Predictive role of ITPA genetic variants in thiopurine-related myelotoxicity in Crohn's disease patients.

Thiopurines, an effective therapy for Crohn's disease (CD), often lead to adverse events (AEs). Gene polymorphisms affecting thiopurine metabolism may predict AEs. This retrospective study in CD patients (n = 114) with TPMT activity > 5 Units/Red Blood Cells analyzed TPMT (c.238 G > C, c.460 G > A, c.719 A > G), ITPA (c.94 C > A, IVS2 + 21 A > C), and NUDT15 (c.415 C > T) polymorphisms. All patients received azathioprine (median dose 2.2 mg/kg) with 41.2% experiencing AEs, mainly myelotoxicity (28.1%). No NUDT15 polymorphisms were found, 7% had TPMT, and 31.6% had ITPA polymorphisms. AEs led to therapy modifications in 41.2% of patients. Multivariate analysis identified advanced age (OR 1.046, p = 0.007) and ITPA IVS2 + 21 A > C (OR 3.622, p = 0.015) as independent predictors of AEs. IVS2 + 21 A > C was also associated with myelotoxicity (OR 2.863, p = 0.021). These findings suggest that ITPA IVS2 + 21 A > C polymorphism and advanced age predict AEs during thiopurine therapy for CD with intermediate-normal TPMT activity.

Impact of Body Mass Index in the Cardioverter Efficacy of Amiodarone in Persistent Atrial Fibrillation.

BACKGROUND: Amiodarone is an anti-arrhythmic drug that has extensive tissue distribution and substantial storage in the fat tissue. Different studies have described some implications of body fat composition in its pharmacokinetics and pharmacodynamics. However, no clinical studies have described its implications for clinical efficacy. METHODS: We studied 878 patients with persistent atrial fibrillation (AF) treated with a regimen of amiodarone and referred to electrical cardioversion (ECV), included prospectively in two Spanish registries. We analyzed the influence of body mass index (BMI), as well as overweight and obesity, in the efficacy of amiodarone for achieving pharmacologic cardioversion to sinus rhythm (SR) before ECV. RESULTS: A total of 185 patients (21.1%) reverted to SR before ECV. Patients who reverted to SR had a lower BMI than those who did not revert (27.45 ± 4.36 kg/m2 vs. 29.11 ± 4.09 kg/m2; p < 0.001). We observed a progressively lower probability of reverting to SR in overweight and obese patients (normal weight 28.3%, overweight 21.3%, obesity 13.1%; p < 0.001). In the logistic regression, BMI (kg/m2) adjusted for other related variables remained as the main factor inversely related to reversion to SR (OR = 0.904 × kg/m2); CI 75% 0.864-0.946). CONCLUSIONS: We observed a negative relationship between an increased BMI and the efficacy of amiodarone for reversion to SR, suggesting a negative clinical impact of excess body fat in its efficacy.

Histopathological, Clinical, And Molecular (HICAM) score for patients with colorectal liver metastases.

BACKGROUND: Histopathological and molecular features have been proposed to hold prognostic information, but few have been validated. The aim of this retrospective study was to validate the Genetic And Morphological Evaluation ('GAME') score and assess the impact of histological characteristics on the prognosis in patients with colorectal liver metastases. METHODS: Data were collected from 176 patients with metastatic colorectal cancer undergoing liver resection at Hospital de la Santa Creu i Sant Pau. Patients were classified into Genetic And Morphological Evaluation score groups and relapse-free survival and overall survival were calculated. Histopathological changes in colorectal liver metastases were documented and prognostic variables were selected to create a post-surgery score, called the Histopathological, Clinical, And Molecular ('HICAM') score. RESULTS: Regarding the Genetic And Morphological Evaluation score, the high-risk group had a median relapse-free survival of 8.8 months, compared with 20.5 months for the low-risk group (P = 0.005), and the high-risk group had a median overall survival of 37.8 months, compared with 67.0 months for the low-risk group (P = 0.005). Histological examination of 144 liver samples showed that the desertic immune phenotype was associated with worse overall survival in the multivariable analysis (P = 0.020). The Histopathological, Clinical, And Molecular score variables were age at diagnosis, tumour burden score, carcinoembryonic antigen levels greater than or equal to 20 ng/ml, primary tumour resection, TNM stage at diagnosis, molecular status, histopathological growth patterns, and immune phenotypes of the liver. The high-risk group had a median relapse-free survival of 8.4 months, compared with 20.4 months for the low-risk group (P < 0.001), and a median overall survival of 30.4 months, compared with 105.0 months for the low-risk group (P < 0.001). CONCLUSION: The Genetic And Morphological Evaluation score was validated as a preoperative prognostic tool to predict candidacy for liver resection. The Histopathological, Clinical, And Molecular score could be useful to assess adjuvant treatment after hepatic resection.

Impact of IL6R genetic variants on treatment efficacy and toxicity response to sarilumab in rheumatoid arthritis.

BACKGROUND: Sarilumab, an IL-6 receptor antagonist, is a first-line biologic disease-modifying anti-rheumatic drug for rheumatoid arthritis. The identification of genetic biomarkers as predictors of response to sarilumab could allow for a personalized treatment strategy to improve clinical outcomes. METHODS: We conducted a retrospective cohort study of 62 patients treated with sarilumab to determine whether single-nucleotide polymorphisms (SNP) in the IL6R gene could predict efficacy and toxicity responses. Six SNPs previously described in the IL6R gene (rs12083537, rs11265618, rs4329505, rs2228145, rs4537545, and rs4845625) were genotyped in DNA samples obtained from these patients. Using parametric tests, we evaluated the association between these polymorphisms and clinicopathological features. Treatment response was assessed six months after treatment initiation. Satisfactory response was based on EULAR criteria. Low disease activity was determined according to DAS28 and CDAI and quantitative improvements in DAS28 and CDAI scores. RESULTS: Three SNPs (rs4845625, rs4329505 and rs11265618) were significantly associated with response outcomes. All of the SNPs, except for rs12083537, had at least one significant association with dyslipidemia or hepatotoxicity. CONCLUSIONS: These findings support the potential clinical value of SNPs, particularly rs4845625, as potentially useful biomarkers to predict response to sarilumab in patients with RA.

Allelic Frequency of DPYD Genetic Variants in Patients With Cancer in Spain: The PhotoDPYD Study.

INTRODUCTION: Identifying polymorphisms in the dihydropyrimidine dehydrogenase (DPYD) gene is gaining importance to be able to predict fluoropyrimidine-associated toxicity. The aim of this project was to describe the frequency of the DPYD variants DPYD*2A (rs3918290); c.1679T>G (rs55886062); c.2846A>T (rs67376798) and c.1129-5923C>G (rs75017182; HapB3) in the Spanish oncological patients. MATERIAL AND METHODS: Cross-sectional and multicentric study (PhotoDPYD study) conducted in hospitals located in Spain designed to register the frequency of the most relevant DPYD genetic variants in oncological patients. All oncological patients with DPYD genotype were recruited in the participant hospitals. The measures determined where the presence or not of the 4 DPYD previously described variants. RESULTS: Blood samples from 8054 patients with cancer from 40 different hospitals were used to determine the prevalence of the 4 variants located in the DPYD gene. The frequency of carriers of one defective DPYD variant was 4.9%. The most frequently identified variant was c.1129-5923C>G (rs75017182) (HapB3), in 2.9%, followed by c.2846A>T (rs67376798) in 1.4%, c.1905 + 1G>A (rs3918290, DPYD*2A) in 0.7% and c.1679T>G (rs55886062) in 0.2% of the patients. Only 7 patients (0.08%) were carrying the c.1129-5923C>G (rs75017182) (HapB3) variant, 3 (0.04%) the c.1905 + 1G>A (rs3918290, DPYD*2A) and one (0.01%) the DPYD c.2846A>T (rs67376798, p.D949V) variant in homozygosis. Moreover, 0.07% were compound heterozygous patients, 3 carrying the DPYD variants DPYD*2A + c.2846A>T, 2 the DPYD c.1129-5923C>G + c.2846A>T and one the DPYD*2A + c.1129-5923C>G variants. CONCLUSIONS: Our results demonstrate the relatively high frequency of DPYD genetic variants in the Spanish patient with cancer population, which highlights the relevance of their determination before initiating a fluoropirimidine-containing regimen.

An Integrated Multidisciplinary Circuit Led by Hospital and Community Pharmacists to Implement Clopidogrel Pharmacogenetics in Clinical Practice.

The use of pharmacogenetics to optimize pharmacotherapy is growing rapidly. This study evaluates the feasibility and operability of a collaborative circuit involving hospital and community pharmacists to implement clopidogrel pharmacogenetics in Barcelona, Catalonia, Spain. We aimed to enroll patients with a clopidogrel prescription from cardiologists at the collaborating hospital. Community pharmacists collected patients' pharmacotherapeutic profiles and saliva samples, which were then sent to the hospital for CYP2C19 genotyping. Hospital pharmacists collated the obtained data with patients' clinical records. Data were analyzed jointly with a cardiologist to assess the suitability of clopidogrel. The provincial pharmacists' association coordinated the project and provided IT and logistic support. The study began in January 2020. However, it was suspended in March 2020 due to the COVID-19 pandemic. At that moment, 120 patients had been assessed, 16 of whom met the inclusion criteria and were enrolled in the study. The processing of samples obtained before the pandemic had an average delay of 13.8 ± 5.4 days. A total of 37.5% patients were intermediate metabolizers and 18.8% were ultrarapid metabolizers. No poor metabolizers were detected. Pharmacists rated their experience with a 7.3 ± 2.7 likelihood of recommending that fellow pharmacists participate. The net promoter score among participating pharmacists was +10%. Our results show that the circuit is feasible and operable for further initiatives.

Developing a mHealth intervention to redesign the current journey for people living with HIV: A qualitative study.

OBJECTIVE: People living with human immunodeficiency virus could particularly benefit from mobile health (mHealth). The objective of the study was to  contribute to the design and development of a new standard of care for people  living with human immunodeficiency virus and the mHealth app needed to  support it by 1) exploring the view of people living with human  immunodeficiency virus and healthcare professionals on the possibilities of  mHealth tools on HIV care, and 2) implementing their feedback into the new  app and into the new journey of people living with human immunodeficiency  virus. METHOD: The study was conducted in two different phases: phase one was to  apprise patients' and healthcare professionals' perspectives on mHealth using  the qualitative methodology of the focus groups, whereas phase two aimed to  implement their feedback into the application. RESULTS: A total of five people living with human immunodeficiency virus and  nine healthcare professionals (three clinical pharmacists, three nurses, two  physicians, and one pharmacy technician) participated in the focus groups. The  patients identified the following main aspects to be improved in the  current patients' journey: insufficient information (n = 5), lack of general  population disease awareness (n = 5), and medication dispensation model (n =  3). Moreover, healthcare professionals identified the next health outcomes  to be enhanced with mHealth tools: patients' quality of life (n = 7), control of  the disease (n = 5) and comorbidities (n = 3), and adherence to medication (n = 5). According to these needs, the new healthcare model was designed. The  mHealth was provided with different features, such as information about the  disease, health promotion and prevention, the possibility of two-way patient- healthcare professionals communication, or synchronization with other devices. The new human immunodeficiency virus care journey and the app are currently being tested in a group of people living with human immunodeficiency virus in real-world conditions in our hospital. CONCLUSIONS: Improving patients' quality of life, therapeutic adherence, or  disease control are key objectives for optimizing people living with human  immunodeficiency virus care. Our digital health tool and the new healthcare  model have been implemented based on end-users' feedback to achieve better  patients-healthcare professionals communication and patient engagement with their care.

OBJETIVO: Las personas que viven con el virus de la inmunodeficiencia humana podrían beneficiarse de nuevas estrategias de salud móvil (mSalud). El  objetivo del estudio fue contribuir al diseño y desarrollo de un nuevo modelo  asistencial en la población con virus de la inmunodeficiencia humana y de la  aplicación móvil necesaria para apoyarlo mediante: 1) la exploración de la  visión de personas que viven con el virus de la inmunodeficiencia humana y  profesionales sanitarios sobre las herramientas digitales en la atención a este  colectivo, y 2) la implementación de sus perspectivas en la nueva aplicación y  en la nueva ruta asistencial.Método: El estudio se realizó en dos fases: la primera tenía como objetivo conocer las perspectivas de los participantes sobre la salud móvil mediante la metodología cualitativa de los grupos focales, y la segunda implementar estas valoraciones en la aplicación. RESULTADOS: Participaron cinco pacientes y nueve profesionales sanitarios (tres farmacéuticos clínicos, tres enfermeras, dos médicas y una  técnico de farmacia). Los pacientes consideraron que debían mejorarse los siguientes aspectos en su ruta asistencial: información insuficiente (n = 5),  falta de conocimiento de la enfermedad (n = 5) y modelo de dispensación de la medicación (n = 3). Los profesionales identificaron que debían mejorarse: la  calidad de vida de los pacientes (n = 7), el control de su enfermedad (n = 5) y de sus comorbilidades (n = 3), y la adherencia terapéutica (n = 5). De acuerdo con estas necesidades, se diseñó el nuevo modelo asistencial. Las siguientes  características se incorporaron a la mHealth: información sobre la enfermedad,  promoción y prevención de la salud, posibilidad de comunicación  bidireccional profesional-paciente o sincronización con otros dispositivos. La  nueva ruta asistencial y la aplicación están siendo estudiadas en un grupo de  personas que viven con el virus de la inmunodeficiencia humana en  condiciones de vida real y en seguimiento en nuestro hospital. CONCLUSIONES: La mejora de la calidad de vida, la adherencia terapéutica y el  control de la enfermedad son factores clave para la optimización de la atención de las personas que viven con el virus de la inmunodeficiencia humana.  Nuestra herramienta de salud digital y el modelo asistencial han sido diseñados en base a la opinión de pacientes para mejorar la comunicación profesional- paciente sanitario y conseguir un mayor compromiso de los pacientes con su  cuidado.

Desarrollo de una intervención mHealth para rediseñar la ruta asistencial de las personas que viven con VIH: Estudio cualitativo / Developing a mHealth intervention to redesign the current journey for people living with HIV: A qualitative study

Objetivo: Las personas que viven con el virus de la inmunodeficienciahumana podrían beneficiarse de nuevas estrategias de salud móvil (mSalud). El objetivo del estudio fue contribuir al diseño y desarrollo de unnuevo modelo asistencial en la población con virus de la inmunodeficiencia humana y de la aplicación móvil necesaria para apoyarlo mediante:1) la exploración de la visión de personas que viven con el virus de lainmunodeficiencia humana y profesionales sanitarios sobre las herramientas digitales en la atención a este colectivo, y 2) la implementación desus perspectivas en la nueva aplicación y en la nueva ruta asistencial.Método: El estudio se realizó en dos fases: la primera tenía como objetivo conocer las perspectivas de los participantes sobre la salud móvilmediante la metodología cualitativa de los grupos focales, y la segundaimplementar estas valoraciones en la aplicación.Resultados: Participaron cinco pacientes y nueve profesionales sanitarios (tres farmacéuticos clínicos, tres enfermeras, dos médicas y una técnico de farmacia). Los pacientes consideraron que debían mejorarse lossiguientes aspectos en su ruta asistencial: información insuficiente (n = 5), falta de conocimiento de la enfermedad (n = 5) y modelo de dispensación de la medicación (n = 3). Los profesionales identificaron que debíanmejorarse: la calidad de vida de los pacientes (n = 7), el control de suenfermedad (n = 5) y de sus comorbilidades (n = 3), y la adherencia terapéutica (n = 5). De acuerdo con estas necesidades, se diseñó el nuevomodelo asistencial. (AU)

Objective: People living with human immunodeficiency virus couldparticularly benefit from mobile health (mHealth). The objective of thestudy was to contribute to the design and development of a new standard of care for people living with human immunodeficiency virus andthe mHealth app needed to support it by 1) exploring the view of peopleliving with human immunodeficiency virus and healthcare professionals onthe possibilities of mHealth tools on HIV care, and 2) implementing theirfeedback into the new app and into the new journey of people living withhuman immunodeficiency virus.Method: The study was conducted in two different phases: phase onewas to apprise patients’ and healthcare professionals’ perspectives onmHealth using the qualitative methodology of the focus groups, whereasphase two aimed to implement their feedback into the application.Results: A total of five people living with human immunodeficiency virusand nine healthcare professionals (three clinical pharmacists, three nurses, two physicians, and one pharmacy technician) participated in thefocus groups. The patients identified the following main aspects to be improved in the current patients’ journey: insufficient information (n = 5),lack of general population disease awareness (n = 5), and medicationdispensation model (n = 3). Moreover, healthcare professionals identifiedthe next health outcomes to be enhanced with mHealth tools: patients’quality of life (n = 7), control of the disease (n = 5) and comorbidities(n = 3), and adherence to medication (n = 5). According to these needs,the new healthcare model was designed. (AU)

Efficacy and safety of high doses of irinotecan in patients with metastatic colorectal cancer treated with the FOLFIRI regimen based on the UGT1A1 genotype: A systematic review.

OBJECTIVE: The purpose of this systematic review is to analyze the published data on the efficacy and safety of doses higher than 180 mg/m2 of irinotecan recommended in the drug's summary of product characteristics in  metastatic colorectal cancer patients with genotypes UGT1A1*1/*1 or *1/*28  who are treated with the FOLFIRI regimen. METHOD: A systematic review of the literature was carried out in Medline and  Embase searching for articles published up to December 2021. The methods  used were based on the recommendations of the Preferred Reporting Items for  Systematic Reviews and Meta-Analyses (PRISMA) statement. The criteria  for the inclusion of studies were previously defined based on the two secondary goals addressed in this review: 1) To analyze the magnitude of the differences  in clinical responses and 2) To study the magnitude of the differences in  adverse effects of irinotecan at high doses, as compared to the doses  described in the summary of product characteristics corresponding to the  FOLFIRI regimen in patients with metastatic colorectal cancer with genotypes  UGT1A1*1/* 1 or *1/*28. RESULTS: The search yielded a total of 985 references, of which 13 were selected for analysis. Seven evaluated both efficacy and safety and six  only safety. With regard to the studies that evaluated both efficacy and safety,  six out of seven (85.7%) were in favor of increasing irinotecan dose according  to the objective response rate and progression-free survival. Two of them even  recommended dose increases based on overall survival. Irinotecan safety  studies suggest that doses higher than 180 mg/m2 are tolerated by  most UGT1A1*1/*1 and *1/*28 patients. CONCLUSIONS: The present systematic review shows the advisability of considering adjusting the dose of irinotecan when used as part of the FOLFIRI regimen based on the polymorphisms of the UGT1A1 gene as this may increase the likelihood of an adequate clinical response.

OBJETIVO: El objetivo de la presente revisión sistemática es analizar los datos  publicados sobre la eficacia y seguridad de las dosis superiores a los 180  mg/m2 de irinotecán recomendadas en la ficha técnica en pacientes con cáncer  colorrectal metastásico tratados con el esquema FOLFIRI y con  genotipo UGT1A1*1/*1 y *1/*28.Método: Se realizó una revisión sistemática mediante una búsqueda bibliográfica en Medline y Embase de los artículos publicados hasta diciembre de 2021. Los métodos utilizados se basaron en los  recomendados según Preferred Reporting Items for Systematic Reviews and  Meta-Analyses (PRISMA). Los criterios para la inclusión de los estudios se  definieron previamente en base a los dos objetivos secundarios que aborda  esta revisión: 1) Analizar la magnitud de la diferencia de la respuesta clínica y 2) estudiar la magnitud de la diferencia de los efectos  dversos a irinotecán a dosis altas, en comparación con las dosis descritas en la ficha técnica para el esquema FOLFIRI en pacientes con cáncer colorrectal metastásico con el genotipo UGT1A1*1/*1 o *1/*28. RESULTADOS: La estrategia de búsqueda reportó un total de 98 referencias, de  las que 13 fueron seleccionadas para el análisis, 7 (53,8%)  evaluando tanto  eficacia como seguridad y 6 (46,2%) únicamente seguridad. En relación con  los estudios que evaluaron eficacia y seguridad, 6 (85,7%) se mostraron  favorables al aumento de dosis en términos de tasa de respuesta objetiva y  supervivencia libre de progresión e, incluso, en 2 de ellos en supervivencia  global. Los estudios que evaluaron seguridad apuntan a que dosis de irinotecán  superiores a 180 mg/m2 son toleradas por la mayor parte de los  pacientes UGT1A1*1/*1 y *1/*28. CONCLUSIONES: La presente revisión sistemática muestra la conveniencia de  valorar el ajuste de dosis de irinotecán dentro del esquema FOLFIRI en función  de los polimorfismos del gen UGT1A1, con un potencial aumento de  las probabilidades de una adecuada respuesta clínica.

Drug-drug interactions in an intensive care unit and comparison of updates in two databases.

OBJECTIVE: Critically ill patients are at increased risk of drug-drug interactions  but their prevalence and clinical relevance remains unclear. The prevalence of  potential drug-drug interactions in an intensive care unit according to  Micromedex Drug-Reax® and Lexi-Interact® databases was studied and the  concordance between the two databases was assessed. In addition, drug-drug  interactions detected in 2013 were compared with those identified in 2018 to  determine updates between these years. METHOD: Between January and June 2013, 152 critical care patients were  prospectively included. Cardiac patients were excluded. Demographic and  clinical data together with the drugs administered on the first calendar day of  intensive care unit admission were recorded. Potential drug-drug interactions  were searched in both Drug-Reax® and Lexi-Interact ® and their prevalence,  level of severity and evidence were compared considering the same sample in  2013 and 2018. RESULTS: In 2013, 1,025 potential drug-drug interactions were identified, corresponding to 438 unique pairs. Lexi-Interact® identified more  interactions (92.8%) than Drug-Reax® (34.0%). The percentage of agreement between databases was 27.4%. The number of interactions  included in both databases increased after the five years but their level of  evidence   decreased. The most common potential drug-drug interactions involved sedatives and analgesics, intentionally prescribed concomitantly. Only two potential drug-drug interactions were classified as contraindicated by both  databases. None of the potential drug-drug interactions identified had a  noticeable clinical impact. Neither did they imply a prescription change. CONCLUSIONS: This study shows that the prevalence of potential drugdrug interactions in the intensive care unit is high, although their clinical relevance is generally low. Our data also show a lack of concordance between Drug-Reax® and Lexi-Interact®, as well as their  updates.

OBJETIVO: Los pacientes críticos presentan un mayor riesgo de interacciones farmacológicas, aunque su prevalencia y relevancia clínica siguen  sin estar claras. En el presente estudio se analizó la prevalencia de  interacciones farmacológicas potenciales en una unidad de cuidados intensivos  mediante las bases de datos Micromedex Drug-Reax® y Lexi-Interact® y se  evaluó la concordancia entre ambas bases de datos. También se compararon  las interacciones farmacológicas detectadas en 2013 con las identificadas en  2018 para evaluar las actualizaciones realizadas durante este periodo de  tiempo. Método: Entre enero y junio de 2013 se incluyeron de forma prospectiva 152  pacientes críticos. Los pacientes cardiacos fueron excluidos. Se registraron los  datos demográficos y clínicos junto con los fármacos administrados durante el  primer día de ingreso en la unidad de cuidados intensivos. Las interacciones se  buscaron tanto en Micromedex Drug-Reax® como en Lexi-Interact® y se  comparó su prevalencia, el nivel de severidad y la evidencia considerando la  misma muestra en 2013 y 2018. Resultados: En 2013 se identificaron 1.025 interacciones farmacológicas potenciales, correspondientes a 438 pares únicos. Lexi- Interact® identificó más interacciones (92,8%) que Drug-Reax® (34,0%). El  porcentaje de concordancia entre las dos bases de datos fue del 27,4%. El  número de interacciones incluidas en ambas bases de datos aumentó durante  los cinco años, pero su nivel de evidencia disminuyó. Las interacciones  farmacológicas potenciales más comunes incluyeron sedantes y analgésicos,  rescritos intencionadamente de forma concomitante. Sólo dos interacciones farmacológicas potenciales fueron clasificadas como contraindicadas por ambas  bases de datos. Ninguna de las interacciones identificadas tuvo un impacto clínico notable ni supuso un cambio de prescripción. CONCLUSIONES: ste estudio muestra que la prevalencia de interacciones farmacológicas potenciales en las unidades de cuidados intensivos es alta,  aunque su relevancia clínica es generalmente baja. Nuestros datos también  muestran la falta de concordancia entre Drug-Reax® y Lexi- Interact®, así  como sus actualizaciones.

Role of IL6R Genetic Variants in Predicting Response to Tocilizumab in Patients with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a prevalent autoimmune disease characterized by chronic arthritis that may lead to irreversible joint damage and significant disability. Patients with RA are commonly treated with Tocilizumab (TCZ), an IL-6 receptor (IL-6R) antagonist, but many patients refractorily respond to this therapy. Identifying genetic biomarkers as predictors of TCZ response could be a key to providing a personalized medicine strategy. We aimed to evaluate whether functional single nucleotide polymorphisms (SNPs) in the IL6R gene could predict TCZ response in patients with RA. We retrospectively included 88 RA patients treated with TCZ. Six SNPs previously described in the IL6R gene (rs12083537, rs11265618, rs4329505, rs2228145, rs4537545, and rs4845625) were genotyped in DNA samples from these patients. Using parametric tests, we evaluated the association between these polymorphisms and clinicopathological features. Responses to treatments were assessed at six months using three variables: a quantitative improvement in Disease activity score including 28 joints (DAS28), a satisfactory European League Against Rheumatism (EULAR) response, and low disease activity (LDA) achievement. The three response variables studied were associated with genetic variant rs4845625, and no association was found with the other five SNPs. Our findings support the potential clinical value of SNPs in the IL6R gene as predictive biomarkers for TCZ response.

Interacciones farmacológicas en una unidadde cuidados intensivos y comparación de lasactualizaciones de dos bases de datos / Drug-drug interactions in an intensive care unit and comparison of updates in two databases

Objetivo: Los pacientes críticos presentan un mayor riesgo de interacciones farmacológicas, aunque su prevalencia y relevancia clínica siguen sinestar claras. En el presente estudio se analizó la prevalencia de interaccionesfarmacológicas potenciales en una unidad de cuidados intensivos mediantelas bases de datos Micromedex Drug-Reax® y Lexi-Interact® y se evaluó laconcordancia entre ambas bases de datos. También se compararon las interacciones farmacológicas detectadas en 2013 con las identificadas en 2018para evaluar las actualizaciones realizadas durante este periodo de tiempo.Método: Entre enero y junio de 2013 se incluyeron de forma prospectiva 152 pacientes críticos. Los pacientes cardiacos fueron excluidos. Seregistraron los datos demográficos y clínicos junto con los fármacos administrados durante el primer día de ingreso en la unidad de cuidados intensivos. Las interacciones se buscaron tanto en Micromedex Drug-Reax®como en Lexi-Interact® y se comparó su prevalencia, el nivel de severidady la evidencia considerando la misma muestra en 2013 y 2018.Resultados: En 2013 se identificaron 1.025 interacciones farmacológicas potenciales, correspondientes a 438 pares únicos. Lexi-Interact® identificó más interacciones (92,8%) que Drug-Reax® (34,0%). El porcentajede concordancia entre las dos bases de datos fue del 27,4%. El número deinteracciones incluidas en ambas bases de datos aumentó durante los cinco años, pero su nivel de evidencia disminuyó. Las interacciones farmacológicas potenciales más comunes incluyeron sedantes y analgésicos, prescritos intencionadamente de forma concomitante. Sólo dos interaccionesfarmacológicas potenciales fueron clasificadas como contraindicadas porambas bases de datos. Ninguna de las interacciones identificadas tuvo unimpacto clínico notable ni supuso un cambio de prescripción. (AU)

Objective: Critically ill patients are at increased risk of drug-druginteractions but their prevalence and clinical relevance remains unclear.The prevalence of potential drug-drug interactions in an intensive careunit according to Micromedex Drug-Reax® and Lexi-Interact® databaseswas studied and the concordance between the two databases wasassessed. In addition, drug-drug interactions detected in 2013 werecompared with those identified in 2018 to determine updates betweenthese years.Method: Between January and June 2013, 152 critical care patientswere prospectively included. Cardiac patients were excluded. Demographic and clinical data together with the drugs administered on the firstcalendar day of intensive care unit admission were recorded. Potentialdrug-drug interactions were searched in both Drug-Reax® and Lexi-Interact® and their prevalence, level of severity and evidence were comparedconsidering the same sample in 2013 and 2018.Results: In 2013, 1,025 potential drug-drug interactions were identified,corresponding to 438 unique pairs. Lexi-Interact® identified more interactions (92.8%) than Drug-Reax® (34.0%). The percentage of agreementbetween databases was 27.4%. The number of interactions included inboth databases increased after the five years but their level of evidence decreased. The most common potential drug-drug interactions involvedsedatives and analgesics, intentionally prescribed concomitantly. Onlytwo potential drug-drug interactions were classified as contraindicated byboth databases. None of the potential drug-drug interactions identifiedhad a noticeable clinical impact. Neither did they imply a prescriptionchange. (AU)

Eficacia y seguridad de dosis altas de irinotecán en pacientes con cáncer colorrectal metastásico tratados con el esquema FOLFIRI en función delgenotipo de UGT1A1: Revisión sistemática / Efficacy and safety of high doses of irinotecan in patients with metastatic colorectal cancer treated with the FOLFIRI regimen based on the UGT1A1 genotype: A systematic review

Objetivo: El objetivo de la presente revisión sistemática es analizar losdatos publicados sobre la eficacia y seguridad de las dosis superioresa los 180 mg/m2 de irinotecán recomendadas en la ficha técnica enpacientes con cáncer colorrectal metastásico tratados con el esquemaFOLFIRI y con genotipo UGT1A1*1/*1 y *1/*28.Método: Se realizó una revisión sistemática mediante una búsquedabibliográfica en Medline y Embase de los artículos publicados hastadiciembre de 2021. Los métodos utilizados se basaron en los recomendados según Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA). Los criterios para la inclusión de los estudios se definieron previamente en base a los dos objetivos secundarios que abordaesta revisión: 1) Analizar la magnitud de la diferencia de la respuestaclínica y 2) estudiar la magnitud de la diferencia de los efectos adversosa irinotecán a dosis altas, en comparación con las dosis descritas en laficha técnica para el esquema FOLFIRI en pacientes con cáncer colorrectal metastásico con el genotipo UGT1A1*1/*1 o *1/*28.Resultados: La estrategia de búsqueda reportó un total de 98 referencias, de las que 13 fueron seleccionadas para el análisis, 7 (53,8%) evaluando tanto eficacia como seguridad y 6 (46,2%) únicamente seguridad. En relación con los estudios que evaluaron eficacia y seguridad,6 (85,7%) se mostraron favorables al aumento de dosis en términos detasa de respuesta objetiva y supervivencia libre de progresión e, incluso,en 2 de ellos en supervivencia global. Los estudios que evaluaron seguridad apuntan a que dosis de irinotecán superiores a 180 mg/m2 sontoleradas por la mayor parte de los pacientes UGT1A1*1/*1 y *1/*28. (AU)

Objective: The purpose of this systematic review is to analyze the published data on the efficacy and safety of doses higher than 180 mg/m2 ofirinotecan recommended in the drug’s summary of product characteristicsin metastatic colorectal cancer patients with genotypes UGT1A1*1/*1 or*1/*28 who are treated with the FOLFIRI regimen.Method: A systematic review of the literature was carried out in Medlineand Embase searching for articles published up to December 2021. Themethods used were based on the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.The criteria for the inclusion of studies were previously defined based on thetwo secondary goals addressed in this review: 1) To analyze the magnitudeof the differences in clinical responses and 2) To study the magnitude of thedifferences in adverse effects of irinotecan at high doses, as compared tothe doses described in the summary of product characteristics corresponding to the FOLFIRI regimen in patients with metastatic colorectal cancerwith genotypes UGT1A1*1/* 1 or *1/*28.Results: The search yielded a total of 985 references, of which 13 wereselected for analysis. Seven evaluated both efficacy and safety and six only safety. With regard to the studies that evaluated both efficacy andsafety, six out of seven (85.7%) were in favor of increasing irinotecan doseaccording to the objective response rate and progression-free survival.Two of them even recommended dose increases based on overall survival.Irinotecan safety studies suggest that doses higher than 180 mg/m2 aretolerated by most UGT1A1*1/*1 and *1/*28 patients. (AU)

A cohort study of guselkumab in the treatment of psoriasis refractory to previous biologic therapies: effectiveness, safety and adherence.

Background Guselkumab is indicated for moderate-to-severe plaque psoriasis. Data from real-life clinical practice regarding its use are scarce, especially concerning patients who relapse after previous biologic therapies. Aim This study aimed to evaluate the effectiveness, safety, and adherence to guselkumab in psoriasis refractory to biologic therapies. Method This real-life, retrospective study included patients who initiated guselkumab between February 2019 and October 2020. The main objective was to assess effectiveness, expressed as the psoriasis area and severity index (PASI) ≤5, ≤2 and 0, at the first follow-up medical visit. As secondary effectiveness outcomes, we assessed the body surface area (BSA) and dermatology life quality index (DLQI). We also evaluated adverse events and adherence (using the medication possession ratio [MPR]). Results The study included 35 patients who had previously received a median of two biologic drugs. The median basal PASI score (IQR) was 11 (7.3-15.9), decreasing to 0 (0-1.4) at first follow-up medical visit. At this point, 32 patients (94.1%) reached PASI ≤5, 28 (82.4%) PASI ≤2 and 19 (55.9%) PASI 0. We also found statistically significant improvements in PASI, BSA and DLQI at first follow-up (p<0.001). Three patients developed adverse events. Most patients (N=29, 85.3%) had an MPR ≥90%. The MPR was not associated with PASI score at first follow-up. Conclusion Our study supports evidence that guselkumab is an effective and safe drug in psoriasis refractory to biologic therapies. Adherence to treatment is not related to effectiveness, suggesting that, in some cases, the interval between doses could be increased.

Hernia enlargement and pancreatitis in a patient with short bowel syndrome treated with teduglutide.

INTRODUCTION: Introduction: teduglutide (TED) is indicated for the treatment of patients with short-bowel syndrome (SBS) who are dependent on parenteral support. Case report: we report the case of a 60-year-old woman with SBS treated with TED. She had previously undergone multiple surgical resections due to Crohn's disease. Her remnant bowel included only the duodenum and 50-60 centimeters of jejunum. The patient was dependent on intravenous fluids (2,320 mL/48 h) and had a high stoma output (3,000 mL/day). After four months of TED the jejunostomy output had decreased to 2,200 mL/day with a thicker consistency, and intravenous fluid therapy was reduced to 2,010 mL/48 h. TED was withdrawn due to acute pancreatitis and enlargement of two supraumbilical hernias with high strangulation risk. Discussion: pancreatitis has been reported in clinical studies, and determination of amylase and lipase is recommended in all patients receiving TED. In contrast, there are no recommendations for the surveillance of hernia enlargement in patients on TED therapy, but we suggest the need for surveillance based on this case report.

INTRODUCCIÓN: Introducción: la teduglutida (TED) está indicada para el tratamiento de pacientes con síndrome de intestino corto (SBS) que precisen soporte parenteral. Caso clínico: mujer de 60 años con SBS tratada con TED. Previamente se había sometido a múltiples resecciones quirúrgicas por su enfermedad de Crohn. Su intestino remanente incluía el duodeno y 50-60 centímetros de yeyuno. La paciente era dependiente de líquidos por vía intravenosa (2320 ml/48 h) y tenía una ostomía de alto débito (3000 ml/día). Después de cuatro meses de TED, el débito de la yeyunostomía disminuyó a 2200 ml/día, con una consistencia más espesa, y la fluidoterapia intravenosa se redujo a 2010 ml/48 h. Se retiró la TED por pancreatitis aguda y agrandamiento de dos hernias supraumbilicales con alto riesgo de estrangulamiento. Discusión: se han descrito casos de pancreatitis en estudios previos, por lo que se recomienda la determinación de la amilasa y la lipasa en los pacientes tratados con TED. Sin embargo, no hay recomendaciones específicas sobre la vigilancia del agrandamiento de hernias, pero sugerimos su idoneidad basada en este caso clínico.

Clinical Value of IL6R Gene Variants as Predictive Biomarkers for Toxicity to Tocilizumab in Patients with Rheumatoid Arthritis.

Tocilizumab is a first-line biologic disease-modifying anti-rheumatic drug (bDMARD) that inhibits the interleukin-6 (IL-6) pathway by antagonizing the IL-6 receptor (IL-6R). Tocilizumab is widely used to treat rheumatoid arthritis (RA), a prevalent autoimmune disease that can cause irreversible joint damage and disability. Although many bDMARDs have been developed for RA, there is a lack of validated biomarkers which could guide personalized medicine strategies. To evaluate whether single-nucleotide polymorphisms (SNPs) in the IL6R gene could predict tocilizumab toxicity in patients with RA, we conducted a retrospective cohort study of 88 patients treated with tocilizumab. Six SNPs previously described in the IL6R gene were genotyped (rs12083537, rs11265618, rs4329505, rs2228145, rs4537545, and rs4845625). Using parametric tests, we studied the association between the SNPs and hepatotoxicity, infection, hypersensitivity, gastrointestinal, hematological, and dyslipidemia adverse events (AEs). We found associations between dyslipidemia and rs4845625 and between hematological AEs and rs11265618 and rs4329505. No further associations were found for the remaining SNPs and other AEs. Our findings support the potential clinical value of SNPs in the IL6R gene as predictive biomarkers for toxicity to tocilizumab in patients with RA.

Elucidating the role of pharmacogenetics in irinotecan efficacy and adverse events in metastatic colorectal cancer patients.

INTRODUCTION: Irinotecan is a cytotoxic agent that is widely used in the treatment of several types of solid tumors. However, although it is generally well tolerated, approximately 20% to 35% of patients develop severe toxicity, particularly delayed-type diarrhea and neutropenia. As the incidence of such toxicities is often associated with the UGT1A1 *28/*28, *6/*28 and *6/*6 genotypes, individualized dosing could reduce these adverse events. Furthermore, prospective trials have shown that patients harboring the UGT1A1 *1/*1 and *1/*28 genotypes can tolerate higher doses of irinotecan, which may in turn impact on a better outcome. Upfront UGT1A1 genotyping could therefore be a usefulness strategy in order to individualize irinotecan dosing, but consensus on the recommended dose based on the UGT1A1 genotype is still lacking. AREAS COVERED: This review summarizes the results of the main pharmacogenetic studies focused on irinotecan. We provide an overview of current evidence and recommendations for individualized dosing of irinotecan in metastatic colorectal cancer patients. EXPERT OPINION: Implementation of UGT1A1*28 and UGT1A1*6 genotyping in clinical practice is a first step toward personalizing irinotecan therapy. This approach is likely to improve patient care and reduce healthcare costs. Future large and prospective studies will help to clarify the clinical value of other genetic markers in irinotecan treatment personalization.

Frequency and clinical relevance of DPYD genetic variants in gastrointestinal cancer patients.

OBJECTIVE: To determine the prevalence of loss-of-function variants in the dihydropyrimidine dehydrogenase gene in patients with gastrointestinal neoplasms, assess their clinical relevance, and evaluate the  implementation of a multidisciplinary circuit at three months from its  implementation. METHOD: This is a descriptive, observational and retrospective study, which  included adult patients with gastrointestinal cancer treated at a tertiary  university hospital who underwent dihydropyrimidine dehydrogenase genotyping between September 2019 and December 2020. The  variables collected were sex, age, type of cancer, location, stage, treatment received, indication of treatment and degree of toxicity  developed during the first three cycles. The genotyped variants were  rs3918290 (c.1905+1G>A), rs55886062 (c.1679T>G), rs67376798  (c.2846A>T) and rs75017182 (c.1129-5923C>G). RESULTS: A total of 115 patients were included. The frequency of heterozygous dihydropyrimidine dehydrogenase variant carriers was 9.6% (11  patients). The most frequently identified variant was rs75017182 (6 patients). The second most common variant was rs67376798 (3 patients),  followed by rs3918290 (2 patients). No patients presented with the  rs55886062 variant. Two of the dihydropyrimidine dehydrogenase carriers  developed  grade 3-5 toxicity after the first cycle of a regimen that included  fluoropyrimidines. Both received full doses of fluoropyrimidine, since their  dihydropyrimidine dehydrogenase genotype was unknown before treatment  initiation. None of the dihydropyrimidine dehydrogenase carriers who began treatment with a reduced dose of fluoropyrimidine experienced grade 3-5  toxicity. Since the creation in October 2020 of a multidisciplinary team, with  the active participation of hospital pharmacists, the monthly average of dihydropyrimidine dehydrogenase genotyping studies has increased from 6.4  (January-October) to 17.5 (November-December). CONCLUSIONS: The present study shows a relatively high prevalence of loss-of- function variants in the dihydropyrimidine dehydrogenase gene as well as the  importance of genotyping such variants before starting a treatment with  fluoropyrimidines. Hospital pharmacists can contribute to the implementation  of pharmacogenetics in daily clinical practice in a tertiary hospital.

OBJETIVO: Determinar la prevalencia de variantes de pérdida de función en el  gen de la dihidropirimidina deshidrogenasa (DPYD) en pacientes con tumores  digestivos, valorar su relevancia clínica y evaluar la implementación de un  circuito multidisciplinar tras tres meses de funcionamiento.Método: Estudio descriptivo, observacional y retrospectivo donde se incluyeron los pacientes adultos afectos de tumores digestivos, atendidos en  un hospital universitario de tercer nivel, a los que se había  afectuado el genotipado de DPYD entre septiembre de 2019 y diciembre de  2020. Las variables recogidas fueron sexo, edad, tipo de cáncer, localización,  estadio, tratamiento recibido, indicación del tratamiento y grado de toxicidad desarrollado durante los tres primeros ciclos. Se genotiparon las  variantes rs3918290 (c.1905+1G>A), rs55886062 (c.1679T>G), rs67376798 (c.2846A>T) y rs75017182 (c.1129-5923C>G). RESULTADOS: Se incluyeron 115 pacientes. La frecuencia de portadores en  heterocigosis de variantes del gen DPYD fue del 9,6% (11 pacientes). La  variante más frecuentemente identificada fue el rs75017182 (6 pacientes). La  segunda variante más frecuente fue el rs67376798 (3 pacientes), seguida del  rs3918290 (2 pacientes). Ningún paciente presentó la variante rs55886062.  Dos de los pacientes portadores desarrollaron toxicidad  grados 3-5 tras el  primer ciclo de un esquema que incluía fluoropirimidinas. Ambos recibieron  dosis plenas de fluoropirimidina, puesto que no se conocía el genotipo de DPYD antes de iniciar el tratamiento. Ninguno de los pacientes portadores que  tmpezó el tratamiento con una dosis reducida de fluoropirimidina experimentó  toxicidad grados 3-5. Desde la creación en octubre de 2020 de un equipo  multidisciplinar, con participación activa del farmacéutico hospitalario, se ha  incrementado el número de estudios de genotipado de DPYD de una media de  6,4 estudios mensuales (enero-octubre) a 17,5 (noviembre-diciembre). CONCLUSIONES: Nuestro estudio muestra la relativamente elevada prevalencia de variantes de pérdida de función en el gen DPYD, así como la  importancia de genotiparlas antes de empezar un esquema de tratamiento que  contenga fluoropirimidinas. El farmacéutico hospitalario puede contribuir a la implementación de la farmacogenética en la  práctica clínica diaria en un hospital de tercer nivel.

Frecuencia y relevancia clínica de las variantes del gen DPYD en pacientes con tumores digestivos / Frequency and clinical relevance of DPYD genetic variants in gastrointestinal cancer patients

Objetivo: Determinar la prevalencia de variantes de pérdida de funciónen el gen de la dihidropirimidina deshidrogenasa (DPYD) en pacientescon tumores digestivos, valorar su relevancia clínica y evaluar la implementación de un circuito multidisciplinar tras tres meses de funcionamiento.Método: Estudio descriptivo, observacional y retrospectivo donde seincluyeron los pacientes adultos afectos de tumores digestivos, atendidosen un hospital universitario de tercer nivel, a los que se había efectuado elgenotipado de DPYD entre septiembre de 2019 y diciembre de 2020. Lasvariables recogidas fueron sexo, edad, tipo de cáncer, localización, estadio, tratamiento recibido, indicación del tratamiento y grado de toxicidaddesarrollado durante los tres primeros ciclos. Se genotiparon las variantesrs3918290 (c.1905+1G>A), rs55886062 (c.1679T>G), rs67376798(c.2846A>T) y rs75017182 (c.1129-5923C>G).Resultados: Se incluyeron 115 pacientes. La frecuencia de portadoresen heterocigosis de variantes del gen DPYD fue del 9,6% (11 pacientes).La variante más frecuentemente identificada fue el rs75017182 (6 pacientes). La segunda variante más frecuente fue el rs67376798 (3 pacientes),seguida del rs3918290 (2 pacientes). Ningún paciente presentó la varianters55886062. (AU)

Objective: To determine the prevalence of loss-of-function variants in thedihydropyrimidine dehydrogenase gene in patients with gastrointestinalneoplasms, assess their clinical relevance, and evaluate the implementation of a multidisciplinary circuit at three months from its implementation.Method: This is a descriptive, observational and retrospective study,which included adult patients with gastrointestinal cancer treated at atertiary university hospital who underwent dihydropyrimidine dehydrogenase genotyping between September 2019 and December 2020.The variables collected were sex, age, type of cancer, location, stage,treatment received, indication of treatment and degree of toxicity developed during the first three cycles. The genotyped variants were rs3918290(c.1905+1G>A), rs55886062 (c.1679T>G), rs67376798 (c.2846A>T)and rs75017182 (c.1129-5923C>G).Results: A total of 115 patients were included. The frequency of heterozygous dihydropyrimidine dehydrogenase variant carriers was 9.6%(11 patients). The most frequently identified variant was rs75017182 (6 patients).The second most common variant was rs67376798 (3 patients), followedby rs3918290 (2 patients). No patients presented with the rs55886062variant. (AU)