Estudio de la farmacocinética y la farmacodinámica de Natalizumab: hacia la individualización del tratamiento en pacientes con esclerosis múltiple

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina. Fecha de Lectura: 03-11-2022Natalizumab es un anticuerpo monoclonal (AcMo) muy eficaz en el tratamiento de la esclerosis múltiple remitente recurrente (EMRR), sin embargo, se ha relacionado con el desarrollo de leucoencefalopatía multifocal progresiva (LMP). Está aprobado a una dosis fija en base a los resultados de los estudios pivotales, en los que la concentración media del fármaco en el estado estacionario osciló entre 23 μg/ml y 29 μg/ml, aunque una concentración de entre 1-2 μg/ml es suficiente para lograr la saturación de la integrina α4β1 (su diana de acción). A este hecho hay que añadir que la mayoría de AcMo son dosificados de forma individualizada. Con estos antecedentes, nos propusimos analizar el impacto de diferentes parámetros que incluyen peso, altura, superficie corporal (SC), índice de masa corporal (IMC), edad, género, duración del tratamiento e intervalo de dosis sobre la farmacología de natalizumab, con la hipotesis de que la optimización de las dosis de natalizumab en función de las características individuales de los pacientes, puede garantizar la máxima efectividad del fármaco y reducir al mínimo la posibilidad de aparición de LMP. Para ello, realizamos un estudio prospectivo en el que reclutamos 32 pacientes con EMRR en tratamiento con natalizumab en nuestro hospital desde hacía al menos 7 meses. La farmacocinética se caracterizó midiendo las concentraciones de natalizumab en el suero de los pacientes mediante ensayo inmunoenzimático y la farmacodinamia se estudió midiendo la ocupación del receptor de integrina α4β1 (OR) por citometría de flujo. Las concentraciones detectadas en las muestras fueron muy dispares entre los pacientes (con un rango de entre 0.72 y 67 μg/ml). La mayoría de los pacientes tenían concentraciones de más de 5 μg/ml. El análisis de la OR también reveló gran variabilidad (con un rango de entre 44% a 100%). El peso y el IMC influenciaron de forma significativa tanto la OR como las concentraciones (estas últimas también dependían del esquema de dosis). Por último, se calculó la concentración de natalizumab a la cual la correlación con la OR era máxima, resultando ser de 9 μg/ml. En conclusión, el peso, el IMC y el esquema de tratamiento tienen un impacto significativo sobre la farmacología de natalizumab en cada paciente. Como consecuencia de ello, la mayoría de nuestros pacientes estaban sobretratados, y alguno podría estar infratratado debido a la tendencia clínica actual a utilizar el esquema de dosis extendida. Además, la OR depende en gran medida de la concentración hasta alcanzar 9 μg/ml, a partir de la cual se produce una saturación de los receptores en la mayoría de los pacientes. Nuestros hallazgos sientan las bases para recomendar vivamente la medida de la concentración de natalizumab en suero y de la OR, con el fin de personalizar su esquema de tratamiento y evitar así un uso ineficiente del mism

Anakinra for the treatment of adult-onset Still's disease

ABSTRACT: Introduction: Adult onset Still's disease (AOSD) is an uncommon systemic inflammatory disease on the clinical spectrum of autoinflammatory disorders. Its presentation and clinical course may result in several well-differentiated phenotypes: from a systemic and highly symptomatic pattern to a chronic articular pattern. Overproduction of numerous pro-inflammatory cytokines is observed in AOSD. Anakinra (ANK), a human interleukin (IL)-1R antagonist, has recently been approved in the EU for the treatment of AOSD. Areas covered: In this review, we discuss the main studies on the efficacy and safety on ANK for the treatment of AOSD. The vast majority of them are retrospective studies and case series. Expert commentary: Overall, ANK is an effective biologic agent for the treatment of AOSD, especially for the systemic pattern and also for those patients who have life-threatening complications, which frequently occur over the course of the disease. The initial dose usually indicated of ANK in adults is 100 mg/day subcutaneously, although dose reduction can be performed in some cases once the disease is under control. The safety profile of ANK is favorable and similar to that described in other rheumatic diseases. In conclusion, ANK is an effective and safe agent for the treatment of AOSD

Effect of excess weight and immune-related adverse events on the efficacy of cancer immunotherapy with anti-PD-1 antibodies

Immunotherapy is an effective treatment in advanced cancer, although predictors of response are limited. We studied whether excess weight influences the efficacy outcomes of immunotherapy. We have also evaluated the combined prognostic effect of excess weight and immune-related adverse events (irAEs). Efficacy of anti-PD-1 treatment was evaluated with both objective radiological response (ORR) rate and progression-free survival (PFS), and toxicity with irAEs. We studied the association between excess weight and ORR, PFS or irAEs. 132 patients diagnosed with advanced cancer were included. Median body mass index (BMI) was 24.9 kg/m2. 64 patients had normal weight (BMI<25 kg/m2), and 64 patients had excess weight (BMI≥25 kg/m2). Four patients had underweight and were excluded from further analysis. ORR was achieved in 50 patients (38.0%), median PFS was 6 months. 44 patients developed irAEs (33.3%). ORR was higher in excess weight patients than in patients with normal weight (51.6% vs 25.0%; OR 3.45, p = .0009). PFS was improved in patients with excess weight (7.25 months vs 4 months, HR 1.72, p = .01). The incidence of IrAEs was not different in patients with excess weight (54.5% vs 43.2%, p = .21). When high BMI and irAEs were combined, we observed a marked prognostic trend in ORR rate (87.5% vs 6.2%; OR 161.0, p < .00001), and in PFS (14 months vs 3 months; HR 5.89, p < .0001). Excess weight patients with advanced cancer that receive single-agent anti-PD-1 antibody therapy exhibit a significantly improved clinical outcome compared with normal BMI patients. This association was especially marked when BMI and irAEs were considered combined.This study was funded in part by the project Discovery, Validation and Implementation of Biomarkers for Precision Oncology [PIE15/00068], and the project FIS PI17/01865 from the Instituto de Salud Carlos III, Ministerio de Economia y Competitividad, awarded to RC, and the projects [JR 17/00007 and PI17/008], awarded to NRL

Effectiveness and Safety of the COVID-19 Vaccine in Patients with Rheumatoid Arthritis in a Real-World Setting

Novel mechanisms of COVID-19 vaccines raised concern about their potential immunogenicity in patients with rheumatoid arthritis (RA) undergoing immunomodulatory treatments. We designed a retrospective single-center study to investigate their effectiveness and safety in this population, analyzing data from the first vaccination program (December 2020–October 2021). Inclusion criteria were availability of post-vaccination serology and a minimum subsequent follow-up of 6 months. Binding antibody units (BAU/mL) ≥ 7.1 defined an adequate serological response. Post-vaccine COVID-19 incidence and its timing since vaccination, adverse events (AEs), and RA flares were recorded. Adjusted logistic and linear multivariate regression analyses were carried out to identify factors associated with vaccine response. We included 118 patients (87.2% women, age 65.4 ± 11.6 years, evolution 12.0 ± 9.6 years), of whom 95.8% had a complete vaccination schedule. Adequate humoral immunogenicity was achieved in 88.1% of patients and was associated with previous COVID-19 and mRNA vaccines, whereas smoking, aCCP, age, and DMARDs exerted a negative impact. Post-vaccine COVID-19 occurred in 18.6% of patients, a median of 6.5 months after vaccination. Vaccine AE (19.5%) and RA flares (1.7%) were mostly mild and inversely associated with age. Our results suggest that COVID-19 vaccines induce adequate humoral immunogenicity, with an acceptable safety profile in RA patients