Genetic biomarkers of methotrexate response and safety in Crohn's disease: Data from the Spanish ENEIDA registry.

AIMS: Methotrexate (MTX) is used to induce and maintain remission in patients with steroid-dependent Crohn's disease (CD). Despite its proven efficacy, its use is limited due to associated adverse events. Polymorphisms involving folate pathway genes might influence MTX efficacy and toxicity. We aimed to assess the impact of certain polymorphisms on the therapeutic outcomes of MTX in CD. METHODS: Patients with CD who exclusively followed MTX monotherapy and fulfilled inclusion criteria were identified from the GETECCU ENEIDA registry. Variants of ATIC, DHFR, MTHFR, SLC19A1, ABCB1 and ABCC3 genes were analysed and their association with efficacy and toxicity was assessed. RESULTS: A total of 129 patients were included in the analysis. MTX was used at a median weekly dose of 25 mg (interquartile range, 15-25 mg) and a median time of 14 months (interquartile range, 4-52 months). Thirty-seven percent of the patients achieved disease remission with MTX monotherapy, while 34% were nonresponders (MTX failure). MTX-related toxicity occurred in 40 patients (30%), leading to MTX discontinuation in 19%. DHFR rs408626 (odds ratio [OR] 3.12, 95% confidence interval [CI] 1.22-7.69; P = .017) and MTHFR rs1801133 (OR 2.86, 95% CI 1.23-6.68; P = .015) variants, and smoking (OR 2.61, 95% CI 1.12-6.05; P = .026) were associated with a higher risk of MTX failure. Additionally, the MTHFR rs1801131 variant was associated with a higher risk of MTX-related adverse effects (OR 2.78, 95% CI 1.26-6.13, P = .011). CONCLUSION: Our study shows that variants of MTHFR and DHFR genes may be associated with MTX efficacy and adverse events in patients with CD.

Incidence of herpes zoster in patients with inflammatory bowel disease. / Incidencia de herpes zóster en pacientes con enfermedad inflamatoria intestinal: estudio observacional y retrospectivo en dos hospitales españoles de tercer nivel.

BACKGROUND: Herpes zoster (HZ) is a prevalent disease caused by the reactivation of the varicella-zoster virus (VZV) and associated with chronic morbidity, particularly with post-herpetic neuralgia (PHN). Inflammatory bowel disease (IBD) has been associated with an increased risk of HZ, mainly when immunosuppressive treatment (IMT) is used. However, studies assessing the risk of HZ in IBD are scarce. AIMS: To evaluate the incidence rate and risk factors of HZ in IBD. METHODS: Retrospective study in IBD patients with a positive VVZ serology from two referral hospitals from the area of Barcelona. Diagnosis of HZ and its clinical features were recorded. RESULTS: A total of 398 IBD patients with a positive IgG-VVZ serology were identified. Fifty-eight percent of the patients received IMT (46.5% immunosuppressants monotherapy, 20.6% biologics monotherapy and, 32.7% combination therapy). After a median follow-up of 71 months (IQR 41.5-138.0), 17 (4.3%) patients developed HZ (cumulative incidence of 5.2 per 1000 person-year), 12 of them (70.6%) while receiving IMT. Median age at HZ episode was 38 years (IQR 27.5-52.5). Two (11%) developed PHN. Biological therapy was the only risk factor for developing HZ (OR 3.8 IC 95% 1.3-11.5; p=0.018). CONCLUSIONS: HZ is quite prevalent in IBD, occurring at early ages and particularly among patients using IMT. NPH appears to occur in a notable proportion of cases.

Recommendations on the management of severe obesity in patients with inflammatory bowel disease of the Spanish Group on Crohn's Disease and Ulcerative Colitis (GETECCU), Spanish Society of Obesity (SEEDO), Spanish Association of Surgery (AEC) and Spanish Society of Digestive Endoscopy (SEED). / Recomendaciones sobre el manejo de la obesidad grave en pacientes con enfermedad inflamatoria intestinal del Grupo Español de Trabajo en Enfermedad Inflamatoria Intestinal (GETECCU), Sociedad Española de Obesidad (SEEDO), Asociación Española de Cirugía (AEC) y Sociedad Española de Endoscopia Digestiva (SEED).

Obesity is a multifactorial, chronic, progressive and recurrent disease considered a public health issue worldwide and an important determinant of disability and death. In Spain, its current prevalence in the adult population is about 24% and an estimated prevalence in 2035 of 37%. Obesity increases the probability of several diseases linked to higher mortality such as diabetes, cardiovascular disease, hyperlipidemia, arterial hypertension, non-alcoholic fatty liver disease, several types of cancer, or obstructive sleep apnea. On the other hand, although the incidence of inflammatory bowel disease (IBD) is stabilizing in Western countries, its prevalence already exceeds 0.3%. Paralleling to general population, the current prevalence of obesity in adult patients with IBD is estimated at 15-40%. Obesity in patients with IBD could entail, in addition to its already known impact on disability and mortality, a worse evolution of the IBD itself and a worse response to treatments. The aim of this document, performed in collaboration by four scientific societies involved in the clinical care of severe obesity and IBD, is to establish clear and concise recommendations on the therapeutic possibilities of severe or typeIII obesity in patients with IBD. The document establishes general recommendations on dietary, pharmacological, endoscopic, and surgical treatment of severe obesity in patients with IBD, as well as pre- and post-treatment evaluation.

IMPACT OF MESALAZINE ON THE RESPONSE TO COVID-19 VACCINATION IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE. RESULTS OF A PROSPECTIVE MULTICENTRE STUDY OF GETECCU (VACOVEII STUDY). / IMPACTO DE LA MESALAZINA EN LA RESPUESTA A LA VACUNACIÓN CONTRA EL COVID-19 EN PACIENTES CON ENFERMEDAD INFLAMATORIA INTESTINAL. RESULTADOS DE UN ESTUDIO PROSPECTIVO MULTICÉNTRICO DE GETECCU (VACOVEII).

OBJECTIVE: the recommendations of the Spanish Ministry of Health on vaccination in risk groups include mesalazine among the treatments with a possible negative effect on its effectiveness. However, this is not the recommendation of most experts. Our objective was to evaluate the effect of mesalazine on the humoral response to the SARS-CoV-2 vaccine in patients with inflammatory bowel disease (IBD). METHODS: VACOVEII is a Spanish, prospective, multicenter study promoted by GETECCU, which evaluates the effectiveness of the SARS-CoV-2 vaccine in patients with IBD. This study includes IBD patients who have recieved the full vaccination schedule and without previous COVID-19 infection. Seroconversion was set at 260 BAU/mL (centralized determination) and was assessed 6 months after full vaccination. In this subanalysis of the study, we compare the effectivenes of the vaccine between patients treated with mesalazine and patients without treatment. RESULTS: A total of 124 patients without immunosuppressive therapy were included, of which 32 did not receive any treatment and 92 received only mesalazine. Six months after full vaccination, no significant differences are observed in the mean concentrations of IgG anti-S between both groups. In the multivariate analysis, antibody titers were independently associated with the use of mRNA vaccines and with SARS-CoV-2 infection. CONCLUSION: Mesalazine does not have a negative effect on the response to SARS-CoV-2 vaccines in IBD patients.

Systematic review of the role of calprotectin in cirrhosis.

BACKGROUND: Calprotectin is a calcium-binding-S100-protein synthetized mainly in neutrophils which has been demonstrated to be an accurate biomarker of the presence of these cells. Gut barrier dysfunction in patients with advanced chronic liver disease (ACLD), in addition to the lack of noninvasive tools for diagnosis and prognosis of cirrhosis decompensations, has raised interest in this biomarker. AIMS: Our aim is to summarize the current evidence regarding the role of calprotectin in terms of its diagnostic and prognostic utility in ACLD. METHODS: We performed a systematic search (PROSPERO registration no. CRD42023389069) of original articles published without any restrictions on the publication date until January 2023 providing information about calprotectin for the prognosis or diagnosis of ACLD and its decompensations in adult patients. RESULTS: A total 227 articles were identified, and 26 observational studies finally met the inclusion criteria. In 14 studies, calprotectin was measured in ascitic fluid, all of which reported higher calprotectin values in spontaneous bacterial peritonitis, while cut-off points for its diagnosis were proposed in nine studies. Three studies reported higher faecal calprotectin levels in patients with hepatic encephalopathy and portal hypertension. Four studies evaluated faecal calprotectin and one plasma calprotectin as biomarkers for gut barrier integrity and bacterial translocation. CONCLUSIONS: Calprotectin is emerging as a promising biomarker in ACLD, particularly for the management of bacterial infections and alcohol-related liver disease. Further research with better study designs should help to determine the feasibility of calprotectin measurement in routine clinical practice.

Comparative Study of the Effectiveness of Vedolizumab Versus Ustekinumab After Anti-TNF Failure in Crohn's Disease (Versus-CD): Data from the ENEIDA Registry.

BACKGROUND: Both vedolizumab and ustekinumab are approved for the management of Crohn's disease [CD]. Data on which one would be the most beneficial option when anti-tumour necrosis factor [anti-TNF] agents fail are limited. AIMS: To compare the durability, effectiveness, and safety of vedolizumab and ustekinumab after anti-TNF failure or intolerance in CD. METHODS: CD patients from the ENEIDA registry who received vedolizumab or ustekinumab after anti-TNF failure or intolerance were included. Durability and effectiveness were evaluated in both the short and the long term. Effectiveness was defined according to the Harvey-Bradshaw index [HBI]. The safety profile was compared between the two treatments. The propensity score was calculated by the inverse probability weighting method to balance confounder factors. RESULTS: A total of 835 patients from 30 centres were included, 207 treated with vedolizumab and 628 with ustekinumab. Dose intensification was performed in 295 patients. Vedolizumab [vs ustekinumab] was associated with a higher risk of treatment discontinuation (hazard ratio [HR] 2.55, 95% confidence interval [CI]: 2.02-3.21), adjusted by corticosteroids at baseline [HR 1.27; 95% CI: 1.00-1.62], moderate-severe activity in HBI [HR 1.79; 95% CI: 1.20-2.48], and high levels of C-reactive protein at baseline [HR 1.06; 95% CI: 1.02-1.10]. The inverse probability weighting method confirmed these results. Clinical response, remission, and corticosteroid-free clinical remission were higher with ustekinumab than with vedolizumab. Both drugs had a low risk of adverse events with no differences between them. CONCLUSION: In CD patients who have failed anti-TNF agents, ustekinumab seems to be superior to vedolizumab in terms of durability and effectiveness in clinical practice. The safety profile is good and similar for both treatments.

Defining Comprehensive Disease Control for Use as a Treatment Target for Ulcerative Colitis in Clinical Practice: International Delphi Consensus Recommendations.

BACKGROUND AND AIMS: Treatment of ulcerative colitis [UC] requires a patient-centric definition of comprehensive disease control that considers improvements in aspects not typically captured by classical landmark trial endpoints. In an international initiative, we reviewed aspects of UC that affect patients and/or indicate mucosal inflammation, to achieve consensus on which aspects to combine in a definition of comprehensive disease control, using a modified Delphi process. METHODS: The Delphi panel comprised 12 gastroenterologists and one patient advocate. Two gastroenterologists were elected as chairs and did not vote. To inform statements, we asked 18 patients and the panel members about their experiences of remission and reviewed published literature. Panel members voted on statements anonymously in three rounds, with a live discussion before Round 3. Consensus was met if ≥67% of the panel agreed. Statements without consensus in Rounds 1 and 2 were revised or discarded after Round 3. RESULTS: The panel agreed to measure individual patient benefit using a definition of comprehensive disease control that combines aspects currently measured in trials [rectal bleeding, stool frequency, disease-related quality of life, endoscopy, histological inflammatory activity, inflammatory biomarkers, and corticosteroid use] with additional patient-reported symptoms [bowel urgency, abdominal pain, extraintestinal manifestations, fatigue, and sleep disturbance]. The panel agreed on scoring systems and thresholds for many aspects. CONCLUSIONS: Using a robust methodology, we defined comprehensive disease control in UC. Next, we will combine the measurement and scoring of these aspects into a multicomponent tool and will adopt comprehensive disease control as a treatment target in clinical practice and trials.

Hepatosplenic T-cell lymphoma and inflammatory bowel disease

A 48-year-old man with a diagnosis of ulcerative colitis 18 years ago, under immunosuppressive treatment with azathioprine in the last 6 years due to corticosteroid dependence, was admitted to the Emergency Department due to fever of one week’s evolution. Blood tests showed thrombocytopenia, CRP 96.9mg/L, ferritin 3021ng/mL and hypertriglyceridemia. Blood and urine cultures were negative. Viral serologies (hepatitis B and C, HIV, parvovirus, CMV, HSV), atypical bacteria (Borrelia, Chlamydia, Coxiella) and screening for latent tuberculosis were also negative. Thoracoabdominal CT scan only showed splenomegaly. The bone marrow aspirate revealed immature lymphoid cells and a hemophagocyte figure, fulfilling the criteria for hemophagocytic syndrome, starting corticosteroid therapy at a dose of 1mg/Kg. Subsequently, the existence of an intrasinusoidal CD3 + CD5- lymphoid infiltrate and a FISH study with isochromosome 7q was reported, a characteristic pattern of hepatosplenic T-cell lymphoma (HSTCL). The study was completed with liver biopsy appreciating a 70% infiltration of T lymphocytes (50% gamma-delta) therefore the diagnosis was confirmed. Chemotherapy (cyclophosphamide, doxorubicin, vincristine, etoposide) was started with the aim of considering hematopoietic stem cell transplantation. Unfortunately, the patient died 6 months later. (AU)

Splanchnic Vein Thrombosis in Inflammatory Bowel Disease: An Observational Study from the ENEIDA Registry and Systematic Review.

BACKGROUND: Thromboembolic events are frequent among patients with inflammatory bowel disease (IBD). However, there is little information on the prevalence, features and outcomes of splanchnic vein thrombosis (SVT) in patients with IBD. AIMS: To describe the clinical features and outcomes of SVT in patients with IBD and to perform a systematic review of these data with published cases and series. METHODS: A retrospective observational study from the Spanish nationwide ENEIDA registry was performed. A systematic search of the literature was performed to identify studies with at least one case of SVT in IBD patients. RESULTS: A new cohort of 49 episodes of SVT from the Eneida registry and 318 IBD patients with IBD identified from the literature review (sixty studies: two multicentre, six single-centre and fifty-two case reports or case series) were analysed. There was a mild predominance of Crohn's disease and the most frequent clinical presentation was abdominal pain with or without fever followed by the incidental finding in cross-sectional imaging techniques. The most frequent SVT location was the main portal trunk in two-thirds of the cases, followed by the superior mesenteric vein. Anticoagulation therapy was prescribed in almost 90% of the cases, with a high rate of radiologic resolution of SVT. Thrombophilic conditions other than IBD itself were found in at least one-fifth of patients. CONCLUSIONS: SVT seems to be a rare (or underdiagnosed) complication in IBD patients. SVT is mostly associated with disease activity and evolves suitably when anticoagulation therapy is started.

A booster dose of SARS-COV-2 vaccine improves suboptimal seroconversion rates in patients with inflammatory bowel disease. Results of a prospective multicenter study of GETECCU (VACOVEII study).

BACKGROUND: The response to SARS-CoV-2 vaccination decreases in inflammatory bowel disease (IBD) patients, specially under anti-TNF treatment. However, data on medium-term effectiveness are limited, specially using new recommended seroconversion rate (>260BAU/mL). Our aim was to evaluate the 6-month>260 BAU-seroconversion rate after full vaccination and after booster-dose. METHODS: VACOVEII is a Spanish multicenter, prospective study promoted by GETECCU. IBD patients full vaccinated against SARS-CoV-2 and without previous COVID-19 infection, treated or not with immunosuppressants, were included. The booster dose was administered 6 months after the full vaccination. Seroconversion was set at 260BAU/mL, according to most recent recommendations and was assessed 6 months after the full vaccination and 6 months after booster-dose. RESULTS: Between October 2021 and March 2022, 313 patients were included (124 no treatment or mesalazine; 55 immunomodulators; 87 anti-TNF; 19 anti-integrin; and 28 ustekinumab). Most patients received mRNA-vaccines (86%). Six months after full vaccination, overall seroconversion rate was 44.1%, being significantly lower among patients on anti-TNF (19.5%, p<0.001) and ustekinumab (35.7%, p=0.031). The seroconversion rate after booster was 92%. Again, anti-TNF patients had a significantly lower seroconversion rate (67%, p<0.001). mRNA-vaccine improved seroconversion rate (OR 11.720 [95% CI 2.26-60.512]). CONCLUSION: The full vaccination regimen achieves suboptimal response in IBD patients, specially among those anti-TNF or ustekinumab. The booster dose improves seroconversion rate in all patients, although it remains limited in those treated with anti-TNF. These results reinforce the need to prioritize future booster doses in patients on immunosuppressants therapy, specially under anti-TNF, and using mRNA-vaccines.

Initial management of intraabdominal abscesses and preventive strategies for abscess recurrence in penetrating Crohn's disease: a national multicenter study based on ENEIDA registry.

INTRODUCTION: Intra-abdominal abscesses complicating Crohn's disease (CD) are a challenging situation. Their management, during the hospitalization and after resolution, is still unclear. METHODS: Adult patients with CD complicated with intraabdominal abscess who required hospitalization were included from the prospectively maintained ENEIDA registry from GETECCU. Initial strategy effectiveness and safety to resolve abscess was assessed. Survival analysis was performed to evaluate recurrence risk. Predictive factors associated with resolution were evaluated by multivariate regression and predictive factors associated with recurrence were assessed by Cox regression. RESULTS: 520 patients from 37 Spanish hospitals were included; 322 (63%) were initially treated with antibiotics alone, 128 (26%) with percutaneous drainage, and 54 (17%) with surgical drainage. The size of the abscess was critical to the effectiveness of each treatment. In abscesses < 30mm, the antibiotic was as effective as percutaneous or surgical drainage. However, in larger abscesses, percutaneous or surgical drainage was superior. In abscesses > 50mm, surgery was superior to percutaneous drainage, although it was associated with a higher complication rate. After abscess resolution, luminal resection was associated with a lower 1-year abscess recurrence risk (HR 0.43, 95% CI 0.24-0.76). However, those patients who initiated anti-TNF therapy had a similar recurrence risk whether luminal resection had been performed. CONCLUSIONS: Small abscesses (<30mm) can be managed with antibiotics alone, while larger ones require drainage. Percutaneous drainage will be effective and safer than surgery in many cases. After discharge, anti-TNF therapy reduces abscess recurrence risk in a similar way to bowel resection.

Mesalazine dose modification based on faecal calprotectin levels in patients with ulcerative colitis in clinical remission. / Modificación de la dosis de mesalazina en función de los niveles de calprotectina fecal en pacientes con colitis ulcerosa en remisión clínica.

BACKGROUND: Faecal calprotectin (FC) shows an excellent correlation with endoscopic and histological activity of ulcerative colitis (UC) and it is the best predictor of clinical relapse. Our aim was to evaluate the usefulness of modifying the dose of mesalazine based on FC levels, in clinical practice. METHODS: Retrospective, single-centre study in UC patients in clinical remission while treated with mesalazine which dosage was decreased (DOWN) or increased (UP) according to FC levels. The main endpoint was the long-term maintenance of clinical remission. RESULTS: A total of 56 patients were included (39 DOWN, 17 UP). In the DOWN group, the median baseline dose of mesalazine was 3.6g/day and the median baseline FC was 36µg/g. After a median follow-up of 22 months, 28% required rescue therapy. The cumulative relapse-free survival after tapering was 91% and 82% at 12 and 24 months, respectively. In the UP group, the median baseline dose of mesalazine was 2.4g/day, with a median baseline FC of 524µg/g. After a median follow-up of 12 months, 29% required rescue therapy. The cumulative relapse-free survival after dose increase was 86% and 72% at 12 and 24 months, respectively. CONCLUSIONS: Mesalazine dose modification based on FC monitoring seems to be a safe strategy in patients with UC in clinical remission, with a probability of clinical relapse around 20% at two years.

Hepatosplenic T-cell lymphoma and inflammatory bowel disease.

A 48-year-old man with a diagnosis of ulcerative colitis 18 years ago, under immunosuppressive treatment with azathioprine in the last 6 years due to corticosteroid dependence, was admitted to the Emergency Department due to fever of one week's evolution. Blood tests showed thrombocytopenia, CRP 96.9mg/L, ferritin 3021ng/mL and hypertriglyceridemia. Blood and urine cultures were negative. Viral serologies (hepatitis B and C, HIV, parvovirus, CMV, HSV), atypical bacteria (Borrelia, Chlamydia, Coxiella) and screening for latent tuberculosis were also negative. Thoracoabdominal CT scan only showed splenomegaly. The bone marrow aspirate revealed immature lymphoid cells and a hemophagocyte figure, fulfilling the criteria for hemophagocytic syndrome, starting corticosteroid therapy at a dose of 1mg/Kg. Subsequently, the existence of an intrasinusoidal CD3 + CD5- lymphoid infiltrate and a FISH study with isochromosome 7q was reported, a characteristic pattern of hepatosplenic T-cell lymphoma (HSTCL). The study was completed with liver biopsy appreciating a 70% infiltration of T lymphocytes (50% gamma-delta) therefore the diagnosis was confirmed. Chemotherapy (cyclophosphamide, doxorubicin, vincristine, etoposide) was started with the aim of considering hematopoietic stem cell transplantation. Unfortunately, the patient died 6 months later.

Results of the Eighth Scientific Workshop of ECCO: Prevention and Treatment of Postoperative Recurrence in Patients With Crohn's Disease Undergoing an Ileocolonic Resection With Ileocolonic Anastomosis.

Despite the introduction of biological therapies, an ileocolonic resection is often required in patients with Crohn's disease [CD]. Unfortunately, surgery is not curative, as many patients will develop postoperative recurrence [POR], eventually leading to further bowel damage and a decreased quality of life. The 8th Scientific Workshop of ECCO reviewed the available scientific data on both prevention and treatment of POR in patients with CD undergoing an ileocolonic resection, dealing with conventional and biological therapies, as well as non-medical interventions, including endoscopic and surgical approaches in case of POR. Based on the available data, an algorithm for the postoperative management in daily clinical practice was developed.

Response Variability to Drug Testing in Two Models of Chemically Induced Colitis.

The lack of knowledge regarding the pathogenesis of IBD is a challenge for the development of more effective and safer therapies. Although in vivo preclinical approaches are critical for drug testing, none of the existing models accurately reproduce human IBD. Factors that influence the intra-individual response to drugs have barely been described. With this in mind, our aim was to compare the anti-inflammatory efficacy of a new molecule (MTADV) to that of corticosteroids in TNBS and DSS-induced colitis mice of both sexes in order to clarify further the response mechanism involved and the variability between sexes. The drugs were administered preventively and therapeutically, and real-time bioluminescence was performed for the in vivo time-course colitis monitoring. Morphometric data were also collected, and colonic cytokines and acute plasma phase proteins were analyzed by qRT-PCR and ELISA, respectively-bioluminescence images correlated with inflammatory markers. In the TNBS model, dexamethasone worked better in females, while MTADV improved inflammation in males. In DSS-colitis, both therapies worked similarly. Based on the molecular profiles, interaction networks were constructed to pinpoint the drivers of therapeutic response that were highly dependent on the sex. In conclusion, our results suggest the importance of considering sex in IBD preclinical drug screening.