Maneig i pronòstic actual dels brots de colitis ulcerosa moderats-greus tractats amb corticoides endovenosos : implicacions del fracàs de corticoides orals i de la utilització precoç de predictors de resposta i tractaments de rescat /

Aquesta tesi doctoral es centra en el maneig i el pronòstic dels brots moderats-greus de colitis ulcerosa (CU) que requereixen tractament amb corticoides endovenosos (Cev) mitjançant tres estudis. Els Cev són el tractament d'elecció pels brots moderats-greus de CU. La seva utilització està perfectament establerta en els brots greus, no així en els brots moderats, on el tractament inicial poden ser tant aminosal·licilats orals o, en pacients que ja estan en tractament de manteniment amb aminosal·licilats, corticoides orals (Cvo). A més, també és habitual en la pràctica clínica diària la utilització directe de Cev pels brots moderats. D'altra banda, en cas de no respondre a l'administració oral, es recomana la seva administració endovenosa o iniciar un tractament de rescat (infliximab o fàrmacs anticalcineurínics), sense existir gaire evidència al respecte. Ara bé, sabem que entorn del 30-40% dels pacients no respondran al tractament amb Cev i requeriran de tractaments de rescat (ciclosporina, infliximab o colectomia). La eficàcia a curt termini dels tractaments de rescat ha estat avaluada prèviament en diferents estudis. No obstant, pocs estudis han avaluat la eficàcia a llarg termini d'ambdós tractaments, malgrat que els costos i el perfil de seguretat són prou diferents. Finalment, la disponibilitat dels tractaments de rescat així com la utilització de factors predictius de resposta precoç als Cev, podrien haver canviat el pronòstic a curt i llarg termini d'aquests pacients, tot i que les dades al respecte són escasses. El primer article inclou pacients amb brots moderats de CU tractats amb Cev i valora la resposta en funció del fracàs previ a Cvo. L'estudi aporta dues troballes rellevants: la resposta inicial dels Cev és del 76%, taxa molt superior a la descrita amb els Cvo; i que tot i no detectar-se diferències en la resposta inicial als Cev entre els tractats directament amb Cev i aquells amb fracàs previ de Cvo, la proporció de pacients que desenvolupa corticodependència en el seguiment és significativament superior en els pacients que vénen de fracàs de Cvo. Per tant, en brots moderats sense resposta a Cvo, la seva administració endovenosa pot ser una alternativa, tot i que el seu seguiment hauria de ser més intensiu. El segon article compara el pronòstic dels pacients no responedors a Cev en funció de dues estratègies de tractament segons el primer tractament de rescat (ciclosporina primer i després infliximab o viceversa). La principal aportació de l'estudi és la troballa de que tot i no observar-se diferències entre les dues estratègies, el tractament seqüencial pot evitar la colectomia en una proporció important de pacients. També es va trobar que valors menors de PCR s'associen a eficàcia inicial i que l'exposició prèvia a tiopurines s'associa a major risc de colectomia i menor resposta a ciclosporina. Per tant, en cas de pacients no naïve a tiopurines, infliximab sembla la millor opció. La ciclosporina, en canvi, sembla la millor opció pels pacients naïve a tiopurines amb brot corticorefractari sense activitat greu. El tercer article té com a objectiu descriure el pronòstic actual dels brots greus de CU en base a la necessitat de tractament de rescat i de colectomia a curt i llarg termini. Les principals aportacions de l'estudi són la constatació d'una reducció en la taxa de colectomia a curt i llarg termini en comparació a la descrita en estudis previs i la troballa del fracàs dels Cvo per al brot índex com a factor predictiu de necessitat de tractament de rescat i colectomia. Per tant, en cas de brots moderats que empitjoren durant el tractament amb Cvo estaria indicat iniciar un tractament de rescat en lloc d'intentar la seva administració endovenosa.This doctoral thesis explores the prognosis and management of moderate to severe flares of ulcerative colitis (UC) requiring treatment with intravenous corticosteroids (CS) through three multicentre retrospective studies. Intravenous CS is the treatment of choice for moderate to severe UC flares. However, the use of CS is not well established in moderate cases. In such cases, oral aminosalicylates are considered the first-line treatment, although in patients on maintenance therapy with aminosalicylates, oral CS is an accepted alternative. Moreover, in daily clinical practice, the use of intravenous CS is widespread. When patients do not respond to oral CS, the recommended approach is intravenous administration or rescue therapy (infliximab or calcineurin inhibitors), though scarce evidence exists with respect to them. The response to intravenous CS has remained stable and we know that around 30-40% of patients do not respond to treatment and require rescue therapy (cyclosporine, infliximab or colectomy). The short term efficacy of rescue therapy has been assessed by a number of studies, though few studies have assessed the long term efficacy of both treatments, despite their significantly divergent costs and safety profiles. Finally, both the availability of rescue therapies and early predictors of poor response to CS may have changed the short and long term prognoses for these patients, though data with respect to this issue is scarce. In line with this, the first article addresses patients with moderate UC flares treated with intravenous CS and evaluates their response in terms of their previous failure to respond to oral CS treatment. The study offers two important findings. Firstly, the initial response rate to intravenous CS in moderate flares is 76%, a higher rate than that described for oral CS. Secondly, although no differences were observed in the initial response to intravenous CS by the patients treated directly via the intravenous route and those with a previous failure to oral CS, the proportion of patients who develop steroid-dependency during the follow up was significantly higher in patients with a previous failure to oral CS. Therefore, in cases of moderate flares that do not respond to oral CS treatment, intravenous administration may be an alternative to rescue therapies, though follow up should be more intensive. In the second article, the short and long term prognoses of non-responders to intravenous CS treatment are compared in terms of two strategies adopted depending on the first rescue therapy (cyclosporine followed by infliximab and vice-versa). The study's main finding is that although no differences were found between these strategies in the short or long term, sequential treatment made it possible to avoid colectomy in a substantial proportion of patients. Furthermore, it was observed that lower PCR values were associated with initial efficacy and previous exposure to thiopurines was associated with a higher risk of colectomy and a reduced response to cyclosporine. Taking these results into account, in cases of non thiopurine-naïve patients, infiximab seems to be the best option. Ciclosporine, seems to be the best option for thiopurine-naive patients with a corticosteroid-resistant flare without severe activity. Finally, the third article aims to describe the current prognosis of severe UC flares based on the need for rescue therapy and colectomy. The main contribution of this study is the observation of a dramatic reduction in the colectomy rate compared to those described in previous studies and the failure of oral CS therapy for the index flare as a predictor of the need for rescue therapy and colectomy. Therefore, in cases of moderate flares that worsen during treatment with oral CS, initiating rescue therapy could be indicated, rather than an attempt at utilizing the intravenous route

How and when should NSAIDs be used for preventing post-ERCP pancreatitis? A systematic review and meta-analysis

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to be efficacious to prevent pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). However, the target patients, the type of NSAID, the route of administration and the time of drug delivery remain unclear, as well as the potential efficacy in reducing the severity of pancreatitis, length of hospital stay and mortality. The objective of the study was to evaluate these questions by performing a systematic review and meta-analysis. Methods: Multiple searches were performed in the main databases. Randomized controlled trials (RCTs) comparing NSAIDs vs. placebo in the prevention of post-ERCP pancreatitis were included. Primary endpoint of the study was the efficacy for pancreatitis prevention. Sub-analyses were performed to determine the risk reduction in high and low risk patients, and to define optimal time, route of administration, and type of NSAID. Secondary endpoints were safety, moderate to severe pancreatitis prevention and reduction of hospital stay and mortality. Results: Nine RCTs enrolling 2133 patients were included. The risk of pancreatitis was lower in the NSAID group than in the placebo group (RR 0.51; 95%CI 0.39-0.66). The number needed to treat was 14. The risk of moderate to severe pancreatitis was also lower in the NSAID group. (RR 0.46; 95%CI 0.28-0.76). No adverse events related to NSAID use were reported. NSAIDs were effective in both high-risk and unselected patients (RR 0.53; 95%CI 0.30-0.93 and RR 0.57; 95%CI 0.37-0.88). In the subanalyses, only rectal administration of either indomethacin (RR 0.54; 95%CI 0.38-0.75) or diclofenac (RR 0.42; 95%CI 0.21-0.84) was shown to be effective. There were not enough data to perform a meta-analysis in hospital stay reduction. No deaths occurred. Conclusion: A single rectal dose of indomethacin or diclofenac before or immediately after ERCP is safe and prevents procedure-related pancreatitis both in high risk and in unselected patients

Endoscopic treatment (endoscopic balloon dilation/self-expandable metal stent) vs surgical resection for the treatment of de novo stenosis in Crohn's disease (ENDOCIR study): an open-label, multicentre, randomized trial.

Background: Stenosis is one of the most common complications in patients with Crohn's disease (CD). Endoscopic balloon dilation (EBD) is the treatment of choice for a short stenosis adjacent to the anastomosis from previous surgery. Self-expandable metal stents (SEMS) may be a suitable treatment option for longer stenoses. To date, however, there is no scientific evidence as to whether endoscopic (EBD/SEMS) or surgical treatment is the best approach for de novo or primary stenoses that are less than 10 cm in length. Methods/design: Exploratory study as "proof-of-concept", multicentre, open-label, randomized trial of the treatment of de novo stenosis in the CD; endoscopic treatment (EBD/SEMS) vs surgical resection (SR). The type of endoscopic treatment will initially be with EDB; if a therapeutic failure occurs, then a SEMS will be placed. We estimate 2 years of recruitment and 1 year of follow-up for the assessment of quality of life, costs, complications, and clinical recurrence. After the end of the study, patients will be followed up for 3 years to re-evaluate the variables over the long term. Forty patients with de novo stenosis in CD will be recruited from 15 hospitals in Spain and will be randomly assigned to the endoscopic or surgical treatment groups. The primary aim will be the evaluation of the patient quality of life at 1 year follow-up (% of patients with an increase of 30 points in the 32-item Inflammatory Bowel Disease Questionnaire (IBDQ-32). The secondary aim will be evaluation of the clinical recurrence rate, complications, and costs of both treatments at 1-year follow-up. Discussion: The ENDOCIR trial has been designed to determine whether an endoscopic or surgical approach is therapeutically superior in the treatment of de novo stenosis in CD

Effectiveness and Safety of the Sequential Use of a Second and Third Anti-TNF Agent in Patients With Inflammatory Bowel Disease: Results From the Eneida Registry

Background: The effectiveness of the switch to another anti-tumor necrosis factor (anti-TNF) agent is not known. The aim of this study was to analyze the effectiveness and safety of treatment with a second and third anti-TNF drug after intolerance to or failure of a previous anti-TNF agent in inflammatory bowel disease (IBD) patients. Methods: We included patients diagnosed with IBD from the ENEIDA registry who received another anti-TNF after intolerance to or failure of a prior anti-TNF agent. Results: A total of 1122 patients were included. In the short term, remission was achieved in 55% of the patients with the second anti-TNF. The incidence of loss of response was 19% per patient-year with the second anti-TNF. Combination therapy (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.8-3; P < 0.0001) and ulcerative colitis vs Crohn's disease (HR, 1.6; 95% CI, 1.1-2.1; P = 0.005) were associated with a higher probability of loss of response. Fifteen percent of the patients had adverse events, and 10% had to discontinue the second anti-TNF. Of the 71 patients who received a third anti-TNF, 55% achieved remission. The incidence of loss of response was 22% per patient-year with a third anti-TNF. Adverse events occurred in 7 patients (11%), but only 1 stopped the drug. Conclusions: Approximately half of the patients who received a second anti-TNF achieved remission; nevertheless, a significant proportion of them subsequently lost response. Combination therapy and type of IBD were associated with loss of response. Remission was achieved in almost 50% of patients who received a third anti-TNF; nevertheless, a significant proportion of them subsequently lost response

Risk Factors for COVID-19 in Inflammatory Bowel Disease: A National, ENEIDA-Based Case–Control Study (COVID-19-EII)

(1) Scant information is available concerning the characteristics that may favour the acquisition of COVID-19 in patients with inflammatory bowel disease (IBD). Therefore, the aim of this study was to assess these differences between infected and noninfected patients with IBD. (2) This nationwide case-control study evaluated patients with inflammatory bowel disease with COVID-19 (cases) and without COVID-19 (controls) during the period March-July 2020 included in the ENEIDA of GETECCU. (3) A total of 496 cases and 964 controls from 73 Spanish centres were included. No differences were found in the basal characteristics between cases and controls. Cases had higher comorbidity Charlson scores (24% vs. 19%; p = 0.02) and occupational risk (28% vs. 10.5%; p < 0.0001) more frequently than did controls. Lockdown was the only protective measure against COVID-19 (50% vs. 70%; p < 0.0001). No differences were found in the use of systemic steroids, immunosuppressants or biologics between cases and controls. Cases were more often treated with 5-aminosalicylates (42% vs. 34%; p = 0.003). Having a moderate Charlson score (OR: 2.7; 95%CI: 1.3-5.9), occupational risk (OR: 2.9; 95%CI: 1.8-4.4) and the use of 5-aminosalicylates (OR: 1.7; 95%CI: 1.2-2.5) were factors for COVID-19. The strict lockdown was the only protective factor (OR: 0.1; 95%CI: 0.09-0.2). (4) Comorbidities and occupational exposure are the most relevant factors for COVID-19 in patients with IBD. The risk of COVID-19 seems not to be increased by immunosuppressants or biologics, with a potential effect of 5-aminosalicylates, which should be investigated further and interpreted with caution

Maneig i pronòstic actual dels brots de colitis ulcerosa moderats-greus tractats amb corticoides endovenosos: implicacions del fracàs de corticoides orals i de la utilització precoç de predictors de resposta i tractaments de rescat

Aquesta tesi doctoral es centra en el maneig i el pronòstic dels brots moderats-greus de colitis ulcerosa (CU) que requereixen tractament amb corticoides endovenosos (Cev) mitjançant tres estudis. Els Cev són el tractament d’elecció pels brots moderats-greus de CU. La seva utilització està perfectament establerta en els brots greus, no així en els brots moderats, on el tractament inicial poden ser tant aminosal.licilats orals o, en pacients que ja estan en tractament de manteniment amb aminosal.licilats, corticoides orals (Cvo). A més, també és habitual en la pràctica clínica diària la utilització directe de Cev pels brots moderats. D’altra banda, en cas de no respondre a l’administració oral, es recomana la seva administració endovenosa o iniciar un tractament de rescat (infliximab o fàrmacs anticalcineurínics), sense existir gaire evidència al respecte. Ara bé, sabem que entorn del 30-40% dels pacients no respondran al tractament amb Cev i requeriran de tractaments de rescat (ciclosporina, infliximab o colectomia). La eficàcia a curt termini dels tractaments de rescat ha estat avaluada prèviament en diferents estudis. No obstant, pocs estudis han avaluat la eficàcia a llarg termini d’ambdós tractaments, malgrat que els costos i el perfil de seguretat són prou diferents. Finalment, la disponibilitat dels tractaments de rescat així com la utilització de factors predictius de resposta precoç als Cev, podrien haver canviat el pronòstic a curt i llarg termini d’aquests pacients, tot i que les dades al respecte són escasses. El primer article inclou pacients amb brots moderats de CU tractats amb Cev i valora la resposta en funció del fracàs previ a Cvo. L’estudi aporta dues troballes rellevants: la resposta inicial dels Cev és del 76%, taxa molt superior a la descrita amb els Cvo; i que tot i no detectar-se diferències en la resposta inicial als Cev entre els tractats directament amb Cev i aquells amb fracàs previ de Cvo, la proporció de pacients que desenvolupa corticodependència en el seguiment és significativament superior en els pacients que vénen de fracàs de Cvo. Per tant, en brots moderats sense resposta a Cvo, la seva administració endovenosa pot ser una alternativa, tot i que el seu seguiment hauria de ser més intensiu. El segon article compara el pronòstic dels pacients no responedors a Cev en funció de dues estratègies de tractament segons el primer tractament de rescat (ciclosporina primer i després infliximab o viceversa). La principal aportació de l’estudi és la troballa de que tot i no observar-se diferències entre les dues estratègies, el tractament seqüencial pot evitar la colectomia en una proporció important de pacients. També es va trobar que valors menors de PCR s’associen a eficàcia inicial i que l’exposició prèvia a tiopurines s’associa a major risc de colectomia i menor resposta a ciclosporina. Per tant, en cas de pacients no naïve a tiopurines, infliximab sembla la millor opció. La ciclosporina, en canvi, sembla la millor opció pels pacients naïve a tiopurines amb brot corticorefractari sense activitat greu. El tercer article té com a objectiu descriure el pronòstic actual dels brots greus de CU en base a la necessitat de tractament de rescat i de colectomia a curt i llarg termini. Les principals aportacions de l’estudi són la constatació d’una reducció en la taxa de colectomia a curt i llarg termini en comparació a la descrita en estudis previs i la troballa del fracàs dels Cvo per al brot índex com a factor predictiu de necessitat de tractament de rescat i colectomia. Per tant, en cas de brots moderats que empitjoren durant el tractament amb Cvo estaria indicat iniciar un tractament de rescat en lloc d’intentar la seva administració endovenosa.This doctoral thesis explores the prognosis and management of moderate to severe flares of ulcerative colitis (UC) requiring treatment with intravenous corticosteroids (CS) through three multicentre retrospective studies. Intravenous CS is the treatment of choice for moderate to severe UC flares. However, the use of CS is not well established in moderate cases. In such cases, oral aminosalicylates are considered the first-line treatment, although in patients on maintenance therapy with aminosalicylates, oral CS is an accepted alternative. Moreover, in daily clinical practice, the use of intravenous CS is widespread. When patients do not respond to oral CS, the recommended approach is intravenous administration or rescue therapy (infliximab or calcineurin inhibitors), though scarce evidence exists with respect to them. The response to intravenous CS has remained stable and we know that around 30-40% of patients do not respond to treatment and require rescue therapy (cyclosporine, infliximab or colectomy). The short term efficacy of rescue therapy has been assessed by a number of studies, though few studies have assessed the long term efficacy of both treatments, despite their significantly divergent costs and safety profiles. Finally, both the availability of rescue therapies and early predictors of poor response to CS may have changed the short and long term prognoses for these patients, though data with respect to this issue is scarce. In line with this, the first article addresses patients with moderate UC flares treated with intravenous CS and evaluates their response in terms of their previous failure to respond to oral CS treatment. The study offers two important findings. Firstly, the initial response rate to intravenous CS in moderate flares is 76%, a higher rate than that described for oral CS. Secondly, although no differences were observed in the initial response to intravenous CS by the patients treated directly via the intravenous route and those with a previous failure to oral CS, the proportion of patients who develop steroid-dependency during the follow up was significantly higher in patients with a previous failure to oral CS. Therefore, in cases of moderate flares that do not respond to oral CS treatment, intravenous administration may be an alternative to rescue therapies, though follow up should be more intensive. In the second article, the short and long term prognoses of non-responders to intravenous CS treatment are compared in terms of two strategies adopted depending on the first rescue therapy (cyclosporine followed by infliximab and vice-versa). The study’s main finding is that although no differences were found between these strategies in the short or long term, sequential treatment made it possible to avoid colectomy in a substantial proportion of patients. Furthermore, it was observed that lower PCR values were associated with initial efficacy and previous exposure to thiopurines was associated with a higher risk of colectomy and a reduced response to cyclosporine. Taking these results into account, in cases of non thiopurine-naïve patients, infiximab seems to be the best option. Ciclosporine, seems to be the best option for thiopurine-naive patients with a corticosteroid-resistant flare without severe activity. Finally, the third article aims to describe the current prognosis of severe UC flares based on the need for rescue therapy and colectomy. The main contribution of this study is the observation of a dramatic reduction in the colectomy rate compared to those described in previous studies and the failure of oral CS therapy for the index flare as a predictor of the need for rescue therapy and colectomy. Therefore, in cases of moderate flares that worsen during treatment with oral CS, initiating rescue therapy could be indicated, rather than an attempt at utilizing the intravenous route

Flow diagram of included and excluded trials.

<p>Flow diagram of included and excluded trials.</p

Summary of subanalyses comparing NSAIDs vs. placebo in reducing the number of patients with PEP according to: type of NSAID, route and time of administration and patients inclusion criteria.

<p>Summary of subanalyses comparing NSAIDs vs. placebo in reducing the number of patients with PEP according to: type of NSAID, route and time of administration and patients inclusion criteria.</p

Subanalysis: rectal NSAIDs <i>vs.</i> placebo in reducing the number of pancreatitis in subgroup of patients with a risk factor.

<p><i>SOH:</i> sphincter of Oddi hypertension; <i>ERCP:</i> endoscopic retrograde cholangiopancreatography; <i>NSAIDs:</i> non-steroidal anti-inflammatory drugs.</p>a<p>The two different studies used different cut-off values to separate young and old patients, one using 45 years and the other 60 years.</p>b<p>Prophylactic measure, not risk factor.</p

Meta-analysis comparing NSAIDs vs. placebo in reducing the number of moderate to severe pancreatitis.

<p><i>CI,</i> confidence interval; <i>M-H</i>, Mantel-Haenszel; <i>NSAIDs</i>, non-steroidal anti-inflammatory drugs.</p