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Repetitive exposure to antigen in chronic infection and cancer drives T cell exhaustion, limiting adaptive immunity. In contrast, aberrant, sustained T cell responses can persist over decades in human allergic disease. To understand these divergent outcomes, we employed bioinformatic, immunophenotyping and functional approaches with human diseased tissues, identifying an abundant population of type 2 helper T (TH2) cells with co-expression of TCF7 and LEF1, and features of chronic activation. These cells, which we termed TH2-multipotent progenitors (TH2-MPP) could self-renew and differentiate into cytokine-producing effector cells, regulatory T (Treg) cells and follicular helper T (TFH) cells. Single-cell T-cell-receptor lineage tracing confirmed lineage relationships between TH2-MPP, TH2 effectors, Treg cells and TFH cells. TH2-MPP persisted despite in vivo IL-4 receptor blockade, while thymic stromal lymphopoietin (TSLP) drove selective expansion of progenitor cells and rendered them insensitive to glucocorticoid-induced apoptosis in vitro. Together, our data identify TH2-MPP as an aberrant T cell population with the potential to sustain type 2 inflammation and support the paradigm that chronic T cell responses can be coordinated over time by progenitor cells.
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Fator 1-alfa Nuclear de Hepatócito , Hipersensibilidade , Fator 1 de Ligação ao Facilitador Linfoide , Células-Tronco Multipotentes , Fator 1 de Transcrição de Linfócitos T , Células Th2 , Humanos , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Fator 1 de Ligação ao Facilitador Linfoide/genética , Células Th2/imunologia , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Fator 1-alfa Nuclear de Hepatócito/genética , Hipersensibilidade/imunologia , Células-Tronco Multipotentes/metabolismo , Células-Tronco Multipotentes/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Diferenciação Celular , Citocinas/metabolismo , Linfopoietina do Estroma do Timo , Animais , Células Cultivadas , CamundongosRESUMO
There has been an increased ability to investigate human microbiota through next-generation sequencing and functional assessment. This advancement has rapidly expanded our ability to study and manipulate the gastrointestinal microbiome to mitigate disease. Fecal microbiota transplantation, a therapy that broadly transfers the entire intestinal ecosystem, has been explored as a potential therapeutic in a variety of gastrointestinal, hepatic, and extraintestinal conditions. The field, however, continues to evolve, with a movement toward precision microbiome therapeutics individualizing care for various disorders. This review will describe the use of fecal microbiota transplantation, microbiota restoration, and precision microbiome therapeutics focusing on gastrointestinal and hepatic diseases.
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Inflammatory bowel disease (IBD) comprises chronic and relapsing disorders of the gastrointestinal tract, characterized by dysregulated immune responses to the gut microbiome. The gut microbiome and diet are key environmental factors that influence the onset and progression of IBD and can be leveraged for treatment. In this review, we summarize the current evidence on the role of the gut microbiome and diet in IBD pathogenesis, and the potential of microbiome-directed therapies and dietary interventions to improve IBD outcomes. We discuss available data and the advantages and drawbacks of the different approaches to manipulate the gut microbiome, such as fecal microbiota transplantation, next-generation and conventional probiotics, and postbiotics. We also review the use of diet as a therapeutic tool in IBD, including the effects in induction and maintenance, special diets, and exclusive enteral nutrition. Finally, we highlight the challenges and opportunities for the translation of diet and microbiome interventions into clinical practice, such as the need for personalization, manufacturing and regulatory hurdles, and the specificity to take into account for clinical trial design.
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BACKGROUND & AIMS: The QUASAR Phase 2b Induction Study evaluated the efficacy and safety of guselkumab, an interleukin-23p19 subunit antagonist, in patients with moderately to severely active ulcerative colitis (UC) with prior inadequate response and/or intolerance to corticosteroids, immunosuppressants, and/or advanced therapy. METHODS: In this double-blind, placebo-controlled, dose-ranging, induction study, patients were randomized (1:1:1) to receive intravenous guselkumab 200 or 400 mg or placebo at weeks 0/4/8. The primary endpoint was clinical response (compared with baseline, modified Mayo score decrease ≥30% and ≥2 points, rectal bleeding subscore ≥1-point decrease or subscore of 0/1) at week 12. Guselkumab and placebo week-12 clinical nonresponders received subcutaneous or intravenous guselkumab 200 mg, respectively, at weeks 12/16/20 (uncontrolled study period). RESULTS: The primary analysis population included patients with baseline modified Mayo scores ≥5 and ≤9 (intravenous guselkumab 200 mg, n = 101; 400 mg, n = 107; placebo, n = 105). Week-12 clinical response percentage was greater with guselkumab 200 mg (61.4%) and 400 mg (60.7%) vs placebo (27.6%; both P < .001). Greater proportions of guselkumab-treated vs placebo-treated patients achieved all major secondary endpoints (clinical remission, symptomatic remission, endoscopic improvement, histo-endoscopic mucosal improvement, and endoscopic normalization) at week 12. Among guselkumab week-12 clinical nonresponders, 54.3% and 50.0% of patients in the 200- and 400-mg groups, respectively, achieved clinical response at week 24. Safety was similar among guselkumab and placebo groups. CONCLUSIONS: Guselkumab intravenous induction was effective vs placebo in patients with moderately to severely active UC. Guselkumab was safe, and efficacy and safety were similar between guselkumab dose groups. CLINICALTRIALS: gov number: NCT04033445.
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Colite Ulcerativa , Humanos , Anticorpos Monoclonais Humanizados/efeitos adversos , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/complicações , Método Duplo-Cego , Imunossupressores/uso terapêutico , Indução de Remissão , Resultado do TratamentoRESUMO
INTRODUCTION: The comparative effectiveness of upadacitinib and tofacitinib for ulcerative colitis (UC) is poorly understood. METHODS: In this retrospective cohort study, we compared steroid-free clinical remission (SFCR) and endoscopic response/remission at 52 weeks among adults initiating upadacitinib or tofacitinib for UC. RESULTS: A total of 155 patients initiated upadacitinib (n = 81; 30% prior tofacitinib exposure) or tofacitinib (n = 74; 0% prior upadacitinib exposure). After inverse probability of treatment-weighted logistic regression, upadacitinib was associated with significantly higher odds of SFCR (odds ratio 3.01, 95% confidence interval 1.39-6.55) vs tofacitinib. There were no differences for endoscopic response/remission. DISCUSSION: Upadacitinib was more effective at achieving SFCR in UC at 52 weeks vs tofacitinib.
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INTRODUCTION: Patients with inflammatory bowel diseases (IBD) commonly require analgesic medications to treat pain, which may be associated with complications. We examined trends of analgesic use according to age at IBD onset. METHODS: This nationwide cohort study included adults diagnosed with IBD between 1996 and 2021 in Denmark. Patients were stratified according to their age at IBD onset: 18-39 years (young adult), 40-59 years (adult), and older than 60 years (older adult). We examined the proportion of patients who received prescriptions for analgesic medications within 1 year after IBD diagnosis: strong opioids, tramadol, codeine, nonsteroidal anti-inflammatory drugs, and paracetamol. Multivariable logistic regression analysis was performed to examine the association between age at IBD onset and strong opioid prescriptions and the composite of strong opioid/tramadol/codeine prescriptions. RESULTS: We identified 54,216 adults with IBD. Among them, 25,184 (46.5%) were young adults, 16,106 (29.7%) were adults, and 12,926 (23.8%) were older adults at IBD onset. Older adults most commonly received analgesic prescriptions of every class. Between 1996 and 2021, strong opioid, tramadol, and codeine prescriptions were stable, while paracetamol prescriptions increased and nonsteroidal anti-inflammatory drug prescriptions decreased. After multivariable logistic regression analysis, older adults had higher adjusted odds of receiving strong opioid prescriptions (adjusted odds ratio 1.95, 95% confidence interval 1.77-2.15) and the composite of strong opioid/tramadol/codeine prescriptions (adjusted odds ratio 1.93, 95% confidence interval 1.81-2.06) within 1 year after IBD diagnosis compared with adults. DISCUSSION: In this nationwide cohort, older adults most commonly received analgesic prescriptions within 1 year after IBD diagnosis. Additional research is needed to examine the etiology and sequelae of increased analgesic prescribing to this demographic.
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Doenças Inflamatórias Intestinais , Tramadol , Adulto Jovem , Humanos , Idoso , Adolescente , Adulto , Analgésicos Opioides/uso terapêutico , Tramadol/uso terapêutico , Estudos de Coortes , Acetaminofen/uso terapêutico , Analgésicos/uso terapêutico , Codeína/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/epidemiologia , Prescrições de MedicamentosRESUMO
ABSTRACT: Fecal microbiota transplantation (FMT) prevents recurrent Clostridioides difficile infections (rCDI) in patients with inflammatory bowel disease. Bezlotoxumab is also indicated to prevent rCDI. We assess the impact of FMT in combination with bezlotoxumab in patients with inflammatory bowel disease and rCDI. We conducted a multicenter randomized placebo-controlled trial. All received a single colonoscopic FMT. Patients were randomized 1:1 to receive bezlotoxumab or placebo. Sixty-one patients were enrolled (30 received treatment and 31 received placebo). Overall, 5 participants (8%) experienced a CDI recurrence; 4 in the treatment arm, 1 in the placebo arm (13% vs 3%, P = 0.15). There was no clear benefit to the combination approach compared with FMT alone.
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Anticorpos Amplamente Neutralizantes , Infecções por Clostridium , Transplante de Microbiota Fecal , Doenças Inflamatórias Intestinais , Recidiva , Humanos , Transplante de Microbiota Fecal/métodos , Masculino , Feminino , Infecções por Clostridium/terapia , Anticorpos Amplamente Neutralizantes/uso terapêutico , Adulto , Pessoa de Meia-Idade , Doenças Inflamatórias Intestinais/terapia , Doenças Inflamatórias Intestinais/microbiologia , Resultado do Tratamento , Terapia Combinada , Clostridioides difficile , Anticorpos Monoclonais/uso terapêutico , ColonoscopiaRESUMO
BACKGROUND AND AIM: Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis. These post hoc analyses evaluated early improvement in patient-reported outcomes with tofacitinib 10 mg twice daily (BID) in OCTAVE Open among patients with ulcerative colitis who experienced treatment failure with placebo (retreatment subpopulation) or tofacitinib 5 mg BID (dose escalation subpopulation) during maintenance. METHODS: Endpoints based on Mayo subscores (rectal bleeding improvement, stool frequency improvement, and symptomatic [both rectal bleeding and stool frequency] improvement) were analyzed overall and by prior tumor necrosis factor inhibitor (TNFi) failure status from month (M)1-M6 in OCTAVE Open. Changes from baseline in partial Mayo score, rectal bleeding subscore, and stool frequency subscore at M1 were also analyzed, by M2 clinical response status. RESULTS: At M1 of OCTAVE Open, 83.2%, 70.3%, and 64.4% of patients in the retreatment subpopulation (n = 101) had rectal bleeding improvement, stool frequency improvement, and symptomatic improvement, respectively. Corresponding values in the dose escalation subpopulation (n = 57) were 59.6%, 50.9%, and 38.6%. For both subpopulations, results were generally consistent regardless of prior TNFi failure. In the dose escalation subpopulation, mean decrease from baseline in partial Mayo score and stool frequency subscore at M1 was greater in patients with versus without a clinical response at M2. CONCLUSIONS: Rectal bleeding improvement and stool frequency improvement were achieved by M1 in many patients receiving tofacitinib 10 mg BID in both subpopulations, with no apparent difference by prior TNFi failure. Analyses were limited by small sample sizes for some subgroups.
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Colite Ulcerativa , Piperidinas , Pirimidinas , Humanos , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Indução de Remissão , Redução da Medicação , Interrupção do Tratamento , Resultado do TratamentoRESUMO
The Infectious Diseases Society of America/Society for Healthcare Epidemiology of America and the American College of Gastroenterology recently released updated guidelines on management of patients with Clostridioides difficile infection. Although these 2 guidelines generally agree, there are a few important differences in their advice to clinicians. In these rounds, 2 experts, an infectious diseases specialist and a gastroenterologist, discuss antibiotic treatment options for nonsevere disease, the role of fecal microbiota transplantation for fulminant disease, and the use of bezlotoxumab to prevent recurrence in the context of Ms. C, a 48-year-old woman with fulminant C difficile infection.
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Clostridioides difficile , Infecções por Clostridium , Feminino , Humanos , Pessoa de Meia-Idade , Antibacterianos/uso terapêutico , Infecções por Clostridium/terapia , Transplante de Microbiota Fecal , Visitas de Preceptoria , Guias de Prática Clínica como AssuntoRESUMO
Research and innovation around Clostridium difficile infection (CDI) has been a multidisciplinary endeavor since discovery of the organism in 1978. The field of gastroenterology has contributed to our understanding of CDI as a disease caused by disruptions in the gut microbiome and led to advances in therapeutic manipulation of gut microbiota, including fecal microbiota transplantation. The high incidence of CDI in patients with inflammatory bowel disease and treatment of the infection in this population have been of particular interest to gastroenterologists. The emergence of standardized, approved live biotherapeutic products for treatment of recurrent CDI is an inflection point in our management of this difficult clinical problem, and real-world performance of these therapies will inform optimal treatment algorithms.
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Clostridioides difficile , Infecções por Clostridium , Gastroenterologia , Humanos , Fezes , Trato Gastrointestinal , Infecções por Clostridium/terapia , Transplante de Microbiota Fecal , Recidiva , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: Fecal microbiota transplantation (FMT) emerged as rescue treatment for multiply recurrent Clostridioides difficile infections (rCDIs) nonresponsive to standard therapy. However, estimation of FMT efficacy varies among different protocols and formulations, while placebo-controlled clinical trials have excluded most rCDI patients because of medical comorbidities. This study aimed to determine the safety and effectiveness of capsule FMT (cap-FMT) and colonoscopy FMT (colo-FMT) for rCDI using standardized products in a large, multicenter, prospective, real-world cohort. METHODS: Clinical outcomes and adverse events after FMT performed for rCDI at 6 sites were captured in a prospective registry. FMT was performed using 1 of 2 standardized formulations of microbiota manufactured by the University of Minnesota Microbiota Therapeutics Program, freeze-dried/encapsulated or frozen-thawed/liquid. The FMT administration route was determined by the treating physician. The rCDI cure rate was assessed at 1 and 2 months. Safety data were collected within the first 72 hours and at 1 and 2 months. Logistic regression was used to investigate factors associated with FMT failure. RESULTS: A total of 301 FMTs were performed in 269 unique patients. Two-thirds were cap-FMT. CDI cure rates were 86% (95% CI, 82%-90%) at 1 month and 81% (95% CI, 75%-86%) at 2 months. There was no difference in the 1-month or 2-month cure rate between cap-FMT and colo-FMT. Cap-FMT recipients were older and less likely to be immunosuppressed or have inflammatory bowel disease. Patient factors of older age and hemodialysis were associated with FMT failure by 2 months on multivariate logistic regression. In addition, post-FMT antibiotic use was associated with FMT failure at 2 months. One serious adverse event was related to colonoscopy (aspiration pneumonia), otherwise no new safety signals were identified. CONCLUSIONS: Cap-FMT using freeze-dried capsules has a similar safety and effectiveness profile compared with colo-FMT, without the procedural risks of colonoscopy. Although highly effective overall, patient selection is a key factor to optimizing FMT success.
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Clostridioides difficile , Infecções por Clostridium , Humanos , Transplante de Microbiota Fecal/efeitos adversos , Transplante de Microbiota Fecal/métodos , Fezes , Resultado do Tratamento , Infecções por Clostridium/terapia , RecidivaRESUMO
GOALS: Characterize and compare the risk of Clostridioides difficile infection (CDI) and cytomegalovirus colitis (CMVC) after initiation of vedolizumab or anti-tumor necrosis factor (TNF)α agents for ulcerative colitis (UC). BACKGROUND: Immunosuppression is a risk factor for gastrointestinal infections including CDI and CMVC among patients with UC; however, the risk according to the biological class is poorly understood. STUDY: A retrospective cohort study of adults with UC involving the initiation of vedolizumab or anti-TNFα agents during June 1, 2014 to December 31, 2020 was conducted at a large academic health system. The primary outcomes for both CDI and CMVC analyses were first CDI or CMVC after biological initiation. The secondary outcome for the CDI analysis was severe CDI (>10,000 white blood cells or serum creatinine >1.5 mg/dL). Independent variables included demographics and UC history/severity factors. Inverse probability of treatment weighted Cox regression was performed to assess the hazard of CDI by biological group. Due to few outcomes, CMVC was reported descriptively. RESULTS: A total of 805 UC patients initiated vedolizumab (n=195) or anti-TNFα agents (n=610). There were 43 CDIs and 11 severe CDIs over 1436 patient-years. The inverse probability of treatment weighted Cox regression demonstrated no association between CDI and vedolizumab versus anti-TNFα (hazard ratio 0.33, 95% confidence interval 0.05-2.03), but identified a significantly lower hazard of severe CDI for vedolizumab versus anti-TNFα (hazard ratio 0.10, 95% confidence interval 0.01-0.76). There were 5 cases of CMVC, all in the anti-TNFα group. CONCLUSIONS: There was a lower adjusted risk of severe CDI but not total CDI associated with vedolizumab. CMVC was not observed after initiating vedolizumab. These findings may provide reassurance regarding the use of vedolizumab when also considering the risk of gastrointestinal infections.
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Infecções por Clostridium , Colite Ulcerativa , Infecções por Citomegalovirus , Adulto , Humanos , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Fator de Necrose Tumoral alfa , Estudos Retrospectivos , Fármacos Gastrointestinais/efeitos adversos , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Clostridium/tratamento farmacológico , Resultado do TratamentoRESUMO
BACKGROUND: Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis. We evaluated tofacitinib efficacy and safety in the 52-week maintenance study, OCTAVE Sustain, by baseline Mayo endoscopic subscore (MES) following 8-week induction. METHODS: The proportion of patients achieving efficacy endpoints at Week 24 or 52 of OCTAVE Sustain was evaluated by baseline MES following 8-week induction. Using logistic regression, the difference in treatment effect (tofacitinib vs. placebo) between baseline MES (0 vs. 1) for each endpoint was assessed. Adverse events were evaluated. RESULTS: At Week 52 of OCTAVE Sustain, a numerically higher proportion of tofacitinib-treated patients achieved remission with OCTAVE Sustain baseline MES of 0 versus 1 (61.9% vs. 36.5% for tofacitinib 5 mg twice daily [BID] and 75.0% vs. 54.2% for tofacitinib 10 mg BID). Similar trends were observed for endoscopic remission and endoscopic improvement. Logistic regression analyses showed a larger treatment effect at Week 52 in patients with baseline MES of 0 versus 1 for clinical response (p = 0.0306) in the tofacitinib 5 mg BID group (other endpoints all p > 0.05); differences were not significant for any endpoint in the 10 mg BID group (all p > 0.05). Infection adverse events were less frequent among patients with baseline MES 0 versus 1. CONCLUSIONS: MES may be important in predicting long-term efficacy outcomes for tofacitinib maintenance treatment. Aiming for endoscopic remission during induction with tofacitinib 10 mg BID may allow successful maintenance with tofacitinib 5 mg BID. Safety was consistent with the known tofacitinib safety profile. Trial registration NCT01458574.
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Colite Ulcerativa , Humanos , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Piperidinas/efeitos adversos , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: The comparative long-term survival of first-line biologics for UC and reasons for drug discontinuation are poorly understood. We sought to compare the long-term drug survival related to non-response (NR) and adverse effects (AEs) for vedolizumab, adalimumab, and infliximab among biologic-naïve patients with UC. METHODS: This was a retrospective cohort study of adult biologic-naïve patients with moderate-to-severe UC initiating vedolizumab, adalimumab, or infliximab 6/1/14-12/31/20 at a large academic medical center. The primary outcome was time to biologic discontinuation for primary or secondary NR (including colectomy). The secondary outcome was time to biologic discontinuation due to AEs. Inverse probability of treatment-weighted (IPTW) Cox regression was used to perform three pair-wise comparisons of drug survival. RESULTS: The cohort included 805 patients with UC who initiated vedolizumab (n = 195), adalimumab (n = 278), or infliximab (n = 332). The adjusted hazard of biologic discontinuation for NR was significantly lower for vedolizumab vs adalimumab (HR 0.51, 95% CI 0.34-0.75), similar for vedolizumab vs infliximab (HR 1.32, 95% CI 0.79-2.18), and greater for adalimumab vs infliximab (HR 2.07, 95% CI 1.51-2.86). The adjusted hazard of discontinuation for AEs was significantly lower for vedolizumab vs adalimumab (HR 0.25, 95% CI 0.09-0.64), lower for vedolizumab vs infliximab (HR 0.21, 95% CI 0.10-0.46), and similar for adalimumab vs infliximab (HR 0.85, 95% CI 0.53-1.35). CONCLUSIONS: There was greater survival of vedolizumab compared to adalimumab for clinical response and greater survival of vedolizumab compared to both adalimumab and infliximab for AEs. These long-term data support the use of vedolizumab as a first-line biologic over adalimumab for biologic-naïve patients with UC.
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Produtos Biológicos , Colite Ulcerativa , Adulto , Humanos , Adalimumab/efeitos adversos , Infliximab/efeitos adversos , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Estudos RetrospectivosRESUMO
Ustekinumab has been shown to be effective for the treatment of ulcerative colitis (UC); however, >40% of patients have suboptimal clinical response after induction and maintenance dosing every 8 weeks.1,2 The best management approach for these patients is unclear. Many undergo empiric dose intensification to every 4 weeks or every 6 weeks, a nonstandardized decision because of limited data supporting therapeutic drug monitoring of ustekinumab.3 In Crohn's disease, approximately 50% of patients undergo ustekinumab dose intensification, which seems to be effective based on prior work from our group and others.4-8 However, similar data in UC are lacking. In this real-world multicenter cohort study, we sought to identify predictors and outcomes of ustekinumab dose intensification in UC.
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Colite Ulcerativa , Doença de Crohn , Estudos de Coortes , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Humanos , Indução de Remissão , Resultado do Tratamento , Ustekinumab/uso terapêuticoRESUMO
BACKGROUND & AIMS: Fecal microbiota transplantation (FMT) is an effective therapy for recurrent Clostridioides difficile infection (rCDI). However, the overall mechanisms underlying FMT success await comprehensive elucidation, and the safety of FMT has recently become a serious concern because of the occurrence of drug-resistant bacteremia transmitted by FMT. We investigated whether functional restoration of the bacteriomes and viromes by FMT could be an indicator of successful FMT. METHODS: The human intestinal bacteriomes and viromes from 9 patients with rCDI who had undergone successful FMT and their donors were analyzed. Prophage-based and CRISPR spacer-based host bacteria-phage associations in samples from recipients before and after FMT and in donor samples were examined. The gene functions of intestinal microorganisms affected by FMT were evaluated. RESULTS: Metagenomic sequencing of both the viromes and bacteriomes revealed that FMT does change the characteristics of intestinal bacteriomes and viromes in recipients after FMT compared with those before FMT. In particular, many Proteobacteria, the fecal abundance of which was high before FMT, were eliminated, and the proportion of Microviridae increased in recipients. Most temperate phages also behaved in parallel with the host bacteria that were altered by FMT. Furthermore, the identification of bacterial and viral gene functions before and after FMT revealed that some distinctive pathways, including fluorobenzoate degradation and secondary bile acid biosynthesis, were significantly represented. CONCLUSIONS: The coordinated action of phages and their host bacteria restored the recipients' intestinal flora. These findings show that the restoration of intestinal microflora functions reflects the success of FMT.
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Enterocolite Pseudomembranosa/terapia , Transplante de Microbiota Fecal , Microbioma Gastrointestinal , Trato Gastrointestinal/microbiologia , Viroma , Adulto , Idoso , Bacteriófagos , Clostridioides difficile , Enterocolite Pseudomembranosa/microbiologia , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/genética , Trato Gastrointestinal/virologia , Humanos , Masculino , Metagenômica , Microviridae , Pessoa de Meia-Idade , Proteobactérias , Viroma/genéticaRESUMO
BACKGROUND & AIMS: Fecal microbiota transplantation (FMT) is used commonly for treatment of Clostridioides difficile infections (CDIs), although prospective safety data are limited and real-world FMT practice and outcomes are not well described. The FMT National Registry was designed to assess FMT methods and both safety and effectiveness outcomes from North American FMT providers. METHODS: Patients undergoing FMT in clinical practices across North America were eligible. Participating investigators enter de-identified data into an online platform, including FMT protocol, baseline patient characteristics, CDI cure and recurrence, and short and long-term safety outcomes. RESULTS: Of the first 259 participants enrolled at 20 sites, 222 had completed short-term follow-up at 1 month and 123 had follow-up to 6 months; 171 (66%) were female. All FMTs were done for CDI and 249 (96%) used an unknown donor (eg, stool bank). One-month cure occurred in 200 patients (90%); of these, 197 (98%) received only 1 FMT. Among 112 patients with initial cure who were followed to 6 months, 4 (4%) had CDI recurrence. Severe symptoms reported within 1-month of FMT included diarrhea (n = 5 [2%]) and abdominal pain (n = 4 [2%]); 3 patients (1%) had hospitalizations possibly related to FMT. At 6 months, new diagnoses of irritable bowel syndrome were made in 2 patients (1%) and inflammatory bowel disease in 2 patients (1%). CONCLUSIONS: This prospective real-world study demonstrated high effectiveness of FMT for CDI with a good safety profile. Assessment of new conditions at long-term follow-up is planned as this registry grows and will be important for determining the full safety profile of FMT.
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Infecções por Clostridium/terapia , Transplante de Microbiota Fecal , Doenças Inflamatórias Intestinais/terapia , Síndrome do Intestino Irritável/terapia , Sistema de Registros , Adolescente , Adulto , Clostridioides difficile , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Estados Unidos , Adulto JovemRESUMO
BACKGROUND: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. We aimed to describe the real-world treatment experience and corticosteroid utilisation of patients treated with tofacitinib in a US claims database. METHODS: Patients with a UC diagnosis who initiated tofacitinib, vedolizumab or tumour necrosis factor inhibitor (TNFi) treatment between May 2018 and July 2019 were identified from the Optum Research Database. Demographic and clinical characteristics of patients who initiated tofacitinib, vedolizumab or TNFi were described. Oral corticosteroid use prior to and following tofacitinib initiation was evaluated. Tofacitinib adherence (proportion of days covered) and continuation was assessed for 6 months following initiation. Analyses were descriptive and stratified by prior biologic use (naïve, 1 or ≥ 2; minimum of 12 months prior to tofacitinib initiation). RESULTS: Among patients initiating tofacitinib (N = 225), mean age was 45.6 (SD 16.5) years and 50.2% were female. Of these, 43 (19.1%) patients were biologic-naïve and 182 (80.9%) had prior biologic use (92 [40.9%], 1 prior biologic; 90 [40.0%], ≥ 2 prior biologics). Among patients with 1 prior biologic, 82.6% were previously treated with a TNFi. Among patients with ≥ 2 prior biologics, 54.4% were previously treated with vedolizumab and a TNFi, 16.7% with two TNFi and 28.9% with ≥ 3 prior biologics. In the 6 months prior to tofacitinib initiation, 65.8% of patients had received oral corticosteroids (74.4%, 60.9% and 66.7% for biologic-naïve, 1 and ≥ 2 prior biologics, respectively). The proportion of patients with ongoing oral corticosteroid use 3-6 months after tofacitinib initiation decreased to 13.3% (9.3%, 18.5% and 10.0% for biologic-naïve, 1 and ≥ 2 prior biologics, respectively), and 19.6% of patients discontinued oral corticosteroid use during the 6 months after tofacitinib initiation. Overall, tofacitinib adherence, as determined by the mean proportion of days covered during the 6-month follow-up, was 0.7 (median 0.8). During the 6-month follow-up, 84.9% of patients continued tofacitinib. CONCLUSIONS: Among patients with UC initiating tofacitinib, the majority had prior biologic use. Tofacitinib adherence was high, discontinuation was low and oral corticosteroid utilisation decreased irrespective of prior biologic use. Further research with longer follow-up and a larger sample size is required.
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Produtos Biológicos , Colite Ulcerativa , Corticosteroides/uso terapêutico , Produtos Biológicos/uso terapêutico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Feminino , Humanos , Pessoa de Meia-Idade , Piperidinas/uso terapêutico , PirimidinasRESUMO
The transfer of live gut microbes may transform patient care across a range of autoimmune, metabolic, hepatic, and infectious diseases. One early approach, fecal microbiota transplantation, has shown promise in Clostridiodes difficile infection and the potential for improving clinical and public health outcomes for other antibiotic-resistant bacteria. These clinical successes have motivated the development of microbiome drugs, which will need to address challenges in safety, uniformity, and delivery while seeking to preserve the benefits of using whole microbiome communities as novel therapeutics and an innovative platform for drug discovery.
Assuntos
Antibacterianos/uso terapêutico , Transplante de Microbiota Fecal , Microbiota , Antibacterianos/isolamento & purificação , Clostridioides difficile/efeitos dos fármacos , Infecções por Clostridium/terapia , Desenvolvimento de Medicamentos , Descoberta de Drogas , Farmacorresistência Bacteriana/efeitos dos fármacos , HumanosRESUMO
A subset of patients with ulcerative colitis (UC) present with, or progress to, moderate to severe disease activity. These patients are at high risk for colectomy, hospitalization, corticosteroid dependence, and serious infections. The risk of life-threatening complications and emergency colectomy is particularly high among those patients hospitalized with acute severe ulcerative colitis. Optimal management of outpatients or inpatients with moderate to severe UC often requires the use of immunomodulator and/or biologic therapies, including thiopurines, methotrexate, cyclosporine, tacrolimus, TNF-α antagonists, vedolizumab, tofacitnib, or ustekinumab, either as monotherapy or in combination (with immunomodulators), to mitigate these risks. Decisions about optimal drug therapy in moderate to severe UC are complex, with limited guidance on comparative efficacy and safety of different treatments, leading to considerable practice variability. Therefore, the American Gastroenterological Association prioritized development of clinical guidelines on this topic. To inform the clinical guidelines, this technical review was completed in accordance with the Grading of Recommendations Assessment, Development and Evaluation framework. Focused questions in adult outpatients with moderate to severe UC included: (1) overall and comparative efficacy of different medications for induction and maintenance of remission in patients with or without prior exposure to TNF-α antagonists, (2) comparative efficacy and safety of biologic monotherapy vs combination therapy with immunomodulators, (3) comparative efficacy of top-down (upfront use of biologics and/or immunomodulator therapy) vs step-up therapy (acceleration to biologic and/or immunomodulator therapy only after failure of 5-aminosalicylates, and (4) role of continuing vs stopping 5-aminosalicylates in patients being treated with immunomodulator and/or biologic therapy for moderate to severe UC. Focused questions in adults hospitalized with acute severe ulcerative colitis included: (5) overall and comparative efficacy of pharmacologic interventions for inpatients refractory to corticosteroids, in reducing risk of colectomy, (6) optimal dosing regimens for intravenous corticosteroids and infliximab in these patients, and (7) role of adjunctive antibiotics in the absence of confirmed infections.