To evaluate the effectiveness and safety of tofacitinib in ulcerative colitis UC in real life.
Patients from the prospectively maintained ENEIDA registry and treated with tofacitinib due to active UC ...were included. Clinical activity and effectiveness were defined based on Partial Mayo Score PMS. Short-term response/remission was assessed at Weeks 4, 8, and 16.
A total of 113 patients were included. They were exposed to tofacitinib for a median time of 44 weeks. Response and remission at Week 8 were 60% and 31%, respectively. In multivariate analysis, higher PMS at Week 4 (odds ratio OR = 0.2; 95% confidence interval CI = 0.1-0.4) was the only variable associated with lower likelihood of achieving remission at Week 8. Higher PMS at Week 4 OR = 0.5; 95% CI = 0.3-0.7 and higher PMS at Week 8 OR = 0.2; 95% CI = 0.1-0.5 were associated with lower probability of achieving remission at Week 16. A total of 45 patients 40% discontinued tofacitinib over time. Higher PMS at Week 8 was the only factor associated with higher tofacitinib discontinuation hazard ratio = 1.5; 95% CI = 1.3-1.6. A total of 34 patients had remission at Week 8; of these, 65% had relapsed 52 weeks after achieving remission; the dose was increased to 10 mg/12 h in nine patients, and five of them reached remission again. Seventeen patients had adverse events.
Tofacitinib is effective and safe in UC patients in real practice, even in a highly refractory cohort. A relevant proportion of patients discontinue the drug over time, mainly due to primary failure.
Summary
Background
The advent of new therapeutic agents and the improvement of supporting care might change the management of acute severe ulcerative colitis (ASUC) and avoid colectomy.
Aims
To ...evaluate the colectomy‐free survival and safety of a third‐line treatment in patients with ASUC refractory to intravenous steroids and who failed either infliximab or ciclosporin.
Methods
Multicentre retrospective cohort study of patients with ASUC refractory to intravenous steroids who had failed infliximab or ciclosporin and received a third‐line treatment during the same hospitalisation. Patients who stopped second‐line treatment due to disease activity or adverse events (AEs) were eligible. We assessed short‐term colectomy‐free survival by logistic regression analysis. Kaplan–Meier curves and Cox regression models were used for long‐term assessment.
Results
Among 78 patients, 32 received infliximab and 46 ciclosporin as second‐line rescue treatment. Third‐line treatment was infliximab in 45 (58%), ciclosporin in 17 (22%), tofacitinib in 13 (17%) and ustekinumab in 3 (3.8%). Colectomy was performed in 29 patients (37%) during follow‐up (median 21 weeks). Of the 78 patients, 32 and 18 were in clinical remission at, respectively, 12 and 52 weeks. At the last visit, 25 patients were still on third‐line rescue treatment, while 12 had stopped it due to clinical remission. AEs were reported in 26 (33%) patients. Two patients died (2.6%), including one following colectomy.
Conclusion
Third‐line rescue treatment avoided colectomy in over half of the patients with ASUC and may be considered a therapeutic strategy.
The aim was to assess the colectomy‐free survival and safety of a third‐line treatment in acute severe ulcerative colitis (ASUC) refractory to intravenous steroids who fail either infliximab or ciclosporin. A third‐line treatment avoids colectomy in more than half of ASUC patients, albeit one third suffered at least one adverse event.
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) document has modified the grading system directing pharmacotherapy, but how this relates to the previous one from 2015 and to ...comorbidities, hospitalizations, and mortality risk is unknown.
The aim of this study was to evaluate the changes in the GOLD groups from 2015 to 2017 and to assess the impact on severity, comorbidities, and mortality within each group.
We prospectively enrolled and followed, for a mean of 5 years, 819 patients with chronic obstructive pulmonary disease (84% male) in clinics in Spain and the United States. We determined anthropometrics, lung function (FEV
%), dyspnea score (modified Medical Research Council scale), ambulatory and hospital exacerbations, and the body mass index, obstruction, dyspnea, and exercise capacity (BODE) and Charlson indexes. We classified patients by the 2015 and 2017 GOLD ABCD system, and compared the differential realignment of the same patients. We related the effect of the reclassification in BODE and Charlson distribution as well as chronic obstructive pulmonary disease and all-cause mortality between the two classifications.
Compared with 2015, the 2017 grading decreased by half the proportion of patients in groups C and D (20.5% vs. 11.2% and 24.6% vs. 12.9%; P < 0.001). The distribution of Charlson also changed, whereas group D was higher than B in 2015, they become similar in the 2017 system. In 2017, the BODE index and risk of death were higher in B and D than in A and C. The mortality risk was better predicted by the 2015 than the 2017 system.
Compared with 2015, the GOLD ABCD 2017 classification significantly shifts patients from grades C and D to categories A and B. The new grading system equalizes the Charlson comorbidity score in all groups and minimizes the differences in BODE between groups B and D, making the risk of death similar between them.
The proepicardium is a transient structure comprising epicardial progenitor cells located at the posterior limit of the embryonic cardiac inflow. A network of signals regulates proepicardial cell ...fate and defines myocardial and nonmyocardial domains at the venous pole of the heart. During cardiac development, epicardial-derived cells also contribute to coronary vessel morphogenesis.
To study Notch function during proepicardium development and coronary vessel formation in the mouse.
Using in situ hybridization, RT-PCR, and immunohistochemistry, we find that Notch pathway elements are differentially activated throughout the proepicardial-epicardial-coronary transition. Analysis of RBPJk-targeted embryos indicates that Notch ablation causes ectopic procardiogenic signaling in the proepicardium that in turn promotes myocardial differentiation in adjacent mesodermal progenitors, resulting in a premature muscularization of the sinus venosus horns. Epicardium-specific Notch1 ablation using a Wt1-Cre driver line disrupts coronary artery differentiation, reduces myocardium wall thickness and myocyte proliferation, and reduces Raldh2 expression. Ectopic Notch1 activation disrupts epicardium development and causes thinning of ventricular walls.
Epicardial Notch modulates cell differentiation in the proepicardium and adjacent pericardial mesoderm. Notch1 is later required for arterial endothelium commitment and differentiation and for vessel wall maturation during coronary vessel development and myocardium growth.
Abstract
Background and Aims
The development programm UNIFI has shown promising results of ustekinumab in ulcerative colitis UC treatment which should be confirmed in clinical practice. We aimed to ...evaluate the durability, effectiveness, and safety of ustekinumab in UC in real life.
Methods
Patients included in the prospectively maintained ENEIDA registry, who received at least one intravenous dose of ustekinumab due to active UC Partial Mayo Score PMS>2, were included. Clinical activity and effectiveness were defined based on PMS. Short-term response was assessed at Week 16.
Results
A total of 95 patients were included. At Week 16, 53% of patients had response including 35% of patients in remission. In the multivariate analysis, elevated serum C-reactive protein was the only variable significantly associated with lower likelihood of achieving remission. Remission was achieved in 39% and 33% of patients at Weeks 24 and 52, respectively; 36% of patients discontinued the treatment with ustekinumab during a median follow-up of 31 weeks. The probability of maintaining ustekinumab treatment was 87% at Week 16, 63% at Week 56, and 59% at Week 72; primary failure was the main reason for ustekinumab discontinuation. No variable was associated with risk of discontinuation. Three patients reported adverse events; one of them had a fatal severe SARS-CoV-2 infection.
Conclusions
Ustekinumab is effective in both the short and the long term in real life, even in a highly refractory cohort. Higher inflammatory burden at baseline correlated with lower probability of achieving remission. Safety was consistent with the known profile of ustekinumab.
The COVID-19 outbreak challenges the Spanish health system since March 2020. Some available therapies (antimalarials, antivirals, biological agents) were grounded on clinical case observations or ...basic science data. The aim of this study is to describe the characteristics and impact of different therapies on clinical outcomes in a cohort of severe COVID-19 patients.
In this retrospective, single-center, observational study, we collected sequential data on adult patients admitted to Hospital Universitario Quironsalud Madrid. Eligible patients should have a microbiological (positive test on RT-PCR assay from a nasal swab) or an epidemiological diagnosis of severe COVID-19. Demographic, baseline comorbidities, laboratory data, clinical outcomes, and treatments were compared between survivors and non-survivors. We carried out univariate and multivariate logistic regression models to assess potential risk factors for in-hospital mortality.
From March 10th to April 15th, 2020, 607 patients were included. Median age was 69 years interquartile range, {IQR} 22; 65% male). The most common comorbidities were hypertension (276 46·94%), diabetes (95 16·16%), chronic cardiac (133 22·62%) and respiratory (114 19·39%) diseases. 141 patients (23·2%) died. In the multivariate model the risk of death increased with older age (odds ratio, for every year of age, 1·15, 95% CI 1·11 - 1·2), tocilizumab therapy (2·4, 1·13 - 5·11), C-reactive protein at admission (1·07, per 10 mg/L, 1·04 - 1·10), d-dimer > 2·5 μg/mL (1·99, 1·03 - 3·86), diabetes mellitus (2·61, 1·19 - 5·73), and the PaO2/FiO2 at admission (0·99, per every 1 mmHg, 0·98 - 0·99). Among the prescribed therapies (tocilizumab, glucocorticoids, lopinavir/ritonavir, hydroxychloroquine, cyclosporine), only cyclosporine was associated with a significant decrease in mortality (0·24, 0·12 - 0·46; p<0·001).
In a real-clinical setting, inhibition of the calcineurin inflammatory pathway, NF-κΒ, could reduce the hyperinflammatory phase in COVID-19. Our findings might entail relevant implications for the therapy of this disease and could boost the design of new clinical trials among subjects affected by severe COVID-19.
Hospital Universitario Quironsalud Madrid. Own fundings for COVID-19 research.
Summary
Background and Aims
Data on the outcomes after switching from adalimumab (ADA) originator to ADA biosimilar are limited. The aim was to compare the treatment persistence, clinical efficacy, ...and safety outcomes in inflammatory bowel disease patients who maintained ADA originator vs. those who switched to ADA biosimilar.
Methods
Patients receiving ADA originator who were in clinical remission at standard dose of ADA originator were included. Patients who maintained ADA originator formed the non‐switch cohort (NSC), and those who switched to different ADA biosimilars constituted the switch cohort (SC). Clinical remission was defined as a Harvey–Bradshaw index ≤4 in Crohn's disease and a partial Mayo score ≤2 in ulcerative colitis. To control possible confounding effects on treatment discontinuation, an inverse probability treatment weighted proportional hazard Cox regression was performed.
Results
Five hundred and twenty‐four patients were included: 211 in the SC and 313 in the NSC. The median follow‐up was 13 months in the SC and 24 months in the NSC (p < 0.001). The incidence rate of ADA discontinuation was 8% and 7% per patient‐year in the SC and in the NSC, respectively (p > 0.05). In the multivariate analysis, switching from ADA originator to ADA biosimilar was not associated with therapy discontinuation. The incidence rate of relapse was 8% per patient‐year in the SC and 6% per patient‐year in the NSC (p > 0.05). Six percent of the patients had adverse events in the SC vs. 5% in the NSC (p > 0.05).
Conclusion
Switching to ADA biosimilar did not impair patients' outcomes in comparison with maintaining on the originator.
Biological therapies only benefit one-third of patients with Crohn’s disease (CD). For this reason, a deeper understanding of the mechanisms by which biologics elicit their effect on intestinal ...mucosa is needed. Increasing evidence points toward the involvement of long noncoding RNAs (lncRNAs) in the pathogenesis of CD, although their role remains poorly studied. We aimed to characterize lncRNA profiles in the ileum and colon from CD patients and evaluate the effect of anti-TNF-α treatment on their transcription. Terminal ileum and left colon samples from 30 patients (active CD = 10, quiescent CD = 10, and healthy controls (HCs) = 10) were collected for RNA-seq. The patients were classified according to endoscopic activity. Furthermore, biopsies were cultured with infliximab, and their transcriptome was determined by Illumina gene expression array. A total of 678 differentially expressed lncRNAs between the terminal ileum and left colon were identified in HCs, 438 in patients with quiescent CD, and 468 in patients with active CD. Additionally, we identified three new lncRNAs in the ileum associated with CD activity. No differences were observed when comparing the effect of infliximab according to intestinal location, presence of disease (CD vs. HC), and activity (active vs. quiescent). The expression profiles of lncRNAs are associated with the location of intestinal tissue, being very different in the ileum and colon. The presence of CD and disease activity are associated with the differential expression of lncRNAs. No modulatory effect of infliximab has been observed in the lncRNA transcriptome.
Summary
Background
Crohn's disease (CD) with upper gastrointestinal involvement (UGI) may have a more aggressive and refractory course. However, evidence on this phenotype of patients is scarce.
Aims
...To identify the clinical characteristics, therapeutic requirements and complications associated with UGI in CD
Methods
Nationwide study of cases (UGI, UGI plus ileal/ileocolonic involvement) paired with controls (ileal/ileocolonic involvement) from the ENEIDA registry. Cases were matched to 2 controls by year of diagnosis ± 2.5 years. Patients with exclusive/predominant colonic location or complex perianal fistula were excluded.
Results
Of 24 738 patients with CD in the ENEIDA registry, we identified 4058 with UGI (16% of the total CD cohort). Finally, 854 cases and 1708 controls were included. Cases were independently associated to extensive involvement (OR 2.7 2.2‐3.3, P < 0.0001), strictures OR 1.8 (1.5‐2.2), P < 0.0001, chronic iron deficiency anaemia OR 2.2 (1.3‐3.2), P < 0.001 and use of second‐line biologics OR 1.7 (1.1‐2.6), P = 0.021. The median stricture‐free time was 14 years (95% CI, 12‐16) for cases vs 21 years (95% CI, 19‐23) for controls (P < 0.0001). Cases with isolated UGI compared to UGI plus ileal/ileocolonic more frequently had localised disease OR 0.5(0.3‐0.8), P = 0.003 and underwent more endoscopic stricture dilations OR 2.7(1.3‐5.4), P = 0.006.
Conclusions
The largest cohort of patients with CD and UGI provides information on the natural history of this particular phenotype. Increased awareness of the clinical picture and therapeutic requirements of these patients could lead to earlier diagnosis and treatment of upper gastrointestinal lesions, preventing the structural damage frequently seen in these patients at diagnosis and during follow‐up.
Clinical features, therapeutic requirements and evolution of patients with Crohn's disease and upper gastrointestinal involvement (CROHNEX study)Study population: Cases: patients with Crohn'sdisease and upper gastrointestinal involvement (n = 854).Controls: patients with Crohn's disease and ileal/ilecocolonic involvement (n = 1708). Patients were identified from the ENEIDA registry (Spanish cohort of patients with inflammatory bowel disease). Cases were matched to 2 controls by year of diagnosis ± 2.5 years. Patients with exclusive/predominant colonic location and those with complex perianal fistula were excluded. Results:
Cases were more likely to have:
Extensive involvement (OR 2.7 2.2‐3.3, P < 0.0001).
Strictures (OR 1.8 1.5‐2.2, P < 0.0001).
Chronic iron deficiency anaemia (OR 2.2 1.3‐3.2, P < 0.001).
Use of second‐line biologics (OR 1.7 1.12.6, P = 0.021).
The median stricture‐free time was 14 years (95% CI, 12‐16) for cases vs 21 years (95% CI, 19‐23) for controls (P < 0.0001).
(1) Aims: To assess the incidence of inflammatory bowel disease (IBD) in Spain, to describe the main epidemiological and clinical characteristics at diagnosis and the evolution of the disease, and to ...explore the use of drug treatments. (2) Methods: Prospective, population-based nationwide registry. Adult patients diagnosed with IBD-Crohn's disease (CD), ulcerative colitis (UC) or IBD unclassified (IBD-U)-during 2017 in Spain were included and were followed-up for 1 year. (3) Results: We identified 3611 incident cases of IBD diagnosed during 2017 in 108 hospitals covering over 22 million inhabitants. The overall incidence (cases/100,000 person-years) was 16 for IBD, 7.5 for CD, 8 for UC, and 0.5 for IBD-U; 53% of patients were male and median age was 43 years (interquartile range = 31-56 years). During a median 12-month follow-up, 34% of patients were treated with systemic steroids, 25% with immunomodulators, 15% with biologics and 5.6% underwent surgery. The percentage of patients under these treatments was significantly higher in CD than UC and IBD-U. Use of systemic steroids and biologics was significantly higher in hospitals with high resources. In total, 28% of patients were hospitalized (35% CD and 22% UC patients,
< 0.01). (4) Conclusion: The incidence of IBD in Spain is rather high and similar to that reported in Northern Europe. IBD patients require substantial therapeutic resources, which are greater in CD and in hospitals with high resources, and much higher than previously reported. One third of patients are hospitalized in the first year after diagnosis and a relevant proportion undergo surgery.
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