RESUMEN
Views on the clinical presentation and symptomatology of celiac disease have evolved alongside advances in disease detection and understanding of disease pathogenesis. Although historically regarded as a pediatric illness characterized by malabsorption, it is now better viewed as an immune illness of gluten-specific T cells with systemic manifestations affecting all ages. Its broad presentation, including frequent extraintestinal manifestations and asymptomatic disease, contributes to suboptimal disease detection. Adverse symptoms greatly impact patient quality of life and can result from chronic gluten exposure in untreated disease or those poorly responsive to the gluten-free diet. They can also present as acute symptoms after episodic gluten exposure. Functional gastrointestinal disease is a common comorbidity. Biomarkers like interleukin-2 that are highly sensitive and specific for celiac disease highlight a role for gluten-specific T cells in acute gluten symptomatology. A mechanistic understanding of symptoms will inform approaches to better measure and treat them effectively.
Asunto(s)
Enfermedad Celíaca , Dieta Sin Gluten , Glútenes , Enfermedad Celíaca/diagnóstico , Enfermedad Celíaca/inmunología , Enfermedad Celíaca/dietoterapia , Enfermedad Celíaca/epidemiología , Humanos , Glútenes/inmunología , Glútenes/efectos adversos , Biomarcadores/sangre , Calidad de Vida , Linfocitos T/inmunologíaRESUMEN
Background: TNF-α has a major role in the pathogenesis of Crohn's disease (CD). In contrast, GM-CSF may be beneficial for its anti-inflammatory role in a subset of patients with CD with antibodies against GM-CSF as seen in prior trials of GM-CSF which resulted in clinical improvement in CD. We developed butanol purified Food Allergy Herbal Formula-2 (B-FAHF-2) by refining FAHF-2. FAHF-2 suppressed TNF-α production by human peripheral blood mononuclear cells (PBMCs) and colonic mucosa, and abrogated colitis in a murine model. We sought to examine the effect of B-FAHF-2 and the herbs that comprise it on TNF-α and GM-CSF production as a potential herbal therapy for the treatment of CD. Methods: B-FAHF-2 was examined using high pressure liquid chromatography (HPLC) and compared to the original formulation, FAHF-2. PBMCs from pediatric patients with CD were cultured with lipopolysaccharide and B-FAHF-2, individual herbs or medium alone. Colonic biopsy specimens were cultured with or without B-FAHF-2. TNF-α and GM-CSF were measured by enzyme-linked immunosorbent assay (ELISA). B-FAHF-2 efficacy was tested in vivo in the CD45Rbhi transfer model. Results: B-FAHF-2 had a similar HPLC fingerprint as FAHF-2 but decreased TNF-α production by PBMCs and colonic mucosa from pediatric CD subjects at 20% of the FAHF-2 dose. B-FAHF-2 increased GM-CSF production by PBMCs and colonic mucosa from pediatric CD subjects including those with antibodies to GM-CSF. Of B-FAHF-2's herbal constituents, only Huang Bai suppressed TNF-α and increased GM-CSF production. In the murine model, B-FAHF-2 treatment alleviated colitis. Conclusions: B-FAHF-2 decreased TNF-α production by PBMCs and colonic mucosa from pediatric subjects at a lower dose than FAHF-2. B-FAHF-2 also increased GM-CSF production by PBMCs independent of antibodies. B-FAHF-2 may have a benefit in CD patients.
Asunto(s)
Enfermedad Celíaca , Autoanticuerpos , Autoinmunidad , Enfermedad Celíaca/epidemiología , Humanos , Incidencia , IsraelRESUMEN
BACKGROUND: Vedolizumab (VDZ) is effective for treating both adult and pediatric onset inflammatory bowel disease (IBD). Clinical outcomes, however, have been reported to be superior in patients naïve to anti-tumor necrosis factor (TNF). With the growing interest in endoscopic endpoints, we aimed to describe rates of mucosal healing in pediatric patients being treated with VDZ and examine the influence of anti-TNF on outcomes. METHODS: We conducted a retrospective review of all IBD patients ≤21 years of age who initiated VDZ and underwent endoscopy. Primary outcome was mucosal healing (composite of endoscopic [SES-CD] and Mayo score UC) and histological remission [Nancy index-UC and Crohn disease (CD) histologic activity]. Descriptive statistics summarized the data. Comparisons were made for endpoints based on anti-TNF exposure using univariate testing. RESULTS: Sixty-eight patients were included in the final analysis; 35 with UC and 33 with CD. Thirty-two patients (22 UC and 10 CD) were anti-TNF-naïve and 36 patients (13 UC and 23 CD) were anti-TNF-exposed. The median duration on VDZ before endoscopic assessment was 49 (IQR 32-73) weeks. A total of 38% (25/66) of patients met the primary outcome of mucosal healing and did not differ between anti-TNF-naïve or anti-TNF-exposed. Endoscopic remission was achieved by 51% with significantly more anti-TNF naïve patients reaching this endpoint (66% vs 40%, Pâ=â0.03). Histologic remission was achieved by 42% of patients with a nonsignificant trend towards improved histologic remission rates in anti-TNF-naïve patients (52% vs 33%, Pâ=â0.13). CONCLUSIONS: VDZ is associated with mucosal healing in pediatric IBD. Anti-TNF exposure significantly impacted endoscopic remission, but not histologic remission in children on VDZ.
Asunto(s)
Colitis Ulcerosa , Enfermedades Inflamatorias del Intestino , Adulto , Anticuerpos Monoclonales Humanizados , Niño , Colitis Ulcerosa/tratamiento farmacológico , Fármacos Gastrointestinales/uso terapéutico , Humanos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Inducción de Remisión , Estudios Retrospectivos , Resultado del Tratamiento , Inhibidores del Factor de Necrosis TumoralRESUMEN
BACKGROUND: Approximately 10% of children with ulcerative colitis (UC) undergo colectomy with ileal pouch-anal anastomosis (IPAA). We aimed to describe the postoperative outcomes, with an emphasis on chronic pouch inflammation including de novo Crohn disease (CD) at a tertiary care inflammatory bowel disease center. METHODS: Electronic medical records of all children who underwent colectomy ≤18 years between 2008 and 2017 were reviewed. Clinical and laboratory data were recorded. Primary outcome was frequency of chronic pouch inflammation including de novo CD. Secondary outcomes included early (≤30 days from index surgery) and late postoperative complications. Descriptive statistics (median and interquartile range) summarized the data and univariate analysis tested associations with outcomes. RESULTS: Fifty-eight children underwent colectomy and 56 completed IPAA. Median age at diagnosis was 14 years (12-16.2) and at colectomy 16.2 years (14.2-17.7) with median follow-up of 13 months (5-43). Sixty-six percent underwent 3-stage IPAA and 78% were biologic exposed. Eleven had chronic pouchitis, 73% antibiotic refractory and 25% met criteria for de novo CD by median of 19 months (9-41). A total of 21% and 50% experienced early and late surgical complications, most commonly ileus and recurrent IPAA stricture. The pouch failure rate was 3.6%. Chronic pouch inflammation was associated with a later diagnosis of de novo CD (Pâ=â0.0025). CONCLUSIONS: In pediatric UC, CD is not uncommon after IPAA. Chronic pouch inflammation often precedes a diagnosis of de novo CD. Families should be informed of the short- and long-term outcomes in children before UC surgery.
Asunto(s)
Colitis Ulcerosa/cirugía , Enfermedad de Crohn/epidemiología , Reservoritis/epidemiología , Proctocolectomía Restauradora/efectos adversos , Adolescente , Niño , Enfermedad de Crohn/etiología , Femenino , Humanos , Masculino , Registros Médicos , Ciudad de Nueva York/epidemiología , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Reservoritis/etiología , Estudios RetrospectivosRESUMEN
BACKGROUND: Ustekinumab is an effective therapy for Crohn disease currently approved for adults. Off-label use in the pediatric population is increasing, but its effectiveness in this age group has not been reported. AIMS: The aim of the study was to describe real-world experience with ustekinumab at a tertiary care pediatric inflammatory bowel disease (IBD) center. METHODS: As part of an ongoing observational cohort study of biologic-treated pediatric IBD patients initiated in October 2014, data on demographics, disease behavior, location and activity, treatment, and surgical history were collected for all patients receiving ustekinumab. Disease activity was assessed using the Harvey Bradshaw index or partial Mayo score. Primary outcome was steroid-free remission at 52 weeks. Descriptive statistics summarized the safety and efficacy outcomes, and univariate analyses were performed to examine associations of clinical characteristics with efficacy. RESULTS: Fifty-two children and young adults initiating ustekinumab were analyzed; 81% Crohn Disease, 8% ulcerative colitis, and 11% IBD-unspecified. Median [IQR] age at induction was 16.8 [14-18] years. Patients were followed for a minimum of 12 months. Most patients (81%) failed >1 anti-TNF, and 37% failed anti-TNF and vedolizumab; 10 patients were biologic-naïve. At week 52, 75% were still on ustekinumab, and 50% (bio-exposed) and 90% (bio-naïve) were in steroid-free remission. Two infusion reactions and neither serious adverse events nor serious infections were observed. CONCLUSIONS: Our results suggest that ustekinumab is efficacious and safe in pediatric patients with IBD. Controlled clinical trial data are needed to confirm these observations.
Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Fármacos Gastrointestinales/uso terapéutico , Ustekinumab/uso terapéutico , Adolescente , Anticuerpos/sangre , Productos Biológicos/uso terapéutico , Niño , Femenino , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/efectos adversos , Fármacos Gastrointestinales/inmunología , Humanos , Masculino , Uso Fuera de lo Indicado , Inducción de Remisión , Retratamiento , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Centros de Atención Terciaria , Resultado del Tratamiento , Ustekinumab/administración & dosificación , Ustekinumab/efectos adversos , Ustekinumab/inmunología , Adulto JovenRESUMEN
BACKGROUND AND AIMS: Vedolizumab is an anti-α4ß7 biologic approved for ulcerative colitis [UC] and Crohn's disease [CD]. We aimed to examine the association of maintenance vedolizumab concentrations with remission. METHODS: We performed a cross-sectional multi-centre study of inflammatory bowel disease [IBD] patients on maintenance vedolizumab. A homogeneous mobility shift assay [HMSA] was used to determine trough serum concentrations of vedolizumab and anti-drug antibodies [ATVs]. The primary outcome was corticosteroid-free clinical and biochemical remission defined as a composite of clinical remission, normalized C-reactive protein [CRP] and no corticosteroid use in 4 weeks. Secondary outcomes included corticosteroid-free endoscopic and deep remission. Vedolizumab concentrations were compared between patients in remission and with active disease. Logistic regression, adjusting for confounders, assessed the association between concentrations and remission. RESULTS: In total, 258 IBD patients were included [55% CD and 45% UC]. Patients in clinical and biochemical remission had significantly higher vedolizumab concentrations [12.7 µg/mL vs 10.1 µg/mL, p = 0.002]. Concentrations were also higher among patients in endoscopic and deep remission [14.2 µg/mL vs 8.5 µg/mL, p = 0.003 and 14.8 µg/mL vs 10.1 µg/mL, p = 0.01, respectively]. After controlling for potential confounders, IBD patients with vedolizumab concentrations >11.5 µg/mL were nearly 2.4 times more likely to be in corticosteroid-free clinical and biochemical remission. Only 1.6% of patients had ATVs. CONCLUSIONS: In a large real-world cohort of vedolizumab maintenance concentrations, IBD patients with remission defined by objective measures [CRP and endoscopy] had significantly higher trough vedolizumab concentrations and immunogenicity was uncommon.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Monitoreo de Drogas/métodos , Enfermedades Inflamatorias del Intestino , Quimioterapia de Mantención/métodos , Inducción de Remisión/métodos , Adulto , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/sangre , Estudios de Cohortes , Estudios Transversales , Ensayo de Cambio de Movilidad Electroforética , Endoscopía del Sistema Digestivo/métodos , Femenino , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/sangre , Glucocorticoides/uso terapéutico , Humanos , Enfermedades Inflamatorias del Intestino/sangre , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Estados UnidosRESUMEN
OBJECTIVES: Autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC) are progressive immune-mediated inflammatory diseases that may require liver transplant (LT). Outcomes in children undergoing LT for these diseases are poorly studied in the pediatric end-stage liver disease era. We aimed to characterize the outcome of LT in children with AIH and PSC. METHODS: Children 18 years or younger with PSC or AIH who had a first, isolated LT from 2002 to 2012 were identified from the United Network for Organ Sharing database. Graft and patient outcomes were studied. RESULTS: A total of 174 children with AIH and 113 with PSC were transplanted in the study period. One-year patient survival was 95.4% for AIH and 97.3% for PSC. Five-year patient survival was 91.4% for AIH and 92.9% for PSC. Patient survival was not significantly different between the 2 groups. Forty-four (25.2%) children with AIH were listed as status 1 for transplant (fulminant hepatic failure at presentation or acute-on-chronic disease). Patients transplanted as status 1 had significantly lower patient survival compared with patients transplanted with AIH and end-stage liver disease. The one- and five-year graft survival rates were not significantly different between patients with AIH and PSC. CONCLUSION: Children with AIH transplanted as status 1 had significantly lower patient survival rates but similar graft survival rates to children with chronic AIH. Children transplanted for AIH versus PSC showed no significant differences in patient or graft survival at both 1 and 5 years.
Asunto(s)
Colangitis Esclerosante/complicaciones , Enfermedad Hepática en Estado Terminal/cirugía , Hepatitis Autoinmune/complicaciones , Fallo Hepático Agudo/cirugía , Trasplante de Hígado , Adolescente , Niño , Preescolar , Bases de Datos Factuales , Enfermedad Hepática en Estado Terminal/etiología , Enfermedad Hepática en Estado Terminal/mortalidad , Femenino , Estudios de Seguimiento , Supervivencia de Injerto , Humanos , Lactante , Recién Nacido , Fallo Hepático Agudo/etiología , Fallo Hepático Agudo/mortalidad , Masculino , Tasa de SupervivenciaRESUMEN
PURPOSE OF REVIEW: There are an expanding number of therapies available to treat pediatric inflammatory bowel disease (IBD). As pediatric gastroenterologists attempt to achieve complete intestinal mucosal healing for their patients, it has become more important to gain an understanding of how to maximize the efficacy of our medications while minimizing their toxicities. We aim to provide an overview of therapeutic drug monitoring in IBD with an emphasis on the biologic therapies (antitumor necrosis factor and anti-integrin monoclonal antibodies). RECENT FINDINGS: Recent findings do support optimized drug dosing for infliximab based on early trough levels, but question the utility of checking these values in patients doing well in maintenance therapy. Patients with severe colonic inflammation may be at increased risk for needing optimization with dose escalation because of medication loss in the stool. Dose escalation can recapture response in some patients with a secondary loss of response, including those with low level antibody formation. The monitoring of nontrough drug levels to allow timelier dose adjustment as well as the role of drug monitoring with anti-integrin therapy are areas of active research. SUMMARY: Therapeutic drug monitoring is an effective strategy in the management of pediatric IBD that can help patients achieve mucosal healing and aid the clinical decision-making of the pediatric gastroenterologist.
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Antiinflamatorios/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Monitoreo de Drogas , Fármacos Gastrointestinales/uso terapéutico , Adalimumab/farmacocinética , Adalimumab/uso terapéutico , Antiinflamatorios/farmacocinética , Anticuerpos Monoclonales/farmacocinética , Azatioprina/farmacocinética , Azatioprina/uso terapéutico , Niño , Colitis Ulcerosa/metabolismo , Enfermedad de Crohn/metabolismo , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Fármacos Gastrointestinales/farmacocinética , Humanos , Infliximab/farmacocinética , Infliximab/uso terapéutico , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
BACKGROUND: Though vedolizumab has received regulatory approval for the treatment of Crohn's disease (CD) and ulcerative colitis (UC) in adults, there is increasing off-label use in children. AIMS: To describe the experience with vedolizumab in pediatric inflammatory bowel disease (IBD) patients at 3 tertiary IBD centers and examine predictors of remission. METHODS: A retrospective review identified pediatric IBD patients (age < 18 yrs) receiving vedolizumab. Data on demographics, disease behavior, location, activity, and previous treatments/surgeries were collected. Disease activity was assessed using the weighted pediatric CD activity index or pediatric UC activity index. Primary outcome was week 14 remission, defined as pediatric UC activity index <10 or weighted pediatric CD activity index <12.5. Descriptive statistics and univariate analyses were performed to examine associations of clinical characteristics with efficacy. RESULTS: Fifty-two patients, 58% CD and 42% UC, initiated vedolizumab between June 2014 and August 2015. Median age at vedolizumab initiation was 14.9 (range 7-17) years. Ninety percent had failed ≥1 anti-tumor necrosis factor (TNF) agent. Week 14 remission rates for UC and CD were 76% and 42%, respectively (P < 0.05). Eighty percent of anti-TNF-naive patients experienced week 14 remission. At week 22, anti-TNF-naive patients had higher remission rates than TNF-exposed patients (100% versus 45%, P = 0.04). There were no infusion reactions or serious adverse events/infections. CONCLUSIONS: Our results suggest that vedolizumab is efficacious and safe in pediatric IBD patients, with UC patients experiencing earlier and higher rates of remission than CD patients. Anti-TNF-naive patients experienced higher remission rates than those with anti-TNF exposure. Controlled clinical trial data are needed to confirm these observations.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Fármacos Gastrointestinales/uso terapéutico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adolescente , Niño , Femenino , Humanos , Masculino , Uso Fuera de lo Indicado , Inducción de Remisión , Estudios Retrospectivos , Centros de Atención Terciaria , Estados UnidosRESUMEN
OBJECTIVES: Epstein Barr virus (EBV) is a human herpes virus that infects 90% of the world's population and has been linked to the development of lymphoproliferative disorders (LPDs) and immunosuppression. Primary EBV infection in patients with IBD on thiopurines is a risk factor for LPD, including lymphoma. We aimed to describe EBV status in a pediatric population with IBD with an emphasis on those initiating thiopurines. METHODS: Electronic medical records and EBV serologies were reviewed and categorized into asymptomatic screening versus suspicion for acute infection. EBV status before therapy was described by sex, age, and therapeutic regimen. Descriptive statistics and univariate analysis were employed. RESULTS: Only 150 (22%) of our 688 pediatric patients with IBD had documented EBV status regardless of age or treatment regimen. Only 17% were assessed for suspicion of acute infection and 83% for screening. Sixty-four (52%) screened patients were checked before starting any treatment and only 40% were immunoglobulin (Ig)G positive. There was no difference in mean age between the seronegative and seropositive group. The majority (63%) of thiopurine-treated patients were IgG negative before starting therapy. Eighty percent of primary EBV infections occurred on thiopurines at a mean (SD) of 2â±â1.5 years after initiating therapy. CONCLUSIONS: The majority of our pediatric patients with IBD with documented EBV status were IgG negative at thiopurine initiation. Thiopurines were also associated with primary EBV infection. EBV status may be an important determinate of whether physicians prescribe thiopurines given the risk of primary EBV infections and lymphoproliferative diseases.
Asunto(s)
Infecciones por Virus de Epstein-Barr/diagnóstico , Herpesvirus Humano 4/aislamiento & purificación , Inmunosupresores/uso terapéutico , Enfermedades Inflamatorias del Intestino/epidemiología , Linfoma/diagnóstico , Mercaptopurina/uso terapéutico , Adolescente , Niño , Estudios Transversales , Femenino , Humanos , Inmunosupresores/efectos adversos , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/virología , Linfoma/etiología , Masculino , Mercaptopurina/efectos adversos , Ciudad de Nueva York/epidemiología , Estudios Retrospectivos , Carga Viral , Adulto JovenRESUMEN
EBV-SMT are a rare entity following organ transplantation. Given the rarity of the tumor, there is no standard approach to diagnosis and treatment. A literature search identified 28 reported cases of EBV-SMT in addition to our own experience with one case. The aim of this review is to summarize the existing data regarding pathogenesis, diagnosis, and treatment.