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Background and Aims: Early biologic therapy treatment has demonstrated better outcomes in Crohn's disease (CD). We evaluated the impact of CD duration in patients with moderately to severely active CD treated with risankizumab therapy. Methods: This post hoc analysis evaluated clinical, endoscopic, and safety outcomes by baseline CD duration (<2, 2-5, >5-10, and >10 years) in patients from ADVANCE, MOTIVATE, and FORTIFY. Pooled induction analyses included patients who received intravenous 600-mg dose of risankizumab or placebo for 12 weeks. Maintenance analyses included patients who responded to induction risankizumab and received subcutaneous 180-mg or 360-mg dose of risankizumab for 52 weeks. Duration subgroups were compared using Cochrane-Armitage trend tests with nominal P values. Results: Among 527 patients who received risankizumab 600-mg induction therapy, higher outcome rates were observed at week 12 among patients with shorter vs longer baseline disease duration (for <2, 2-5, >5-10, and >10 years, clinical remission: 42.7%, 46.9%, 43.5%, and 33.2% [P = .046]; endoscopic response: 48.3%, 36.3%, 32.0%, and 33.4% [P = .025]). Among 298 patients receiving risankizumab (180 mg or 360 mg) maintenance therapy, shorter vs longer baseline disease duration was generally associated with numerically higher endoscopic outcome rates at week 52. Higher clinical remission and endoscopic outcome rates were generally observed with shorter disease duration with 180-mg risankizumab dose only. Adverse event rates were generally similar across duration subgroups. Conclusion: Clinical benefits of risankizumab are observed across disease duration subgroups; clinical and endoscopic outcome rates are higher with risankizumab initiation earlier in the disease course (ClinicalTrials.gov numbers: NCT03105128, NCT03104413, and NCT03105102).
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BACKGROUND & AIMS: The Lemann Index (LI), an endpoint to measure cumulative structural bowel damage in Crohn's disease (CD), has been recently updated and validated. We applied this to investigate predictors of bowel damage in a real-world cohort. METHODS: We performed a retrospective study (2008-2022) involving two tertiary referral IBD centers in the US. MR or CT enterographies were reviewed by study radiologists and endoscopy reports by study gastroenterologists, to calculate LI. Baseline and follow-up LI were calculated. We defined high bowel damage as LI ≥2. Factors associated with high LI were identified in patients with ≥2 LI scores using multivariate logistic regression and then assessed for a change in LI (increase vs. no change/decrease) using a multivariate linear mixed-effects model. RESULTS: 447 patients with CD had a median first LI of 7 [IQR, 1.25-14.55]. Median LI scores were significantly different when categorized by disease duration; 2.0 [IQR, 0.6-5.9] for <2 years, 2.6 [IQR, 0.6-9.6] for ≥2 and <10 years, and 12.5 [IQR, 6.4-21.5] for ≥10 years with a p <0.01. Disease duration, presence of perianal disease, elevated C-reactive protein, and Harvey-Bradshaw index, were associated with a high LI at inclusion and increase in LI during follow-up (all p <0.01). CONCLUSIONS: The updated LI quantified cross-sectional and longitudinal cumulative bowel damage in a real-world cohort of patients with CD with predictors identified for a longitudinal increase in LI. Further studies for prospective validation of LI and identification of multi-omic predictors of bowel damage are needed.
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Interleukin (IL) 23, a member of the IL12 family of cytokines, maintains intestinal homeostasis, but is also implicated in the pathogenesis of inflammatory bowel diseases (IBDs). The IL23 receptor is a heterodimer composed of disulfide-linked p19 and p23 subunits. Humanized monoclonal antibodies selectively targeting the p19 subunit of IL23 are poised to become prominent drugs in IBDs. In this review, we discuss the pharmacodynamic and pharmacokinetic properties of the currently available IL23p19 inhibitors and discuss the mechanistic underpinnings of their therapeutic effects, including the mechanism of action, epitope affinity, potency, and downstream signaling. Furthermore, we address available data on the efficacy, safety, and tolerability of IL23-specific p19 inhibitors in the treatment of IBDs and discuss important studies performed in other immune-mediated inflammatory diseases. Finally, we evaluate the potential for combining classes of biological therapies and provide future directions on the development of precision medicine-guided positioning of IL23p19 inhibitors in IBD.
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BACKGROUND AND AIMS: COVID-19 vaccination prevents severe disease in most patients with inflammatory bowel disease (IBD), but immunosuppressive medications can blunt serologic response. We followed adults with IBD for >1 year post-COVID-19 vaccination to describe factors associated with SARS-CoV-2 infection after vaccination, evaluate for a protective SARS-CoV-2 antibody level, characterize SARS-CoV-2 antibody persistence, and identify factors associated with humoral immune response durability. METHODS: Using a prospective cohort of COVID-19 immunized adults with IBD, we analyzed factors associated with SARS-CoV-2 infection after vaccination. We evaluated for an association between SARS-CoV-2 antibody level 12 weeks postvaccination and subsequent SARS-CoV-2 infection and assessed for a threshold of protection using receiver-operating characteristic curve analysis. We then conducted a separate analysis evaluating factors associated with persistence of SARS-CoV-2 antibodies 52 weeks postimmunization. RESULTS: Almost half (43%) of 1869 participants developed COVID-19 after vaccination, but most infections were mild, and <1% required hospitalization. Older age and corticosteroid use were associated with a decreased risk of SARS-CoV-2 infection postvaccination (50-59 years of age vs 18-29 years of age: adjusted hazard ratio, 0.57; 95% confidence interval, 0.44-0.74; steroid users vs nonusers: adjusted hazard ratio, 0.58; 95% confidence interval, 0.39-0.87). Most (98%) participants had detectable antibody levels at 52 weeks postvaccination. Antibody levels at 12 weeks and number of vaccine doses were positively associated with higher antibody levels at 52 weeks, while anti-tumor necrosis factor α therapy was negatively associated. CONCLUSIONS: COVID-19 vaccination generates an effective and durable protective response for the vast majority of adults with IBD, including vulnerable populations such as corticosteroid users and older individuals. Patients with IBD benefit from COVID-19 booster vaccination.
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Anticorpos Antivirais , Vacinas contra COVID-19 , COVID-19 , Doenças Inflamatórias Intestinais , SARS-CoV-2 , Humanos , COVID-19/prevenção & controle , COVID-19/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Doenças Inflamatórias Intestinais/imunologia , Adulto , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/imunologia , Estudos Prospectivos , Anticorpos Antivirais/sangue , SARS-CoV-2/imunologia , Vacinação , Idoso , Adulto JovemRESUMO
INTRODUCTION: A significant proportion of patients with acute severe ulcerative colitis (ASUC) require colectomy. METHODS: Patients with ASUC treated with upadacitinib and intravenous corticosteroids at 5 hospitals are presented. The primary outcome was 90-day colectomy rate. Secondary outcomes included frequency of steroid-free clinical remission, adverse events, and all-cause readmissions. RESULTS: Of the 25 patients with ASUC treated with upadacitinib, 6 (24%) patients underwent colectomy, 15 (83%) of the 18 patients with available data and who did not undergo colectomy experienced steroid-free clinical remission (1 patient did not have complete data), 1 (4%) patient experienced a venous thromboembolic event, while 5 (20%) patients were readmitted. DISCUSSION: Upadacitinib along with intravenous corticosteroids may be an effective treatment for ASUC.
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BACKGROUND: Early initiation of biologics in moderate-to-severe Crohn's disease (CD) may significantly alter disease progression, resulting in better patient outcomes. Limited real-world data exist on the impact of early biologic use in patients with CD in the United States. AIMS: We aimed to characterize biologic initiation and subsequent healthcare resource utilization (HCRU) in adults with recently diagnosed CD. METHODS: Patients with CD who initiated biologic treatment within 2 years of diagnosis (index date) were identified from medical and pharmacy claims (Merative L.P. MarketScan Database from 2010 to 2016) and classified as early (≤ 12 months post-index) or late (> 12-24 months post-index) biologic initiators. Propensity score matching balanced patient characteristics up to 1 year post-index. Differences in HCRU frequency and costs 1-2 years post-index were compared between the matched groups. RESULTS: After propensity score matching, 672 pairs of early and late biologic initiators were identified. Patients who initiated biologics early had fewer outpatient visits (15.5 vs 19.8, 95% confidence interval [CI] for difference: 2.7, 6.1) and lower total medical costs ($13,646.20 vs $22,180.70, 95% CI for difference: 4748.9, 12,320.1) 1-2 years post-index than late biologic initiators. Early biologic initiators had higher medication costs 1-2 years post-index ($33,766.30 vs $30,580.70, 95% CI: 546.1, 5825.1) but lower combined medical and medication costs ($47,412.50 vs $52,761.50, 95% CI: 801.5, 9896.40). CONCLUSIONS: While biologic treatments are costly, patients initiating biologics sooner after diagnosis appear to have better HCRU outcomes and require fewer healthcare resources at 1-2 years post-index, potentially leading to overall cost savings.
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Produtos Biológicos , Doença de Crohn , Adulto , Humanos , Estados Unidos , Doença de Crohn/diagnóstico , Doença de Crohn/tratamento farmacológico , Estudos Retrospectivos , Custos de Cuidados de Saúde , Custos de Medicamentos , Produtos Biológicos/uso terapêuticoRESUMO
INTRODUCTION: The American Gastroenterological Association (AGA) has compiled risk factors that may be predictive of disease complications in Crohn's disease (CD) and ulcerative colitis (UC). The aim of this study was to evaluate the performance of the AGA risk factors for risk stratification in UC and CD. METHODS: We included participants of 2 cohorts: the Ocean State Crohn's and Colitis Area Registry cohort and the Mayo Clinic cohort. Baseline clinical risk factors were extracted according to the AGA pathway. Our primary end point was defined as follows: (i) any inflammatory bowel disease related-hospitalization, (ii) any inflammatory bowel disease-related bowel surgery, or (iii) any progression of disease. We analyzed the association of the number of AGA risk factors with our end point. Statistical multivariable modeling was performed with Cox proportional hazards model. RESULTS: A total of 412 patients with CD were included. Comparing ≥3 risk factors with 0-1 risk factor, we found a significantly increased risk of complications in both the Ocean State Crohn's and Colitis Area Registry cohort (hazard ratio [HR] 2.75, 95% confidence interval 1.71-4.41) and Mayo Clinic cohort (HR 2.07, 95% confidence interval 1.11-3.84). Diagnosis at younger age (HR 2.07), perianal disease (HR 1.99), and B2/B3 behavior (HR 1.92) were significantly associated with disease complications. We did not observe a consistent association between number of risk factors nor any specific individual risk factors and risk of disease complications in the 265 patients with UC included. DISCUSSION: We found a significant association between the number of AGA risk factors and the risk of disease complication in CD; this association was not significant in UC. The presence of ≥ 3 risk factors in CD leads to the highest risk of complications. The AGA care pathway is a useful tool to stratify patients who are at higher risk of disease complications in patients with CD.
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Colite Ulcerativa , Colite , Doença de Crohn , Doenças Inflamatórias Intestinais , Humanos , Doença de Crohn/complicações , Doença de Crohn/terapia , Procedimentos Clínicos , Colite Ulcerativa/complicações , Doenças Inflamatórias Intestinais/complicações , Fatores de Risco , Colite/complicaçõesRESUMO
INTRODUCTION: We previously reported the results of tofacitinib induction therapy in the prospective multisite US real-world Tofacitinib Response in Ulcerative Colitis registry. We now assessed patient-reported outcomes (PROs) and predictors of success during tofacitinib maintenance therapy. METHODS: Tofacitinib Response in Ulcerative Colitis included 103 patients with refractory ulcerative colitis (UC); 67% had failed ≥ 2 biologics. Patients reported the Simple Clinical Colitis Activity Index (SCCAI), Patient-Reported Outcome Measurement Information System measures for anxiety, depression, social satisfaction, and adverse events between weeks 8 and 52 using a web-based system. Paired t test and P for trend were used to compare changes in PRO measures over time. Bivariate analyses and logistic regression models were used to determine factors associated with response (SCCAI <5) or remission (SCCAI <2) at week 52. RESULTS: Of 103 patients, 82.5% entered the maintenance phase and 43.7% remained on tofacitinib at week 52. Tofacitinib de-escalation to 5 mg BID occurred in 15% of patients. At week 52, 42.7% and 31.1% of all patients reported an SCCAI <5 and SCCAI ≤2, respectively. Normalization of bowel frequency, rectal bleeding, and urgency occurred in 79%, 61%, and 48% of patients remaining on maintenance therapy. Social satisfaction improved significantly ( P < 0.001), while anxiety and depression scores only numerically improved. No consistent predictors for tofacitinib long-term treatment efficacy were identified, and safety findings were consistent with the known safety profile of tofacitinib. DISCUSSION: Tofacitinib is an effective maintenance therapy in patients with refractory UC. Dose reductions infrequently occurred during maintenance. Unmet needs in UC maintenance include improvement of urgency and psychosocial factors (NCT03772145).
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Colite Ulcerativa , Pirimidinas , Humanos , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/tratamento farmacológico , Estudos Prospectivos , Piperidinas/efeitos adversos , Sistema de RegistrosAssuntos
Insuficiência Adrenal , Colite Ulcerativa , Doenças Inflamatórias Intestinais , Humanos , Insuficiência Adrenal/induzido quimicamente , Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/tratamento farmacológico , Colite Ulcerativa/diagnóstico , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Esteroides/efeitos adversos , Corticosteroides/efeitos adversosRESUMO
BACKGROUND & AIMS: Although biologics have revolutionized the treatment of Crohn's disease (CD), an efficacy ceiling has been reached. Combining biologic therapies may improve remission rates. METHODS: EXPLORER, a phase 4, single-arm, open-label study, evaluated triple combination therapy with vedolizumab (300 mg on day 1, weeks 2 and 6, and then every 8 weeks), adalimumab (160 mg on day 2, 80 mg at week 2, then 40 mg every 2 weeks), and methotrexate (15 mg weekly) in biologic-naïve patients with newly diagnosed, moderate- to high-risk CD. Endoscopic remission at week 26 (primary end point; Simple Endoscopic Score for CD ≤2), clinical remission at weeks 10 and 26 (secondary end point; Crohn's Disease Activity Index <150), and incidences of adverse events and serious adverse events were evaluated. RESULTS: Among 55 enrolled patients, the mean CD duration was 0.4 years, the mean baseline Simple Endoscopic Score for CD was 12.6, and the mean baseline Crohn's Disease Activity Index was 265.5. At week 26, 19 patients (34.5%) were in endoscopic remission. At weeks 10 and 26, 34 (61.8%) and 30 patients (54.5%), respectively, were in clinical remission. Post hoc Bayesian analysis showed that the probabilities that triple combination therapy produced a higher endoscopic remission rate (33.5%; 95% credible interval, 22.4-45.7) than placebo (14%), vedolizumab monotherapy (27%), or adalimumab monotherapy (30%) were 99.9% or higher, 86.3%, and 71.4%, respectively. Six patients had serious adverse events. CONCLUSIONS: Combination therapy resulted in endoscopic and clinical remission at week 26 in 34.5% and 54.5% of patients, respectively, with no safety signal related to the treatment regimen. This supports further evaluation of combination therapy in CD. CLINICALTRIALS: gov number: NCT02764762.
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BACKGROUND: Given the complexity of inflammatory bowel disease (IBD) care, utilization of multidisciplinary teams is recommended to optimize outcomes. There is a growing recognition that clinical pharmacists should be an integral part of this care model. We sought to define the roles of IBD clinical pharmacists in the United States. METHODS: A national multidisciplinary expert panel of 12 gastroenterologists and clinical pharmacists practicing in IBD clinics was assembled. We used the RAND/University of California, Los Angeles appropriateness method, with a total of 281 statements generated based on a systematic literature review and expert opinion. Each statement was anonymously rated as appropriate, uncertain, or inappropriate in 2 rounds of voting. RESULTS: The number of publications evaluating the clinical pharmacists' roles in IBD is limited, primarily focusing on thiopurine initiation and monitoring, medication adherence, and switching to biosimilars. Medication education; medication initiation and monitoring; therapeutic drug monitoring; biosimilar management; health maintenance review; and transitions of care were deemed by the panel to be appropriate roles for IBD clinical pharmacists. In considering real-world settings, IBD clinical pharmacists should practice clinically under a predefined scope and primarily focus on complex treatments (eg, immunomodulators, biologics, and small molecules). Clinical pharmacists should also be included in practice settings with IBD specialized physicians. Additionally, clinical pharmacists caring for patients with IBD should be residency trained and board certified. CONCLUSIONS: This consensus defines IBD clinical pharmacists' roles and provides a framework for embedded clinical pharmacists in IBD care.
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BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) can lead to long-term complications that significantly impact patients' quality of life and healthcare resource utilization. Prior studies have demonstrated improved short-term outcomes to early exposure of biologics in patients with Crohn's disease (CD) but not in patients with ulcerative colitis (UC). However, there are conflicting data on impact of early intervention on longer-term adverse events. Therefore, we conducted a systematic review and meta-analysis assessing the impact of early biologic treatment on rates of IBD-related surgery. METHODS: A systematic search was conducted in April 2022. Studies were included if biologic initiation was compared between patients starting early (<3 years of diagnosis or top-down treatment) vs later (>3 years of diagnosis or step-up treatment). Studies with <1 year of follow-up were excluded. The outcomes were colectomy and CD-related surgery for patients with UC and CD, respectively. Random-effects analyses were conducted to compare rates of IBD surgery between early and late biologic treatment. RESULTS: Eighteen studies were included in the meta-analysis. Three studies included patients with UC and 15 studies included patients with CD. In patients with CD, early biologic therapy was associated with lower odds of surgery (odds ratio, 0.63; 95% confidence interval, 0.48-0.84) compared with late treatment. Conversely, in patients with UC, the odds of colectomy were increased (odds ratio, 2.86; 95% confidence interval, 1.30-6.30). CONCLUSIONS: Early biologic treatment is associated with lower rates of surgery in patients with CD. In contrast, early biologic therapy appears to be associated with higher rates of colectomy in patients with UC, which may be confounded by disease severity.
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The emergence of advanced therapies [eg, biologics, Janus kinase inhibitors] over the past few decades has revolutionised the treatment of ulcerative colitis. However, the limitations of these therapies leave an unmet need for safer and more effective or convenient treatment options. There is growing interest in the development of novel oral small molecule therapies for the treatment of ulcerative colitis. Ozanimod is an oral small molecule therapy that is approved in the USA, the European Union, and other countries as the first sphingosine 1-phosphate receptor modulator for the treatment of moderately to severely active ulcerative colitis in adults. This review provides guidance for ozanimod use for the treatment of ulcerative colitis, based on the prescribing information, clinical trial and real-world data, and the authors' clinical experiences. This guidance outlines patient characteristics to consider when deciding if ozanimod treatment is suitable and describes how to educate patients on risks and best practices. It also details the nature and frequency of monitoring during treatment, which should be adapted to the individual patient based on pre-existing risk factors and events that possibly occur during treatment. This review also provides insights into the patient characteristics and clinical scenarios best suited for ozanimod treatment, based on its efficacy, safety profile, and risks compared with other therapies.
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Colite Ulcerativa , Adulto , Humanos , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Indanos/efeitos adversos , Oxidiazóis/efeitos adversos , Fatores Imunológicos/uso terapêuticoRESUMO
BACKGROUND AND AIMS: The benefit of continuing 5-aminosalicylic acid [5-ASA] treatment when escalating to advanced therapies in patients with inflammatory bowel disease [IBD] is unclear. Vedolizumab is a gut-selective monoclonal anti-α4ß7-integrin antibody used to treat moderate to severe IBD. Clinical trial data were analysed post hoc to assess the impact of 5-ASA co-treatment on vedolizumab efficacy and safety in patients with IBD. METHODS: Data were analysed from patients aged 18-80 years with moderate to severe ulcerative colitis [UC]/Crohn's disease [CD] receiving intravenous [IV]/subcutaneous [SC] vedolizumab. Efficacy data were from four studies [GEMINI 1 and 2 and VISIBLE 1 and 2]; safety data were from seven studies [GEMINI 1â3 and long-term, VISIBLE 1, 2, and open-label extension]. The impact of 5-ASA co-treatment on clinical and endoscopic outcomes at Weeks 6 and 52 was assessed using multivariate analysis (adjusted odds ratios [aORs] with 95% confidence intervals [CIs]). RESULTS: There were no significant differences in UC clinical remission [Mayo score ≤2, no subscore >1] rates with vs without 5-ASA at Week 6 [20.7% vs 20.4%, respectively; aOR 0.77, 95% CI 0.43-1.38] or at Week 52 [45.1% vs 40.6%; aOR 1.14, 0.70-1.86], and in CD clinical remission [CD activity index scoreâ ≤150] rates at Week 6 [41.4% vs 35.1%; 1.26, 0.86-1.85] or at Week 52 [49.6% vs 37.8%; 1.35, 0.91-1.99]. The incidence of enteric and all infections in vedolizumab IV/SC-treated patients was low with and without 5-ASA. CONCLUSION: Continuation of concomitant oral 5-ASA after starting vedolizumab had no significant impact on clinical and endoscopic outcomes. CLINICAL TRIAL IDENTIFIERS: GEMINI 1: NCT00783718, EudraCT 2008-002782-32; GEMINI 2: NCT00783692, EudraCT 2008-00278-33; GEMINI 3: NCT01224171, EudraCT 2009-016488-12; GEMINI long-term safety study: NCT00790933, EudraCT 2008-002784-14; VISIBLE 1: NCT02611830, EudraCT 2015-000480-14; VISIBLE 2: NCT02611817, EudraCT 2015-000481-58; VISIBLE open-label extension: NCT02620046, EudraCT 2015-000482-31.
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Anticorpos Monoclonais Humanizados , Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Humanos , Mesalamina/uso terapêutico , Fármacos Gastrointestinais/efeitos adversos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Doença de Crohn/tratamento farmacológico , Resultado do TratamentoRESUMO
BACKGROUND: We evaluated the clinical relevance of achieving histologic endoscopic mucosal improvement (HEMI) and the more stringent target of histologic endoscopic mucosal remission (HEMR) in the phase 3 maintenance trial of upadacitinib for moderately to severely active ulcerative colitis. METHODS: Clinical and patient-reported outcomes were assessed in patients with clinical response after 8- or 16-week upadacitinib induction who received 52-week upadacitinib maintenance treatment. Cross-sectional and predictive analyses evaluated the relationship between HEMR or HEMI at Week 8/16 and Week 52, respectively, and outcomes at Week 52. Adjusted odds ratios (aOR) were derived from logistic regressions for patients achieving HEMR or HEMI without HEMR versus those not achieving HEMI. RESULTS: Cross-sectional analyses showed that patients with HEMR had greater odds of achieving all clinical and patient-reported outcomes at Week 52 than those not achieving HEMI. In predictive analyses, patients with HEMR at Week 8/16 had significantly greater odds of achieving clinical remission (aOR = 3.6, p = 0.001) and endoscopic remission (aOR = 3.9, p < 0.001) at Week 52 than patients not achieving HEMI and HEMR. For patients achieving HEMI without HEMR, these odds were lower: clinical remission (aOR = 3.2, p < 0.001) and endoscopic remission (aOR = 2.4, p = 0.010). The odds of achieving clinically meaningful improvements in most patient-reported outcomes were directionally similar between HEMI and HEMR, but not statistically different to patients not achieving HEMI. No hospitalizations or surgeries were observed in patients with HEMR at Week 52. CONCLUSIONS: Achievement of HEMR or HEMI is clinically relevant with HEMR being associated with greater likelihood of improvement in long-term clinical and patient-reported outcomes. https://www. CLINICALTRIALS: gov NCT02819635.
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Colite Ulcerativa , Humanos , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Estudos Transversais , Endoscopia , Mucosa Intestinal/patologia , Indução de Remissão , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Ulcerative colitis (UC) is an idiopathic chronic inflammatory disease of the colon with sharply rising global prevalence. Dysfunctional epithelial compartment (EC) dynamics are implicated in UC pathogenesis although EC-specific studies are sparse. Applying orthogonal high-dimensional EC profiling to a Primary Cohort (PC; n=222), we detail major epithelial and immune cell perturbations in active UC. Prominently, reduced frequencies of mature BEST4+OTOP2+ absorptive and BEST2+WFDC2+ secretory epithelial enterocytes were associated with the replacement of homeostatic, resident TRDC+KLRD1+HOPX+ γδ+ T cells with RORA+CCL20+S100A4+ TH17 cells and the influx of inflammatory myeloid cells. The EC transcriptome (exemplified by S100A8, HIF1A, TREM1, CXCR1) correlated with clinical, endoscopic, and histological severity of UC in an independent validation cohort (n=649). Furthermore, therapeutic relevance of the observed cellular and transcriptomic changes was investigated in 3 additional published UC cohorts (n=23, 48 and 204 respectively) to reveal that non-response to anti-Tumor Necrosis Factor (anti-TNF) therapy was associated with EC related myeloid cell perturbations. Altogether, these data provide high resolution mapping of the EC to facilitate therapeutic decision-making and personalization of therapy in patients with UC.
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Over the last 2 years the lives of millions have changed because of the emergence of Coronavirus disease 2019 (COVID-19). Patients living with inflammatory bowel disease (IBD) represent a sizable population with their own sets of challenges to providers in the wake of so much uncertainty. The Centers for Disease Control considers immunocompromised individuals at higher risk of infection and complications from COVID-19. Early in the pandemic, the specific risks for IBD patients were unclear as guidance was based on expert opinion regarding the management of IBD during a COVID-19 era. Fortunately, after considerable work in the field, the overwhelming evidence suggests that IBD patients as a whole do not appear to be at increased risk for more severe disease from COVID-19. Certain risk factors such as age, steroids, comorbidities, combination immunomodulatory therapy, and IBD disease activity have been associated with worse outcomes. Most IBD medications are low risk, with the exception of immunomodulator monotherapy and combination therapy with thiopurine and anti-TNF. Vaccination remains safe and effective for all IBD patients, although additional booster doses may be necessary, particularly in patients taking anti-TNF agents.
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BACKGROUND & AIMS: Early Crohn's disease (CD) treatment involves anti-tumor necrosis factor (TNF) agents, whereas ileocecal resection (ICR) is reserved for complicated CD or treatment failure. We compared long-term outcomes of primary ICR and anti-TNF therapy for ileocecal CD. METHODS: Using cross-linked nationwide registers, we identified all individuals diagnosed with ileal or ileocecal CD between 2003 and 2018 and treated with ICR or anti-TNF agents within 1 year of diagnosis. The primary outcome was a composite of ≥1 of the following: CD-related hospitalization, systemic corticosteroid exposure, CD-related surgery, and perianal CD. We conducted adjusted Cox's proportional hazards regression analyses and determined the cumulative risk of different treatments after primary ICR or anti-TNF therapy. RESULTS: Of 16,443 individuals diagnosed with CD, 1279 individuals fulfilled the inclusion criteria. Of these, 45.4% underwent ICR and 54.6% received anti-TNF. The composite outcome occurred in 273 individuals (incidence rate, 110/1000 person-years) in the ICR group and in 318 individuals (incidence rate, 202/1000 person-years) in the anti-TNF group. The risk of the composite outcome was 33% lower with ICR compared with anti-TNF (adjusted hazard ratio, 0.67; 95% confidence interval, 0.54-0.83). ICR was associated with reduced risk of systemic corticosteroid exposure and CD-related surgery, but not other secondary outcomes. The proportion of individuals on immunomodulator, anti-TNF, who underwent subsequent resection, or were on no therapy 5 years post-ICR was 46.3%, 16.8%, 1.8%, and 49.7%, respectively. CONCLUSION: These data suggest that ICR may have a role as first-line therapy in CD management and challenge the current paradigm of reserving surgery for complicated CD refractory or intolerant to medications. Yet, given inherent biases associated with observational data, our findings should be interpreted and applied cautiously in clinical decision making.
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Doença de Crohn , Humanos , Doença de Crohn/diagnóstico , Doença de Crohn/tratamento farmacológico , Doença de Crohn/cirurgia , Adalimumab/uso terapêutico , Infliximab/uso terapêutico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Estudos de Coortes , Fator de Necrose Tumoral alfa , Necrose , Estudos Retrospectivos , Resultado do TratamentoAssuntos
Produtos Biológicos , Colangite Esclerosante , Colite Ulcerativa , Humanos , Colite Ulcerativa/complicações , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/tratamento farmacológico , Vancomicina/uso terapêutico , Colangite Esclerosante/complicações , Colangite Esclerosante/tratamento farmacológico , Produtos Biológicos/uso terapêuticoRESUMO
BACKGROUND: At diagnosis, up to one-third of patients with Crohn's disease (CD) have a complicated phenotype with stricturing (B2) or penetrating (B3) behavior or require early surgery. We evaluated protein biomarkers and antimicrobial antibodies in serum archived years before CD diagnosis to assess whether complicated diagnoses were associated with a specific serological signature. METHODS: Prediagnosis serum was obtained from 201 patients with CD and 201 healthy controls. Samples were evaluated with a comprehensive panel of 1129 proteomic markers (SomaLogic) and antimicrobial antibodies. CD diagnosis and complications were defined by the International Classification of Diseases-Ninth Revision and Current Procedural Terminology codes. Cox regression models were utilized to assess the association between markers and the subsequent risk of being diagnosed with complicated CD. In addition, biological pathway and network analyses were performed. RESULTS: Forty-seven CD subjects (24%) had a B2 (n = 36) or B3 (n = 9) phenotype or CD-related surgery (n = 2) at diagnosis. Subjects presenting with complicated CD at diagnosis had higher levels of antimicrobial antibodies six years before diagnosis as compared with those diagnosed with noncomplicated CD. Twenty-two protein biomarkers (reflecting inflammatory, fibrosis, and tissue protection markers) were found to be associated with complicated CD. Pathway analysis of the altered protein biomarkers identified higher activation of the innate immune system and complement or coagulation cascades up to six years before diagnosis in complicated CD. CONCLUSIONS: Proteins and antimicrobial antibodies associated with dysregulated innate immunity, excessive adaptive response to microbial antigens, and fibrosis precede and predict a complicated phenotype at the time of diagnosis in CD patients.