Monitorización farmacocinética de terapias biológicas en enfermedad inflamatoria intestinal / Pharmacokinetic monitoring of biological therapies in inflammatory bowel disease

Objective: To analyze the activity developed by a multidisciplinary team of pharmacists, digestive specialists and clinical analysts for the therapeutic drug monitoring (TDM) of anti-TNFa therapies in inflammatory bowel disease (IBD).Methods: A prospective observational study (January-December 2019) was conducted of referrals from digestive specialists to the Clinical Pharmacokinetics Unit (CPU) of our general hospital for the TDM of anti-TNFa drugs (infliximab/adalimumab) in adults with IBD. Serum anti-TNFa concentrations were quantified in our Clinical Analysis Laboratory using lateral flow chromatography. When concentrations were undetectable, the presence of anti-drug antibodies (ADAs) was analyzed.CPU recommendations were based on the correct interpretation of anti-TNFa concentrations, therapeutic algorithms, and populational pharmacokinetic models implemented using MW-Pharm++® software. Results: Referrals were received for 84 patients (81.0% with Crohn’s disease, 8.3% with ADAs) treated with infliximab (46.4%) or adalimumab (53.6%); 64.3% were also treated with concomitant immunomodulators (IMMs). Sixty-three referrals (75.0%) were for proactive monitoring (treatment optimization) and the remainder for reactive monitoring after therapeutic failure. Anti-TNFa concentrations were subtherapeutic in 36.9% of patients, therapeutic in 39.3%, and supratherapeutic in 23.8%. Subtherapeutic/undetectable concentrations were significantly more frequent (p≤0.004) in patients treated with infliximab versus adalimumab (64.1% vs.. 13.3%) and in concomitant IMM non-adherents versus adherents (85.7% vs. 25.5%). Conclusions: Anti-TNFa TDM is frequently proactive in patients with IBD. The wide variability in anti-TNFa concentrations is in part explained by the type of anti-TNFa drug and adherence to IMM. (AU)

Objetivo: Analizar la actividad desarrollada por un equipo multidisciplinar formado por farmacéuticos, digestólogos y analistas clínicos para la monitorización farmacocinética (TDM) de terapias anti-TNFa en la enfermedad inflamatoria intestinal (EII).Métodos: Estudio observacional prospectivo (enero–diciembre 2019) de las interconsultas de TDM de anti-TNFa (infliximab/adalimumab) en pacientes adultos con EII, solicitadas por digestólogos a la Unidad de Farmacocinética Clínica (UFC) del Servicio de Farmacia de un hospital general. Las concentraciones séricas (Cs) de anti-TNFa fueron cuantificadas en el Laboratorio de Análisis Clínicos mediante cromatografía de flujo lateral. Cuando las Cs fueron indetectables, se analizó la presencia de anticuerpos anti-fármaco (AAF).La UFC realizó recomendaciones en base a la correcta interpretación de las Cs de anti-TNFa, algoritmos terapéuticos y modelos farmacocinéticos poblacionales implementados en el programa informático de ajuste bayesiano MW-Pharm++®. Resultados: Se solicitaron interconsultas para 84 pacientes (81,0% enfermedad de Crohn, 8,3% AAF positivos) con infliximab (46,4%) ó adalimumab (53,6%). 64,3% recibía otros inmunomoduladores (IMM) concomitantes. 63 interconsultas (75,0%) se relacionaron con monitorización ‘pro-activa’ (optimizar tratamiento); el resto fueron ‘re-activas’ a fallo terapéutico. Se observaron Cs de anti-TNFa subterapéuticas en 36,9% de pacientes, terapéuticas en 39,3% y supraterapéuticas en 23,8%. Las Cs subterapéuticas/indetectables fueron significativamente (p≤0,004) más frecuentes en pacientes tratados con infliximab versus adalimumab (64,1% vs. 13,3%); y en ‘no-adherentes’ versus ‘sí-adherentes’ al IMM concomitante (85,7% vs. 25,5%). Conclusiones: En estos pacientes, la TDM de anti-TNFa es frecuentemente ‘pro-activa’. Existe gran variabilidad en las Cs de anti-TNFa, explicada en parte por el fármaco anti-TNFa y la adherencia al IMM. (AU)

Monitorización farmacocinética de niveles supraterapéuticos de adalimumab en paciente con enfermedad de Crohn / Pharmacokinetic monitoring of supratherapeutic adalimumab levels in patient with Crohn's disease

La monitorización farmacocinética de terapias biológicas dirigidas frente al factor de necrosis tumoral-a (TNF-a) ha sido recientemente introducida en nuestro centro hospitalario gracias a la iniciativa de nuestro equipo de enfermedad inflamatoria intestinal, formado por farmacéuticos, digestólogos y analistas clínicos, con la finalidad de optimizar la terapia en los pacientes que se mantienen en remisión clínica (monitorización "pro-activa"), o que presentan un fracaso terapéutico (monitorización "re-activa"). Se presenta un caso clínico de una paciente diagnosticada de enfermedad de Crohn y en tratamiento combinado con metotrexato y adalimumab. En septiembre de 2018, adalimumab fue intensificado de forma empírica a dosis de 40 mg administrados semanalmente por la aparición de manifestaciones extradigestivas (artralgias y parestesias en miembros inferiores). En febrero de 2019, la paciente se mantenía en remisión clínica con respecto a los síntomas intestinales, pero continuaba con las manifestaciones extradigestivas y refería aftas orales recurrentes. Por este motivo, se monitorizaron los niveles séricos de adalimumab, los cuales superaron ampliamente el intervalo terapéutico recomendado (5-12 mig/ml). En este sentido, se describe el seguimiento multidisciplinar del caso clínico y el ajuste posológico realizado en base a predicciones bayesianas, principios farmacocinéticos y farmacodinámicos y la clínica de la paciente. La monitorización farmacocinética de los niveles supraterapéuticos de adalimumab fue una herramienta útil para la optimización de dosis de adalimumab y la valoración objetiva de reacciones adversas en esta paciente. Este caso se ha notificado al Sistema Español de Farmacovigilancia

The pharmacokinetic monitoring of biological therapies against tumor necrosis-a (TNF-a) was recently introduced at our hospital thanks to the initiative of our inflammatory bowel disease team, composed of specialists in pharmacology, digestive system disease, and clinical analysis. The aim of the program was to optimize the therapy delivered to patients in clinical remission (pro-active monitoring) or clinical failure (reactive monitoring). We report the case of a patient diagnosed with Crohn's disease and under combined treatment with methotrexate and adalimumab. In September 2018, the dose of adalimumab was empirically increased to 40 mg/week due to the onset of extraintestinal manifestations (arthralgias and paraesthesias in lower limbs). In February 2019, the patient was in clinical remission with respect to the intestinal symptoms, but the extraintestinal manifestations persisted and the patient also reported anal aphthae. Consequently, serum adalimumab concentrations were monitored and found to widely exceed the recommended therapeutic interval (5-12 mig/ml). We report the multidisciplinary follow-up of the clinical case and the dosage adjustment based on Bayesian predictions, pharmacokinetic and pharmacodynamic principles, and the patient's clinical situation. Pharmacokinetic monitoring of supratherapeutic adalimumab levels proved to be a useful tool to achieve the optimal dosage of this drug and to objectively evaluate the patient's adverse reactions. The Spanish Pharmacosurveillance System has been notified of this case

Usefulness of biodegradable polydioxanone stents in the treatment of postsurgical colorectal strictures and fistulas.

Benign colonic strictures and fistulas are a growing problem presenting most commonly after bowel resection. Standard treatment is with endoscopic bougies or, more usually, balloon dilation. When these approaches are not successful, other solutions are available and different endoscopic and surgical approaches have been used to treat fistulas. We present an additional option--biodegradable stents--for the treatment of colonic strictures and fistulas that have proven refractory to other endoscopic interventions. We analyzed the results from 10 patients with either a postsurgical colorectal stricture (n =7) or rectocutaneous fistula (n =3) treated with the biodegradable SX-ELLA esophageal stent (covered or uncovered). Stents were successfully placed in nine patients, although early migration subsequently occurred in one. Placement was impossible in one patient due to deformity of the area and the fact that the stricture was approximately 30cm from the anus. The fistulas were successfully closed in all patients, although symptoms reappeared in one patient. In the six patients who received stents for strictures, symptoms resolved in five; in the remaining patient, the stent migrated shortly after the endoscopy. Treatment of colonic strictures and rectocutaneous fistulas with biodegradable stents is an effective alternative in the short-to-medium term. The stent does not have to be removed and is subject to very few complications. The drawbacks of this approach are the need to repeat the procedure in some patients and the lack of published series on efficacy.

Efficacy of pediatric colonoscopy used as push enteroscopy in the management of capsule endoscopy findings.

BACKGROUND: recent advances in endoscopy have enabled us to explore the small intestine more efficiently, both with capsule endoscopy and double-balloon enteroscopy. However, these methods are not available in all hospitals. Therefore, when capsule endoscopy reveals proximal jejunal lesions, a possible alternative for treatment could involve push enteroscopy combined with colonoscopy. Lesions can thus be marked for subsequent monitoring. OBJECTIVES: to describe the efficacy of pediatric colonoscopy for diagnosis, the marking of the area explored, and therapeutic options. MATERIAL AND METHODS: between October 2007 and September 2008 a total of 21 enteroscopies were performed using a pediatric colonoscope. Nine of these were used to take jejunal biopsy samples due to suspected disease of the mucosa. In 10 of the remaining 12, capsule endoscopy revealed lesions (vascular malformations or jejunal bleeding), and in 2 intestinal transit time was analyzed due to suspected jejunal stenosis. We used a PENTAX EC-3470-LK pediatric colonoscope, whose 11.6-mm sectional diameter and 3.8-mm working channel make it possible to administer all the usual endoscopic treatments. RESULTS: therapeutic endoscopy was performed on 7 men and 5 women (mean age 63.3 years). Jejunal lesions were observed in 10 cases (5 cases of angiodysplasia, 2 cases of jejunal stenosis, 1 case of nonmalignant thickened jejunal folds, 1 eroded submucosal tumor, and 1 case of duodenal and jejunal varices). The most distal area was marked with India ink (2), hemoclips (4), or both to help locate the lesions using simple abdominal radiography or capsule endoscopy. CONCLUSIONS: jejunal enteroscopy enabled a firm diagnosis to be made in most of the patients studied. We were able to treat 58% of patients and mark the areas explored for subsequent follow-up. With hemoclips we were able to locate the most distal point explored using simple abdominal radiography.

Eficacia del colonoscopio pediátrico como enteroscopio de pulsión en el manejo de los hallazgos de la cápsula endoscópica / Efficacy of pediatric colonoscopy used as push enteroscopy in the management of capsule endoscopy findings

Introducción: los recientes avances en endoscopia nos hanpermitido explorar de una forma más eficaz el intestino delgado,tanto con la cápsula endoscópica (CE) como con enteroscopia dedoble balón. El problema que aparece es la no disponibilidad deestos dos métodos en todos los hospitales. Por ello, cuando se venlesiones en la CE, una alternativa posible para el tratamiento delas lesiones de yeyuno proximal podría ser la realización de unaenteroscopia de pulsión con colonoscopio con fines terapéuticosy de marcaje para control de las lesiones.Objetivos: describir la eficacia del colonoscopio pediátrico encuanto al diagnóstico, señalización de zona explorada y posibilidadesterapéuticas.Material y métodos: durante el periodo comprendido entreoctubre de 2007 y septiembre de 2008, se han realizado 21 enteroscopiascon colonoscopio pediátrico, de las cuales 9 eran paratomar biopsias yeyunales por sospecha de patología mucosa. Delas otras 12, en 10 se vieron lesiones por la cápsula endoscópica(malformaciones vasculares o sangrado yeyunal) y en 2 se hizotránsito intestinal sospecha de estenosis yeyunal.Se utilizó un colonoscopio pediátrico PENTAX EC-3470-LKque presenta un diámetro de sección de 11,6 mm y un canal detrabajo de 3,8 mm, lo cual nos permite realizar cualquier tipo detratamiento endoscópico habitual.Resultados: se hizo enteroscopia con fines terapéuticos en7 hombres y 5 mujeres, con una edad media de 63,3 años. Sevieron lesiones endoscópicas en yeyuno en diez casos: 5 angiodisplasias,2 estenosis yeyunales, uno con pliegues engrosados yeyunalescon histología normal, un tumor submucoso erosionado yun caso de varices duodenales y yeyunales.En los últimos pacientes se hizo marcaje de la zona más distalexplorada con tinta china (2) o con hemoclips (4) o con ambos,para ayudar a localizar topográficamente las lesiones mediante radiologíasimple de abdomen o cápsula endoscópica...(AU)

Background: recent advances in endoscopy have enabled us toexplore the small intestine more efficiently, both with capsule endoscopyand double-balloon enteroscopy. However, these methodsare not available in all hospitals. Therefore, when capsule endoscopyreveals proximal jejunal lesions, a possible alternative for treatmentcould involve push enteroscopy combined with colonoscopy. Lesionscan thus be marked for subsequent monitoring.Objectives: to describe the efficacy of pediatric colonoscopyfor diagnosis, the marking of the area explored, and therapeuticoptions.Material and methods: between October 2007 and September2008 a total of 21 enteroscopies were performed using apediatric colonoscope. Nine of these were used to take jejunalbiopsy samples due to suspected disease of the mucosa. In 10 ofthe remaining 12, capsule endoscopy revealed lesions (vascularmalformations or jejunal bleeding), and in 2 intestinal transit timewas analyzed due to suspected jejunal stenosis. We used a PENTAXEC-3470-LK pediatric colonoscope, whose 11.6-mm sectionaldiameter and 3.8-mm working channel make it possible toadminister all the usual endoscopic treatments.Results: therapeutic endoscopy was performed on 7 men and5 women (mean age 63.3 years). Jejunal lesions were observed in10 cases (5 cases of angiodysplasia, 2 cases of jejunal stenosis, 1case of nonmalignant thickened jejunal folds, 1 eroded submucosaltumor, and 1 case of duodenal and jejunal varices). The mostdistal area was marked with India ink (2), hemoclips (4), or both tohelp locate the lesions using simple abdominal radiography orcapsule endoscopy.Conclusions: jejunal enteroscopy enabled a firm diagnosis tobe made in most of the patients studied. We were able to treat58% of patients and mark the areas explored for subsequent follow-up. With hemoclips we were able to locate the most distalpoint explored using simple abdominal radiography(AU)

Enfermedad de Castleman multicéntrica: hallazgos ecoendoscópicos / Multicentric Castleman disease: endoscopic ultrasonographic findings

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Esophagoenteral stents in patients with recurrent gastric adenocarcinoma.

One of the problems that can appear in patients with total gastrectomy for adenocarcinoma with esophagoenteral anastomosis is the appearance of a stenosis of the anastomosis. These stenosis are frequently malignant due to relapse of neoplasia. The therapeutic possibilities available are the surgical bypass or palliative treatment. There is very little experience described in the literature (21 cases) on the placing of self-expandable metal stents as a palliative treatment for the symptoms of stenosis.We present our experience of 3 patients, in whom 4 esophageal stents were fitted (1 covered and 3 uncovered) with good results. The dysphagia disappeared or improved, it allowed the ingestion of a soft diet and meant an improvement in the quality of life and at the same time stopped the weight loss. It seems an effective palliative treatment as a treatment for dysphagia in patients with tumoral relapse in the anastomosis of total gastrectomies.

Hepatitis inducida por infliximab en un paciente con enfermedad de Crohn / Infliximab-induced hepatitis in a patient with Crohn’s disease

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Prótesis esofagoenterales en pacientes con recidiva de adenocarcinoma gástrico / Esophagoenteral stents in patients with recurrent gastric adenocarcinoma

Uno de los problemas que puede aparecer en los pacientescon gastrectomía total por adenocarcinoma con anastomosis esofagoenterales la aparición de estenosis de la anastomosis o próximaa ella. Estas estenosis con frecuencia son malignas debido a laaparición de recidiva en la neoplasia. Las posibilidades terapéuticasde las que disponemos son el bypass quirúrgico o bien el tratamientopaliativo. Existe muy poca experiencia descrita en la literatura(21 casos) sobre la colocación de prótesis metálicasautoexpandibles como tratamiento paliativo de los síntomas de laestenosis.Presentamos nuestra experiencia en 3 pacientes, en los que secolocaron 4 prótesis esofágicas (1 recubierta y 3 no recubiertas)con buenos resultados. Desapareció o mejoró la disfagia, permitióla ingesta de dieta blanda y supuso una mejora en la calidad devida a la vez que impide la pérdida ponderal. Parece un tratamientopaliativo eficaz como tratamiento de la disfagia en pacientescon recidiva tumoral en la anastomosis de las gastrectomías totales

One of the problems that can appear in patients with total gastrectomyfor adenocarcinoma with esophagoenteral anastomosisis the appearance of a stenosis of the anastomosis. These stenosisare frequently malignant due to relapse of neoplasia. The therapeuticpossibilities available are the surgical bypass or palliativetreatment. There is very little experience described in the literature(21 cases) on the placing of self-expandable metal stents as a palliativetreatment for the symptoms of stenosis.We present our experience of 3 patients, in whom 4esophageal stents were fitted (1 covered and 3 uncovered) withgood results. The dysphagia disappeared or improved, it allowedthe ingestion of a soft diet and meant an improvement in the qualityof life and at the same time stopped the weight loss. It seemsan effective palliative treatment as a treatment for dysphagia inpatients with tumoral relapse in the anastomosis of total gastrectomies

Endoscopic resection of large colorectal polyps.

BACKGROUND: Endoscopic polypectomy is a common technique, but there are discrepancies over which treatment--surgical or endoscopic--to follow in case of polyps of 2 cm or larger. OBJECTIVES: To analyse the efficacy and complications of colonoscopic polypectomy of large colorectal polyps. PATIENTS AND METHODS: 147 polypectomies were performed on 142 patients over an eight-year period. The technique used was that of submucosal adrenaline 1:10000 or saline injection at the base of the polyp, followed by resection of the polyp using a diathermic snare in the smallest number of fragments. Remnant adenomatous tissue was fulgurated with an argon plasma coagulator. Lately, prophylactic hemoclips have been used for thick-pedicle polyps. Complete removal was defined as when a polyp was completely resected in one or more polypectomy sessions. Polypectomy failure was defined as when a polyp could not be completely resected or contained an invasive carcinoma. RESULTS: The mean patient age was 67.9 years (range, 4-90 years), with 68 men and 79 women. There were 74 sessile polyps, and the most common location was the sigmoid colon. The most frequent histology was tubulovillous. Most of the polyps (96.6%), were resected and cured. This was not achieved in four cases of invasive carcinoma, and a villous polyp of the cecum. All pedunculated polyps were resected in one session, whereas the average number of colonoscopies for sessile polyps was 1.35 +/- 0.6 (range, 1-4). The polypectomy was curative in all of the in situ carcinomata except one. As for complications, 2 colonic perforations (requiring surgery) and 8 hemorrhages appeared, which were controlled via endoscopy. There was no associated mortality. CONCLUSIONS: Endoscopic polypectomy of large polyps (> or =2 cm) is a safe, effective treatment, though it is not free from complications. Complete resection is achieved in a high percentage, and there are few relapses. It should be considered a technique of choice for this type of polyp, except in cases of invasive carcinoma.

Long-term outcome of patients with non-cardiac chest pain.

OBJECTIVE: To assess long-term outcome for patients with chest pain in our environment, to estimate direct resource use, and to evaluate the influence of patient views regarding pain origin on outcome. PATIENTS AND METHODS: All patients referred to our Department between 1994 and 1998 to undergo pH-metry as a result of chest pain were identified. Those detected were subjected to a structured direct interview on the telephone. RESULTS: 104 patients with a follow-up period (since pH-metry) of 3.76 years were evaluated. Thirty nine percent of patients were free from pain (37.5%), and one had died from a seemingly unrelated cause (1%), whereas the rest still suffered from pain. The mean number of visits per patient during the last year was 2.83 to their general practitioner, 1.04 to an specialist, and 0.99 to an Emergency Unit; hospitalisations were 0.26, and ICU admissions 0.09. Patients who trusted medical diagnoses showed better outcomes than those who did not trust or understand them, in association with lower resource use, particularly Emergency Unit use. CONCLUSION: Patients with chest pain had a favourable life prognosis, but 60% still suffer from pain after nearly 4 years of follow-up, which entails a relevant use of health-care resources. Trust in medical diagnosis seemingly influences outcome, and the use of diagnostic procedures to determine pain origin is thus likely beneficial for patient.

Los médicos y la justicia (IV) / The physicians and justice (IV)

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Evolución a largo plazo del dolor torácico no cardiaco / Long-term outcome of patients with non-cardiac chest pain

Objetivo: evaluar la evolución a largo plazo de los pacientes con dolor torácico en nuestro medio, estimar el consumo directo de recursos y evaluar la influencia de la opinión del paciente sobre el origen del dolor en la evolución. Pacientes y métodos: se identificó a todos los pacientes remitidos a nuestro Servicio para la realización de pHmetría por dolor torácico entre 1994 y 1998, realizándose una entrevista estructurada telefónica directa a los que se logró contactar. Resultados: se evaluaron 104 pacientes con un periodo de seguimiento (desde la realización de pHmetría) de 3,76 años. El 39 por ciento de los pacientes no presentaban dolor (37,5 por ciento) y 1 había fallecido de causa aparentemente no relacionada (1 por ciento), persistiendo el resto con dolor . El número medio por paciente de consultas realizadas a su médico de Atención Primaria en el último año fue de 2,83, al médico Especialista 1,04, al Servicio de Urgencia 0,99, ingresos hospitalarios 0,26 e ingresos en UCI 0,09. Los pacientes que confiaban en el diagnóstico del médico mostraba una evolución mejor comparado con los que no confiaban y los que no comprendían el diagnóstico, asociándose con un menor recursos de recursos, especialmente visitas a urgencia. Conclusión: los pacientes con dolor torácico presentan un buen pronóstico vital aunque el 60 por ciento continua presentando dolor después de casi 4 años de seguimiento, conllevando un importante consumo de recursos sanitarios. La confianza en el diagnóstico médico parece influir sobre la evolución por lo que perseguir con estudios diagnósticos el origen del dolor es probablemente beneficioso para el paciente (AU)