Estrategias de diagnóstico y tratamiento en la enfermedad inflamatoria intestinal

[spa] Las enfermedades inflamatorias intestinales (EII) son un conjunto de entidades de etiopatogenia no claramente conocida dentro de las cuales la EC y la CU son sus máximos exponentes y se asocian a una elevada morbilidad y necesidad de recursos personales, laborales y sanitarios. El arsenal terapéutico disponible para su manejo es relativamente escaso y de eficacia limitada e incluye salicilatos, corticoides, inmunomodulares y tratamientos biológicos. Determinar de forma precisa tanto la presencia de actividad, como la extensión y gravedad de la enfermedad, es esencial para definir el tratamiento más adecuado. Dado que no existe una buena correlación entre la sintomatología referida por el paciente, los biomarcadores y la presencia de enfermedad activa, la endoscopia y las pruebas de imagen aportan información objetiva para el diagnóstico y seguimiento de la EII. La endoscopia es una exploración invasiva no exenta de complicaciones que en un elevado porcentaje de casos no permite una exploración completa por la presencia de lesiones graves, estenosis o dificultad técnica, y que además no tiene la capacidad de evaluar la presencia de complicaciones penetrantes, como fístulas y abscesos, muy frecuentes en la EC. Las pruebas de imagen, como el TC y la RM, logran explorar la mayoría de segmentos intestinales, proporcionan una valiosa información sobre la presencia de complicaciones penetrantes y definen de forma precisa las características funcionales de las estenosis; es por ello que se consideran exploraciones complementarias a la colonoscopia dentro del algoritmo de manejo de la EII. Ambas pruebas tienen similar precisión diagnóstica pero la RM a diferencia del TC no expone al paciente a radiación ionizante lo que la hace especialmente adecuada en la evaluación de la enfermedad. En espera del desarrollo de nuevos fármacos la estrategia actual de manejo de la EII busca optimizar los tratamientos disponibles con la combinación de fármacos y el inicio precoz de biológicos e inmunomoduladores. Dentro de la terapia biológica, los fármacos anti-TNFα como infliximab y adalimumab, han demostrado su eficacia como tratamiento de ambas enfermedades. Determinar factores predictores de buena respuesta a estos fármacos evita prolongar un tratamiento ineficaz, minimiza el riesgo de aparición de efectos secundarios y permite reducir gastos. Los ensayos clínicos aportan por su diseño la información más robusta sobre la eficacia de estos fármacos; sin embargo, a diferencia de los estudios de práctica clínica, incluyen a un subgrupo muy seleccionado de pacientes y no se permite el ajuste de dosis o la adición de tratamientos concomitantes, lo que en muchos casos es fundamental para incrementar la eficacia terapéutica y ofrecer el máximo beneficio clínico al paciente. Para los clínicos que tratan pacientes con EII la información que proporcionan los estudios de práctica clínica, más próxima a la realidad de manejo, puede ser por lo tanto muy valiosa. HIPÓTESIS -La endoscopia presenta limitaciones en la evaluación de la enfermedad de Crohn (EC), que podrían ser superadas con el uso de técnicas de imagen crossectional (TC Y RM). -Identificar predictores de respuesta al tratamiento anti-TNFα permite seleccionar los mejores candidatos a estos tratamientos. OBJETIVOS -Determinar si la RM puede ser una alternativa a la colonoscopia en la evaluación de la EC y en la identificación de candidatos a recibir fármacos anti-TNFα. -Evaluar la eficacia de infliximab y adalimumab como tratamiento de la colitis ulcerosa (CU) en la práctica clínica e identificar predictores de respuesta. METODOLOGÍA 1º estudio: 4 especialistas evaluaron la información de la RM y la endoscopia proporcionada en 2 secuencias alternativas para el manejo de la EC con sospecha de actividad.[eng] Inflammatory bowel disease is associated with high morbidity and resource consumption. An adequate management strategy must accurately determine both the presence of activity and the extent and severity of the disease, as well as optimizing the available treatments. The clinical evaluation has a low accuracy for the diagnosis of inflammatory activity and also for the detection of complications in Crohn's disease (CD), and therefore objective measurements of disease activity are required. Endoscopy and imaging tests are complementary explorations for the evaluation of CD; however the improvement in the quality of the MR image and its ability to explore the most of intestinal segments, as well as to assess the presence of penetrating complications and to determine the functional characteristics of the stenosis, suggest that it should be the exploration of choice in patients with severe or complicated CD when the diagnosis is already established. In the scenario of suspicion of mild disease activity, the examination of choice should be colonoscopy, but the need to complete the evaluation by MRI should always be considered given the high frequency of CD complications. It should be highlighted that the intestinal damage, including stenosis and fistulas, determined by MRI has been previously established as a predictor for the need of surgery in the era of biologics. The anti-TNFα therapy has demonstrated their efficacy in the short and medium term as a treatment for ulcerative colitis (UC). It can be identified a subgroup of UC patients with poor prognosis factors in which the anti-TNFα treatment is ineffective in the short term or have a high probability of loss of response, and in which it would be necessary to consider using drugs with another therapeutic target or even surgery. In UC, the biological treatment combined with thiopurines seems to have higher efficacy than monotherapy with biologics, even after previous failure to thiopurines, and its association should be considered, especially in those patients with poor prognostic factors. In UC patients who suffer loss of response to a first anti-TNFα, the efficacy of a second anti-TNFα drug as a rescue therapy is influenced by the primary response to this previous first anti-TNFα

Are we giving biologics too late? The case for early versus late use

Corticosteroids and immunomodulators have been the mainstay therapies for Crohn’s disease. Corticosteroids are highly effective to control symptoms in the short-term, but they are not effective in maintaining remission, they heal the mucosa in a reduced proportion of cases, and long-time exposure is associated with an increased risk of infections and mortality. Immunomodulators, azathioprine and methotrexate, heal the mucosa in a higher proportion of patients that corticosteroids but their onset of action is slow and they benefit less than half of patients with Crohn’s disease. In the last decade, medical therapy for Crohn’s disease has experienced a remarkable change due to the introduction of biologic therapy, and particularly the use of anti-tumour necrosis factor-alpha agents. Infliximab, adalimumab, and certolizumab pegol have demonstrated efficacy for induction and maintenance of remission in active Crohn’s disease. These agents have raised the bar for what is a suitable symptomatic response in Crohn’s disease and modification of the natural history of the disease has become a major goal in the treatment of Crohn’s disease. There are several data in the literature that suggest that early use of biologic therapy and achievement of mucosal healing contribute to disease course modification. However, many questions on early biological therapy for Crohn’s disease remain still unanswered

Interleukin-19 impairment in active Crohn's disease patients

The exact function of interleukin-19 (IL-19) on immune response is poorly understood. In mice, IL-19 up-regulates TNFalpha and IL-6 expression and its deficiency increases susceptibility to DSS-induced colitis. In humans, IL-19 favors a Th2 response and is elevated in several diseases. We here investigate the expression and effects of IL-19 on cells from active Crohn"s disease (CD) patient. Twenty-three active CD patients and 20 healthy controls (HC) were included. mRNA and protein IL-19 levels were analyzed in monocytes. IL-19 effects were determined in vitro on the T cell phenotype and in the production of cytokines by immune cells. We observed that unstimulated and TLR-activated monocytes expressed significantly lower IL-19 mRNA in active CD patients than in HC (logFC =21.97 unstimulated; 21.88 with Pam3CSK4; and 21.91 with FSL-1; p<0.001). These results were confirmed at protein level. Exogenous IL-19 had an anti-inflammatory effect on HC but not on CD patients. IL-19 decreased TNFalpha production in PBMC (850.7675.29 pg/ml vs 2626.06350 pg/ml; p<0.01) and increased CTLA4 expression (22.0461.55% vs 13.9862.05%; p<0.05) and IL-4 production (32.568.9 pg/ml vs 13.562.9 pg/ml; p<0.05) in T cells from HC. IL-10 regulated IL-19 production in both active CD patients and HC. We observed that three of the miRNAs that can modulate IL-19 mRNA expression, were up-regulated in monocytes from active CD patients. These results suggested that IL-19 had an anti-inflammatory role in this study. Defects in IL-19 expression and the lack of response to this cytokine could contribute to inflammatory mechanisms in active CD patients