RESUMEN
BACKGROUND AND AIMS: Tacrolimus is recommended for the treatment of steroid-refractory ulcerative colitis (UC). Concomitantly started purine analogues (PAs) are used for the maintenance of remission, though their therapeutic relevance remains uncertain. Here we studied the role of PAs in the long-term outcome of steroid-refractory UC after tacrolimus treatment. METHODS: In five centres, charts of tacrolimus-treated UC patients with a steroid-refractory moderate to severe course were reviewed. Long-term efficacy was determined by colectomy rates and clinical remission in cases of colectomy-free survival for 3 months. RESULTS: We identified 156 patients (median age 34 years) with a median Lichtiger score of 12 (4-17) and pancolitis (E3) in 65% (101). The Kaplan-Meier curve for colectomy-free survival after month 3 showed a benefit in the PA group (p = 0.02). In patients treated with PA clinical remission was achieved in 82% (65/79) vs 67% (39/58) in those not treated with PA (p = 0.02). Time to colectomy was 2 years (median, 0.7-5.8) in the PA group and 0.8 years (0.3-4.7) in the group not treated with PAs (p = 0.02). Time to relapse was 1.2 years (median, 0.3-6.2) in patients with PA treatment and 0.5 years (0.3-3.9) in those without PA treatment (p = 0.05). Overall, clinical remission was achieved in 67% (104/156) of patients. Colectomy was performed in 29% (45/156) 0.5 years (median, 0.04-5.79) after initiation of tacrolimus. Ten (6%) patients had to stop tacrolimus due to adverse events and two (without PA treatment) died. CONCLUSIONS: Our study supports the efficacy of tacrolimus in steroid-refractory UC. Purine analogues appear to be beneficial for the long-term outcome of these patients.
Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Mucosa Intestinal/efectos de los fármacos , Mercaptopurina/administración & dosificación , Tacrolimus/administración & dosificación , Adulto , Anciano , Estudios de Cohortes , Colectomía/métodos , Colectomía/estadística & datos numéricos , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/mortalidad , Colitis Ulcerosa/cirugía , Colonoscopía/métodos , Bases de Datos Factuales , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Alemania , Humanos , Inmunosupresores/administración & dosificación , Mucosa Intestinal/patología , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Medición de Riesgo , Índice de Severidad de la Enfermedad , Estadísticas no Paramétricas , Esteroides/administración & dosificación , Esteroides/efectos adversos , Tasa de Supervivencia , Factores de Tiempo , Resultado del Tratamiento , Cicatrización de Heridas/efectos de los fármacos , Cicatrización de Heridas/fisiología , Adulto JovenAsunto(s)
Colitis Ulcerosa/complicaciones , Neoplasias Colorrectales/etiología , Complicaciones Posoperatorias , Reservoritis/etiología , Enfermedad Aguda , Cuidados Posteriores/métodos , Enfermedad Crónica , Colitis Ulcerosa/psicología , Colitis Ulcerosa/cirugía , Colonoscopía , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/terapia , Progresión de la Enfermedad , Humanos , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/terapia , Reservoritis/diagnóstico , Reservoritis/terapia , Proctocolectomía Restauradora , Factores de RiesgoRESUMEN
Thiopurines (azathioprine and 6-mercaptopurine) are the most frequently used drugs in the treatment of patients with Crohn's disease. In current guidelines published by the German Society of Gastroenterology, Nutritional and Metabolic Diseases (DGVS) in 2014 and by the European Crohn´s and Colitis Organisation (ECCO) in 2010 different indications have been suggested. However, efficacy of azathioprine has been substantially questioned by recent publications in adults as well as in children examining the efficacy of early initiation of this treatment. These articles were published after release of the aforementioned guidelines. Therefore, in this survey recently published data are discussed on the background of our knowledge on the efficacy of azathioprine and 6-mercaptopurine developed in many years, and suggestions for the future use of these substances in the treatment of patients with Crohn's disease will be provided.
Asunto(s)
Azatioprina/administración & dosificación , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/tratamiento farmacológico , Guías de Práctica Clínica como Asunto , Relación Dosis-Respuesta a Droga , Medicina Basada en la Evidencia , Humanos , Inmunosupresores/administración & dosificación , Resultado del TratamientoRESUMEN
Crohn's disease and ulcerative colitis are the most common forms of chronic inflammatory bowel disease. The therapeutic algorithm is complex and individualized especially in complicated courses of the disease. This article gives a comprehensive overview on the typical courses of disease and the standard therapy of both diseases. Furthermore, ongoing controversies will be highlighted including early immunosuppression and immunomodulation as well as new therapeutic goals, such as mucosal healing. Finally, a perspective on future therapeutic options is given focusing especially on vedolizumab, the new antibody against the bowel-specific α4ß7-integrin.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Azatioprina/uso terapéutico , Factores Inmunológicos/uso terapéutico , Inmunosupresores/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Guías de Práctica Clínica como Asunto , Enfermedad Crónica , Fármacos Gastrointestinales/uso terapéutico , Humanos , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
BACKGROUND: Vidofludimus (SC12267) is a novel oral immunomodulator inhibiting dihydroorotate dehydrogenase (DHODH) and the expression of proinflammatory cytokines including interleukin-17 (IL17A and IL17F) and interferon-gamma. The objective of the study was to explore the efficacy, safety and tolerability of vidofludimus in steroid-dependent inflammatory bowel disease (IBD). METHODS: The open label uncontrolled ENTRANCE study (ClinicalTrials.gov NCT00820365) has been conducted at 13 study centers in Germany, Bulgaria and Romania. Thirty-four steroid-dependent patients with a confirmed diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) were treated with a once daily 35mg oral dose of vidofludimus over 12weeks. Steroids were tapered during the first 8weeks followed by a steroid-free treatment period of 4weeks. Complete response was defined as steroid-free clinical remission at week 12; partial response was defined as being in remission at steroid dose equal or lower than the individual patient's threshold dose for relapse. RESULTS: Of the thirty-four patients enrolled in this trial 26 were evaluable for primary efficacy assessment. After completion of the 12weeks treatment phase 8 out of 14 (57.1%) patients with CD and 6 out of 12 (50.0%) patients with UC were in steroid-free remission (complete responders). Another 4 (28.6%) patients in CD and 5 (41.7%) patients in UC were partial responders. Vidofludimus was well tolerated, no drug-related serious adverse events were observed. CONCLUSIONS: This trial provides first evidence of clinical efficacy of vidofludimus in IBD. Although the safety and tolerability profile seems favorable, long-term controlled studies are needed to further investigate its potential as novel IBD therapy.
Asunto(s)
Compuestos de Bifenilo/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Ácidos Dicarboxílicos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Factores Inmunológicos/uso terapéutico , Adulto , Anciano , Antiinflamatorios/uso terapéutico , Azatioprina/uso terapéutico , Compuestos de Bifenilo/efectos adversos , Sedimentación Sanguínea , Proteína C-Reactiva/metabolismo , Colitis Ulcerosa/sangre , Enfermedad de Crohn/sangre , Ácidos Dicarboxílicos/efectos adversos , Dihidroorotato Deshidrogenasa , Inhibidores Enzimáticos/efectos adversos , Heces/química , Femenino , Humanos , Factores Inmunológicos/efectos adversos , Inmunosupresores/uso terapéutico , Análisis de Intención de Tratar , Complejo de Antígeno L1 de Leucocito/análisis , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/antagonistas & inhibidores , Prednisolona/uso terapéutico , Inducción de Remisión , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
BACKGROUND: Steroid-refractory ulcerative colitis (UC) remains a challenging condition warranting surgery upon failure of pharmacological treatment. Calcineurin inhibitors or infliximab are alternatives in this situation. Data on the efficacy and safety of tacrolimus in this setting are limited. AIM: To study the short-term efficacy and safety of tacrolimus in moderate-to-severe steroid-refractory UC. The role of thiopurines in this situation and predictors of colectomy were evaluated. METHODS: In three centers, all charts from tacrolimus-treated patients with steroid-refractory UC were reviewed. Efficacy was assessed by colectomy-free survival and clinical remission at 3 months. RESULTS: We identified 130 patients with pancolitis in 75 (59%), left-sided disease in 35 (27%) and proctitis in 18 patients (14%) (disease localisation not obtainable in two patients). The median age was 40 (range: 18-81). Clinical activity according to the median Lichtiger score decreased from 13 (range: 4-17) at baseline to 3 (0-14) at week 12. Eighteen patients underwent colectomy within the first 3 months of treatment with tacrolimus (14%). Clinical remission was achieved in 94 patients (72%) in this period. Thiopurines given in parallel to tacrolimus tended to limit colectomy and significantly increased remission (P = 0.002) in the short-term. No other predictors of colectomy or remission were identified. Side effects were noticed in 53% of patients and no severe events occurred. CONCLUSION: This large survey confirms the efficacy and safety of tacrolimus in patients with steroid-refractory ulcerative colitis.
Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Inmunosupresores/administración & dosificación , Tacrolimus/administración & dosificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Colectomía , Femenino , Humanos , Inmunosupresores/efectos adversos , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Inducción de Remisión , Índice de Severidad de la Enfermedad , Tacrolimus/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
HISTORY AND ADMISSION FINDINGS: A 19-year-old HIV-positive man was admitted with fever of unknown origin and poor general condition. Antiretroviral therapy had been stopped by the patient eight months prior to admission. INVESTIGATIONS: Laboratory tests revealed pancytopenia, high viral load and low count of T-helper cells (13/µl). Computer tomography of the thorax showed small patchy infiltrations. Extensive examinations (microbiology, laboratory tests, multiple investigations) revealed no pathogen. Liver biopsy proved disseminated histoplasmosis. TREATMENT AND COURSE: Liposomal amphotericin B was started and switched to oral itraconazole after 14 days with itraconazole. With this treatment the patient condition improved and fever stopped. T-helper cells increased and the patient was discharged. CONCLUSION: Disseminated histoplasmosis as an AIDS-defining opportunistic infection is uncommon (particularly as the patient had not been abroad in the last four years) and can be a life-threatening complication. Diagnosis must be confirmed by invasive methods especially in patients with compromised immune status and rapid clinical progression.
Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/diagnóstico , Histoplasmosis/diagnóstico , Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Anfotericina B/uso terapéutico , Antibacterianos/uso terapéutico , Fármacos Anti-VIH/uso terapéutico , Antifúngicos/uso terapéutico , Terapia Antirretroviral Altamente Activa , Biopsia , Broncoscopía , Diagnóstico Diferencial , Quimioterapia Combinada , Histoplasmosis/tratamiento farmacológico , Humanos , Infusiones Intravenosas , Hígado/patología , Masculino , Tomografía Computarizada por Rayos X , Adulto JovenAsunto(s)
Antiinflamatorios/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Productos Biológicos/uso terapéutico , Enfermedad de Crohn/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Antiinflamatorios/efectos adversos , Antiinflamatorios/economía , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/economía , Azatioprina/efectos adversos , Azatioprina/economía , Azatioprina/uso terapéutico , Productos Biológicos/efectos adversos , Productos Biológicos/economía , Análisis Costo-Beneficio/economía , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/economía , Costos de los Medicamentos , Quimioterapia Combinada , Alemania , Humanos , Infliximab , Cuidados a Largo Plazo , Ensayos Clínicos Controlados Aleatorios como Asunto , Recurrencia , Sesgo de Selección , Resultado del TratamientoAsunto(s)
Colitis Ulcerosa , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/terapia , Colonoscopía , Alemania , HumanosRESUMEN
Tacrolimus (Tac) is effective in the treatment of steroid-refractory ulcerative colitis (UC); however, nonresponse and unpredictable side effects are major limitations. Because Tac response in patients who have undergone solid-organ transplantation has been associated with the presence of variants in CYP3A and ABCB1, we elucidated the contributions of CYP3A4*1B and CYP3A5*3 and of ABCB1 1236C>T, 2677G>T,A, and 3435C>T polymorphisms to Tac response in 89 patients with UC. Short-term remission and response were achieved in 61 and 14% of the patients, respectively, and were associated with colectomy-free survival. In a linear logistic regression model, patients with homozygous variants for one of the three ABCB1 alleles showed significantly higher short-term remission rates as compared with those of other genotypes. The effects held true after multivariate analysis including multiple comparisons and were more pronounced after correction for dose-adjusted Tac blood trough levels. We suggest that ABCB1, but not CYP3A5, may predict short-term remission of Tac in steroid-refractory UC.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Colitis Ulcerosa/tratamiento farmacológico , Citocromo P-450 CYP3A/genética , Inmunosupresores/uso terapéutico , Tacrolimus/uso terapéutico , Subfamilia B de Transportador de Casetes de Unión a ATP , Adolescente , Adulto , Anciano , Alelos , Colitis Ulcerosa/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Inmunosupresores/farmacocinética , Inmunosupresores/farmacología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Polimorfismo de Nucleótido Simple , Inducción de Remisión/métodos , Tacrolimus/farmacocinética , Tacrolimus/farmacología , Resultado del Tratamiento , Adulto JovenRESUMEN
Here we report 2 cases of fatal Pneumocystis jirovecii pneumonia in patients with severe ulcerative colitis receiving combination immunosuppression including tacrolimus. We discuss the necessity of a P. jirovecii prophylaxis especially in elderly patients according to the European evidence-based consensus on the prevention and management of opportunistic infections in inflammatory bowel disease.
Asunto(s)
Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/tratamiento farmacológico , Terapia de Inmunosupresión/efectos adversos , Inmunosupresores/efectos adversos , Infecciones Oportunistas/complicaciones , Pneumocystis carinii/aislamiento & purificación , Neumonía por Pneumocystis/complicaciones , Tacrolimus/efectos adversos , Anciano , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/microbiología , Resultado Fatal , Humanos , Masculino , Infecciones Oportunistas/diagnóstico , Infecciones Oportunistas/inmunología , Neumonía por Pneumocystis/diagnóstico , Neumonía por Pneumocystis/inmunología , Factores de RiesgoRESUMEN
The upper gastrointestinal bleeding remains the most frequent emergency in gastroenterology. Due to the different therapeutic approach a distinction between the variceal and the non-variceal bleeding has been established. A risk assessment for the individual patient is crucial for timing of the endoscopic procedure as well as for the estimation of prognosis. This review gives an overview on modern therapeutic techniques for both, variceal and non-variceal bleeding highlighting on success rates but also on potential complications of the different therapeutic interventions.
Asunto(s)
Urgencias Médicas , Hemorragia Gastrointestinal/clasificación , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/terapia , Diagnóstico Diferencial , Endoscopía del Sistema Digestivo , Várices Esofágicas y Gástricas/clasificación , Várices Esofágicas y Gástricas/complicaciones , Várices Esofágicas y Gástricas/terapia , Humanos , Lipresina/análogos & derivados , Lipresina/uso terapéutico , Pronóstico , Factores de Riesgo , Escleroterapia/métodos , Terlipresina , Vasoconstrictores/uso terapéuticoAsunto(s)
Corticoesteroides/administración & dosificación , Antiinflamatorios/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Colectomía , Enfermedad de Crohn/tratamiento farmacológico , Inmunosupresores/administración & dosificación , Corticoesteroides/efectos adversos , Adulto , Algoritmos , Antiinflamatorios/efectos adversos , Anticuerpos Monoclonales/efectos adversos , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/patología , Progresión de la Enfermedad , Quimioterapia Combinada , Endoscopía Gastrointestinal , Estudios de Seguimiento , Humanos , Inmunosupresores/efectos adversos , Infliximab , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Cuidados a Largo Plazo , Recurrencia , Factores de RiesgoRESUMEN
Numerous reports on fundamental research and clinical studies have appeared in the past 1-2 decades which have contributed decisively to understanding inflammatory diseases of the small intestine. Illustrated by the examples of Crohn's disease, celiac disease, refractory sprue, and Whipple's disease, the rationale and evidence for treatment approaches are presented that are based on these pathophysiological findings. Emphasis is placed on modulation of the intestinal flora with antibiotics and probiotics as well as immunomodulatory/immunosuppressive measures with so-called biological agents. Future treatment options that directly intervene in the disease process are discussed.
Asunto(s)
Antibacterianos/administración & dosificación , Factores Inmunológicos/administración & dosificación , Inmunosupresores/administración & dosificación , Enfermedades Intestinales/tratamiento farmacológico , Intestinos/efectos de los fármacos , Probióticos/administración & dosificación , HumanosRESUMEN
BACKGROUND: The calcineurin inhibitor tacrolimus and the anti-TNF-antibody infliximab are established options in steroid-refractory ulcerative colitis (UC). AIM: To evaluate the efficacy of infliximab-salvage therapy in patients with refractory UC failing to respond to tacrolimus. METHODS: Twenty-four patients were enrolled in this evaluation. Reasons for tacrolimus therapy were steroid-refractory disease in 19 patients and steroid-dependency in five patients. All patients receiving infliximab had tacrolimus-refractory active disease (Lichtiger score >10) and were treated with 5 mg/kg at weeks 0, 2 and 6 and every 8 weeks thereafter, if tolerated. RESULTS: Six of 24 patients (25%) achieved remission following infliximab infusion and four of 24 (17%) had an initial response only, but underwent proctocolectomy later because of loss of response (3) or development of a delayed hypersensitivity reaction (1). Fourteen patients (58%) completely failed to respond with 10 undergoing colectomy. Eight patients experienced side effects under infliximab, including two infectious complications (herpes zoster and herpes pneumonia). CONCLUSIONS: Infliximab offers a therapeutic option as rescue therapy in about a quarter of patients with active UC after failing to respond to tacrolimus. This benefit has to be weighed against the risks of infectious complications.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Fármacos Gastrointestinales/uso terapéutico , Adolescente , Adulto , Anciano , Resistencia a Medicamentos , Femenino , Humanos , Infliximab , Masculino , Persona de Mediana Edad , Tacrolimus , Resultado del Tratamiento , Adulto JovenRESUMEN
The recently updated German S 3-guideline regarding the diagnosis and treatment of Crohn's disease incorporates several changes concerning the radiological approach compared to the former guideline. This article focuses on guideline-based radiological imaging techniques for patients with Crohn's disease. The new guideline is also compared to former European and German guidelines in the context of recently published radiological literature.
Asunto(s)
Colonoscopía , Enfermedad de Crohn/diagnóstico , Medicina Basada en la Evidencia , Imagen por Resonancia Magnética , Tomografía Computarizada por Rayos X , Ultrasonografía , Adolescente , Adulto , Biopsia , Niño , Enfermedad de Crohn/epidemiología , Enfermedad de Crohn/patología , Estudios Transversales , Alemania , Humanos , Mucosa Intestinal/patología , Garantía de la Calidad de Atención de Salud , Sensibilidad y Especificidad , Adulto JovenRESUMEN
The pathogenesis and therapy of chronic inflammatory intestinal diseases are characterized by an obvious discrepancy. There is extensive agreement that the pathogenesis is substantially based on a disruption of the barrier of the intestinal mucous membrane against luminal bacteria. This has been demonstrated in recent years by evidence from various disciplines, in particular from genetics, microbiology, morphology and innate immunology. However, there is also the evidence-based therapy which, as in the past, is aimed against the effectors of the adaptive immune system. In this case the therapy with biologicals is more aggressive and takes the risk of a series of undesired side-effects. This dichotomy of pathological knowledge and therapeutic innovation is not only medically unsatisfactory but also makes it difficult to present a consistent picture of these symptoms. Despite this an attempt will be made to bridge these inconsistencies and to demonstrate possible future developments which will lead to a final causal therapy. An extended version of this article appears in our newly published book "Colitis ulcerosa und Morbus Crohn".