Evaluation of Genetic Variants Associated with the Risk of Thiopurine-Related Pancreatitis: A Case Control Study from ENEIDA Registry.

INTRODUCTION: Risk factors for developing pancreatitis due to thiopurines in patients with inflammatory bowel disease (IBD) are not clearly identified. Our aim was to evaluate the predictive pharmacogenetic risk of pancreatitis in IBD patients treated with thiopurines. METHODS: We conducted an observational pharmacogenetic study of acute pancreatitis events in a cohort study of IBD patients treated with thiopurines from the prospectively maintained ENEIDA registry biobank of GETECCU. Samples were obtained and the CASR, CEL, CFTR, CDLN2, CTRC, SPINK1, CPA1, and PRSS1 genes, selected based on their known association with pancreatitis, were fully sequenced. RESULTS: Ninety-five cases and 105 controls were enrolled; a total of 57% were women. Median age at pancreatitis diagnosis was 39 years. We identified 81 benign variants (50 in cases and 67 in controls) and a total of 35 distinct rare pathogenic and unknown significance variants (10 in CEL, 21 in CFTR, 1 in CDLN2, and 3 in CPA1). None of the cases or controls carried pancreatitis-predisposing variants within the CASR, CPA1, PRSS1, and SPINK1 genes, nor a pathogenic CFTR mutation. Four different variants of unknown significance were detected in the CDLN and CPA1 genes; one of them was in the CDLN gene in a single patient with pancreatitis and 3 in the CPA1 gene in 5 controls. After the analysis of the variants detected, no significant differences were observed between cases and controls. CONCLUSION: In patients with IBD, genes known to cause pancreatitis seem not to be involved in thiopurine-related pancreatitis onset.

Headache in patients with inflammatory bowel disease: Migraine prevalence according to the Migraine Screening-Questionnaire (MS-Q) and headache characteristics.

BACKGROUND: The gut-brain axis describes a complex bidirectional association between neurological and gastrointestinal (GI) disorders. In patients with migraine, GI comorbidities are common. We aimed to evaluate the presence of migraine among patients with inflammatory bowel disease (IBD) according to Migraine Screen-Questionnaire (MS-Q) and describe the headache characteristics compared to a control group. Additionally, we explored the relationship between migraine and IBD severities. METHODS: We performed a cross-sectional study through an online survey including patients from the IBD Unit at our tertiary hospital. Clinical and demographic variables were collected. MS-Q was used for migraine evaluation. Headache disability scale HIT-6, anxiety-depression scale HADS, sleep scale ISI, and activity scale Harvey-Bradshaw and Partial Mayo scores were also included. RESULTS: We evaluated 66 IBD patients and 47 controls. Among IBD patients, 28/66 (42%) were women, mean age 42 years and 23/66 (34.84%) had ulcerative colitis. MS-Q was positive in 13/49 (26.5%) of IBD patients and 4/31 (12.91%) controls (p=0.172). Among IBD patients, headache was unilateral in 5/13 (38%) and throbbing in 10/13 (77%). Migraine was associated with female sex (p=0.006), lower height (p=0.003) and weight (p=0.002), anti-TNF treatment (p=0.035). We did not find any association between HIT-6 and IBD activity scales scores. CONCLUSIONS: Migraine presence according to MS-Q could be higher in patients with IBD than controls. We recommend migraine screening in these patients, especially in female patients with lower height and weight and anti-TNF treatment.

Long-Term Outcomes of Biological Therapy in Crohn's Disease Complicated With Internal Fistulizing Disease: BIOSCOPE Study From GETECCU.

INTRODUCTION: The prevalence of penetrating complications in Crohn's disease (CD) increases progressively over time, but evidence on the medical treatment in this setting is limited. The aim of this study was to evaluate the effectiveness of biologic agents in CD complicated with internal fistulizing disease. METHODS: Adult patients with CD-related fistulae who received at least 1 biologic agent for this condition from the prospectively maintained ENEIDA registry were included. Exclusion criteria involved those receiving biologics for perianal disease, enterocutaneous, rectovaginal, anastomotic, or peristomal fistulae. The primary end point was fistula-related surgery. Predictive factors associated with surgery and fistula closure were evaluated by multivariate logistic regression and survival analyses. RESULTS: A total of 760 patients from 53 hospitals (673 receiving anti-tumor necrosis factors, 69 ustekinumab, and 18 vedolizumab) were included. After a median follow-up of 56 months (interquartile range, 26-102 months), 240 patients required surgery, with surgery rates of 32%, 41%, and 24% among those under anti-tumor necrosis factor, vedolizumab, or ustekinumab, respectively. Fistula closure was observed in 24% of patients. Older patients, ileocolonic disease, entero-urinary fistulae, or an intestinal stricture distal to the origin of the fistula were associated with a higher risk of surgery, whereas nonsmokers and combination therapy with an immunomodulator reduced this risk. DISCUSSION: Biologic therapy is beneficial in approximately three-quarters of patients with fistulizing CD, achieving fistula closure in 24%. However, around one-third still undergo surgery due to refractory disease. Some patient- and lesion-related factors can identify patients who will obtain more benefit from these drugs.

Tumor cells in light-chain amyloidosis and myeloma show distinct transcriptional rewiring of normal plasma cell development.

Although light-chain amyloidosis (AL) and multiple myeloma (MM) are characterized by tumor plasma cell (PC) expansion in bone marrow (BM), their clinical presentation differs. Previous attempts to identify unique pathogenic mechanisms behind such differences were unsuccessful, and no studies have investigated the differentiation stage of tumor PCs in patients with AL and MM. We sought to define a transcriptional atlas of normal PC development in secondary lymphoid organs (SLOs), peripheral blood (PB), and BM for comparison with the transcriptional programs (TPs) of tumor PCs in AL, MM, and monoclonal gammopathy of undetermined significance (MGUS). Based on bulk and single-cell RNA sequencing, we observed 13 TPs during transition of normal PCs throughout SLOs, PB, and BM. We further noted the following: CD39 outperforms CD19 to discriminate newborn from long-lived BM-PCs; tumor PCs expressed the most advantageous TPs of normal PC differentiation; AL shares greater similarity to SLO-PCs whereas MM is transcriptionally closer to PB-PCs and newborn BM-PCs; patients with AL and MM enriched in immature TPs had inferior survival; and protein N-linked glycosylation-related TPs are upregulated in AL. Collectively, we provide a novel resource to understand normal PC development and the transcriptional reorganization of AL and other monoclonal gammopathies.

Cross-Cultural Adaptation and Validation of the European Portuguese Dysphagia Handicap Index.

The Dysphagia Handicap Index (DHI) is a valid Health-related Quality of Life (HRQoL) 25-item questionnaire assessing the physical, functional, and emotional aspects of patients with oropharyngeal dysphagia (OD), of heterogeneous etiologies. The purpose of this study is to translate and validate the European Portuguese-DHI (EP-DHI). This is a prospective study that was carried out at Centro Hospitalar Universitário do Porto (CHUPorto). The generated EP-DHI was administered to 132 patients with OD and 112 healthy control subjects. 132 patients undergoing fiberoptic endoscopic examination of swallowing (FEES). 15 patients were contacted by phone, 2 or 3 weeks later after the first interview to repeat the questionnaire. The validity of concurrent criteria was evaluated by comparing the results of the EP-DHI score with the score attributed to the pathological findings found in FEES and, consequently, Functional Oral Intake Scale (FOIS). The internal consistency of EP-DHI was successful: Cronbach's alpha coefficient for total EP-DHI was 0.874. The test-retest reliability for the total and the three EP-DHI subscales obtained a Pearson's correlation coefficient ranged from 0.990 to 0.712. This study demonstrates that EP-DHI is a valid tool for self-assessment of the handicapping effect of dysphagia on physical, functional, and emotional aspects of patient's quality of life, among an European Portuguese sample.

Long Non-Coding RNA Signatures in the Ileum and Colon of Crohn's Disease Patients and Effect of Anti-TNF-α Treatment on Their Modulation.

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.

Prediction of Relapse After Anti-Tumor Necrosis Factor Cessation in Crohn's Disease: Individual Participant Data Meta-analysis of 1317 Patients From 14 Studies.

BACKGROUND & AIMS: Tools for stratification of relapse risk of Crohn's disease (CD) after anti-tumor necrosis factor (TNF) therapy cessation are needed. We aimed to validate a previously developed prediction model from the diSconTinuation in CrOhn's disease patients in stable Remission on combined therapy with Immunosuppressants (STORI) trial, and to develop an updated model. METHODS: Cohort studies were selected that reported on anti-TNF cessation in 30 or more CD patients in remission. Individual participant data were requested for luminal CD patients and anti-TNF treatment duration of 6 months or longer. The discriminative ability (concordance-statistic [C-statistic]) and calibration (agreement between observed and predicted risks) were explored for the STORI model. Next, an updated prognostic model was constructed, with performance assessment by cross-validation. RESULTS: This individual participant data meta-analysis included 1317 patients from 14 studies in 11 countries. Relapses after anti-TNF cessation occurred in 632 of 1317 patients after a median of 13 months. The pooled 1-year relapse rate was 38%. The STORI prediction model showed poor discriminative ability (C-statistic, 0.51). The updated model reached a moderate discriminative ability (C-statistic, 0.59), and included clinical symptoms at cessation (hazard ratio [HR], 2.2; 95% CI, 1.2-4), younger age at diagnosis (HR, 1.5 for A1 (age at diagnosis ≤16 years) vs A2 (age at diagnosis 17 - 40 years); 95% CI, 1.11-1.89), no concomitant immunosuppressants (HR, 1.4; 95% CI, 1.18-172), smoking (HR, 1.4; 95% CI, 1.15-1.67), second line anti-TNF (HR, 1.3; 95% CI, 1.01-1.69), upper gastrointestinal tract involvement (HR, 1.3 for L4 vs non-L4; 95% CI, 0.96-1.79), adalimumab (HR, 1.22 vs infliximab; 95% CI, 0.99-1.50), age at cessation (HR, 1.2 per 10 years younger; 95% CI, 1-1.33), C-reactive protein (HR, 1.04 per doubling; 95% CI, 1.00-1.08), and longer disease duration (HR, 1.07 per 5 years; 95% CI, 0.98-1.17). In subanalysis, the discriminative ability of the model improved by adding fecal calprotectin (C-statistic, 0.63). CONCLUSIONS: This updated prediction model showed a reasonable discriminative ability, exceeding the performance of a previously published model. It might be useful to guide clinical decisions on anti-TNF therapy cessation in CD patients after further validation.

Canine endotheliitis: Clinical characteristics, advanced imaging features, and treatment.

OBJECTIVE: To describe the clinical findings, multimodal corneal imaging features and treatment in canine patients diagnosed with endotheliitis. ANIMALS STUDIED: Four canine patients met inclusion criteria for bilateral corneal disease with endothelial inflammation and secondary corneal edema that responded to topical anti-inflammatory treatment. METHODS: The patients selected underwent a complete ophthalmic examination with emphasis on the cornea including ultrasound pachymetry (USP), Fourier-domain optical coherence tomography (FD-OCT), in vivo confocal microscopy (IVCM), and digital slit lamp photography. RESULTS: All patients in this study demonstrated thickened corneas due to edema with USP and FD-OCT. With IVCM, mild to severe polymegathism and pleomorphism of corneal endothelial cells, reduced endothelial cell density, hyperreflective keratic precipitates (KPs), and extracellular debris as well as hyporeflective pseudoguttata were observed. With FD-OCT, hyperreflective KPs were commonly observed on the inferior cornea. Clinical examination and advanced imaging results were consistent with a diagnosis of endotheliitis. All patients initially responded to topical anti-inflammatory treatment and required continued therapy; two patients also received topical netarsudil, a rho-associated coiled-coil kinase inhibitor. CONCLUSION: Endotheliitis should be considered for canine patients with bilateral edema that is most severe in the inferior cornea. Careful inspection of Descemet's membrane-endothelial complex should be performed for KPs or inflammatory debris. Chronic administration of topical anti-inflammatories may be necessary to prevent flare-ups of endotheliitis.

May Measurement Month 2019: an analysis of blood pressure screening results from Colombia.

Hypertension awareness and control is poor in low- and middle-income countries. Thus, implementing strategies to increase hypertension detection is needed. Colombia participated as one of the 92 countries involved in the third campaign of the May Measurement Month in 2019. Blood pressure (BP) was measured in 48 324 volunteers from 13 departments in Colombia. In total, 27.9% individuals were identified with hypertension. Of those with hypertension, 63.7% were aware of their condition, 60.0% were on antihypertensive medication, and 38.4% had controlled BP. These results showed low levels of awareness, treatment, and control of hypertension in this sample of subjects volunteered to participate, suggest the urgent necessity of implementing programmes to improve the diagnosis and management of hypertension in Colombia.

CYLD Inhibits the Development of Skin Squamous Cell Tumors in Immunocompetent Mice.

Cylindromatosis (CYLD) is a deubiquitinase (DUB) enzyme that was initially characterized as a tumor suppressor of adnexal skin tumors in patients with CYLD syndrome. Later, it was also shown that the expression of functionally inactive mutated forms of CYLD promoted tumor development and progression of non-melanoma skin cancer (NMSC). However, the ability of wild-type CYLD to inhibit skin tumorigenesis in vivo in immunocompetent mice has not been proved. Herein, we generated transgenic mice that express the wild type form of CYLD under the control of the keratin 5 (K5) promoter (K5-CYLDwt mice) and analyzed the skin properties of these transgenic mice by WB and immunohistochemistry, studied the survival and proliferating characteristics of primary keratinocytes, and performed chemical skin carcinogenesis experiments. As a result, we found a reduced activation of the nuclear factor kappa B (NF-κB) pathway in the skin of K5-CYLDwt mice in response to tumor necrosis factor-α (TNF-α); accordingly, when subjected to insults, K5-CYLDwt keratinocytes are prone to apoptosis and are protected from excessive hyperproliferation. Skin carcinogenesis assays showed inhibition of tumor development in K5-CYLDwt mice. As a mechanism of this tumor suppressor activity, we found that a moderate increase in CYLD expression levels reduced NF-κB activation, which favored the differentiation of tumor epidermal cells and inhibited its proliferation; moreover, it decreased tumor angiogenesis and inflammation. Altogether, our results suggest that increased levels of CYLD may be useful for anti-skin cancer therapy.

Epidemiological and clinical characteristics, and response to treatment in 113 patients with microscopic colitis. / Características epidemiológicas, clínicas y respuesta al tratamiento en 113 pacientes con colitis microscópica.

OBJECTIVE: To study the epidemiological and clinical characteristics, and response to treatment in patients with microscopic colitis. PATIENTS AND METHOD: Epidemiological, clinical, blood test and endoscopic data were retrospectively collected from 113 patients with microscopic colitis. Response to treatment was analyzed in 104 of them. Efficacy and relapse after treatment with budesonide were assessed using survival curves (Kaplan-Meier). RESULTS: 78% of the patients were women, with a mean age of 65 ± 16 years. In smokers, the mean age was 10 years younger. 48% of them had some concomitant autoimmune disease; 60% suffered a single outbreak of the disease. The clinical presentation was similar in both subtypes, although patients with collagenous colitis had a chronic course more frequently (48% vs. 29%, p = 0.047). The remission rate with budesonide was 93% (95% CI 82-98). The cumulative incidence of relapse, after a median follow-up of 21 months, was 39% (95% CI 26-54%): 19% at one year, 32% at two years, and 46% at three years of follow-up. There were no differences in clinical response to budesonide based on smoking habit or microscopic colitis subtype. CONCLUSIONS: Microscopic colitis is more frequent in elderly women. Smoking was associated with earlier onset of the disease, although it did not influence the clinical course or response to treatment. The majority (> 90%) of patients treated with budesonide achieved remission, although nearly half subsequently relapsed.

Correction to: Efficacy and safety of endoscopic balloon dilation in inflammatory bowel disease: results of the large multicenter study of the ENEIDA registry.

Javier P. Gisbert was listed incorrectly as Javier Pérez-Gisbert.

Efficacy and safety of endoscopic balloon dilation in inflammatory bowel disease: results of the large multicenter study of the ENEIDA registry.

BACKGROUND: There is no information regarding the outcome of Crohn's disease (CD) patients treated with endoscopic balloon dilation (EBD) in non-referral hospitals, nor on the efficacy of EBD in ulcerative colitis (UC). We report herein the results of the largest series published to date. AIM: To assess the efficacy and safety of EBD for inflammatory bowel disease (IBD) stenosis performed in 19 hospitals with different levels of complexity and to determine factors related to therapeutic success. METHODS: We identified IBD patients undergoing EBD in the ENEIDA database. Efficacy of EBD was compared between CD and UC and between secondary and tertiary hospitals. Predictive factors of therapeutic success were assessed with multivariate analysis. RESULTS: Four-hundred dilations (41.2% anastomotic) were performed in 187 IBD patients (13 UC/Indeterminate colitis). Technical and therapeutic success per dilation was achieved in 79.5% and 55.3%, respectively. Therapeutic success per patient was achieved in 78.1% of cases (median follow-up: 40 months) with 49.7% requiring more than one dilation. No differences related to either diagnosis or hospital complexity was found. Technical success [OR 4.12 (95%CI 2.4-7.1)] and not receiving anti-TNF at the time of dilation [OR 1.7 (95% CI 1.1-2.6)] were independently related to therapeutic success per dilation. A stricture length ≤ 2 cm [HR 2.43 (95% CI 1.11-5.31)] was a predictive factor of long-term success per patient. The rate of major complications was 1.3%. CONCLUSIONS: EBD can be performed with similar efficacy and safety in hospitals with differing levels of complexity and it might be a suitable treatment for UC with short stenosis. To achieve a technical success and the short length of the stenosis seem to be critical for long-term therapeutic success.

May Measurement Month 2018: an analysis of blood pressure screening results from Colombia.

High blood pressure (BP) is the leading global preventable cause of death and the most common risk factor for cardiovascular disease (CVD). However, due to its asymptomatic nature, the lack of awareness of this condition causes underdiagnosis and low rates of adherence to pharmacological treatment. Looking for practical approaches to increase awareness worldwide, the International Society of Hypertension (ISH) implemented the 2nd May Measurement Month campaign in 2018 (MMM18). In order to contribute to this initiative, Colombia participated as one of the 89 countries involved in this hypertension screening programme. Blood pressure was measured in subjects from 11 departments in Colombia. Under the leadership of the Fundación Oftalmológica de Santander (FOSCAL), 400 volunteers across the country collected the data following the MMM protocol. Measurements from 35 548 participants with a mean age of 41.9 years were obtained. In total, 9475 (26.7%) of the total population studied had hypertension. Of those with hypertension, 69.9% of these subjects were aware of their condition, 65.0% were on antihypertensive medication, and 43.1% had controlled BP. Of those on medication, 66.3% had controlled BP. Hypertension screening, awareness, treatment, and control should be a priority in public health objectives due to its elevated burden of disease and direct association with increased CVD. The MMM campaign provided a positive impact in the diagnosis of hypertension across Colombia. Although efforts are being made to expand treatment capability and adherence, still more are needed to insure a broader coverage of antihypertensive medication in Colombia.

Treatment of microscopic colitis: the role of budesonide and new alternatives for refractory patients.

Microscopic colitis is a common cause of chronic watery diarrhea with a great impact on patient quality of life. Microscopic colitis includes two histological subtypes: collagenous colitis and lymphocytic colitis. Due to the increasing incidence and awareness of this disease over the last decades, several international guidelines have been recently published. However, there is still significant heterogeneity in the management of these patients, and treatments without solid scientific evidence support are often used in clinical practice. This article reviews the therapeutic role of budesonide in microscopic colitis and summarizes the current evidence regarding other treatments available for this disease, especially for the management of refractory patients. Finally, an updated treatment algorithm is proposed.

Quality of care through the eyes of the patient in a Spanish inflammatory bowel disease unit.

INTRODUCTION: the quality of care perceived by the patient is a fundamental aspect of the accreditation program of inflammatory bowel disease (IBD) units. The aim of this study was to evaluate the quality of healthcare from the patient's point of view in an IBD Unit. METHODS: consecutive patients diagnosed with Crohn's disease or ulcerative colitis that attended the IBD Unit of the Hospital Universitario de La Princesa and anonymously filled out the Quality of Care through the Patient's Eyes - Inflammatory Bowel Disease (QUOTE-IBD) questionnaire were included in the study. QUOTE-IBD is a validated 23-item questionnaire, which explores the Importance given by patients to care aspects and the Performance of medical practices and healthcare workers. Each item assesses eight care dimensions: Competence, Autonomy, Courtesy, Accessibility, Information, Costs, Continuity of care and Accommodation. RESULTS: one hundred patients from our IBD Unit completed the QUOTE-IBD. In terms of dimensions, patients gave the highest Importance score to aspects related to Information (8.24), followed by Competence in IBD care (7.86). Performance scores ranged from 0.4 for Continuity of care to 0.01 for Cost. CONCLUSIONS: the application of the QUOTE-IBD questionnaire to assess the level of satisfaction of our patients with the quality of healthcare provided by our unit has allowed us to identify areas of improvement in the Information and Continuity of care dimensions. The highest score according to the perspective of our patients was obtained in the Competence in care dimension.

Errors in the care of inflammatory bowel disease patients: "Errata" Study. / Errores en la atención de los pacientes con enfermedad inflamatoria intestinal: estudio «ERRATA¼.

INTRODUCTION: Errors are very common in daily clinical practice; however, they can be prevented. Our aim was to identify the most common errors in the outpatient management of inflammatory bowel disease (IBD) patients. MATERIAL AND METHODS: Patients diagnosed with IBD, being treated at our IBD Unit and who were referred for a second opinion were consecutively enrolled. Data on the strategies implemented by their previous physicians were obtained. These strategies were compared with the currently recommended diagnostic and therapeutic procedures. RESULTS: Seventy-four IBD patients were enrolled. Prior to care in our Unit, screening for tobacco use had been performed in 50% of Crohn's disease patients, while smoking cessation counselling had been provided in 29%. At the time of IBD diagnosis, the hepatitis B virus immunization status had been investigated in 16% of the patients, the hepatitis C virus status in 15%, and the varicella status in 7%. Seven percent of the patients had been vaccinated against hepatitis B virus, and 3% against influenza, tetanus and pneumococcus. Sixty-seven percent of the patients with an indication for use of 5-aminosalicylic acid and 37% of those with an indication for immunosuppressants had received the indicated drug. DISCUSSION: Errors in the outpatient management of IBD patients are very common and relevant.

A phase II study to evaluate lenalidomide in combination with metronomic-dose cyclophosphamide in patients with heavily pretreated classical Hodgkin lymphoma.

BACKGROUND: Relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) after autologous stem cell transplantation (ASCT) remains a challenge. For these patients treatments with different mechanisms of action rather than classical chemotherapy are needed. PATIENTS AND METHODS: Patients with R/R cHL after ASCT were recruited in a phase II trial (EUDRA CT: 2009-016588-12). Lenalidomide was administered at 20 mg/day for 21 days and cyclophosphamide at 50 mg/day for 28 days (cycles every 28 days). Dose escalation for lenalidomide was permitted. In 2009 we considered that this treatment would be promising if response rate were over 60% and a Simon two-stage binomial design was used to calculate the sample size. A total of 46 patients were planned but the trial would be stopped if less than seven responses after four cycles were obtained in the first 16 patients. RESULTS: The trial was closed early because only five responses were observed after four cycles in the first 16 patients included. Median age was 34 years (18-77). The median number of previous lines was five (2-6). At inclusion, 10 patients were primary refractory and 11 refractory to the last therapy. A total of 110 cycles were administered, with grade≥3 toxicity in 43 cycles (39%). One non-neutropenic patient developed septic shock resulting in death. An ORR of 38% (1 CR and 5 PR) was observed and a total of 10 patients (62%) achieved clinical benefit. Median progression free survival and overall survival were seven and 19 months, respectively. With a median follow-up of 19 months (3-38+), three-year progression-free and overall survival were 6% and 31%, respectively. CONCLUSION: The optimistic assumptions of this trial led to an early closure. However, the promising clinical benefit observed with the oral combination of lenalidomide and metronomic cyclophosphamide may justify its use for outpatient palliative treatment.

Discontinuation of Anti-Tumour Necrosis Factor Therapy in Patients with Perianal Fistulizing Crohn's Disease: Individual Participant Data Meta-Analysis of 309 Patients from 12 Studies.

BACKGROUND: The risk of relapse after anti-tumour necrosis factor [TNF] therapy discontinuation in Crohn's disease patients with perianal fistulas [pCD] is unclear. We aimed to assess this risk. METHODS: A systematic literature search was conducted to identify cohort studies on the incidence of relapse following anti-TNF discontinuation in pCD patients. Individual participant data were requested from the original study cohorts. Inclusion criteria were age ≥16 years, pCD as a (co)indication for start of anti-TNF therapy, more than three doses, and remission of luminal and pCD at anti-TNF discontinuation. The primary outcome was the cumulative incidence of CD relapse using Kaplan-Meier estimates. Secondary outcomes included response to re-treatment and risk factors associated with relapse as assessed by Cox regression analysis. RESULTS: In total, 309 patients from 12 studies in ten countries were included. The median duration of anti-TNF treatment was 14 months [interquartile range 5.8-32.5]. Most patients were treated for pCD without active luminal disease [89%], received first-line anti-TNF therapy [87%], and continued immunomodulatory therapy following anti-TNF discontinuation [78%]. The overall cumulative incidence of relapse was 36% (95% confidence interval [CI] 25-48%) and 42% [95% CI 32-53%] at 1 and 2 years after anti-TNF discontinuation, respectively. Risk factors for relapse included smoking (hazard ratio [HR] 1.5 [1.0, 2.1]) and history of proctitis (HR 1.7 [1.1, 2.5]). The overall re-treatment response rate was 82%. CONCLUSIONS: This individual participant data meta-analysis, on predominantly patients with pCD without active luminal disease and first-line anti-TNF therapy, shows that over half of patients remain in remission 2 years after anti-TNF discontinuation. Therefore, anti-TNF discontinuation may be considered in this subgroup.

Effectiveness and safety of a third-line rescue treatment for acute severe ulcerative colitis refractory to infliximab or ciclosporin (REASUC study).

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.