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.

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.

Persistence, effectiveness, and tolerability of anti-calcitonin gene-related peptide monoclonal antibodies in patients with chronic migraine.

OBJECTIVE: To evaluate, in patients with chronic migraine (CM) in real-world conditions, the persistence, effectiveness, and tolerability of erenumab, fremanezumab, and galcanezumab anti-calcitonin gene-related peptide (anti-CGRP) monoclonal antibodies (mAbs) and the persistence and effects of switching. BACKGROUND: Anti-CGRP mAbs represent a novel therapeutic approach to the management of CM; however, real-world data on persistence, effectiveness, and tolerability, especially after switching, are scarce. METHODS: This was a retrospective observational cohort study including all patients with CM treated with erenumab, fremanezumab, and/or galcanezumab in a tertiary hospital between January 2019 and December 2022. Treatment persistence was measured as the number of days between treatment start and end dates or the end of follow-up and also as a percentage of persistent patients at 3, 6, and 12 months; effectiveness as a ≥50% reduction in monthly migraine days (MMD); and tolerability as the number and type of adverse events. RESULTS: Included were 281 patients (383 treatments) with CM (91.5% [257/281] female) receiving anti-CGRP mAbs. Median (interquartile range [IQR]) treatment persistence was 267 (103-550) days. At 12 months, persistence was greater for the first (66.7%) compared to the second (49.8%) and third (37.2%) anti-CGRP mAb treatments (hazard ratio [HR] = 1.93, 95% confidence interval [CI]: 1.35-2.74; HR = 2.75, 95% CI: 1.69-4.47, respectively). Persistence minimum observed median (IQR) was also greater for the first (291 [112-594] days) compared to both the second (188 [90-403] days; p < 0.001) and third (167 [89-352] days; p < 0.001) anti-CGRP mAb treatments. For the first anti-CGRP mAb treatment, there were no differences in persistence among the different drugs. In terms of effectiveness of the first, second, and third anti-CGRP mAb treatments, a ≥50% reduction in MMD was achieved by 57.6% (117/203), 25.0% (11/44), and 11.8% (2/17) of patients, respectively, at 3 months, and by 55.8% (87/156), 29.6% (8/27), and 12.5% (1/8) of patients, respectively, at 6 months. At 12 months, no significant effectiveness differences were observed among anti-CGRP mAb treatments. As for tolerability, 55 adverse events were reported by 43 (15.3%) patients, mostly mild and leading to treatment discontinuation in only 14 (5.0%) patients. The most common adverse events were constipation, injection site reaction, and pruritus. Erenumab patients (3%, 3/99) experienced a higher rate of discontinuation for constipation. CONCLUSIONS: Our findings showed a 12-month higher treatment persistence with the use of a first anti-CGRP mAb treatment when the switch to a second treatment was due to ineffectiveness or severe side events. This persistence was lower after a second or third anti-CGRP. Additionally, in terms of effectiveness, the first anti-CGRP treatment achieved a higher response in terms of ≥50% reduction in MMD; however, some patients may benefit from a switching strategy. Finally, the tolerability profile for anti-CGRP mAbs was favorable. Further studies are needed to identify predictors of response after switching from the first anti-CGRP mAb treatment.

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.

Prognostic effect of VEGF gene variants in metastatic non-small-cell lung cancer patients.

INTRODUCTION: Clinical and pathological characteristics are still considered prognostic markers in metastatic non-small-cell lung cancer (NSCLC) patients but they cannot explain all interindividual variability. Tumoral angiogenesis mediated by the vascular endothelial growth factor (VEGF) is critical for the progression and metastasis of the disease. We aimed to investigate the prognostic role of genetic variants within the VEGF pathway in patients with metastatic NSCLC. MATERIALS AND METHODS: We prospectively included 170 patients with metastatic NSCLC treated with first-line platinum-based chemotherapy. A comprehensive panel of single-nucleotide polymorphisms (SNPs) in genes belonging to the VEGF pathway (VEGFA, VEGFR1/FLT1, VEGFR2/KDR, GRB2, ITGAV, KISS1, KRAS, PRKCE, HIF1α, MAP2K4, MAP2K6, and MAPK11) were genotyped in blood DNA samples. SNPs were evaluated for association with overall survival (OS) and progression-free survival (PFS). RESULTS: In multivariate analyses adjusted for patient characteristics, we found that VEGFA rs2010963 and VEGFR2 rs2071559 were significantly associated with OS [Hazard Ratio (HR) 0.7 (0.5-0.9); p = 0.026 and HR 1.5 (1.1-2.3); p = 0.025, respectively]. Additionally, ITGAV rs35251833 and MAPK11 rs2076139 were significantly associated with PFS [HR 2.5 (1.4-4.3; p = 0.002 and HR 0.6 (0.5-0.9); p = 0.013, respectively]. CONCLUSION: Our findings reinforce the potential clinical value of germline variants in VEGFA and VEGFR2 and show for the first time variants in ITGAV and MAPK11 as promising prognostic markers in metastatic NSCLC patients receiving platinum-based chemotherapy.

Pharmacogenetic clinical randomised phase II trial to evaluate the efficacy and safety of FOLFIRI with high-dose irinotecan (HD-FOLFIRI) in metastatic colorectal cancer patients according to their UGT1A 1 genotype.

BACKGROUND: Patients harbouring the UGT1A1*28/*28 genotype are at risk of severe toxicity with the standard irinotecan dose. However, this dose is considerably lower than the dose that can be tolerated by UGT1A1*1/*1 and *1/*28 patients. This randomised phase II trial evaluated the efficacy and safety of the FOLFIRI regimen with high-dose irinotecan (HD-FOLFIRI) in metastatic colorectal cancer patients. METHODS: Eighty-two patients with the UGT1A1*1/*1 or the *1/*28 genotype were randomised to receive HD-FOLFIRI versus FOLFIRI. Patients with the UGT1A1*28/*28 genotype were excluded. In the experimental group, the irinotecan dose was 300 mg/m2 for UGT1A1*1/*1 and 260 mg/m2 for *1/*28 patients. In the control group, the dose was 180 mg/m2. We analysed the overall response rate (ORR), toxicity, and survival. RESULTS: The ORR was significantly higher in the HD-FOLFIRI group (67.5 versus 43.6%; p = 0.001 OR: 1.73 [95% CI:1.03-2.93]). Neutropenia (17.7%), diarrhoea (5.1%), and asthenia (5.1%) were the most common grade 3-4 toxicity. No differences were observed in severe toxicity (22.5% versus 20.5%), dose reduction (22.5% versus 28.2%), or prophylactic G-CSF (17.5% versus 12.8%). No difference in survival was found. CONCLUSIONS: Patients with the UGT1A1*1/*1 and *1/*28 genotypes can receive high doses of irinotecan to achieve a more favourable ORR without significant adverse events.

Genetic variants in the VEGF pathway as prognostic factors in stages II and III colon cancer.

The role of vascular endothelial growth factor (VEGF) gene polymorphisms in the prognosis of colon cancer prognosis remains unclear. We evaluated the influence of 28 single-nucleotide polymorphisms in 12 genes in the VEGF pathway on the prognosis of 347 patients with stage II-III colon cancer. We found that rs9513070 (VEGFR1) and rs1137282 (KRAS) were associated with overall survival in stage II colon cancer patients (p = 0.025 and p = 0.001, respectively). When primary tumor location was considered, rs9513070 was also associated with relapse-free and overall survival (p = 0.033 and p = 0.031, respectively) in left colon cancer patients. Additionally, rs35251833 in the ITGAV gene correlated with relapse-free survival (p = 0.032). This study provides evidence that germline polymorphisms in VEGFR1, KRAS and ITGAV genes are associated with prognosis in stages II-III colon cancer patients. As stage and tumor location are correlated with prognosis, future genetic studies should stratify colon cancer patients according to these parameters.

Relevance of CYP3A4*20, UGT1A1*37 and UGT1A1*28 variants in irinotecan-induced severe toxicity.

Severe irinotecan-induced toxicity is associated with UGT1A1 polymorphisms. However, some patients develop side-effects despite harbouring a normal UGT1A1 genotype. As CYP3A4 is also an irinotecan-metabolizing enzyme, our study aimed to elucidate the influence of the CYP3A4*20 loss-of-function allele in the toxicity profile of these patients. Three-hundred and eight metastatic colorectal cancer patients treated with an irinotecan-containing chemotherapy were studied. The presence of CYP3A4*20, UGT1A1*37 and UGT1A1*28 alleles was tested. Associations between these genetic variants and toxicity were evaluated. UGT1A1*28 was significantly associated with severe diarrhoea, neutropenia and asthenia (P = 0.002, P = 0.037 and P = 0.041, respectively). One patient with the UGT1A1*28/*37 genotype presented with grade IV neutropenia and lethal septic shock. One heterozygous UGT1A1 (*1/*28) patient also carried the CYP3A4*20 allele but did not develop toxicity. We confirm that UGT1A1*37 and UGT1A1*28 are associated with severe toxicity and suggest that the CYP3A4*20 allele does not play a role in irinotecan-induced toxicity.

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.

Physicochemical Compatibility of Ceftolozane-Tazobactam with Parenteral Nutrition.

Ceftolozane-tazobactam (CT) is used for the treatment of complicated infections and for multidrug-resistant strains of Pseudomonas aeruginosa and extended-spectrum beta-lactamase-producing enterobacteria. In certain cases, simultaneous administration of CT and parenteral nutrition (PN) may be required, but compatibility of Y-site co-administration is unknown. The aim of this study was to analyse the physicochemical compatibility of CT Y-site administered with PN. We evaluated a protocolized PN approach for critical patients in our center. We studied both bolus infusion (2 g ceftolozane/1 g tazobactam in 1 h) and continuous infusion (CI) (6 g ceftolozane/3 g tazobactam) strategies. Samples were visually observed against light, microscopically inspected, and pH was analysed using a pH meter. The mean lipid droplet diameter (MDD) was determined via dynamic light scattering. CT concentration was quantified using HPLC-HRMS. No alterations were observed through visual or microscopic inspection. Changes in pH were ≤0.2, and changes in osmolarity were less than 5%. MDD remained below 500 nm (284.5 ± 2.1 for bolus CT and 286.8 ± 7.5 for CI CT). CT concentrations at t = 0 h and t = 24 h remained within prespecified parameters in both infusion strategies. CT is physiochemically compatible with PN during simulated Y-site administration at the tested concentration and infusion rates.

Designing an integrated care pathway for spondyloarthritis: A Lean Thinking approach.

INTRODUCTION: Integrated care pathways (ICPs) are crucial for delivering individualised care. However, the development of ICPs is challenging and must be well designed to provide the expected benefits. Regarding this, healthcare organisations are increasingly adopting management systems based on Lean Thinking to improve their organisational processes by eliminating non-value-added steps. This study elucidates the process and evaluates the impact of applying Lean Thinking to redesign an ICP for patients with spondyloarthritis, a chronic inflammatory disease affecting young adults. METHODS: A multidisciplinary team was assembled and trained in Lean Thinking. Patient's perspective was gathered through a focus group. Guided by an expert methodologist, the team constructed a value stream map of the entire care pathway and analysed each step. Five work streams were defined to increase value at each step, leading to targeted process improvements. Key process and outcome metrics were collected and compared in 2-month baseline and post-implementation audits. RESULTS: A total of 118 patients were included in the baseline audit (September-October 2022), and 116 in the post-implementation audit (January-February 2023). Process redesign resulted in statistically significant improvements (p < 0.05), including a reduction in the mean number of hospital visits per patient over a 2-month period from 2.54 (SD = 0.93) to 1.84 (SD = 0.79), an increase in complementary exams scheduled on the same day (81.4% to 94.8%) and an increase in baseline disease and treatment education (from 22.2% to 84.2% and from 18.2% to 84.6%, respectively). Regarding standardisation of clinical practice, there were significant increases in collecting data for medical records on composite activity indices (76.3% to 95.7%), reporting of pharmacological treatment adherence (68.6% to 94%) and providing nonpharmacological recommendations (31.3% to 95.7%). CONCLUSIONS: The application of Lean Thinking to redesign the spondyloarthritis ICP led to significant improvements in outpatient appointment scheduling, reduced patient hospital visits, improved interdepartmental coordination and standardised clinical practice.

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.

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.

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.

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.

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.

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.

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.