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OBJECTIVE: Despite being in sustained and stable remission, patients with Crohn's disease (CD) stopping anti-tumour necrosis factor α (TNFα) show a high rate of relapse (~50% within 2 years). Characterising non-invasively the biological profiles of those patients is needed to better guide the decision of anti-TNFα withdrawal. DESIGN: Ninety-two immune-related proteins were measured by proximity extension assay in serum of patients with CD (n=102) in sustained steroid-free remission and stopping anti-TNFα (infliximab). As previously shown, a stratification based on time to clinical relapse was used to characterise the distinct biological profiles of relapsers (short-term relapsers: <6 months vs mid/long-term relapsers: >6 months). Associations between protein levels and time to clinical relapse were determined by univariable Cox model. RESULTS: The risk (HR) of mid/long-term clinical relapse was specifically associated with a high serum level of proteins mainly expressed in lymphocytes (LAG3, SH2B3, SIT1; HR: 2.2-4.5; p<0.05), a low serum level of anti-inflammatory effectors (IL-10, HSD11B1; HR: 0.2-0.3; p<0.05) and cellular junction proteins (CDSN, CNTNAP2, CXADR, ITGA11; HR: 0.4; p<0.05). The risk of short-term clinical relapse was specifically associated with a high serum level of pro-inflammatory effectors (IL-6, IL12RB1; HR: 3.5-3.6; p<0.05) and a low or high serum level of proteins mainly expressed in antigen presenting cells (CLEC4A, CLEC4C, CLEC7A, LAMP3; HR: 0.4-4.1; p<0.05). CONCLUSION: We identified distinct blood protein profiles associated with the risk of short-term and mid/long-term clinical relapse in patients with CD stopping infliximab. These findings constitute an advance for the development of non-invasive biomarkers guiding the decision of anti-TNFα withdrawal.
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Enfermedad de Crohn , Humanos , Infliximab/uso terapéutico , Enfermedad de Crohn/tratamiento farmacológico , Recurrencia Local de Neoplasia , Factor de Necrosis Tumoral alfa , Antiinflamatorios/uso terapéutico , Biomarcadores , Recurrencia , Inducción de Remisión , Glicoproteínas de Membrana , Receptores Inmunológicos , Lectinas Tipo C/uso terapéutico , Péptidos y Proteínas de Señalización IntercelularRESUMEN
BACKGROUND & AIMS: The management of intra-abdominal abscesses complicating Crohn's disease (CD) is challenging, and surgery with delayed intestinal resection is often recommended. The aims of this study were to estimate the success rate of adalimumab (ADA) in patients with CD with an intra-abdominal abscess resolved without surgery, and to identify predictive factors for success. METHODS: A multicenter, prospective study was conducted in biologic-naïve patients with CD with resolved intra-abdominal abscess treated with ADA with a 2-year follow-up. The primary endpoint was ADA failure at week (W) 24 defined as a need for steroids after W12, intestinal resection, abscess recurrence, and clinical relapse. Secondary post-hoc endpoint was the long-term success defined as the survival without abscess relapse or intestinal resection at W104. The factors associated with ADA failure at W24 and W104 were identified using a logistic and a Cox regression, respectively. RESULTS: From April 2013 to December 2017, 190 patients from 27 GETAID centers were screened, and 117 were included in the analysis. Fifty-eight patients (50%) were male, and the median age at baseline was 28 years. At W24, 87 patients (74%; 95% confidence interval [CI], 65.5%-82.0%; n = 117) achieved ADA success. Among the 30 patients with ADA failure, 15 underwent surgery. At W104, the survival rate without abscess recurrence or surgery was 72.9% (95% CI, 62.1%-79.8%; n = 109). Abscess drainage was significantly associated with ADA failure at W24 (odds ratio, 4.18; 95% CI, 1.06-16.5; P =0 .043). Disease duration (hazard ratio [HR], 1.32; 95% CI, 1.09-1.59; P = .008), abscess drainage (HR, 5.59; 95% CI, 2.21-14.15; P = .001), and inflammatory changes in mesenteric fat (HR, 0.4; 95% CI, 0.17-0.94; P = .046) were significantly associated with ADA failure at W104. CONCLUSION: Provided that the abscess was carefully managed before initiating medical treatment, this study showed the high efficacy of ADA in the short and long term in biologic-naïve patients with CD complicated by an intra-abdominal abscess. CLINICALTRIALS: gov, Number: NCT02856763.
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Absceso Abdominal , Productos Biológicos , Enfermedad de Crohn , Humanos , Masculino , Adulto , Femenino , Adalimumab/uso terapéutico , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/tratamiento farmacológico , Estudios Prospectivos , Absceso/tratamiento farmacológico , Resultado del Tratamiento , Absceso Abdominal/tratamiento farmacológico , Recurrencia , Productos Biológicos/uso terapéuticoRESUMEN
OBJECTIVES: PERFUSE is a non-interventional study of 1233 patients [inflammatory rheumatic disease, n = 496; inflammatory bowel disease (IBD), n = 737] receiving infliximab (IFX) biosimilar SB2 therapy. This analysis describes response to treatment and persistence on SB2 for up to 12 months in pediatric IBD patients (n = 126). METHODS: Pediatric IBD patients with Crohn disease (CD) or ulcerative colitis (UC), either naïve or switched from originator IFX, who started SB2 in routine practice after September 2017 were eligible. Data were captured for 12 months following SB2 initiation. Disease activity was measured using C-reactive protein (CRP) levels and the Harvey-Bradshaw Index or Pediatric Ulcerative Colitis Activity Index for CD and UC patients, respectively. Body mass index and height z scores were used to assess patient growth between initiation (M0) and month 12 (M12). RESULTS: One hundred twenty-six pediatric IBD patients were included (102 CD patients, 51 naïve and 51 switched; 24 UC patients, 9 naïve and 15 switched). Naive patients' disease scores decreased between M0 and M12. CRP measurements also decreased in naïve CD patients. Switched patients' disease scores and CRP levels remained stable between M0 and M12. Height z scores improved significantly over the course of the treatment for all groups except for naïve UC patients. CONCLUSIONS: SB2 provides effective disease control for naïve and switched pediatric patients. Clinical remission rates improved in naïve patients and no loss of control was observed in switched patients after 1 year. Growth failure is not observed in IBD patients under SB2 treatment.
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Biosimilares Farmacéuticos , Colitis Ulcerosa , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Humanos , Niño , Infliximab/uso terapéutico , Biosimilares Farmacéuticos/uso terapéutico , Estudios de Cohortes , Fármacos Gastrointestinales/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Inducción de Remisión , Resultado del Tratamiento , Colitis Ulcerosa/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológicoRESUMEN
BACKGROUND: Despite regular need for colonoscopy in patients with Crohn's disease (CD), the efficacy and tolerability of bowel preparation (BP) agents is rarely assessed in this population. Assessing BP quality with existing scales may be challenging in CD due to presence of inflammation, bowel resection, and strictures. AIMS: To provide recommendations for assessing BP quality in clinical trials for CD using a modified Research and Development/University of California, Los Angeles appropriateness process. METHODS: Based on systematic reviews and a literature search, 110 statements relating to BP quality assessment in CD were developed. A panel of 15 gastroenterologists rated the statements as appropriate, uncertain, or inappropriate using a 9-point Likert scale. RESULTS: Panelists considered it appropriate that central readers, either alone or with local assessment, score BP quality in clinical trials. Central readers should be trained on scoring BP quality and local endoscopists on performing high-quality video recording. Both endoscope insertion and withdrawal phases should be reviewed to score BP quality in each colonic segment and segments should align with endoscopic disease activity indices. The Harefield Cleansing Scale and the Boston Bowel Preparation Scale were considered appropriate. The final score should be calculated as the average of all visualized segments. Both total and worst segment scores should also be assessed. CONCLUSIONS: We developed a framework for assessing BP quality in patients with CD based on expert feedback. This framework could support the development or refinement of BP quality scales and the integration of BP quality assessment in future CD studies.
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Colon , Colonoscopía , Enfermedad de Crohn , Humanos , Consenso , Constricción Patológica , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/tratamiento farmacológicoRESUMEN
Inflammatory bowel diseases (IBDs) can be associated with various musculoskeletal (IBD-MSK) manifestations that could be difficult to classify for gastroenterologists. We aimed to evaluate the characteristics of patients with IBD-MSK and the prevalence of spondyloarthritis (SpA). In this observational cross-sectional study, we included patients with IBD-MSK complaints (peripheral or back pain). All patients underwent a standardized rheumatology evaluation including clinical, biological and imaging evaluations (MRI of spine and sacroiliac joints and ultrasonography of enthesis). We included 183 IBD patients (60.7% women; median [interquartile range] age 45 [36-56] years); 159 (87%) had joint pain. In 43 (23.5%) and 25/175 (14.3%) patients, enthesis abnormalities were found on ultrasonography and sacroiliitis on MRI, respectively. SpA was diagnosed in 54 (29.5%) patients. IBD-related arthralgia and degenerative spine disease were diagnosed in 105 (57.4%) and 72 (39.3%) patients. Sixteen (29.6%) SpA patients initiated a new conventional synthetic disease modifying anti-rheumatic drug (DMARD). A biologic DMARD was initiated in 10 patients or changed in 3. More than half of IBD-MSK patients had IBD-related arthralgia, and about one-third had definite SpA. Ultrasonography of enthesis and systematic MRI of sacroiliac joints seem useful for SpA classification and differential diagnosis in these patients who often have musculoskeletal pain complaints. Therapeutics were changed in most patients, which highlights the need for a multidisciplinary approach for managing IBD with extra-intestinal symptoms.
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Antirreumáticos , Enfermedades Inflamatorias del Intestino , Espondiloartritis , Humanos , Femenino , Persona de Mediana Edad , Masculino , Espondiloartritis/diagnóstico , Espondiloartritis/tratamiento farmacológico , Espondiloartritis/epidemiología , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Articulación Sacroiliaca , Imagen por Resonancia Magnética , ArtralgiaRESUMEN
BACKGROUND & AIMS: Crohn's disease (CD) patients included in the Tailored Treatment With Infliximab for Active Crohn's Disease (TAILORIX) trial started infliximab in combination with an immunosuppressant for 1 year. The aim of the present study was to determine the long-term disease course beyond the study period. METHODS: We compared the outcomes of patients who did or did not reach the primary end point of the TAILORIX trial, defined as sustained corticosteroid-free clinical remission from weeks 22 through 54, with no ulcers on ileocolonoscopy at week 54. The primary outcome of this follow-up study was the progression-free survival of CD defined by anal or major abdominal surgery, CD-related hospitalization, or the need for a new systemic CD treatment. RESULTS: The 95 patients (median disease duration, 4.5 mo; interquartile range, 1.0-56.6 mo) analyzed, including 45 (47%) who achieved the primary end point, were followed up for a median duration of 64.2 months (interquartile range, 57.6-69.9 mo) after the end of the study period. There was no significant difference in CD progression-free survival at 1, 3, and 5 years between patients who achieved the TAILORIX primary end point and patients who did not (P = .64). No difference was observed between both groups for each component of CD progression: anal surgery, major abdominal surgery, CD-related hospitalization, or the need for a new systemic CD treatment. CONCLUSIONS: Achieving a sustained clinical remission off steroids with complete endoscopic remission in this cohort of 95 patients with early CD was not associated with less disease progression. Prospective trials to define the therapeutic goals that change the natural history of CD and prevent complications are needed.
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Enfermedad de Crohn , Progresión de la Enfermedad , Estudios de Seguimiento , Humanos , Infliximab , Estudios Prospectivos , Inducción de Remisión , Esteroides , Resultado del TratamientoRESUMEN
INTRODUCTION: The objective of this study was to describe the efficacy and safety of infliximab (IFX) reintroduction in Crohn's disease (CD) after stopping for loss of response or intolerance. METHODS: We conducted a prospective multicenter observational cohort study including adult patients with clinically (CD Activity Index >150) and objectively active luminal CD in whom IFX was reintroduced after at least 6 months of discontinuation. The reasons for the initial discontinuation could be a secondary loss of response or IFX intolerance. The reintroduction schedule included 3 IFX infusions at weeks 0, 4, and 8, after a systematic premedication. The primary end point was the efficacy of IFX retreatment at week 26 defined by a CD Activity Index of <150 in the absence of IFX discontinuation or use of corticosteroids, surgery, or other biologic. RESULTS: At week 26, 24 patients (35%) among the 69 analyzed reached the primary end point. No significant difference was observed between rates of clinical remission at week 26 in patients with prior LOR (n = 48) and those with IFX intolerance (n = 21) (35% and 33%, P = 0.87, respectively). Thirty-two acute infusion reactions were recorded in 27 patients, leading to withdrawal of IFX in 20 patients. No pharmacokinetic characteristic at baseline but detection of positive anti-drug antibodies at week 4 was predictive of IFX failure or infusion reaction at week 26. DISCUSSION: In this first prospective cohort study, IFX retreatment was safe and effective in one-third of the patients with CD, regardless the reason of prior discontinuation. Early detection of anti-drug antibodies can predict subsequent IFX reintroduction failure and infusion reactions.
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Enfermedad de Crohn , Adulto , Anticuerpos , Enfermedad de Crohn/tratamiento farmacológico , Fármacos Gastrointestinales/uso terapéutico , Humanos , Infliximab/uso terapéutico , Estudios Prospectivos , Retratamiento , Resultado del TratamientoRESUMEN
OBJECTIVES: This study aimed to investigate the prevalence, risk factors, and outcomes of colonic involvement in patients with acute mesenteric ischemia (AMI). METHODS: CT scans from a prospective cohort of 114 AMI patients treated in an intestinal stroke center between 2009 and 2018 were blindly reviewed by two radiologists. Colon involvement was defined on CT scan by the presence of at least one of the following CT colonic features: wall thickening, pneumatosis, decreased wall enhancement, dilatation, or perforation. In addition, the clinical, biological, and radiological characteristics of patients with and without colonic involvement were compared to identify risk factors for colonic involvement on CT and its impact on morbidity and mortality. RESULTS: Colonic involvement was identified in 32/114 (28%) patients with AMI, the right colon being more frequently involved (n = 29/32, 91%). Wall thickening (n = 27/32) was the most common CT finding. Occlusion of the inferior mesenteric artery was the only statistically significant risk factor for colonic involvement (35% vs. 15%, p = 0.02). Patients with colonic involvement on CT vs. those without had more frequently transmural colonic necrosis (13% vs. 0%, p = 0.006), short bowel syndrome (16% vs. 4%, p = 0.04), need for long-term parenteral support (19% vs. 5%, p = 0.03), and death during follow-up (22% vs. 10%, p = 0.03). DISCUSSION: In patients with AMI, colonic involvement is associated with increased morbidity and mortality and should be carefully searched for during initial CT scan assessment. KEY POINTS: ⢠In a prospective cohort of acute mesenteric ischemia patients from an intestinal stroke center, 28% had an associated colonic involvement on CT. ⢠Colonic involvement on CT most commonly affected the right colon, and the occlusion of the inferior mesenteric artery was the only risk factor. ⢠Colonic involvement on CT was associated with increased morbidity and mortality and should be carefully searched for during initial CT scan assessment.
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Isquemia Mesentérica , Colon/diagnóstico por imagen , Humanos , Isquemia/diagnóstico por imagen , Isquemia/epidemiología , Isquemia Mesentérica/complicaciones , Isquemia Mesentérica/diagnóstico por imagen , Isquemia Mesentérica/epidemiología , Prevalencia , Estudios Prospectivos , Estudios Retrospectivos , Factores de RiesgoRESUMEN
INTRODUCTION: There are currently no comparative data on the efficacy and safety of vedolizumab and ustekinumab in ulcerative colitis (UC) after anti-TNF therapy fails. METHODS: We retrieved the full datasets of two observational, multicentre, retrospective studies of patients with UC for whom anti-TNF therapy failed and the patients were then treated with either vedolizumab or ustekinumab. The outcomes included steroid-free clinical remission, clinical remission, treatment persistence, colectomy, hospitalization, and serious and infectious adverse events. Propensity scores weighted comparison was applied. RESULTS: In total, 121 patients were included in the vedolizumab group and 97 were included in the ustekinumab group. At week 14 and week 52, in the weighted cohort, no difference was found between vedolizumab and ustekinumab for steroid-free clinical remission (OR = 0.55 [0.21-1.41], p = .21 and 0.94 [0.40-2.22], p = .89, respectively). There was no difference between vedolizumab and ustekinumab for secondary outcomes such as clinical remission, hospitalization, UC-related surgery, treatment persistence and serious and infectious adverse events. CONCLUSION: In patients with UC for whom anti-TNF therapy failed, no difference was found between vedolizumab and ustekinumab after propensity scores weighted comparison. Further studies are required to determine predictive factors of the efficacy of both biological agents.
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Colitis Ulcerosa , Ustekinumab , Humanos , Ustekinumab/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamente , Inhibidores del Factor de Necrosis Tumoral , Estudios Retrospectivos , Resultado del Tratamiento , Estudios de Cohortes , Fármacos Gastrointestinales/uso terapéutico , Inducción de RemisiónRESUMEN
BACKGROUND/AIMS: Few data on the evolution of endoscopic findings are available in patients with acute severe ulcerative colitis (ASUC). The aim of this study was to describe this evolution in a prospective cohort. METHODS: Patients admitted for a steroid-refractory ASUC and included in a randomized trial comparing infliximab and cyclosporine were eligible if they achieved steroid-free clinical remission at day 98. Flexible sigmoidoscopies were performed at baseline, days 7, 42 and 98. Ulcerative colitis endoscopic index of severity (UCEIS) and its sub-scores - vascular pattern, bleeding and ulceration/erosion - were post-hoc calculated. Global endoscopic remission was defined by a UCEIS of 0, and partial endoscopic remission by any UCEIS sub-score of 0. RESULTS: Among the 55 patients analyzed (29 infliximab and 26 cyclosporine), 49 (83%) had UCEIS ≥6 at baseline at baseline. Partial endoscopic remission rates were higher for bleeding than for vascular pattern and for ulcerations/erosions at day 7 (20% vs. 4% and 5% (n = 55); p = .004 and p=.04), for bleeding and ulceration/erosion than for vascular pattern at day 42 [63% and 65% vs. 33% (n=54); p<.001 for both] and at day 98 [78% and 92% vs. 56% (n = 50); p = .007 and p < .001]. Global endoscopic remission rates at day 98 were higher in patients treated with infliximab than with cyclosporine [73% vs. 25% (n = 26 and 24); p < .001]. CONCLUSION: In steroid-refractory ASUC patients responding to a second-line medical therapy, endoscopic remission process started with bleeding remission and was not achieved in half the patients at day 98 for vascular pattern. Infliximab provided a higher endoscopic remission rate than cyclosporine at day 98.
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Colitis Ulcerosa , Colitis Ulcerosa/tratamiento farmacológico , Ciclosporina/uso terapéutico , Humanos , Infliximab/uso terapéutico , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Esteroides , Resultado del TratamientoRESUMEN
OBJECTIVE: A subset of Crohn's disease (CD) patients experiences mid/long-term remission after infliximab withdrawal. Biomarkers are needed to identify those patients. DESIGN: New biomarkers of relapse were searched in the baseline serum of CD patients stopping infliximab when they were under combined therapy (antimetabolite and infliximab) and stable clinical remission (diSconTinuation in CrOhn's disease patients in stable Remission on combined therapy with Immunosuppressors cohort, n=102). From shotgun proteomics experiment (discovery step), biomarker candidates were identified and further targeted by selected reaction monitoring (verification step). The dataset was stratified to search for markers of short-term (<6 months) or mid/long-term relapse (>6 months). The risk of relapse and the predicting capacity associated with biomarker candidates were evaluated using univariate Cox model and log-rank statistic, respectively. To test their complementary predicting capacity, biomarker candidates were systematically combined in pairs. RESULTS: Distinct biomarker candidates were associated with the risk (HR) of short-term (15 proteins, 2.9
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BACKGROUND: Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited. METHODS AND FINDINGS: The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn's disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253-0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437-0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616-4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319-3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923-5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139-6.764], p < 1 × 10-5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106-4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings. CONCLUSION: In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies.
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Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/genética , Productos Biológicos/inmunología , Adalimumab/uso terapéutico , Adulto , Anticuerpos Monoclonales Humanizados/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/genética , Productos Biológicos/uso terapéutico , Terapia Biológica/métodos , Estudios de Cohortes , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/genética , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/genética , Femenino , Estudio de Asociación del Genoma Completo/métodos , Cadenas alfa de HLA-DQ/genética , Humanos , Inmunosupresores/uso terapéutico , Infliximab/uso terapéutico , Interferón beta-1a/uso terapéutico , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/genética , Estudios Prospectivos , Rituximab/uso terapéuticoRESUMEN
BACKGROUND & AIMS: Endoscopic healing, an important target of treatment for Crohn's disease (CD), requires ileocolonoscopy, which is costly and burdensome. We investigated whether published noninvasive models (based on symptoms and biomarkers) to evaluate CD activity have sufficient accuracy to replace ileocolonoscopy. METHODS: We performed a systematic review of published noninvasive diagnostic models to evaluate CD activity that used endoscopic features of activity (endoscopic activity) or healing as the reference standard. We externally validated these models for the outcome endoscopic activity (CD endoscopic index of severity scores, ≥3) using data from the a randomized controlled trial investigating tailored treatment with infliximab for active luminal Crohn's disease (TAILORIX) study (346 ileocolonoscopies in 155 patients) and the Utrecht Activity Index (UAI) study (93 ileocolonoscopies in 82 patients). We calculated the area under the receiver operating characteristic curves (AUROCs) for the models using data from these studies, and compared the performance of these models against measurements of fecal calprotectin (FC) and C-reactive protein (CRP). RESULTS: We screened 5303 articles and identified 27 models (from 21 studies) for our analysis. Seven models could be validated externally; in the TAILORIX data set, these models identified patients with endoscopic activity with AUROC values ranging from 0.61 (95% CI, 0.51-0.70) to 0.81 (95% CI, 0.76-0.86). In this data set, the AUROC value for FC concentration was 0.79 (95% CI, 0.74-0.85) and the AUROC value for CRP level was 0.72 (95% CI, 0.66-0.77). The AUROC values for the validation in the UAI data set were similar. In the TAILORIX and/or UAI data set, 4 of the 7 models, as well as the FC and CRP assays, were able to identify patients with endoscopic activity with positive predictive values of 90% or more. Two of the 7 models (but not the FC or CRP values) identified patients without endoscopic activity with a negative predictive value (NPV) of 90% or more, leading to correct prediction of endoscopic healing in 3.2% to 11.3% of all patients. For example, applying the Herranz-Bachiller model (1 of 7 models) at a NPV of 92.1% and a positive predictive value of 91.9% correctly identified 35.7% of all patients in whom ileocolonoscopy could be avoided for expected endoscopic activity or healing but incorrectly identified 3.2% of all patients. Most ileocolonoscopies (66.5% in TAILORIX and 72.6% in the UAI of all ileocolonoscopies) could be avoided correctly based on concentrations of FC of 100 µg/g or less and 250 µg/g or higher. However, using this range of FC concentrations to identify patients who do not require ileocolonoscopy caused 18.7% of all patients in the TAILORIX cohort and 19.8% of all patients in the UAI cohort to be predicted incorrectly to have endoscopic activity or healing. CONCLUSIONS: In a systematic review and external validation of noninvasive models to identify patients with endoscopic activity of CD, we found only 2 of 7 models evaluated to have NPVs of 90% or more, however, leading to correctly predicted EH in only a small proportion of patients. Ileocolonoscopy therefore remains the mainstay to evaluate CD mucosal disease activity and healing.
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Enfermedad de Crohn , Biomarcadores/análisis , Proteína C-Reactiva/análisis , Colonoscopía , Enfermedad de Crohn/diagnóstico , Heces/química , Humanos , Complejo de Antígeno L1 de Leucocito , Ensayos Clínicos Controlados Aleatorios como Asunto , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND & AIMS: It is a challenge to manage patients with ulcerative proctitis (UP) refractory to standard therapy. We investigated the effectiveness of tumor necrosis factor (TNF) antagonists in a large cohort of patients with refractory UP. METHODS: We conducted a nationwide retrospective cohort study of 104 consecutive patients with active UP refractory to conventional therapies, treated at 1 of 15 centers in France or 1 center in Belgium (the GETAID cohort). Patients received at least 1 injection of anti-TNF (infliximab, adalimumab, golimumab) from October 2006 through February 2017. Clinical response was defined as significant improvement in UC-related symptoms, and remission as complete disappearance of UC-related symptoms, each determined by treating physicians. We collected demographic, clinical, and treatment data. The median duration of follow-up was 24 months (interquartile range, 13-51 months). The primary outcome was clinical response of UP to anti-TNF treatment. RESULTS: Overall, 80 patients (77%) had a clinical response to anti-TNF therapy and 52 patients (50%) achieved clinical remission. Extra-intestinal manifestations (odds ratio OR, 0.24; 95% CI, 0.08-0.7), ongoing treatment with topical steroids (OR, 0.14; 95% CI, 0.03-0.73), and ongoing treatment with topical 5-aminosalycilates (OR, 0.21; 95% CI, 0.07-0.62) were significantly associated with the absence of clinical remission. Sixty percent (38/63) of the patients who had endoscopic assessment during follow up had mucosal healing. Among the overall population (n = 104), the cumulative probabilities of sustained clinical remission were 87.6% ± 3.4% at 1 year and 74.7% ± 4.8% at 2 years. CONCLUSIONS: In a retrospective study of 104 patients with refractory UP, anti-TNF therapy induced clinical remission in 50% and mucosal healing in 60%. About two thirds of the patients were still receiving anti-TNF therapy at 2 years.
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Colitis Ulcerosa , Proctitis , Adalimumab/uso terapéutico , Humanos , Infliximab , Proctitis/tratamiento farmacológico , Estudios Retrospectivos , Resultado del Tratamiento , Inhibidores del Factor de Necrosis Tumoral , Factor de Necrosis Tumoral alfaRESUMEN
BACKGROUND & AIMS: In the TAILORIX trial, no benefit could be shown by infliximab dose escalation based on pharmacokinetic (infliximab serum concentrations) and pharmacodynamic (biomarkers and symptoms) monitoring compared with dose escalation based on symptoms alone in patients with Crohn's disease (CD). We investigated whether integration of pharmacokinetic and pharmacodynamic monitoring can be used to evaluate responses to infliximab induction and maintenance therapy, based on findings from endoscopy. METHODS: We performed a post hoc analysis of patients with CD included in a trial to test the effects of infliximab dose escalation, based on biomarkers and serum concentrations of infliximab, on symptoms (the Study Investigating Tailored Treatment With Infliximab for Active Crohn's Disease trial; n = 122). We analyzed data from this study to determine whether concentrations of biomarkers and serum concentrations of infliximab were associated with endoscopic outcomes (n = 116). The primary end points were endoscopic response (CD endoscopic index of severity decrease ≥50% from baseline), endoscopic remission (CD endoscopic index of severity, <3), and absence of ulcers at weeks 12 and 54 of infliximab treatment. RESULTS: Infliximab trough concentrations greater than 23.1 mg/L at week 2 and greater than 10.0 mg/L at week 6 were associated with endoscopic remission at week 12 (positive predictive values, 72% and 76%; negative predictive values, 65% and 59%, respectively). During maintenance therapy, we found evidence for an exposure-response relationship only after dose escalation; trough concentrations greater than 10.6 mg/L were associated with the absence of ulcers at week 54 (positive predictive value, 49%; negative predictive value, 92%). Low fecal concentrations of calprotectin during therapy were associated with endoscopic response and remission (P < .05). Dose escalations increased trough concentrations of infliximab; persistent increase in fecal concentration of calprotectin, despite dose escalation, was associated with a lack of endoscopic response and remission. A significantly higher proportion of patients with antibodies to infliximab, identified by a drug-tolerant assay, dropped out of the study compared with patients without antibodies (P < .0001). CONCLUSIONS: In a post hoc analysis of data from a trial to test the effects of infliximab dose escalation on symptoms, we found that during maintenance therapy, the combination of fecal concentration of calprotectin and trough concentration of infliximab can guide dose adjustment and increase the chances for endoscopic response and remission. ClinicalTrialsRegister.eu EudraCT no: 2011-003038-14.
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Enfermedad de Crohn , Enfermedad de Crohn/tratamiento farmacológico , Fármacos Gastrointestinales/uso terapéutico , Humanos , Infliximab/uso terapéutico , Complejo de Antígeno L1 de Leucocito , Inducción de Remisión , Resultado del TratamientoRESUMEN
INTRODUCTION: To investigate the factors associated with a delayed diagnosis (DD) of acute mesenteric ischemia (AMI). METHODS: An observational cohort study from an intestinal failure center. The primary outcome was DD >24 hours. RESULTS: Between 2006 and 2015, 74 patients with AMI were included and 39 (53%) had a DD. Plasma lactate <2 mmol/L (odd ratio: 3.2; 95% confidence interval: 1.1-9.1; P = 0.03) and unenhanced computed tomography scan (odds ratio: 5.9; 95% confidence interval: 1.4-25.8; P = 0.01) were independently associated with DD. DISCUSSION: Suspicion of AMI should no longer be affected by normal plasma lactate levels and should prompt evaluation by a contrast-enhanced computed tomography-scan.
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Medios de Contraste , Diagnóstico Tardío/estadística & datos numéricos , Ácido Láctico/sangre , Isquemia Mesentérica/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Dolor Abdominal/fisiopatología , Enfermedad Aguda , Adulto , Anastomosis Quirúrgica , Enfermedad Crónica , Estudios de Cohortes , Colon/cirugía , Diagnóstico Precoz , Intervención Médica Temprana , Femenino , Humanos , Intestino Delgado/cirugía , Yeyunostomía , Masculino , Isquemia Mesentérica/sangre , Isquemia Mesentérica/fisiopatología , Isquemia Mesentérica/cirugía , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Síndrome del Intestino Corto , Vómitos/fisiopatologíaRESUMEN
INTRODUCTION: New therapeutic options for patients with Crohn's disease (CD) with perianal lesions failing anti-tumor necrosis factor (TNF) agents are needed. We aimed to assess the effectiveness of ustekinumab in perianal CD (pCD) and predictors of clinical success in a real-life multicenter cohort. METHODS: We conducted a national multicenter retrospective cohort study in patients with either active or inactive pCD who received ustekinumab. In patients with active pCD at treatment initiation, the success of ustekinumab was defined by clinical success at 6 months assessed by the physician's judgment without additional medical or surgical treatment for pCD. Univariate and multivariable logistic regression analyses were performed to identify predictors of success. In patients with inactive pCD at ustekinumab initiation, the pCD recurrence-free survival was calculated using the Kaplan-Meier method. RESULTS: Two hundred seven patients were included, the mean age was 37.7 years, the mean duration of CD was 14.3 years, and the mean number of prior perianal surgeries was 2.8. Two hundred five (99%) patients had previously been exposed to at least 1 anti-TNF and 58 (28%) to vedolizumab. The median follow-up time was 48 weeks; 56/207 (27%) patients discontinued therapy after a median time of 43 weeks. In patients with active pCD, success was reached in 57/148 (38.5%) patients. Among patients with setons at initiation, 29/88 (33%) had a successful removal. The absence of optimization was associated with treatment success (P = 0.044, odds ratio 2.74; 95% confidence interval: 0.96-7.82). In multivariable analysis, the number of prior anti-TNF agents (≥3) was borderline significant (P = 0.056, odds ratio 0.4; 95% confidence interval: 0.15-1.08). In patients with inactive pCD at initiation, the probability of recurrence-free survival was 86.2% and 75.1% at weeks 26 and 52, respectively. DISCUSSION: Ustekinumab appears as a potential effective therapeutic option in perianal refractory CD. Further prospective studies are warranted.
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Antiinflamatorios/uso terapéutico , Enfermedades del Ano/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Fístula Rectal/tratamiento farmacológico , Ustekinumab/uso terapéutico , Absceso , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/uso terapéutico , Enfermedades del Ano/fisiopatología , Estudios de Cohortes , Enfermedad de Crohn/fisiopatología , Supervivencia sin Enfermedad , Femenino , Fármacos Gastrointestinales/uso terapéutico , Humanos , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Persona de Mediana Edad , Fístula Rectal/fisiopatología , Estudios Retrospectivos , Insuficiencia del Tratamiento , Resultado del Tratamiento , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Adulto JovenRESUMEN
BACKGROUND & AIMS: Acute severe ulcerative colitis (ASUC) is a life-threatening condition managed with intravenous steroids followed by infliximab, cyclosporine, or colectomy (for patients with steroid resistance). There are no biomarkers to identify patients most likely to respond to therapy; ineffective medical treatment can delay colectomy and increase morbidity and mortality. We aimed to identify biomarkers of response to medical therapy for patients with ASUC. METHODS: We performed a retrospective analysis of 47 patients with ASUC, well characterized for their responses to steroids, cyclosporine, or infliximab, therapy at 2 centers in France. Fixed colonic biopsies, collected before or within the first 3 days of treatment, were used for microarray analysis of microRNA expression profiles. Deep neural network-based classifiers were used to derive candidate biomarkers for discriminating responders from non-responders to each treatment and to predict which patients would require colectomy. Levels of identified microRNAs were then measured by quantitative PCR analysis in a validation cohort of 29 independent patients-the effectiveness of the classification algorithm was tested on this cohort. RESULTS: A deep neural network-based classifier identified 9 microRNAs plus 5 clinical factors, routinely recorded at time of hospital admission, that associated with responses of patients to treatment. This panel discriminated responders to steroids from non-responders with 93% accuracy (area under the curve, 0.91). We identified 3 algorithms, based on microRNA levels, that identified responders to infliximab vs non-responders (84% accuracy, AUC = 0.82) and responders to cyclosporine vs non-responders (80% accuracy, AUC = 0.79). CONCLUSION: We developed an algorithm that identifies patients with ASUC who respond vs do not respond to first- and second-line treatments, based on microRNA expression profiles in colon tissues.
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Biomarcadores/análisis , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/patología , Colon/patología , Monitoreo de Drogas/métodos , Perfilación de la Expresión Génica/métodos , MicroARNs/análisis , Adulto , Anciano , Anciano de 80 o más Años , Aprendizaje Profundo , Femenino , Francia , Hospitales , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND & AIMS: A combination of infliximab and immunomodulators is the most efficacious treatment for Crohn's disease (CD). Patients have the best outcomes when their serum concentrations of these drugs are above a determined therapeutic threshold. We performed a prospective, randomized trial to determine whether therapeutic drug monitoring (TDM) to maintain serum levels of infliximab above 3 µg/mL produced higher rates of clinical and endoscopic remission than adapting dose based only on symptoms. METHODS: We performed a double-blind trial in which 122 biologic-naïve adult patients with active CD (71 female, median age 29.8 years) received induction treatment with infliximab in combination with an immunosuppressant, from July 2012 through September 2015 at 27 centers in Europe. At week 14 of treatment, patients were randomly assigned (1:1:1) to 3 infliximab maintenance groups: dose increases (2 maximum) in steps of 2.5 mg/kg based on clinical symptoms and biomarker analysis and/or serum infliximab concentrations (dose intensification strategy [DIS]1 group); dose increase from 5 to 10 mg/kg based on the same criteria (DIS2 group); dose increase to 10 mg/kg based on clinical symptoms alone (controls). Patients' CD activity index scores, levels of C-reactive protein, fecal levels of calprotectin, and serum concentrations of infliximab were determined at baseline and at weeks 2, 4, 6, 12, and 14 of treatment, and then every 4 weeks thereafter until week 54. The primary endpoint was sustained corticosteroid-free clinical remission (CD activity index <150) from weeks 22 through 54 with no ulcers at week 54. RESULTS: The primary endpoint was reached by 15 (33%) of 45 patients in the DIS1 group, 10 (27%) of 37 patients in the DIS2 group, and 16 (40%) of 40 patients in the control group (P = .50). CONCLUSIONS: In a prospective randomized exploratory trial of patients with active CD, we found increasing dose of infliximab based on a combination of symptoms, biomarkers, and serum drug concentrations does not lead to corticosteroid-free clinical remission in a larger proportion of patients than increasing dose based on symptoms alone. EUDRACT NUMBER: 2011-003038-14.
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Corticoesteroides/administración & dosificación , Antiinflamatorios/administración & dosificación , Enfermedad de Crohn/tratamiento farmacológico , Monitoreo de Drogas , Endoscopía Gastrointestinal , Fármacos Gastrointestinales/administración & dosificación , Infliximab/administración & dosificación , Corticoesteroides/efectos adversos , Adulto , Antiinflamatorios/efectos adversos , Antiinflamatorios/sangre , Biomarcadores/sangre , Enfermedad de Crohn/sangre , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/inmunología , Método Doble Ciego , Cálculo de Dosificación de Drogas , Quimioterapia Combinada , Europa (Continente) , Femenino , Fármacos Gastrointestinales/efectos adversos , Fármacos Gastrointestinales/sangre , Humanos , Infliximab/efectos adversos , Infliximab/sangre , Masculino , Valor Predictivo de las Pruebas , Prueba de Estudio Conceptual , Estudios Prospectivos , Inducción de Remisión , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVES: To identify treatments likely to prevent progression towards irreversible transmural intestinal necrosis (ITIN) in acute mesenteric ischemia (AMI). METHODS: Prospective observational cohort study from a French intestinal stroke center. Multivariate analysis using a time-dependent Cox regression model. RESULTS: Between 2009 and 2015, 67 patients with AMI were included. ITIN occurred in 34% of patients and mortality was 13%. Oral antibiotics was independently associated with a decreased risk of ITIN (HR: 0.16 (95% CI = 0.03-0.62); p = 0.01). CONCLUSIONS: By decreasing luminal bacterial load and translocation, oral antibiotics in addition to early revascularization might reduce progression of AMI to ITIN.