F chimeric mice exposed to CS demonstrated an increase in neutrophil abundance and distinct overexpression of bone marrow stromal antigen 2 (Bst2) and retinoic acid early transcript 1 (Raet1) targets. Bst2 and Raet1 are indicative of increased interferon signaling and cellular stress including oxidative stress and DNA damage, respectively. In chimeric mice containing both WT and Tet2-/- cells, we observed an increased percentage of circulating mutant cells in peripheral blood post-cigarette smoke exposure when compared to pre-exposure levels while this difference was absent in air-exposed controls. Conclusion: Altogether, these findings demonstrate that CS results in an inflamed bone marrow environment that provides a selection pressure for existing CHIP mutations such as Jak2V617F and Tet2 loss-of-function.

Selecting the Best Combined Biological Therapy for Refractory Inflammatory Bowel Disease Patients.

Current medical treatment for inflammatory bowel disease (IBD) does not achieve 100% response rates, and a subset of refractory and severely ill patients have persistent active disease after being treated with all possible drug alternatives. The combination of two biological therapies (CoT) seems a reasonable alternative, and has been increasingly tested in very difficult cases. The present review suggests that CoT seems to be safe and effective for refractory and severely ill IBD patients. Ustekinumab plus vedolizumab and vedolizumab plus anti-TNF were the most used CoTs for Crohn's disease. For ulcerative colitis, the most used CoTs were vedolizumab plus anti-TNF and vedolizumab plus tofacitinib. The aforesaid CoTs have shown good efficacy and few adverse events have been reported.