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BACKGROUND & AIMS: We evaluated the efficacy of herbal combination of curcumin-QingDai (CurQD) in active ulcerative colitis (UC). METHODS: Part I was an open-label trial of CurQD in patients with active UC, defined by a Simple Clinical Colitis Activity Index score of 5 or higher and a Mayo endoscopic subscore of 2 or higher. Part II was a placebo-controlled trial conducted in Israel and Greece, randomizing active UC patients at a 2:1 ratio to enteric-coated CurQD 3 g/d or placebo for 8 weeks. The co-primary outcome was clinical response (reduction in the Simple Clinical Colitis Activity Index of ≥3 points) and an objective response (Mayo endoscopic subscore improvement of ≥1 or a 50% fecal calprotectin reduction). Responding patients continued either maintenance curcumin or placebo alone for an additional 8 weeks. Aryl-hydrocarbon receptor activation was assessed by cytochrome P450 1A1 (CYP1A1) mucosal expression. RESULTS: In part I, 7 of 10 patients responded and 3 of 10 achieved clinical remission. Of 42 patients in part II, the week 8 co-primary outcome was achieved in 43% and 8% of CurQD and placebo patients, respectively (P = .033). Clinical response was observed in 85.7% vs 30.7% (P < .001), clinical remission in 14 of 28 (50%) vs 1 of 13 (8%; P = .01), a 50% calprotectin reduction in 46.4% vs 15.4% (P = .08), and endoscopic improvement in 75% vs 20% (P = .036) in the CurQD and placebo groups, respectively. Adverse events were comparable between groups. By week 16, curcumin-maintained clinical response, clinical remission, and clinical biomarker response rates were 93%, 80%, and 40%, respectively. CurQD uniquely up-regulated mucosal CYP1A1 expression, which was not observed among patients receiving placebo, mesalamine, or biologics. CONCLUSIONS: In this placebo-controlled trial, CurQD was effective for inducing response and remission in active UC patients. The aryl-hydrocarbon receptor pathway may merit further study as a potential UC treatment target. CLINICALTRIALS: gov ID: NCT03720002.
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Colitis Ulcerosa , Colitis , Curcumina , Humanos , Colitis Ulcerosa/tratamiento farmacológico , Curcumina/uso terapéutico , Citocromo P-450 CYP1A1/uso terapéutico , Colitis/tratamiento farmacológico , Complejo de Antígeno L1 de Leucocito , Inducción de Remisión , Resultado del Tratamiento , Método Doble CiegoRESUMEN
INTRODUCTION: Patency capsule (PC) is a recommended procedure to rule out small bowel stenosis before video capsule endoscopy (VCE). We examined future clinical outcomes among patients with a failed PC vs patients in whom the PC had passed (passed PC). METHODS: A post hoc analysis of 2 prospective cohort studies of adult patients with quiescent small bowel Crohn's disease (CD) who underwent PC between 2013 and 2020. The primary composite outcome was the need for intestinal surgery or endoscopic dilation during follow-up in patients with or without a failed PC. RESULTS: A total of 190 patients were included (47: failed PC and 143: passed PC, median follow-up 34.12 months). Patients with a failed PC had higher rates of the primary composite outcome (21.3% vs 1.4%, hazard ratio [HR] 20.3, 95% confidence interval [CI] 4.4-93.7, P < 0.001) and also secondary outcomes including intestinal surgery (14.9% vs 0.70%, P < 0.001), endoscopic dilation (14.9% vs 0.70%, P < 0.001), admissions (23.3% vs 5.7%, P < 0.001), and clinical flares (43.9% vs 27.7%, P = 0.005) during follow-up compared with controls. Failed PC was the only statistically significant factor for surgery and/or endoscopic dilation, regardless of a B2/B3 phenotype at baseline. In sensitivity analyses restricted only to patients with a stricturing phenotype (n = 73), a failed PC still predicted the long-term composite outcome (HR 8.68, 95% CI 1.72-43.68, P = 0.002). Of the 190 patients ingesting a PC, only 1 patient with a failed PC had 48 hours of self-limiting mild symptoms. DISCUSSION: Patients with clinically stable CD with a failed PC have worse long-term clinical outcomes than those without, independently of the CD phenotype. Standalone PC may serve as a novel, safe, and affordable prognostic examination to identify patients with quiescent CD who have a higher risk for future worse clinical outcomes.
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Endoscopía Capsular , Enfermedad de Crohn , Obstrucción Intestinal , Humanos , Enfermedad de Crohn/diagnóstico , Estudios Prospectivos , Obstrucción Intestinal/etiología , Obstrucción Intestinal/diagnóstico , Constricción PatológicaRESUMEN
BACKGROUND: Colonoscopy is the gold standard for evaluation of inflammation in inflammatory bowel diseases (IBDs), yet entails cumbersome preparations and risks of injury. Existing non-invasive prognostic tools are limited in their diagnostic power. Moreover, transcriptomics of colonic biopsies have been inconclusive in their association with clinical features. AIMS: To assess the utility of host transcriptomics of faecal wash samples of patients with IBD compared with controls. METHODS: In this prospective cohort study, we obtained biopsies and faecal-wash samples from patients with IBD and controls undergoing lower endoscopy. We performed RNAseq of biopsies and matching faecal-washes, and associated them with endoscopic and histological inflammation status. We also performed faecal mass-spectrometry proteomics on a subset of samples. We inferred cell compositions using computational deconvolution and used classification algorithms to identify informative genes. RESULTS: We analysed biopsies and faecal washes from 39 patients (20 IBD, 19 controls). Host faecal-transcriptome carried information that was distinct from biopsy RNAseq and faecal proteomics. Transcriptomics of faecal washes, yet not of biopsies, from patients with histological inflammation were significantly correlated to one another (p=5.3×10-12). Faecal-transcriptome had significantly higher statistical power in identifying histological inflammation compared with transctiptome of intestinal biopsies (150 genes with area under the curve >0.9 in faecal samples vs 10 genes in biopsy RNAseq). These results were replicated in a validation cohort of 22 patients (10 IBD, 12 controls). Faecal samples were enriched in inflammatory monocytes, regulatory T cells, natural killer-cells and innate lymphoid cells. CONCLUSIONS: Faecal wash host transcriptome is a statistically powerful biomarker reflecting histological inflammation. Furthermore, it opens the way to identifying important correlates and therapeutic targets that may be obscured using biopsy transcriptomics.
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BACKGROUND: Up to 60% of inflammatory bowel disease (IBD) patients treated with infliximab develop antibodies to infliximab (ATI), which are associated with low drug levels and loss of response (LOR). Hence, mapping out predictors of immunogenicity toward infliximab is essential for tailoring patient-specific therapy. Jewish Sephardi ethnicity, in addition to monotherapy, has been previously identified as a potential risk factor for ATI formation and infliximab failure. OBJECTIVES: To explore the association between Jewish sub-group ethnicity among patients with IBD and the risk of infliximab immunogenicity and therapy failure. To confirm findings of a previous cohort that addressed the same question. METHODS: This retrospective cohort study included all infliximab-treated patients of Jewish ethnicity with regular prospective measurements of infliximab trough levels and ATI. Drug and ATI levels were prospectively measured, clinical data was retrieved from medical charts. RESULTS: The study comprised 109 Jewish patients (54 Ashkenazi, 55 Sephardi) treated with infliximab. There was no statistically significant difference in proportion of ATI between Sephardi and Ashkenazi patients with IBD (32% Ashkenazi and 33% Sephardi patients developed ATI, odds ratio [OR] 0.944, P = 0.9). Of all variables explored, monotherapy and older age were the only factors associated with ATI formation (OR 0.336, 95% confidence interval 0.145-0.778, P = 0.01, median 34 vs. 28, interquartile range 28-48, 23-35 years, P = 0.02, respectively). CONCLUSIONS: Contrary to previous findings, Sephardi Jewish ethnicity was not identified as a risk factor for ATI formation compared with Ashkenazi Jewish ethnicity. Other risk factors remained unchanged.
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Etnicidad , Fármacos Gastrointestinales/administración & dosificación , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Infliximab/administración & dosificación , Judíos , Adulto , Estudios de Cohortes , Femenino , Fármacos Gastrointestinales/inmunología , Fármacos Gastrointestinales/farmacocinética , Humanos , Enfermedades Inflamatorias del Intestino/etnología , Enfermedades Inflamatorias del Intestino/inmunología , Infliximab/inmunología , Infliximab/farmacocinética , Masculino , Estudios Prospectivos , Estudios Retrospectivos , Insuficiencia del Tratamiento , Adulto JovenRESUMEN
BACKGROUND & AIMS: Some patients develop anti-drug antibodies (ADAs), which reduce the efficacy of infliximab, a monoclonal antibody against tumor necrosis factor (TNF), in the treatment of immune-mediated diseases, including inflammatory bowel diseases. ADAs arise inconsistently, and it is not clear what factors determine their formation. We investigated features of the immune system, the infliximab antibody, and its complex with TNF that might contribute to ADA generation. METHODS: C57BL/6 mice were given injections of infliximab and recombinant human TNF or infliximab F(ab')2 fragments. Blood samples were collected every 2-3 days for 2 weeks and weekly thereafter for up to 6 weeks; infliximab-TNF complexes and ADAs were measured by enzyme-linked immunosorbent assay (ELISA). Intestinal biopsy and blood samples were obtained from patients having endoscopy who had received infliximab therapy for inflammatory bowel diseases; infliximab-TNF complexes were measured with ELISA. Infliximab-specific plasma cells were detected in patient tissue samples by using mass cytometry. We studied activation of innate immune cells in peripheral blood mononuclear cells (PBMCs) from healthy donors incubated with infliximab or infliximab-TNF complexes; toll-like receptors (TLRs) were blocked with antibodies, endocytosis was blocked with the inhibitor PitStop2, and cytokine expression was measured by real-time polymerase chain reaction and ELISAs. Uptake of infliximab and infliximab-TNF complexes by THP-1 cells was measured with confocal microscopy. RESULTS: Mice given increasing doses of infliximab produced increasing levels of ADAs. Blood samples from mice given injections of human TNF and infliximab contained infliximab-TNF complexes; complex formation was associated with ADA formation with an area under the curve of 0.944 (95% confidence interval, 0.851-1.000; P = .003). Intestinal tissues from patients, but not blood samples, contained infliximab-TNF complexes and infliximab-specific plasma cells. Incubation of PBMCs with infliximab-TNF complexes resulted in a 4.74-fold increase in level of interleukin (IL) 1ß (IL1B) messenger RNA (P for comparison = .005), increased IL1B protein secretion, and a 2.69-fold increase in the expression of TNF messenger RNA (P for comparison = 0.013) compared with control PBMCs. Infliximab reduced only IL1B and TNF expression. Antibodies against TLR2 or TLR4 did not block the increases in IL1B or TNF expression, but endocytosis was required. THP-1 cells endocytosed higher levels of infliximab-TNF complexes than infliximab alone. CONCLUSIONS: In mice, we found ADA formation to increase with dose of infliximab given and concentration of infliximab-TNF complexes detected in blood. Based on studies of human intestinal tissues and blood samples, we propose that infliximab-TNF complexes formed in the intestine are endocytosed by and activate innate immune cells, which increase expression of IL1B and TNF and production of antibodies against the drug complex. It is therefore important to optimize the infliximab dose to a level that is effective but does not activate an innate immune response against the drug-TNF complex.
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Anticuerpos/sangre , Fragmentos Fab de Inmunoglobulinas/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Infliximab/inmunología , Intestinos/inmunología , Inhibidores del Factor de Necrosis Tumoral/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Animales , Estudios de Casos y Controles , Endocitosis , Femenino , Humanos , Inmunidad Innata , Fragmentos Fab de Inmunoglobulinas/administración & dosificación , Enfermedades Inflamatorias del Intestino/sangre , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Infliximab/administración & dosificación , Inyecciones Intravenosas , Interleucina-1beta/inmunología , Interleucina-1beta/metabolismo , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Células THP-1 , Inhibidores del Factor de Necrosis Tumoral/administración & dosificación , Factor de Necrosis Tumoral alfa/administración & dosificación , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Extra-intestinal manifestations (EIM) are common in inflammatory bowel diseases (IBD) and may affect up to 40% of the patients during the course of the disease. Peripheral arthralgia (PA) is by far the most common EIM. To date, TNFα inhibitors are the most established treatment for EIMs in IBD. Infliximab (IFX) trough levels (TL) and anti-IFX antibodies (ATI) are correlated with multiple outcomes in IBD such as clinical response and remission, mucosal healing, fistular healing, and more. So far, a correlation between PA and IFX TL\ATI has not been evaluated. METHODS: This retrospective study included IBD patients followed by the gastroenterology department of Sheba Medical Center. Patients with active PA at onset of IFX treatment were included. IFX TL and ATI were evaluated at week 6, 14, and 26 and correlated with PA persistence. RESULTS: Forty patients (37 Crohn's and 3 ulcerative colitis) with IBD-related PA were included. The overall prevalence of PA was 55% (22/40), 42.5% (17/40), and 55% (22/40) after 6, 14, and 26 weeks, respectively. IFX trough drug levels were not associated with reported PA at week 6 [median, 11.8 µg/ml (IQR 6.6-15.5) vs 10.05 µg/ml (IQR 7.35-12.87), p = 0.56], week 14 [median, 4.7 µg/ml (IQR 2.3-7) vs 3.1 µg/ml (IQR 1.35-7.35), p = 0.55], and week 26 [median, 3 µg/ml (IQR 1.15-5.17) vs 3.4 µg/ml (IQR 0.13-6.75), p = 0.94]. Detectable ATI were significantly more prevalent in patients with PA than in patients without PA at week 26 [11/22 (50%) vs 3/18 (16.7%), p = 0.028]. CONCLUSIONS: In patients with IBD-related PA, ATI are associated with an increased risk of persistence of PA. No direct correlation was demonstrated between IFX TL and persistence of PA.
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Anticuerpos/sangre , Artralgia/sangre , Colitis Ulcerosa/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Fármacos Gastrointestinales/sangre , Infliximab/sangre , Adulto , Artralgia/etiología , Colitis Ulcerosa/complicaciones , Enfermedad de Crohn/complicaciones , Monitoreo de Drogas , Femenino , Fármacos Gastrointestinales/inmunología , Humanos , Infliximab/inmunología , Masculino , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND & AIMS: There are few data available on the real-life pharmacokinetic and pharmacodynamics features of vedolizumab, a monoclonal antibody against integrin α4ß7. We performed a prospective study of patients with inflammatory bowel diseases (IBDs) treated with vedolizumab to determine serum drug concentrations, formation of antivedolizumab antibodies (AVAs), and integrin α4ß7 saturation. METHODS: We performed a prospective study of 106 patients with IBD (67 with Crohn's disease and 39 with ulcerative colitis) treated with vedolizumab from September 2014 through March 2017 at 2 tertiary medical centers in Israel. Clinical data and serum samples were collected before and during induction and maintenance therapy. Clinical remission was defined as Harvey-Bradshaw index scores below 5 or as Simple Clinical Colitis Activity Index scores of 3 or less. We measured serum levels of vedolizumab, AVAs, and markers of inflammation. Peripheral blood mononuclear cells were obtained from some patients at designated trough time points and CD3+ CD45RO+ T cells were isolated from 36 samples. Cells were incubated with fluorescent-conjugated vedolizumab and flow cytometry was used to quantify α4ß7 integrin saturation. We also performed flow cytometry analyses of CD3+ CD45RO+ lamina propria T cells isolated from intestinal mucosa of patients without IBD (non-IBD controls, n = 6), patients with IBD not treated with vedolizumab (untreated IBD controls, n = 8), and patients with IBD treated with vedolizumab (n = 15). RESULTS: Clinical remission was achieved by 48 of 106 patients (45%) by week 6 and 50 of 106 patients (48%) by week 14 of treatment. The median level of vedolizumab at week 6 was higher in patients in clinical remission (40.2 µg/mL) than in patients with active disease (29.7 µg/mL; P = .05). The median serum level of vedolizumab was significantly higher in patients with a normal level of C-reactive protein (21.8 µg/mL vedolizumab) vs the level in those with a high level of C-reactive protein (11.9 µg/mL vedolizumab) during maintenance treatment (P = .0006). The other clinical outcomes measured were not associated with median serum level of vedolizumab at any time point examined. AVAs were detected in 17% of patients during induction therapy and 3% of patients during maintenance therapy, but did not correlate with clinical outcomes. Flow-cytometry analysis of peripheral blood memory T cells (n = 36) showed near-complete occupancy of α4ß7 integrin at weeks 2 and 14 and during the maintenance phase, regardless of response status or drug levels. Most intestinal CD3+CD45RO+ memory T cells of healthy and IBD controls expressed α4ß7 (72%; interquartile range, 56%-81%). In contrast, free α4ß7 was detectable on only 5.6% of intestinal memory cells (interquartile range, 4.4%-11.2%) (P < .0001) from vedolizumab-treated patients, regardless of response. CONCLUSIONS: In a prospective study of real-life patients with IBD, we associated vedolizumab drug levels with remission and inflammatory marker level. Integrin α4ß7 was blocked in almost all T cells from patients treated with vedolizumab, regardless of serum level of the drug or response to treatment. These findings indicate a need to explore alternative mechanisms that prevent response to vedolizumab.
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Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos/sangre , Fármacos Gastrointestinales/farmacocinética , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/patología , Integrinas/antagonistas & inhibidores , Adulto , Animales , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/inmunología , Femenino , Citometría de Flujo , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/inmunología , Humanos , Israel , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Suero/química , Resultado del TratamientoRESUMEN
OBJECTIVES: Adalimumab is usually self-injected at home, making prospective serial-sampling studies challenging and scarce. This has led to a gap in knowledge about evolution of anti-adalimumab antibodies (AAAs) over time and its correlation with clinical and inflammatory outcomes. METHODS: A program for home visits by physicians at induction, every 3 months and at event of relapse, was established prospectively for Crohn's disease (CD) patients. At each visit, patients' clinical scores were determined and sera were obtained for C-reactive protein, drug, and AAA levels. This cohort was compared to a parallel prospective cohort of infliximab-treated CD patients. In a subgroup of 29 patients, trough and in-between-trough levels were compared, to elucidate the importance of timing of sampling during the injection cycle. RESULTS: Ninety-eight CD patients starting adalimumab were prospectively followed (median follow-up 44 weeks) and 621 serum samples were analyzed. Thirty-three patients (32%) developed AAA; 18/33 (55%) of them as early as week 2, and 26/33 (79%) by week 14. Induction period AAAs were strongly associated with primary non-response (odds ratio (OR) = 5.4, 95% confidence interval (CI): 1.6-17.8, p = 0.005). As compared to antibodies-to-infliximab (ATI), AAA formation rate over time was significantly lower (p = 0.01) and AAA were much more specific-85% of AAA events were associated with loss-of-response compared with 58% rate for ATI (p = 0.01). In 29 patients sampled serially during an injection cycle, levels of drug and AAA seemed comparable between four time-points during a single cycle both in patients with or without AAA (n = 8, n = 21, respectively). CONCLUSIONS: When followed prospectively and serially, AAAs are found to arise earlier than previously appreciated and their impact may be more pronounced for primary rather than secondary, non-response. Drug and AAA levels were similar both at trough and in-between injections, enabling to simplify therapeutic drug monitoring of adalimumab.
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Adalimumab/inmunología , Antiinflamatorios/inmunología , Enfermedad de Crohn/tratamiento farmacológico , Monitoreo de Drogas/estadística & datos numéricos , Adalimumab/administración & dosificación , Adalimumab/sangre , Adulto , Antiinflamatorios/administración & dosificación , Antiinflamatorios/sangre , Proteína C-Reactiva/análisis , Enfermedad de Crohn/sangre , Enfermedad de Crohn/inmunología , Femenino , Estudios de Seguimiento , Humanos , Infliximab/administración & dosificación , Infliximab/sangre , Infliximab/inmunología , Masculino , Estudios Prospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVES: While infliximab pharmacokinetics are associated with therapy outcome in adult inflammatory bowel disease (IBD) population, limited data are available in pediatric patients. We aimed to define the relationship between infliximab trough and antibodies' levels (IFX-TL, ATI) and clinical, biomarker remission. METHODS: IFX-TL and ATI were routinely obtained between 2011 and 2017. Associations with clinical and inflammatory (C-reactive protein, CRP) end-points were studied throughout the first year of infliximab therapy. RESULTS: A total of 63 patients (50 Crohn disease, 13 ulcerative colitis, median follow-up 16 months, median 8âsamples/patient) were included, and 773 sera-samples were analyzed. Sera of patients in clinical remission had higher median IFX-TLs than sera of those with active disease (4 vs 2.25âµg/mL, Pâ<â0.0001). In addition, patients with normal CRP had a higher median IFX-TL than those with elevated CRP (Pâ=â0.02). Moreover, IFX-TL > 9.2âµg/mL at week 2 predicted clinical remission by week 14 (sensitivity 71.4%, specificity 81.2%, area under curve (AUC)â=â0.73, Pâ=â0.02) and IFX-TL > 2.2âµg/mL at week 6 predicted infliximab retention beyond 1 year of treatment (sensitivity 88.9%, specificity 100.0%, AUCâ=â0.974, Pâ<â0.0001). CONCLUSIONS: A significant association between IFX-TL and ATI and clinical and biomarker remission status in pediatric IBD patients was demonstrated, including a temporal association between week 2, 6 levels and outcome of induction and between week 6 and 14 levels and remission at 1 year of therapy. These findings suggest that therapeutic drug monitoring may be considered for management guidance among pediatric IBD patients.
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Anticuerpos Monoclonales/sangre , Colitis Ulcerosa/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Fármacos Gastrointestinales/uso terapéutico , Infliximab/uso terapéutico , Adolescente , Anticuerpos Monoclonales/inmunología , Área Bajo la Curva , Biomarcadores/sangre , Proteína C-Reactiva/análisis , Niño , Colitis Ulcerosa/sangre , Enfermedad de Crohn/sangre , Monitoreo de Drogas , Femenino , Fármacos Gastrointestinales/inmunología , Humanos , Quimioterapia de Inducción , Enfermedades Inflamatorias del Intestino/sangre , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Infliximab/inmunología , Masculino , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: Combination thiopurine-infliximab (IFX) therapy is associated with reduced generation of antidrug antibodies (ADA) compared with IFX monotherapy. Whether past clinical response to thiopurine therapy bears an effect on ADA prevention is unknown. METHODS: This was a retrospective observational multicenter study of patients with Crohn's disease (CD) treated by IFX and thiopurines who had serial ADA measurements. Therapy was classified into past thiopurine response or its lack of, de novo combination, or IFX monotherapy. The primary endpoint was risk of ADA appearance. RESULTS: Out of 494 patients with serial ADA measurements 207 eligible patients were included in the final analysis. The 1-year cumulative risk of ADA development was similar in past thiopurine responders (19.3%) compared with past thiopurine failures (16.1%) (log rank P = .54). ADA was found in 46.6% of the monotherapy group and was significantly different compared with past thiopurine responders (P = .007) and past thiopurine failures (P = .007). The adjusted hazards for ADA development were significantly lower in past responders and past failures compared with the monotherapy group (hazard ratio, 0.47 [95% CI, 0.22-1.00] and 0.32 [95% CI, 0.11-0.93], respectively). CONCLUSIONS: Thiopurines-IFX cotherapy in patients with Crohn's disease is associated with reduced ADA formation compared with IFX monotherapy. This is probably regardless of initial thiopurine therapeutic effect.
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Formación de Anticuerpos , Enfermedad de Crohn/tratamiento farmacológico , Factores Inmunológicos/inmunología , Infliximab/inmunología , Mercaptopurina/análogos & derivados , Adolescente , Adulto , Quimioterapia Combinada , Femenino , Humanos , Factores Inmunológicos/administración & dosificación , Infliximab/administración & dosificación , Masculino , Mercaptopurina/administración & dosificación , Mercaptopurina/inmunología , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: The cross-immunogenicity of the recently approved infliximab-biosimilar Remsima (CT-P13) with the originator drug Remicade is still unknown. DESIGN: Sera of patients with IBD with or without measurable anti-Remicade antibodies to infliximab (ATI) were tested for their cross-reactivity to two batches of Remsima. Experiments were repeated after deglycosylation of Remicade/Remsima, IgG purification, excipients' dialysis and monomer purification by size exclusion chromatography. Anti-Remicade antibodies were tested for their functional inhibition of TNF-α binding by Remsima/Remicade by competition assay. Cross-reactivity of anti-adalimumab antibodies with Remicade/Remsima was also investigated. RESULTS: 125 patients' and controls' sera were tested (median age 31 years, IQR 24.5-39.5). All 56 anti-Remicade ATI-negative controls (14 healthy individuals, 42 patients with IBD) were also negative for anti-Remsima ATI. All 69 positive anti-Remicade IBD sera were cross-reactive with Remsima. ATI titres against Remicade or Remsima were strongly correlated (r values between 0.92 and 0.99, p<0.001 for all experiments, Spearman's correlation test). The background ELISA signal for Remsima was slightly higher compared with Remicade in negative controls (1.25±0.6 µg/mL vs 0.76±0.5â µg/mL, respectively, p<0.001), and persisted after deglycosylation, dialysis or protein size filtration, but abolished by IgG purification and significantly diminished by monomer purification. Anti-Remicade ATIs of patients with IBD (n=10) exerted similar functional inhibition on Remsima or Remicade TNF-α binding capacity (p=NS for all inhibition curve points). Antibodies-to-adalimumab in adalimumab-treated patients with IBD (n=7) did not cross-react with either Remicade or Remsima. CONCLUSIONS: Anti-Remicade antibodies in patients with IBD recognise and functionally inhibit Remsima to a similar degree, suggesting similar immunogenicity and shared immunodominant epitopes on these two infliximab agents. In contrast, anti-adalimumab antibodies do not cross-react with Remsima or Remicade.
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Anticuerpos Monoclonales/inmunología , Anticuerpos/inmunología , Fármacos Gastrointestinales/inmunología , Infliximab/inmunología , Adalimumab/inmunología , Adulto , Anciano , Anticuerpos/sangre , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/metabolismo , Biosimilares Farmacéuticos , Reacciones Cruzadas , Fármacos Gastrointestinales/metabolismo , Glicosilación , Humanos , Inmunoglobulina G/inmunología , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Infliximab/química , Infliximab/metabolismo , Persona de Mediana Edad , Factor de Necrosis Tumoral alfa/metabolismo , Adulto JovenRESUMEN
BACKGROUND & AIMS: It is not clear what serum levels of anti-tumor necrosis factor are associated with reduced intestinal inflammation in patients with inflammatory bowel disease (IBD). We aimed to identify serum levels of infliximab and adalimumab associated with mucosal healing in patients with IBD and to evaluate the putative gain in control of inflammation by incremental increases in drug levels. METHODS: We performed a retrospective cross-sectional study of 145 patients with IBD treated with infliximab (n = 78) or adalimumab (n = 67) at a medical center in Israel from 2009 through 2014. We collected data from colonoscopy examinations; mucosal healing was defined as simple endoscopic score of <3 or a Mayo score ≤1. These data were compared with serum levels of anti-tumor necrosis factor agents, clinical scores, and levels of C-reactive protein. RESULTS: Median serum levels of infliximab and adalimumab were significantly higher in patients with mucosal healing than patients with active disease (based on endoscopy) (for infliximab, 4.3 vs 1.7 µg/mL, P = .0002; for adalimumab, 6.2 vs 3.1 µg/mL, P = .01). Levels of infliximab above 5 µg/mL (area under the curve = 0.75; P < .0001) and levels of adalimumab above 7.1 µg/mL (area under the curve = 0.7; P = .004) identified patients with mucosal healing with 85% specificity. Increasing levels of infliximab beyond 8 µg/mL produced only minimal increases in the rate of mucosal healing, whereas the association between higher level of adalimumab and increased rate of mucosal healing reached a plateau at 12 µg/mL. In patients with measurable levels of infliximab >3 µg/mL, the presence of antibodies to infliximab was associated with a lower rate of mucosal healing compared with patients with similar drug level without antibodies (16% vs 50%, respectively; P = .003). CONCLUSIONS: In a retrospective study, we found significant association between serum levels of anti-tumor necrosis factor agents and level of mucosal healing. We propose that serum levels of 6-10 µg/mL for infliximab and 8-12 µg/mL for adalimumab are required to achieve mucosal healing in 80%-90% of patients with IBD, and that this could be considered as a "therapeutic window." Exceeding these levels produces only a negligible gain in proportion of patients with mucosal healing.
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Adalimumab/sangre , Inmunomodulación , Inmunosupresores/sangre , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Infliximab/sangre , Mucosa Intestinal/patología , Suero/química , Adalimumab/administración & dosificación , Adulto , Proteína C-Reactiva/análisis , Colonoscopía , Estudios Transversales , Femenino , Humanos , Inmunosupresores/administración & dosificación , Infliximab/administración & dosificación , Infliximab/farmacocinética , Israel , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adulto JovenRESUMEN
BACKGROUND & AIMS: Infliximab is a safe and effective therapy for ulcerative colitis (UC). We conducted a multicenter retrospective cohort study that included 7 European countries and Israel to examine whether infliximab discontinuation can be considered for patients who achieve sustained remission. METHODS: We performed a retrospective cohort study, collecting medical records from 13 tertiary care referral inflammatory bowel disease centers of all patients with UC treated with infliximab (n = 193). We compared the disease course of patients with at least 12 months of clinical remission who discontinued infliximab (n = 111) with that of patients who continued scheduled treatment (controls, n = 82). We examined the incidence rates of relapse, hospitalization and colectomy, the comparative effectiveness of different therapeutic strategies after discontinuation, and assessed the rates of response, remission, and adverse effects after infliximab re-initiation. Statistical analyses used time-to-event methods. RESULTS: In the entire cohort, 67 patients (34.7%) relapsed during the follow-up period. The incidence rate of relapse was significantly higher after discontinuation (23.3 per 100 person-years) compared with the control group (7.2 per 100 person-years) in univariable analysis (log-rank P < .001; hazard ratio, 3.41; 95% confidence interval, 1.88-6.20) and multivariable analysis (hazard ratio, 3.70; 95% confidence interval, 2.02-6.77). Rates of hospitalization and colectomy did not differ between groups. Thiopurines appeared to be the best treatment option after infliximab discontinuation (incidence of relapse: 15.0 per 100 person-years for thiopurines, 27.4 per 100 person-years for thiopurines plus aminosalicylates, and 31.2 per 100 person-years for aminosalicylates alone; log-rank P = .032). Response was regained in 77.1% of patients and remission in 51.4% of patients who re-initiated infliximab. However, 17.1% had infusion reactions and 17.1% reported other adverse events. CONCLUSIONS: In a multinational retrospective cohort study of patients with UC in sustained clinical remission, we associated discontinuation of infliximab with an increased risk of relapse. Treatment re-initiation is effective and safe.
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Colitis Ulcerosa/tratamiento farmacológico , Fármacos Gastrointestinales/administración & dosificación , Infliximab/administración & dosificación , Privación de Tratamiento , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Europa (Continente) , Femenino , Humanos , Israel , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Medición de Riesgo , Adulto JovenRESUMEN
BACKGROUND: Although 5-amino-salycilic acids (5-ASA) are often used with corticosteroid treatment in moderate-to-severe ulcerative colitis, the value of continuing/initiating 5-ASA in this clinical setting has not been explored. OBJECTIVES: To investigate the impact of a combination 5-ASA+corticosteroid therapy on the outcome of hospitalized patients with acute moderate-severe ulcerative colitis. METHODS: We conducted a retrospective study of patients hospitalized with moderate-severe ulcerative colitis in two centers, Israel and South Korea. Patients were classified into those who received 5-ASA and corticosteroids and those who received corticosteroids alone. Analysis was performed for each hospitalization event. The primary outcome was the rate of treatment failure defined as the need for salvage therapy (cyclosporin-A/infliximab/colectomy). The secondary outcomes were 30 days re-admission rates, in-hospital mortality rates, time to improvement, and length of hospitalization. RESULTS: We analyzed 209 hospitalization events: 151 patients (72%) received 5-ASA+corticosteroids and 58 (28%) corticosteroids alone. On univariate analysis the combination therapy group had a lower risk for treatment failure (11% vs. 31%, odds ratio 0.28, 95% confidence interval 0.13-0.59, P = 0.001). However, this difference disappeared on multivariate analysis, which showed pre-admission oral corticosteroid treatment to be the most significant factor associated with the need for salvage therapy. CONCLUSIONS: A signal for possible benefit of a combination 5-ASA and corticosteroids therapy was found, but was confounded by the impact of pre-admission corticosteroid treatment.
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Corticoesteroides/administración & dosificación , Antiinflamatorios no Esteroideos/administración & dosificación , Colitis Ulcerosa/tratamiento farmacológico , Mesalamina/administración & dosificación , Administración Oral , Adulto , Colitis Ulcerosa/fisiopatología , Quimioterapia Combinada , Femenino , Mortalidad Hospitalaria , Hospitalización , Humanos , Israel , Tiempo de Internación , Masculino , Persona de Mediana Edad , República de Corea , Estudios Retrospectivos , Terapia Recuperativa/métodos , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND & AIMS: There is controversy about whether levels of anti-tumor necrosis factor (TNF) and antidrug antibodies (ADAs) are accurate determinants of loss of response to therapy. We analyzed the association between trough levels of anti-TNF agents or ADAs and outcomes of interventions for patients with loss of response to infliximab or adalimumab. METHODS: We performed a retrospective study of pediatric and adult patients with inflammatory bowel disease and suspected loss of response to anti-TNF agents treated at medical centers throughout Israel from October 2009 through February 2013. We examined the correlation between outcomes of different interventions and trough levels of drug or ADAs during loss of response. An additional subanalysis was performed including only patients with a definite inflammatory loss of response (clinical worsening associated with increased levels of C-reactive protein or fecal calprotectin, or detection of inflammation by endoscopy, fistula discharge, or imaging studies). RESULTS: Among 247 patients (42 with ulcerative colitis), there were 330 loss-of-response events (188 to infliximab and 142 to adalimumab). Trough levels of adalimumab greater than 4.5 mcg/mL and infliximab greater than 3.8 mcg/mL identified patients who failed to respond to an increase in drug dosage or a switch to another anti-TNF agent with 90% specificity; these were set as adequate trough levels. Adequate trough levels identified patients who responded to expectant management or out-of-class interventions with more than 75% specificity. Levels of antibodies against adalimumab >4 microgram per mL equivalent (mcg/mL-eq) or antibodies against infliximab >9 mcg/mL-eq identified patients who did not respond to an increased drug dosage with 90% specificity. Patients with high titers of ADAs had longer durations of response when anti-TNF agents were switched than when dosage was increased (P = .03; log-rank test), although dosage increases were more effective for patients with no or low titers of ADAs (P = .02). An analysis of definite inflammatory loss-of-response events (n = 244) produced similar results; patients with adequate trough levels had a longer duration of response when they switched to a different class of agent than when anti-TNF was optimized by either a dosage increase or by a switch within the anti-TNF class (P = .002; log-rank test). CONCLUSIONS: The results of this retrospective analysis suggest that trough levels of drug or ADAs may guide therapeutic decisions for more than two-thirds of inflammatory bowel disease patients with either clinically suspected or definite inflammatory loss of response to therapy.
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Anticuerpos Monoclonales Humanizados/inmunología , Anticuerpos Monoclonales/inmunología , Anticuerpos/sangre , Factores Inmunológicos/inmunología , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Adalimumab , Adulto , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/uso terapéutico , Estudios de Cohortes , Femenino , Humanos , Factores Inmunológicos/farmacocinética , Factores Inmunológicos/uso terapéutico , Infliximab , Israel , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Insuficiencia del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: To characterise the temporal evolution of antibodies to infliximab (ATI). DESIGN: Prospective observational study of infliximab-treated patients with inflammatory bowel disease between 2009 and 2012. INTERVENTIONS: Trough levels of infliximab and ATI were measured before each infusion by anti-λ ELISA. Patients were monitored for disease activity by clinical activity indexes and for dose-intensification or infliximab cessation. The occurrence of transient ATI disappearing spontaneously without intervention was recorded separately. RESULTS: 125 patients were included (98 Crohn's disease, 27 ulcerative colitis, median follow-up 11.5±22â months) and 1119 sera were analysed for infliximab and ATI levels. Kaplan-Meier analysis showed that 42% of patients remained ATI-free by 4â years of treatment. Most (90%) of the patients who developed ATI did so within the first 12â months of therapy, whereas transient ATI were detected throughout the duration of infliximab therapy (p<0.001). ATI incidence was similar between patients who received infliximab previously (episodic/interrupted therapy patients, n=14) and scheduled-therapy patients (n=111). In the scheduled group, combination immunomodulator+infliximab resulted in longer ATI-free survival compared with monotherapy (p=0.003, logrank test). Survival free of clinical loss of response was enjoyed by 51% of patients, and serial measurements showed that ATI development often preceded the onset of clinical flare. CONCLUSIONS: When followed prospectively, most patients who develop ATI do so within the first 12â months of therapy. This incidence is reduced by concomitant immunomodulator even in scheduled-therapy patients. In contrast, transient ATI, which are of little clinical significance, can appear haphazardly at any time during treatment. The onset of clinical loss of response may lag behind the appearance of anti-infliximab antibodies.
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Antiinflamatorios no Esteroideos/inmunología , Anticuerpos Monoclonales/inmunología , Anticuerpos/sangre , Colitis Ulcerosa/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Resistencia a Medicamentos/inmunología , Adolescente , Adulto , Antiinflamatorios no Esteroideos/sangre , Antiinflamatorios no Esteroideos/uso terapéutico , Anticuerpos Monoclonales/sangre , Anticuerpos Monoclonales/uso terapéutico , Colitis Ulcerosa/inmunología , Enfermedad de Crohn/inmunología , Femenino , Humanos , Infliximab , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Tiempo , Adulto JovenRESUMEN
Small molecule drugs are becoming increasingly used in the treatment of inflammatory bowel diseases (IBD). However, unlike monoclonal antibody drugs, which have few interactions with other medications, the pharmacokinetics of small molecule drugs are complex and may be influenced by a myriad of drug-drug interactions (DDI) as well as by patient characteristics and food intake. This review aims to provide a concise practical guide to small molecule drug interactions for the use of IBD physicians. It starts with a brief overview of the main metabolizing enzymes and transporters involved in drug interactions and the Food and Drug Administration's (FDA) approach to determining drug-interaction hazard thresholds. It is then followed by a more detailed review of the pharmacokinetics of five novel small molecules approved in IBD: Tofacitinib, Upadacitinib, Filgotinib, Ozanimod, and Etrasimod, including their known interactions and specific warnings. This review will also inform readers on challenges in determining the actual magnitude of interactions and their clinical relevance, including the arbitrary nature of some hazard thresholds, the inference of the impact on metabolizing enzymes and transporters from single-drug assays which may not reflect poly-pharmaceutical regimens, and other challenges in this field which the IBD physician needs to be cognizant of. In practice, before administering a small molecule drug, it is advisable to evaluate any potential interactions with other medications the patient is receiving. An increased awareness by health care professionals and patients, may reduce the possible risks associated with DDI of small molecule IBD drugs.
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Interacciones Farmacológicas , Enfermedades Inflamatorias del Intestino , Piperidinas , Humanos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Piperidinas/uso terapéutico , Piperidinas/farmacocinética , Piperidinas/farmacología , Pirimidinas/farmacocinética , Pirimidinas/uso terapéutico , Fármacos Gastrointestinales/uso terapéutico , Fármacos Gastrointestinales/farmacocinética , Gastroenterólogos , United States Food and Drug Administration , Piridinas/farmacocinética , Piridinas/uso terapéutico , Piridinas/efectos adversos , Compuestos Heterocíclicos con 3 Anillos , Indanos , Oxadiazoles , TriazolesRESUMEN
BACKGROUND AND AIMS: Fecal calprotectin (FC) is known to be a sensitive biomarker of colonic inflammation but to a lesser degree of small bowel (SB) inflammation. Moreover, data on FC's diagnostic levels in different SB segments are scarce. We aimed to examine FC's diagnostic levels along the SB-axis in CD. METHODS: This was a post-hoc aggregated analysis of five prospective studies of adult CD patients, who underwent FC testing and SB video capsule endoscopy (VCE). Lewis score (LS) inflammation in different SB segments was tested for correlation with FC level after exclusion of colonic disease. The diagnostic levels of FC for SB inflammatory topographical-gradient were assessed using a receiver operating characteristic. RESULTS: 214 patients were included (age:30 [24-43] year-old, males-57%). For a similar SB inflammatory-activity (LS≥135), FC levels incrementally increased from proximal to distal SB segments (63 [30-121] versus 190 [78-549], p=0.005) and from distal SB segment to the colon (190 [78-549] versus 542 [185-1000], p=0.010). The best FC cutoffs to identify isolated mild proximal/distal SB-inflammation (LS≥135) were 77µgg and 123µgg, respectively. A cutoff of 234µgg was best to detect more significant proximal inflammation (LS≥350) when only mild distal SB-inflammation was present. In sensitivity analyses, this proximal-to-distal FC gradient was maintained when LS≥350 and LS≥790 were used as the inflammatory reference-values. Unlike FC, the magnitude of CRP elevation was unrelated to the topography of inflammation along the SB-axis. CONCLUSIONS: FC may serve as a topographical biomarker of CD-activity, with its sensitivity to identify mucosal inflammation increases from proximal to distal SB segments.
RESUMEN
BACKGROUND AND AIMS: Pan-enteric capsule endoscopy (PillCam Crohn's capsule [PCC]) is a useful tool in diagnosing and monitoring Crohn's disease (CD). Eliakim score [ES] reliability and strong correlation to Lewis score (LS) and inflammatory biomarkers have been previously demonstrated using PCC in quiescent CD. We aimed to examine ES performance in active CD and its responsiveness to clinical/biochemical change over time. METHODS: Patients with CD who have started biologics were included, and were prospectively followed with clinical visits, biomarkers, and PCC at baseline, after 14 and 52 weeks. Crohn's disease activity index (CDAI), C-reactive protein (CRP) and fecal-calprotectin (FC) levels were collected, and LS and ES were calculated (independently reviewed by two experienced readers). Inter-class classification (ICC), Spearman's baseline correlation, and repeated-measures correlation (RMC) analyses were performed. RESULTS: 74 patients were included (age: 30.5 [23.3-45.0] years-old, male-50%). 142 PCCs were read (baseline-62, week-14-58, week-52-22). Inter-rater agreement was high for both LS and ES (ICC: 0.872 [p<0.001] and 0.925 [<0.001], respectively). Baseline correlations between FC&ES (r=0.509 [p<0.001]) and FC&LS (r=0.467 [p<0.001]) were comparable (p=0.56). RMC between the inflammatory biomarkers and ES were higher than between the former and LS (Reader-1: CRP- r=0.306 vs. r=0.138 [p=0.057], FC- r=0.479 vs. r=0.297 [p=0.034]; Reader-2 CRP- r=0.376 vs. r=0.204 [p=0.035], FC- r=0.549 vs. r=0.412 [p=0.075]). Moreover, ES was better correlated to CDAI than LS (p=0.036). CONCLUSIONS: ES is a reliable scoring system in assessing pan-enteric mucosal inflammation in active CD, and might have a better responsiveness to clinical/biochemical change over time compared to LS.
RESUMEN
BACKGROUND AND AIMS: Home self-injection of the human anti-tumour necrosis alpha [anti-TNFα] monoclonal adalimumab complicates prospective serial-sampling studies. Although a recent study examined adalimumab levels and immunogenicity in Crohn's disease [CD] patients, prospective real-world data from ulcerative colitis [UC] patients are lacking. METHODS: A three-monthly home-visit programme from induction was established prospectively for UC patients. Clinical scores were determined at each visit, and sera were obtained for assessment of drug and anti-adalimumab antibody levels. Calprotectin was measured using a smartphone-based app. This cohort was compared to a parallel prospective cohort of adalimumab-treated CD patients [POETIC1]. RESULTS: Fifty UC patients starting adalimumab [median follow-up 28 weeks] were compared to 98 adalimumab-treated CD patients [median follow-up 44 weeks]. Only 11/50 UC patients [22%] continued treatment to the end of the follow-up compared with 50/98 [51%] CD patients (odds ratio [OR]â =â 0.27, pâ =â 0.001). Loss of response was significantly more common in UC patients [ORâ =â 3.2, pâ =â 0.001]. Seventeen patients [34%] in the UC cohort developed anti-adalimumab antibodies, 9/17 [52.9%] as early as week 2. There was no difference between patient cohorts in the overall development of anti-adalimumab antibodies [34% vs 30.6%, respectively, ORâ =â 1.67, pâ =â 0.67], nor was there a difference in early immunogenicity [ORâ =â 1.39, pâ =â 0.35]. There was no difference in low drug levels [<3 µg/mL] between the two cohorts [ORâ =â 0.87, pâ =â 0.83]. CONCLUSIONS: Loss of response to adalimumab therapy was significantly more common in the UC compared to the CD cohort and was driven by a higher rate of non-immunogenic, pharmacodynamic parameters.