RESUMO
Noninfective drug-related pneumonitis (DRP) is a well-known adverse effect of several drugs: clinical manifestations have mostly an acute/subacute onset and vary from mild to life-threatening. Several DRP cases have been described in patients receiving anti-tumor necrosis factor α, rituximab, and tocilizumab.1,2 To date, only 4 reports of vedolizumab-related pneumonitis have been presented.3-5.
Assuntos
Colite Ulcerativa , Doenças Inflamatórias Intestinais , Pneumonia , Anticorpos Monoclonais Humanizados , Colite Ulcerativa/tratamento farmacológico , Fármacos Gastrointestinais/efeitos adversos , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Pneumonia/induzido quimicamente , Pneumonia/tratamento farmacológico , Rituximab/uso terapêutico , Fator de Necrose Tumoral alfa/uso terapêuticoRESUMO
INTRODUCTION: The use of ustekinumab and vedolizumab as second-line therapies in patients with Crohn's disease (CD) in which tumour necrosis factor alpha inhibitors (TNFi) failed is still debated. The aim of this study was to compare, in a large multicenter observational retrospective cohort, the effectiveness of ustekinumab and vedolizumab as second-line therapies, as assessed by clinical and objective outcomes including endoscopy and gastrointestinal imaging. METHODS: Clinical response, remission, and steroid-free remission at weeks 26 and 52 were evaluated in a retrospective propensity score-weighted and propensity score-matched cohort of patients in which TNFi failed. Objective response and remission were evaluated by 1 or more techniques among endoscopy, magnetic resonance/computed tomography enteroclysis, and small bowel ultrasound. RESULTS: A total of 470 patients with CD (239 treated with ustekinumab and 231 treated with vedolizumab) were included in the study. At week 26, clinical outcomes were similar between the 2 groups. At week 52, clinical remission (ustekinumab 42.5% vs vedolizumab 55.5%, P = 0.01) and steroid-free remission (ustekinumab 40.6% vs vedolizumab 51.1%, P = 0.038) rates were significantly higher in vedolizumab-treated patients. Three hundred two patients (hundred thirty-five treated with ustekinumab and hundred sixty-seven treated with vedolizumab) had an objective evaluation of disease activity at baseline and week 52. At week 52, objective response and remission rates were similar between the 2 groups. Clinical response at week 26 predicted steroid-free remission at week 52 in both ustekinumab-treated and vedolizumab-treated patients. Safety profiles were similar between the 2 groups. DISCUSSION: In patients with CD in which TNFi failed, both ustekinumab and vedolizumab showed similar clinical effectiveness after 26 weeks of treatment. At 1 year, vedolizumab was associated with a higher rate of clinical remission when compared with ustekinumab. However, no difference was observed between the 2 groups when objective outcomes were investigated at this time point.
Assuntos
Anticorpos Monoclonais Humanizados , Doença de Crohn , Ustekinumab , Anticorpos Monoclonais Humanizados/uso terapêutico , Doença de Crohn/tratamento farmacológico , Humanos , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento , Inibidores do Fator de Necrose Tumoral , Ustekinumab/uso terapêuticoRESUMO
BACKGROUND & AIMS: Mucosal healing, determined by ileocolonoscopy, is a goal for treatment of Crohn's disease (CD), but this is an invasive assessment procedure. We investigated whether response to tumor necrosis factor (TNF) antagonists, determined by small-intestine contrast ultrasonography, associates with long-term outcomes. METHODS: We performed observational study of 80 patients with CD treated with anti-TNF agents for at least 1 year who underwent serial small intestine contrast ultrasonography (SICUS) at the University of Rome, in Italy. SICUS was used to evaluate disease site (based on bowel wall thickness), extent of lesions, and presence of complications. Inclusion criteria required pre-therapy SICUS with follow-up SICUS after 18 months. At second SICUS, patients were assigned to categories of complete or partial responder or non-responder. CD-related outcomes (corticosteroid need, hospitalization, and surgery) were assessed at 1 year from the second SICUS, using multivariate models, and were analyzed after long term follow up (5 years) using Kaplan-Meier survival analysis. RESULTS: Based on SICUS, after a median of 18 months, 36 patients (51%) were complete responders, 30 were partial responders (34%), and 13 were non-responders (15%). At 1 year from the second SICUS, no patients with a complete response, based on ultrasonography, underwent surgery, in comparison to partial responders (P = .0003) or non-responders (P = .001). Complete responders used smaller amounts of corticosteroids than partial responders (P = .0001) or non-responders (P < .0001). Complete responders required fewer hospitalizations than non-responders (P = .001). Kaplan-Meier survival analysis of long-term follow up data demonstrated a lower cumulative probability of need for surgery, hospitalization, and need for steroids among SICUS-categorized complete responders (P < .0001, P = .003 and P = .0001 respectively) than SICUS-categorized non-responders. CONCLUSIONS: In patients with CD, response to anti-TNF agents, determined by SICUS, is associated with better long-term outcomes than partial or no response. Ultrasonographic assessment therefore provides a relatively non-invasive method for monitoring response to treatment in patients with CD.
Assuntos
Doença de Crohn , Doença de Crohn/diagnóstico por imagem , Doença de Crohn/tratamento farmacológico , Humanos , Intestino Delgado/diagnóstico por imagem , Tempo , Inibidores do Fator de Necrose Tumoral , UltrassonografiaRESUMO
Regulatory T cells represent a class of specialized T lymphocytes that suppress unwanted immune responses and size the activation of the immune system whereby limiting collateral damages in tissues involved by inflammation. In cancer, the accumulation of Tregs is generally associated with poor prognosis. Many lines of evidence indicate that Tregs accumulation in the tumor microenvironment (TME) suppresses the immune response against tumor-associated antigens (TAA), thus promoting tumor progression in non-small cell lung carcinoma (NSLC), breast carcinoma and melanoma. In colorectal cancer (CRC) the effect of Tregs accumulation is debated. Some reports describe the association of high number of Tregs in CRC stroma with a better prognosis while others failed to find any association. These discordant results stem from the heterogeneity of the immune environment generated in CRC in which anticancer immune response may coexists with tumor promoting inflammation. Moreover, different subsets of Tregs have been identified that may exert different effects on cancer progression depending on tumor stage and their location within the tumor mass. Finally, Tregs phenotypic plasticity may be induced by cytokines released in the TME by dysplastic and other tumor-infiltrating cells thus affecting their functional role in the tumor. Here, we reviewed the recent literature about the role of Tregs in CRC and in colitis-associated colorectal cancer (CAC), where inflammation is the main driver of tumor initiation and progression. We tried to explain when and how Tregs can be considered to be the "good" or the "bad" in the colon carcinogenesis process on the basis of the available data concluding that the final effect of Tregs on sporadic CRC and CAC depends on their localization within the tumor, the subtype of Tregs involved and their phenotypic plasticity.
Assuntos
Neoplasias Associadas a Colite/imunologia , Neoplasias Colorretais/imunologia , Linfócitos T Reguladores/imunologia , Animais , Carcinogênese/imunologia , Humanos , Linfócitos do Interstício Tumoral/imunologia , Microambiente Tumoral/imunologiaRESUMO
OBJECTIVES: The aim of this 2-year prospective study was to assess the diagnostic and therapeutic effect of a combined gastro-rheumatological approach in enteropathic spondyloarthritis (eSpA) patients. METHODS: Inflammatory bowel disease (IBD) patients with joint pain were referred by IBD-dedicated gastroenterologists to a dedicated rheumatologist. At baseline and at 3, 6, 12, 24 months, the following parameters were recorded: clinical and biochemical variables, SpA and IBD activity scores, treatment (conventional synthetic; csDMARDs, biologics; bDMARDs). Associations between treatment and patient characteristics were evaluated by logistic regression (AOR [95% CI]). RESULTS: Overall, 229 IBD patients were referred to rheumatologists. eSpA was diagnosed in 147 (64.2%) patients: 96 (65.3%) showing peripheral and 51 (34.7%) axial involvement. IBD included Crohn's disease (CD) in 141 (61.6%) and ulcerative colitis (UC) in 88 (38.4%). bDMARD treatment increased over the follow-up (baseline-24 months: 32.7-60%; AOR 3.45 [1.93-6.2], p<0.001). bDMARD use was less frequent in elderly patients (AOR 0.73 [0.56-0.96], p=0.023), in UC (AOR 0.43 [0.2-0.94], p=0.034) and in patients with peripheral involvement (AOR 0.53 [0.3-1.04], p=0.067). csDMARD use was increased in patients with peripheral involvement (AOR 4.65 [2.09-10.33], p<0.001) and in UC (AOR 2.30 [1.13-4.67], p=0.021). CRP, ESR, ASDAS-ESR levels and BASFI significantly decreased over the follow-up, whereas the pMayo score, BASDAI and HAQ-S were unchanged. CONCLUSIONS: In this prospective study in eSpA patients, a multidisciplinary approach was shown to optimise the therapeutic management and outcome (e.g. disease activity scores). bDMARD use paralleled an improvement in disease activity scores and confirmed a good safety profile.
Assuntos
Antirreumáticos , Doenças Inflamatórias Intestinais , Espondilartrite , Idoso , Antirreumáticos/uso terapêutico , Produtos Biológicos , Colite Ulcerativa , Comorbidade , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/epidemiologia , Estudos Prospectivos , Doenças Reumáticas , Espondilartrite/tratamento farmacológico , Espondilartrite/epidemiologiaRESUMO
BACKGROUND: Crohn's disease-related inflammation is characterized by reduced activity of the immunosuppressive cytokine transforming growth factor ß1 (TGF-ß1) due to high levels of SMAD7, an inhibitor of TGF-ß1 signaling. Preclinical studies and a phase 1 study have shown that an oral SMAD7 antisense oligonucleotide, mongersen, targets ileal and colonic SMAD7. METHODS: In a double-blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of mongersen for the treatment of persons with active Crohn's disease. Patients were randomly assigned to receive 10, 40, or 160 mg of mongersen or placebo per day for 2 weeks. The primary outcomes were clinical remission at day 15, defined as a Crohn's Disease Activity Index (CDAI) score of less than 150, with maintenance of remission for at least 2 weeks, and the safety of mongersen treatment. A secondary outcome was clinical response (defined as a reduction of 100 points or more in the CDAI score) at day 28. RESULTS: The proportions of patients who reached the primary end point were 55% and 65% for the 40-mg and 160-mg mongersen groups, respectively, as compared with 10% for the placebo group (P<0.001). There was no significant difference in the percentage of participants reaching clinical remission between the 10-mg group (12%) and the placebo group. The rate of clinical response was significantly greater among patients receiving 10 mg (37%), 40 mg (58%), or 160 mg (72%) of mongersen than among those receiving placebo (17%) (P=0.04, P<0.001, and P<0.001, respectively). Most adverse events were related to complications and symptoms of Crohn's disease. CONCLUSIONS: We found that study participants with Crohn's disease who received mongersen had significantly higher rates of remission and clinical response than those who received placebo. (Funded by Giuliani; EudraCT number, 2011-002640-27.).
Assuntos
Doença de Crohn/tratamento farmacológico , Imunossupressores/administração & dosagem , Oligonucleotídeos/administração & dosagem , Proteína Smad7/antagonistas & inibidores , Adolescente , Adulto , Idoso , Proteína C-Reativa/análise , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Glucocorticoides/administração & dosagem , Humanos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos Antissenso/uso terapêutico , Indução de Remissão , Adulto JovemRESUMO
Inflammatory bowel disease (IBD), a chronic intestinal inflammatory disorder encompassing ulcerative colitis and Crohn's disease can be disabling and often requires lifelong treatment and follow-up. Digital health technologies and distance-management tools are less costly alternatives for IBD management and clinical monitoring. This review discusses how telephone/videoconference appointments enable treatment optimization from an early disease stage, provide complementary value-based patient care and educational resources, and allow consistent follow-up with a high standard of care. Replacing/supplementing traditional clinical consultations with telemedicine reduces healthcare utilization costs and the need for in-person consultations. The COVID-19 pandemic has accelerated the evolution of telemedicine in IBD, with several studies conducted since 2020 reporting high levels of patient satisfaction. Home-based injectable formulations coupled with telemedicine may become permanently embedded in healthcare systems in the post-pandemic period. While telemedicine consultations are well-accepted by many patients with IBD, they do not suit all patients or are not preferred (e.g., by elderly who do not have the means or ability to understand the associated technology). Ultimately, use of telemedicine should be decided by the patient and careful consideration is required to ensure that the patient is willing and capable of a successful remote visit.
Assuntos
Doenças Inflamatórias Intestinais , Telemedicina , Humanos , Idoso , Pandemias , Doenças Inflamatórias Intestinais/terapia , Custos de Cuidados de Saúde , Satisfação do PacienteRESUMO
The nutritional status in inflammatory bowel disease (IBD) is often impaired, and adherence to the Mediterranean diet (MedDiet) remains under-investigated. The aim of this study was to assess diet quality (DQ) and adherence to MedDiet in a cohort of Sardinian IBD patients. We conducted a case-control study in which 50 Crohn's disease (CD) and 50 ulcerative colitis (UC) patients were matched with 100 healthy controls each. The Diet Quality Index (DQI-I) and Medi-Lite were used to assess DQ and adherence to MedDiet, respectively. Subgroup analysis by disease characteristics and use of advanced therapies were also carried out. DQI-I scored significantly lower in IBD, independently of disease localization and behavior (CD) and disease extent (UC): [DQI-I: CD 34.5 (IQR 33-37) vs. CTRL 40 (IQR 38.5-43) p < 0.0001; UC 34.5 (IQR 33-37) vs. CTRL 42 (IQR 40-44) p < 0.0001]. Medi-Lite scores were significantly lower in stricturing and ileo-colonic CD and in extensive UC: [Medi-Lite CD 7.5 (IQR 7-9)] vs. CTRL 9 (IQR 7-10) p = 0.0379]; [UC 8 (IQR7-10) vs. CTRL 9 (IQR 8-10.5) p = 0.0046]. IBD patients had a low DQ independently of disease type and phenotype. Patients with ileo-colonic stenosing CD or extensive UC had lower MedDiet adherence, suggesting that its benefits may be mitigated by low acceptance in specific subgroups.
Assuntos
Colite Ulcerativa , Doença de Crohn , Dieta Mediterrânea , Cooperação do Paciente , Humanos , Feminino , Estudos de Casos e Controles , Masculino , Adulto , Pessoa de Meia-Idade , Cooperação do Paciente/estatística & dados numéricos , Doença de Crohn/dietoterapia , Colite Ulcerativa/dietoterapia , Colite Ulcerativa/terapia , Doenças Inflamatórias Intestinais/dietoterapia , Estado Nutricional , ItáliaRESUMO
BACKGROUND & AIMS: Small-intestine contrast ultrasonography (SICUS) is a radiation-free technique that can detect intestinal damage in patients with Crohn's disease (CD). We evaluated the diagnostic accuracy of SICUS in determining the site, extent, and complications of CD, compared with computed tomography (CT) enteroclysis as the standard. METHODS: We performed a retrospective analysis of data from 59 patients with CD evaluated by SICUS and CT enteroclysis 3 months apart, between January 2007 and April 2012. We evaluated disease site (based on bowel wall thickness), extent of lesions, and presence of complications (stenosis, prestenotic dilation, abscess, or fistulas) using CT enteroclysis as the standard. Sensitivity, specificity, and diagnostic accuracy were calculated. We determined the correlations in maximum wall thickness and disease extent in the small bowel between results from SICUS and CT enteroclysis. RESULTS: SICUS identified the site of small bowel CD with 98% sensitivity, 67% specificity, and 95% diagnostic accuracy; it identified the site of colon CD with 83% sensitivity, 97.5% specificity, and 93% diagnostic accuracy. Results from SICUS and CT enteroclysis correlated in determination of bowel wall thickness (rho, 0.79) and disease extent (rho, 0.89; P < .0001 for both). SICUS detected ileal stenosis with 95.5% sensitivity, 80% specificity, and 91.5% diagnostic accuracy, and prestenotic dilation with 87% sensitivity, 67% specificity, and 75% diagnostic accuracy. SICUS detected abscesses with 78% sensitivity, 100% specificity, and 97% diagnostic accuracy, and fistulas with 78.5% sensitivity, 95.5% specificity, and 91.5% diagnostic accuracy. CONCLUSIONS: SICUS identified lesions and complications in patients with CD with high levels of sensitivity, specificity, and accuracy compared with CT enteroclysis. SICUS might be used as an imaging tool as part of a focused diagnostic examination of patients with CD.
Assuntos
Doença de Crohn/diagnóstico , Doença de Crohn/patologia , Intestino Delgado/patologia , Tomografia Computadorizada por Raios X/métodos , Ultrassonografia/métodos , Adulto , Idoso , Doença de Crohn/diagnóstico por imagem , Feminino , Humanos , Intestino Delgado/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sensibilidade e Especificidade , Adulto JovemRESUMO
In the gut of patients with Crohn's disease (CD), high Smad7 blocks the immune-suppressive activity of transforming growth factor (TGF)-ß1, thereby contributing to amplify inflammatory signals. In vivo in mice, knockdown of Smad7 with a Smad7 antisense oligonucleotide (GED0301) attenuates experimental colitis. Here, we provide results of a phase 1 clinical, open-label, dose-escalation study of GED0301 in patients with active, steroid-dependent/resistant CD, aimed at assessing the safety and tolerability of the drug. Patients were allocated to three treatment groups receiving oral GED0301 once daily for 7 days at doses of 40, 80, or 160 mg. A total of 15 patients were enrolled. No serious adverse event was registered. GED0301 was well tolerated and no patient dropped out during the study. Twenty-five adverse events were documented in 11 patients, the majority of whom were judged to be of mild intensity and unrelated to treatment. GED0301 treatment reduced the percentage of inflammatory cytokine-expressing CCR9-positive T cells in the blood. The study shows for the first time that GED0301 is safe and well tolerated in patients with active CD.
Assuntos
Doença de Crohn/terapia , Oligonucleotídeos Antissenso/uso terapêutico , Proteína Smad7/metabolismo , Adulto , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Oligonucleotídeos Antissenso/administração & dosagem , Farmacocinética , Proteína Smad7/genética , Adulto JovemRESUMO
Inflammatory bowel disease, whose major forms are Crohn's disease and ulcerative colitis, is characterized by chronic inflammation of the gut due to the loss of tolerance toward antigens normally contained in the gut lumen. G protein-coupled receptor (GPR) 120 has gained considerable attention as a potential therapeutic target for metabolic disorders due to its implication in the production of the incretin hormone glucagon-like peptide 1 and the secretion of cholecystokinin. Recent studies have also highlighted the role of GPR120 in regulating immune system activity and inflammation. GPR120, expressed by intestinal epithelial cells, proinflammatory macrophages, enteroendocrine L cells, and CD4+ T cells, suppresses proinflammatory and enhances anti-inflammatory cytokine production, suggesting that GPR120 might have a pivotal role in intestinal inflammation and represent a possible therapeutic target in inflammatory bowel disease. This narrative review aims at summarizing the role of GPR120 in the maintenance of intestinal homeostasis through the analysis of the most recent studies.
Assuntos
Doenças Inflamatórias Intestinais , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Inflamação/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Anti-Inflamatórios , Células EnteroendócrinasRESUMO
BACKGROUND: The management of postoperative recurrence (POR) in Crohn's disease (CD) after ileo-colonic resection is a highly debated topic. Prophylactic immunosuppression after surgery is currently recommended in the presence of at least one clinical risk factor. OBJECTIVE: Our aim was to determine whether early immunosuppression can be avoided and guided by endoscopy in CD patients with only one risk factor. METHODS: CD patients with only one risk factor for POR, including previous intestinal resection, extensive small intestine resection (>50 cm), fistulising phenotype, history of perianal disease, and active smoking, were retrospectively included. Two groups were formed based on whether immunosuppression was started immediately after surgery ("prophylaxis group") or guided by endoscopy ("endoscopy-driven group"). Primary endpoints were rates of any endoscopic recurrence (Rutgeerts ≥ i2a) and severe endoscopic recurrence (i4) within 12 months after surgery. Secondary outcomes were clinical recurrence rates at 6, 12 and 24 months after surgery. RESULTS: A total of 195 patients were enroled, of whom 61 (31.3%) received immunoprophylaxis. No differences between immunoprophylaxis and the endoscopy-driven approach were found regarding any endoscopic recurrence (36.1% vs. 45.5%, respectively, p = 0.10) and severe endoscopic recurrence (9.8% vs. 15.7%, respectively, p = 0.15) at the first endoscopic evaluation. Clinical recurrence rates were also not statistically different (p = 0.43, p = 0.09, and p = 0.63 at 6, 12, and 24 months, respectively). CONCLUSIONS: In operated CD patients with only one risk factor for POR, immediate immunoprophylaxis does not decrease the rate of early clinical and endoscopic recurrence. Prospective studies are needed to confirm our results.
Assuntos
Doença de Crohn , Humanos , Doença de Crohn/complicações , Doença de Crohn/diagnóstico , Doença de Crohn/cirurgia , Colonoscopia/métodos , Estudos Retrospectivos , Recidiva Local de Neoplasia , Colo/cirurgiaRESUMO
In the last few years the management of Crohn's disease (CD) has changed due to the introduction of new therapeutic agents that provide more alternative options in patients with severe diseases, introducing new concepts regarding treatment timing. At the moment, the absence of good predictors of disease outcome and a subclinical marker available to predict relapse during clinical remission are major problems in the management of CD. In recent decades, the evaluation of several variables has been proposed to address this issue, including disease behavior, clinical-endoscopic activity and intestinal damage. In particular, definition of mucosal restitution or healing after therapy has been proposed as a surrogate of efficacy and new goal of the therapy. Regarding this concept, several criticisms have been raised, such as the need to better define the role of mucosal healing in a transmural disease. In order to address this issue, new alternative techniques providing both extraluminal and luminal intestinal damage have been proposed, including ultrasonography, computed tomography and magnetic resonance imaging.
Assuntos
Doença de Crohn/imunologia , Colonoscopia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/patologia , Progressão da Doença , Humanos , Mucosa Intestinal/patologia , Qualidade de Vida , CicatrizaçãoRESUMO
The drug pipeline for the treatment of inflammatory bowel disease (IBD) has dramatically expanded over the last two decades, and it is expected to further grow in the upcoming years with the introduction of new agents with different mechanisms of action. However, such an increase of therapeutic options needs to be paralleled with an appropriate development of research to help physicians in the decision-making process when choosing which drug to prescribe. On the population level, comparative effectiveness research (CER) is intended to explore and identify relevant differences-in terms of both efficacy and safety outcomes-amongst different therapeutic regimens and/or strategies, in order to find the correct placement for each treatment in the therapeutic algorithm. CER revolves around three cornerstones: network meta-analyses, head-to-head trials and real-world studies, each of which has specific pros and cons, and can therefore offer answers to different questions. In this review, we aim to provide an overview on the methodological features specific to each of these research approaches, as well as to illustrate the main findings coming from CER on IBD target therapies (i.e., biologics and small molecules) and to discuss their appropriate interpretation.
RESUMO
Inflammatory bowel diseases, namely ulcerative colitis and Crohn's disease, occur worldwide and affect people of all ages, with a high impact on their quality of life. Sex differences in incidence and prevalence have been reported, and there are also gender-specific issues that physicians should recognize. For women, there are multiple, important concerns regarding issues of body image and sexuality, menstruation, contraception, fertility, pregnancy, breastfeeding and menopause. This practice-based review focuses on the main themes that run through the life of women with inflammatory bowel diseases from puberty to menopause. Gastroenterologists who specialize in inflammatory bowel diseases and other physicians who see female patients with inflammatory bowel diseases should provide support for these problems and offer adequate therapy to ensure that their patients achieve the same overall well-being and health as do women without inflammatory bowel diseases.
Assuntos
Colite Ulcerativa/complicações , Doença de Crohn/complicações , Doenças dos Genitais Femininos/etiologia , Saúde Reprodutiva , Saúde da Mulher , Adulto , Feminino , Humanos , Gravidez , Qualidade de VidaRESUMO
In inflammatory bowel disease (IBD), the loss of immune tolerance against gut microbiota causes chronic inflammation and the progressive accumulation of organ damage in genetically susceptible individuals. In the elderly, IBD is often characterized by a different disease behaviour when compared with paediatric and young adult disease. Besides disease behaviour, another aspect of the multifaceted impact of age on elderly IBD course is increased susceptibility to infections. In this context, age-of-onset-dependent IBD behaviour and clinical course are two major contributors to immune system senescence and change of gut microbiota in older subjects. Here, we review the available literature linking immunosenescence and age-dependent changes in the gut microbiota composition to IBD pathogenesis speculating on their possible implications in disease expression in this age class.
RESUMO
BACKGROUND: Combining immunosuppressors has been proposed as a strategy to enhance treatment efficacy in Inflammatory Bowel Disease (IBD). AIM: To summarize current evidence on combinations of targeted therapies with traditional immunosuppressors or with other targeted therapies. METHODS: A literature search on PubMed and Medline databases was performed to identify relevant articles. RESULTS: Current evidence supports that the combination of infliximab and thiopurines is more effective than monotherapy with both agents in inducing remission in Crohn's Disease and Ulcerative colitis. Data on other combinations of other biologics and traditional immunosuppressors is lacking or show conflicting results. Vedolizumab seems a potentially effective maintenance regimen after calcineurin inhibitors-based rescue therapy in acute severe ulcerative colitis, as an alternative to thiopurines. Dual Targeted Therapy, which is the combination of 2 targeted therapies, might be a reasonable choice in patients with concomitant IBD and extraintestinal manifestations, or in patients with medical-refractory IBD who lack valid alternatives. Combinations with thiopurines are associated with an increased risk of infections and lymphoma. Data on other combinations is scarcer, but no specific safety issue has emerged so far. CONCLUSIONS: Combination therapies seem to be effective in selected patients, with an overall acceptable safety profile.
Assuntos
Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Fatores Biológicos , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , InfliximabRESUMO
BACKGROUND AND AIMS: The COVID-19 pandemic has led to a deep reorganization of hospital services including inflammatory bowel disease (IBD) units. In this situation, conversion of in-person routine follow-up visits into phone consultations might be necessary. Here we explored the feasibility of using the validated Crohn's Disease (CD) or Ulcerative Colitis (UC) Patient-Reported Outcomes Signs and Symptoms (CD- and UC-PRO/SS) to collect data about abdominal symptoms (abdominal/S) and bowel signs and symptoms (bowel/SS) remotely. METHODS: CD- and UC-PRO/SS were collected during phone consultations and compared among patients with active and inactive disease. The effectiveness of therapeutic intervention in patients with active disease was assessed by PRO/SS variation. RESULTS: Twenty-one CD and 56 UC patients were evaluated by phone. Six (28.6%) CD and 15 (26.8%) UC patients were considered to have active disease. In CD the bowel/SS but not the abdominal/S module was significantly higher in active patients (mean bowel/SS 2.50 [SE ± 0.44] active vs 0.76 [SE ± 0.18] remission, p = 0.008, AUC 0.87; mean abdominal/S 1.11 [SE ± 0.38] active vs 0.24 [SE ± 0.13] remission, p = 0.066). UC-PRO/SS measures were significantly higher in active patients as compared to patients in remission (median bowel/SS 1.63 [SE ± 0.24] active vs 0.33 [SE ± 0.04] remission; p < 0.0001, AUC 0.91; mean abdominal/S 1.03 [SE ± 0.24] vs 0.37 [SE ± 0.12]; p = 0.009, AUC 0.71). Therapy was escalated in 12 patients (3 CD and 9 UC) due to disease relapse. Therapy escalation resulted in the reduction of PRO/SS as evaluated at the subsequent phone consultation. CONCLUSIONS: PRO/SS might represent a feasible tool to evaluate disease activity and therapy outcome in IBD patients during periods of limited access to outpatient clinics.
RESUMO
BACKGROUND: A recent phase III trial did not confirm the previous clinical and endoscopic improvements seen in patients with Crohn's disease (CD) receiving Mongersen, an oral Smad7 antisense oligonucleotide. Factors accounting for such a discrepancy are unknown. OBJECTIVE: Our objective was to further assess whether Mongersen was effective as induction therapy in active CD and evaluate the in vitro inhibitory effect of various batches of Mongersen used in the previous and present trials on Smad7 expression. METHODS: In a phase II, open-label study, 18 patients with active CD (Crohn's Disease Activity Index [CDAI] score > 220 and evidence of endoscopic lesions) received Mongersen 160 mg/day for 12 weeks. The rates of clinical remission, defined as CDAI < 150, and clinical response, defined as a CDAI score decrease ≥ 100, were evaluated at week 4, 8, and 12. The fraction of circulating CCR9-expressing leukocytes was assessed by flow cytometry. Smad7 expression was evaluated in the human colorectal cancer cell line HCT-116 transfected with different batches of Mongersen using real-time polymerase chain reaction (PCR) and Western blotting, RESULTS: The proportions of patients experiencing clinical remission were 38.9%, 55.6%, and 50.0% at week 4, 8, and 12, respectively. At the same time points, the rates of clinical response were 72.2%, 77.8%, and 77.8%, respectively. Mongersen reduced the percentages of CCR9-expressing CD45+ cells. The batch of Mongersen used in this study, but not two batches used in the phase III study, inhibited Smad7 expression in HCT-116 cells. CONCLUSIONS: The present findings support the clinical benefit of Mongersen in active CD and show that various batches manufactured during the GED0301 program differ in their ability to inhibit in vitro Smad7. TRIAL REGISTRATION NUMBER: NCT02685683; EudraCT 2015-001693-18.
Assuntos
Doença de Crohn , Doença de Crohn/tratamento farmacológico , Humanos , Quimioterapia de Indução , Oligonucleotídeos , Oligonucleotídeos Antissenso/uso terapêutico , Proteína Smad7/genética , Resultado do TratamentoRESUMO
BACKGROUND: Switching from IFX originator to CT-P13 is safe; however, little data on immunogenicity exists. RESEARCH DESIGN AND METHODS: Consecutive IBD patients on IFX originator were switched to CT-P13 and followed-up for 12 months. Clinical activity, infliximab trough levels (ITLs), anti-drug antibodies (ATIs), and adverse events were recorded at predefined timepoints (baseline, second CT-P13 infusion, 6 and 12 months). The outcomes investigated were immunogenicity, pharmacokinetics, effectiveness and safety. RESULTS: 119 patients were switched to CT-P13 after a median time with IFX of 5.8 years. No changes in mean ITLs were observed. ATIs were detected in 30 patients (25.2%): 14 before and 16 after switch. Mean persistent ATIs were significantly higher compared to mean transient ones (109.74 ng/mL ±84.70 vs 18.22 ng/mL ±11.37, p < 0.001), with significantly lower ITLs associated (mean 0.32 µg/mL ±0.6 vs 3.08 µg/mL ±3.22, p < 0.001). A significant decrease of patients in steroid-fee clinical remission was observed after the switch (p = 0.004), with subsequent improvement at 6 months (p = 0.005). Eighteen patients (15.1%) discontinued IFX, only 6 (5%) for loss of response. CONCLUSIONS: Switching from infliximab originator to CT-P13 seems safe and effective, without differences in immunogenicity. A temporary reduction of clinical benefit after switching could be potentially explained by a 'nocebo-effect response'.