Beneficial effect of temporary methotrexate interruption on B and T cell responses upon SARS-CoV-2 vaccination in patients with rheumatoid arthritis or psoriatic arthritis.

B and T cell responses were evaluated in patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA) after 1 or 2 weeks of methotrexate (MTX) withdrawal following each COVID-19 vaccine dose and compared with those who maintained MTX. Adult RA and PsA patients treated with MTX were recruited and randomly assigned to 3 groups: MTX-maintenance (n = 72), MTX-withdrawal for 1 week (n = 71) or MTX-withdrawal for 2 weeks (n = 73). Specific antibodies to several SARS-CoV-2 antigens and interferon (IFN)-γ and interleukin (IL)-21 responses were assessed. MTX withdrawal in patients without previous COVID-19 was associated with higher levels of anti-RBD IgG and neutralising antibodies, especially in the 2-week withdrawal group and with higher IFN-γ secretion upon stimulation with pools of SARS-CoV-2 S peptides. No increment of RA/PsA relapses was detected across groups. Our data indicate that two-week MTX interruption following COVID-19 vaccination in patients with RA or PsA improves humoral and cellular immune responses.

COVID-19 Vaccination and Immunosuppressive Therapy in Immune-Mediated Inflammatory Diseases.

The COVID-19 vaccination program has probably been the most complex and extensive project in history until now, which has been a challenge for all the people involved in the planning and management of this program. Patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressive therapy have required special attention, not only because of the particular haste in carrying out the process but also because of the uncertainty regarding their response to the vaccines. We now have strong scientific evidence that supports the hypothesis that immunosuppressive therapy inhibits the humoral response to vaccines against other infectious agents, such as influenza, pneumococcus and hepatitis B. This has led to the hypothesis that the same could happen with the COVID-19 vaccine. Several studies have therefore already been carried out in this area, suggesting that temporarily discontinuing the administration of methotrexate for 2 weeks post-vaccination could improve the vaccine response, and other studies with various immunosuppressive drugs are in the same line. However, the fact of withholding or interrupting immunosuppressive therapy when dealing with COVID-19 vaccination remains unclear. On this basis, our article tries to compile the information available on the effect of immunosuppressant agents on COVID-19 vaccine responses in patients with IMIDs and proposes an algorithm for the management of these patients.

Monitoring and safety of CAR-T therapy in clinical practice.

INTRODUCTION: In the last few years, a new T cell therapy, chimeric antigen receptor-T (CAR-T) cells, has been developed. CAR-T cells are highly effective at inhibiting antitumor activity, but they can cause a wide spectrum of unusual side effects. AREAS COVERED: The present review provides an overview of the adverse events of CAR-T cell therapy, focusing on cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, increased risk of infections, and other long-term complications. Representative studies addressing the safety and efficacy of CAR-T cell therapy are summarized. EXPERT OPINION: In the coming years, we predict a great expansion in the use of CAR-T cell therapy with it applied to a higher number of patients with both malignant neoplasms and immune-mediated diseases. Despite physicians and patient expectations about the potential of this therapy, there are still several barriers that may limit providers' ability to supply quality care. This exciting and powerful new therapy requires the formation of new multidisciplinary teams to carry out a safe treatment administration and to successfully manage the resultant complications. The follow-up of these therapies is important for two aspects: effectiveness in different populations and real-life safety in short and in long-term follow-up.

Efficacy and safety of biological drugs in interstitial lung disease associated with connective tissue diseases.

INTRODUCTION: Interstitial lung disease (ILD) is one of the most important manifestations of connective tissue diseases (CTD) due to its association with high morbidity and mortality. AREAS COVERED: Literature review focused on the evidence on efficacy and safety of biological therapy. EXPERT OPINION: Rituximab (RTX) is the most studied drug, though tocilizumab (TCZ) has methodologically more robust evidence, whereas abatacept (ABA) has only anecdotal reports. RTX studies suggest a clinically relevant effect on lung function and fibrosis in refractory to conventional treatment patients, with a good safety profile. Its multi-level efficacy in systemic sclerosis and the potentially more favorable response of anti-synthetase syndrome, especially when administered early in acute-onset or exacerbated ILD stand out over current standard of care, pending the availability of randomized controlled clinical trials. The significant and clinically meaningful benefit found in lung function and fibrosis with TCZ in faSScinate and focuSSced trials represents a change with respect to the usual practice, reinforcing the importance of treatment in early subclinical or clinical SSc-ILD patients with risk factors for ILD progression. This evidence has led to the inclusion of both RTX and TCZ in the expert-based therapeutic algorithms or recommendations for CTD-ILD management.

Evaluation of Natalizumab Pharmacokinetics and Pharmacodynamics: Toward Individualized Doses.

Background: Plasma concentration of natalizumab falls above the therapeutic threshold in many patients who, therefore, receive more natalizumab than necessary and have higher risk of progressive multifocal leukoencephalopathy. Objective: To assess in a single study the individual and treatment characteristics that influence the pharmacokinetics and pharmacodynamics of natalizumab in multiple sclerosis (MS) patients in the real-world practice. Methods: Prospective observational study to analyse the impact of body weight, height, body surface area, body mass index, gender, age, treatment duration, and dosage scheme on natalizumab concentrations and the occupancy of α4-integrin receptor (RO) by natalizumab. Results: Natalizumab concentrations ranged from 0.72 to 67 µg/ml, and RO from 26 to 100%. Body mass index inversely associated with natalizumab concentration (beta = -1.78; p ≤ 0.001), as it did body weight (beta = -0.34; p = 0.001), but not height, body surface area, age or gender Extended vs. standard dose scheme, but not treatment duration, was inversely associated with natalizumab concentration (beta = -7.92; p = 0.016). Similar to natalizumab concentration, body mass index (beta = -1.39; p = 0.001) and weight (beta = -0.31; p = 0.001) inversely impacted RO. Finally, there was a strong direct linear correlation between serum concentrations and RO until 9 µg/ml (rho = 0.71; p = 0.003). Nevertheless, most patients had higher concentrations of natalizumab resulting in the saturation of the integrin. Conclusions: Body mass index and dosing interval are the main variables found to influence the pharmacology of natalizumab. Plasma concentration of natalizumab and/or RO are wide variable among patients and should be routinely measured to personalize treatment and, therefore, avoid either over and underdosing.

Pharmacological Interactions of Nintedanib and Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis in Times of COVID-19 Pandemic.

The discovery of antifibrotic agents have resulted in advances in the therapeutic management of idiopathic pulmonary fibrosis (IPF). Currently, nintedanib and pirfenidone have become the basis of IPF therapy based on the results of large randomized clinical trials showing their safety and efficacy in reducing disease advancement. However, the goal of completely halting disease progress has not been reached yet. Administering nintedanib with add-on pirfenidone is supposed to enhance the therapeutic benefit by simultaneously acting on two different pathogenic pathways. All this becomes more important in the context of the ongoing global pandemic of coronavirus disease 2019 (COVID-19) because of the fibrotic consequences following SARS-CoV-2 infection in some patients. However, little information is available about their drug-drug interaction, which is important mainly in polymedicated patients. The aim of this review is to describe the current management of progressive fibrosing interstitial lung diseases (PF-ILDs) in general and of IPF in particular, focusing on the pharmacokinetic drug-drug interactions between these two drugs and their relationship with other medications in patients with IPF.

Inhibidores de la vía de señalización JAK-STAT en el tratamiento de las enfermedades inmunomediadas / JAK-STAT inhibitors for the treatment of immunomediated diseases

La ruta de señalización de las proteínas de la familia Janus cinasa (JAK) está implicada en la patogenia de muchas enfermedades inflamatorias y autoinmunitarias, como la artritis reumatoide (AR), la psoriasis y la enfermedad inflamatoria intestinal. Una gran cantidad de citocinas implicadas en el desarrollo de estas enfermedades utilizan esta vía de señalización para transducir señales intracelulares. En los últimos años, la aparición de los inhibidores de las proteínas JAK (jakinibs) ha demostrado que los fármacos relacionados con esta ruta patogénica pueden tener gran aplicabilidad clínica. Tofacitinib y baricitinib, primeros jakinibs aprobados para el tratamiento de la AR, están en estudio para el tratamiento de otras enfermedades autoinmunitarias. Asimismo, otros jakinibs se encuentran en diferentes fases de desarrollo. En este trabajo se revisan los principales aspectos en cuanto a eficacia, interacciones farmacológicas y seguridad tanto de los jakinibs clásicos como de los de nueva generación

The Janus kinase (JAK) pathway is implicated in the pathogenesis of many inflammatory and autoimmune diseases including rheumatoid arthritis (RA), psoriasis, and inflammatory bowel disease. There are a lot of proinflammatory cytokines involved in such diseases using this pathway to transduce intracellular signals. In the last years, JAK inhibitors (jakinibs) have appeared with a great success, showing that these kinds of drugs have a great applicability in clinical practice. Tofacitinib and baricitinib, the first jakinibs approved for the treatment of RA, are being investigated also for treating other autoimmune systemic diseases. Likewise, other jakinibs are in several phases of development. This review analyses the safety and clinical efficacy of the jakinibs, starting with the classics and continuing with next-generation jakinibs

JAK-STAT inhibitors for the treatment of immunomediated diseases. / Inhibidores de la vía de señalización JAK-STAT en el tratamiento de las enfermedades inmunomediadas.

The Janus kinase (JAK) pathway is implicated in the pathogenesis of many inflammatory and autoimmune diseases including rheumatoid arthritis (RA), psoriasis, and inflammatory bowel disease. There are a lot of proinflammatory cytokines involved in such diseases using this pathway to transduce intracellular signals. In the last years, JAK inhibitors (jakinibs) have appeared with a great success, showing that these kinds of drugs have a great applicability in clinical practice. Tofacitinib and baricitinib, the first jakinibs approved for the treatment of RA, are being investigated also for treating other autoimmune systemic diseases. Likewise, other jakinibs are in several phases of development. This review analyses the safety and clinical efficacy of the jakinibs, starting with the classics and continuing with next-generation jakinibs.

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

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.

Interacciones farmacológicas de los anticuerpos monoclonales / Pharmacological interactions of monoclonal antibodies

Las interacciones farmacológicas de los agentes biológicos no son bien conocidas. Debido a que los fármacos biológicos no son metabolizados por las enzimas del citocromo P450 (CYP450) ni interaccionan con los transportadores transmembrana, existe la percepción de que estos no presentan interacciones medicamentosas con los fármacos de síntesis química. Sin embargo, el aclaramiento de los agentes biológicos puede variar en función de la respuesta inmune o si se modifica la expresión de sus células diana, lo cual puede ocurrir por la acción de muchos agentes químicos. Además, algunos biológicos son capaces de modular la expresión de las enzimas del sistema CYP450. En esta revisión, se proporciona una descripción de las propiedades farmacocinéticas y posibles interacciones de los fármacos biológicos, centrándonos en los anticuerpos monoclonales, y como estos pueden interaccionar con las moléculas de síntesis química. Creemos que su conocimiento es importante para los clínicos y afecta a varias especialidades médicas

The pharmacological interactions of biological agents are not well known. Because biologic agents are not metabolised by cytochrome P450 (CYP) enzymes and do not interact with cell membrane transporters, it is generally perceived that they are free from interactions with small molecule drugs. However, the clearance of biological agents varies depending on the modulation of the immune response or by either increasing or reducing the expression of target cells of the biological agents, which can occur through the action of multiple synthetic chemical agents. Furthermore, some biological agents may modify the metabolism of chemical drugs through their effects on the expression of P450 system enzymes.. In this review, we will provide an outline of the pharmacokinetics properties and pharmacologic interactions of biological drugs, focusing on monoclonal antibodies, and how these can interact with chemical synthesis molecules. We believe knowledge of them is important for clinicians and affects multiple clinical specialties

Pharmacological interactions of monoclonal antibodies. / Interacciones farmacológicas de los anticuerpos monoclonales.

The pharmacological interactions of biological agents are not well known. Because biologic agents are not metabolised by cytochrome P450 (CYP) enzymes and do not interact with cell membrane transporters, it is generally perceived that they are free from interactions with small molecule drugs. However, the clearance of biological agents varies depending on the modulation of the immune response or by either increasing or reducing the expression of target cells of the biological agents, which can occur through the action of multiple synthetic chemical agents. Furthermore, some biological agents may modify the metabolism of chemical drugs through their effects on the expression of P450 system enzymes.. In this review, we will provide an outline of the pharmacokinetics properties and pharmacologic interactions of biological drugs, focusing on monoclonal antibodies, and how these can interact with chemical synthesis molecules. We believe knowledge of them is important for clinicians and affects multiple clinical specialties.

Fármacos biosimilares: un nuevo escenario en las terapias biológicas / Biosimilars: a new scenario in biologic therapies

No cabe duda de que los productos biológicos aportan un valor añadido a los sistemas de salud, aunque también plantean grandes interrogantes debido a su especial naturaleza, lo que obliga a ser muy rigurosos y exigentes en su control de calidad y seguimiento. Este hecho se ha visto reforzado por la entrada en escena de los fármacos biosimilares, cuyo menor coste está permitiéndoles alcanzar un mayor protagonismo en el mercado mundial. El propósito de este artículo es revisar en profundidad los principales interrogantes que se plantean en su producción, distribución y control, así como los aspectos más importantes relacionados con su seguridad en la práctica clínica. En este trabajo revisamos lo que representa la farmacovigilancia de estos productos, prestando especial atención a su trazabilidad, como herramienta fundamental para la detección precoz de acontecimientos adversos (AU)

There is no doubt that biologic therapies provide added value for health systems. However, due to their special nature, they also raise some questions that make highly rigorous and demanding quality control and monitoring of their use indispensable. This circumstance is reinforced with the appearance on the scene of biosimilars, which, given their lower cost, are having an increasing impact on the international market. The purpose of this article is to review the major issues posed by their manufacture, distribution and control systems, as well as the most important aspects related to their safety in clinical practice. In this report, we assess the pharmacovigilance of these products, with special attention to traceability, as a key tool to enable earlier detection of adverse events (AU)

Biosimilars: A new scenario in biologic therapies. / Fármacos biosimilares: un nuevo escenario en las terapias biológicas.

There is no doubt that biologic therapies provide added value for health systems. However, due to their special nature, they also raise some questions that make highly rigorous and demanding quality control and monitoring of their use indispensable. This circumstance is reinforced with the appearance on the scene of biosimilars, which, given their lower cost, are having an increasing impact on the international market. The purpose of this article is to review the major issues posed by their manufacture, distribution and control systems, as well as the most important aspects related to their safety in clinical practice. In this report, we assess the pharmacovigilance of these products, with special attention to traceability, as a key tool to enable earlier detection of adverse events.