Tofacitinib Monotherapy in Rheumatoid Arthritis: Clinical Trials and Real-World Data Contextualization of Patients, Efficacy, and Treatment Retention.

Purpose: To evaluate the characteristics, efficacy, and retention of tofacitinib monotherapy in patients with rheumatoid arthritis using data from randomized controlled trials (RCTs) and real-world data (RWD). Patients and Methods: Three patient groups receiving tofacitinib 5 mg twice daily (BID) monotherapy were defined for post hoc RCT/long-term extension (LTE) analyses: (1) disease-modifying antirheumatic drug (DMARD)-inadequate responder patients from phase 3/3b/4 RCTs; (2) methotrexate-naïve patients from a phase 3 RCT; and (3) index study patients continuing in an LTE study. Outcomes included low disease activity (LDA)/remission rates defined by Clinical Disease Activity Index (CDAI); Disease Activity Score in 28 joints (DAS28-4), erythrocyte sedimentation rate; DAS28-4, C-reactive protein (DAS28-4[CRP]); and rates of/time to discontinuation due to lack of efficacy/adverse events. RWD were identified by non-systematic literature searches of PubMed, Embase, and American College of Rheumatology/European Alliance of Associations for Rheumatology congress abstracts (2012-2022). Results: RCT/LTE analyses included 1000/498 patients receiving tofacitinib 5 mg BID monotherapy. Baseline disease activity was high; patients tended to receive concomitant glucocorticoids; most were biologic DMARD-naïve. CDAI LDA rates were 32.2-62.2% for Groups 1/2 (months 3-12) and 64.0-70.7% for Group 3 (months 12-72). In Groups 1, 2, and 3, 4.0%, 15.6%, and 27.7% of patients, respectively, discontinued tofacitinib monotherapy due to lack of efficacy/adverse events. From 11 RWD publications, 16.6-66.1% received tofacitinib monotherapy. Consistent with clinical data, tofacitinib monotherapy effectiveness (month 6 CDAI LDA, 30.2%; month 3 DAS28-4[CRP] remission, 53.4%) and persistence were observed in RWD, with retention comparable to tofacitinib combination therapy. Conclusion: Tofacitinib monotherapy demonstrated clinically significant responses/persistence in RCT/LTE analyses, with effectiveness observed and persistence comparable to combination therapy in RWD. Trial Registration: NCT00814307, NCT02187055, NCT01039688, NCT00413699, NCT00661661 (ClinicalTrials.gov).

Contraceptive Recommendations for Women with Immune-Mediated Inflammatory Diseases: A Delphi Consensus.

INTRODUCTION: Immune-mediated inflammatory diseases (IMID) are a group of disorders characterized by chronic inflammation caused by an altered immune regulation in targeted organs or systems. IMID itself could have an implied increased risk of venous thromboembolism (VTE) and this risk varies throughout the course of the disease as well as with some contraceptive methods and treatments. The aim of this study was to present some key considerations in relation to contraception in women with IMID. METHODS: This was an exploratory study conducted in Spain following the online modified Delphi methodology with two rounds of participation. Four questionnaires were designed for each medical specialty: gastroenterology, rheumatology, dermatology, and gynecology. Each questionnaire was divided in three domains: general recommendations about IMID, specific recommendations, and contraceptive methods for patients with IMID. A 5-point Likert scale measured agreement with each statement, with an 80% agreement threshold. Following the first round, the percentage of each response was calculated for every item. Subsequently, a second round was conducted to reach a consensus on the items for which discrepancies were observed. RESULTS: A total of 52 and 50 experts participated in the first and second round, respectively. Participants agreed on the existence of a higher risk of VTE in inflammatory bowel diseases, psoriasis, and rheumatoid arthritis diseases. Regarding recommendations for contraceptive methods in patients with IMID, experts considered the hormonal intrauterine device (IUD) as a first-line contraceptive (80.0%) and low doses of progesterone-only pills if the latter is not recommended (88.0%). Most of the interviewees concurred on the importance of the patients' contraceptive needs during the disease course (98.1%). CONCLUSION: Raising awareness and promoting a multidisciplinary relationship among the physicians involved in the therapeutic decisions by considering all the risk factors when prescribing a contraceptive method is important to prevent VTE in women with IMID.

Real-World Health Care Outcomes and Costs Among Patients With Juvenile Idiopathic Arthritis in Spain.

Background: Juvenile idiopathic arthritis (JIA) is the most frequent chronic rheumatic disease in children. If inflammation is not adequately treated, joint damage, long-term disability, and active disease during adulthood can occur. Identifying and implementing early and adequate therapy are critical for improving clinical outcomes. The burden of JIA on affected children, their families, and the healthcare system in Spain has not been adequately assessed. The greatest contribution to direct costs is medication, but other expenses contribute to the consumption of resources, negatively impacting healthcare cost and the economic conditions of affected families. Objective: To assess the direct healthcare, indirect resource utilization, and associated cost of moderate-to-severe JIA in children in routine clinical practice in Spain. Methods: Children were enrolled in this 24-month observational, multicentric, cross-sectional, retrospective study (N = 107) if they had been treated with biologic disease-modifying anti-rheumatic drugs (bDMARDs), had participated in a previous study (ITACA), and continued to be followed up at pediatric rheumatology units at 3 tertiary Spanish hospitals. Direct costs included medication, specialist and primary care visits, hospitalizations, emergency visits or consultations, surgeries, physiotherapy, and tests. Indirect costs included hospital travel expenses and loss of caregiver working hours. Unitary costs were obtained from official sources (€, 2020). Results: Overall, children had inactive disease/low disease activity according to JADAS-71 score and very low functional disability as measured by Childhood Health Assessment Questionnaire score. Up to 94.4% of children received treatment, mainly with bDMARDs as monotherapy (84.5%). Among anti-TNFα treatments, adalimumab (47.4%) and etanercept (40.2%) were used in similar proportions. Annual mean (SD) total JIA cost was €7516.40 (€5627.30). Average cost of pharmacological treatment was €3021.80 (€3956.20), mainly due to biologic therapy €2789.00 (€3399.80). Direct annual cost (excluding treatments) was €3654.60 (€3899.00). Indirect JIA cost per family was €747.20 (€1452.80). Conclusion: JIA causes significant costs to the Spanish healthcare system and affected families. Public costs are partly due to the high cost of biologic treatments, which nevertheless remain an effective long-term treatment, maintaining inactive disease/low disease activity state; a very low functional disability score; and a good quality of life.

Effect of process variables on the physicochemical and rheological properties of yogurt / Efecto de las variables de proceso sobre las propiedades fisicoquímicas y reológicas de yogur

ABSTRACT In this research, the effect of the lactic starter culture, the fermentation time, the incubation temperature and the percentage of fat on the firmness and consistency of a fermented milk drink was evaluated through physicochemical characteristics of total acidity, pH, syneresis and flow behavior. The purpose was to find the best formulation that extends the shelf life of yogurt, leading to an improvement in the manufacturing process of a local dairy company in Barrancabermeja (Santander, Colombia). Quality criteria were evaluated by means of the percentage of acidity and pH of the yogurt, as well as its syneresis and rheological parameters during a storage time of 24 hours and 7 days in refrigeration. Acceptable quality parameters were obtained for the yogurt prepared with an inoculum concentration of 2%, an incubation temperature of 40°C and an incubation time of 150 minutes. In addition, better properties of firmness and consistency were found, with absence of syneresis and viscosity in the accepted range, for this dairy product.

RESUMEN En esta investigación, se evaluó el efecto del cultivo iniciador láctico, el tiempo de fermentación, la temperatura de incubación y el porcentaje de grasa en la firmeza y consistencia de una bebida de leche fermentada, a través de las características fisicoquímicas de acidez total, pH, sinéresis y comportamiento de flujo. El propósito fue encontrar la mejor formulación que extienda la vida útil del yogur, lo que lleva a un perfeccionamiento del proceso de fabricación de una empresa local de productos lácteos en Barrancabermeja (Santander, Colombia). Se evaluaron criterios de calidad por medio del porcentaje de acidez y pH del yogurt, así como su sinéresis y parámetros reológicos, durante un tiempo de almacenamiento de 24 horas y de 7 días en refrigeración. Se obtuvieron parámetros de calidad aceptables para el yogurt, preparado con una concentración del inóculo de 2%, una temperatura de incubación de 40°C y un tiempo de incubación de 150 minutos. Además, se encontraron mejores propiedades de firmeza y de consistencia, con ausencia de sinéresis y viscosidad en el rango aceptado, para este producto lácteo.

Update on the Safety Profile of Tofacitinib in Rheumatoid Arthritis from Clinical Trials to Real-World Studies: A Narrative Review.

Tofacitinib is approved for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who do not respond adequately or are intolerant to one or more disease-modifying anti-rheumatic drugs. The tofacitinib RA clinical development program included randomized controlled trials of 6-24-month duration and long-term extension studies with > 7061 patients and 22,875 patient-years of exposure. To date, there are no data from other randomized studies in patients with cardiovascular risk factors comparing the long-term safety of a JAK inhibitor versus an anti-TNF. Real-world studies are necessary to complete the body of evidence supporting the effectiveness and safety of a therapeutic agent. In the case of tofacitinib, real-world data derive from health insurance claims databases, registries (US Corrona Registry, Swiss Registry, and others), national pharmacovigilance programs, and hospital databases (case series). The present article provides complete and up-to-date information on the safety profile of tofacitinib in RA, from clinical trials to real-world studies. Tofacitinib has demonstrated a consistent safety profile during up to 9.5 years of experience in randomized controlled trials and long-term extension studies. Real-world evidence has not added new safety issues with respect to those found in the clinical program. In general, the safety profile of tofacitinib is consistent with that of biologic disease-modifying anti-rheumatic drugs, with an increased risk of herpes zoster that seems to be a class effect of Janus kinase inhibitors. The continuous follow-up of therapeutic agents to treat rheumatoid arthritis is needed to adequately establish the safety profile for new mechanisms of action and potential risks associated with their longer term use.

Gaps between research and recommendations in rheumatoid arthritis.

OBJECTIVES: To identify recommendations on the diagnosis and management of rheumatoid arthritis (RA) supported by low recommendation grades, to study the causes of this low grading, and to propose solutions. METHODS: A group of six rheumatologists, with extensive experience in the development of systematic reviews, reviewed national and international RA recommendations and practice guidelines. They identified all recommendations with a low level of evidence or recommendation grade (levels equivalent to 4, 5, or grades C or D of the Oxford Levels of Evidence), classified them by areas (diagnosis, follow-up, treatment, others), and analyzed plausible causes of low graduation. A Delphi was used to select 10 recommendations where it was most important to obtain quality evidence to support them. Subsequently, actions were proposed to improve evidence and recommendation grading. RESULTS: Fourteen documents were analyzed, in which 192 recommendations with low evidence/grade of recommendation were identified, most of which were on treatment. The two most frequent causes of this low level are the absence of studies and the discrepancy between the wording of the recommendation and the evidence used. Finally, the proposed solution to the critical recommendations is a list of unanswered research questions and possible designs to answer them. CONCLUSIONS: We propose to design and promote research that truly supports or rectifies clinical practice and, thus, bridges the gap between existing evidence and critical recommendations.

[Implementation of the strategy "Clean Care is Safer Care" in a third level hospital in Medellín, Colombia]. / Implementación de la estrategia "Atención Limpia es Atención Segura" en un hospital de tercer nivel en Medellín, Colombia.

INTRODUCTION: Hand hygiene is the most cost-effective and simple measure of preventing healthcare associated infections (HAI). The approach to improve low compliance must be through multimodal interventions such as the "Clean Care is Safer Care" strategy (WHO). AIM: To estimate the efficacy of a multimodal strategy in improving hand hygiene in five wards of a tertiary care hospital in Medellín, Colombia (2008-2010). METHODS: Quasi-experimental before-after study. RESULTS: Hand hygiene compliance significantly increased after the intervention (82 to 89%, p = 0.007). The knowledge score increased from a median of 26 (IQR=22-28) to 30 (IQR=26-32, p = 0.001). Alcohol-based hand rub consumption increased significantly from 10.5 liters to 58.1 liters per 1000 patient-days [incidence ratio (IR) = 2.39, 95% CI = 1.99; 2.88]. Monthly HAI rates showed no significant variations during the same period [IR = 0.90, 95% CI = 0.71; 1.13]. DISCUSSION: This and other recent studies demonstrate that implementing a multimodal strategy for hand hygiene significantly increases compliance with this measure, irrespective of type of health worker or hospital department. CONCLUSIONS: Implementing a multimodal strategy we achieved significant increases in hand hygiene compliance but mild or no significant variations in monthly HAI rates.

Implementación de la estrategia "Atención Limpia es Atención Segura" en un hospital de tercer nivel en Medellín, Colombia / Implementation of the strategy "Clean Care is Safer Care" in a third level hospital in Medellín, Colombia

Introduction: Hand hygiene is the most cost-effective and simple measure of preventing healthcare associated infections (HAI). The approach to improve low compliance must be through multimodal interventions such as the "Clean Care is Safer Care" strategy (WHO). Aim: To estimate the efficacy of a multimodal strategy in improving hand hygiene in five wards of a tertiary care hospital in Medellín, Colombia (2008-2010). Methods: Quasi-experimental before-after study. Results: Hand hygiene compliance significantly increased after the intervention (82 to 89%, p = 0.007). The knowledge score increased from a median of 26 (IQR=22-28) to 30 (IQR=26-32, p = 0.001). Alcohol-based hand rub consumption increased significantly from 10.5 liters to 58.1 liters per 1000 patient-days [incidence ratio (IR) = 2.39, 95% CI = 1.99; 2.88]. Monthly HAI rates showed no significant variations during the same period [IR = 0.90, 95% CI = 0.71; 1.13]. Discussion: This and other recent studies demonstrate that implementing a multimodal strategy for hand hygiene significantly increases compliance with this measure, irrespective of type of health worker or hospital department. Conclusions: Implementing a multimodal strategy we achieved significant increases in hand hygiene compliance but mild or no significant variations in monthly HAI rates.

Introducción: La higiene de manos es una medida costo-efectiva para prevenir las infecciones asociadas a la atención de salud (IAAS). Para mejorar el cumplimiento se recomienda implementar estrategias multimodales como "atención limpia es atención segura" de la OMS. Objetivo: Estimar el efecto de la estrategia multimodal en cinco unidades de un hospital de tercer nivel en Medellín, Colombia (2008-2010). Métodos: Estudio cuasi-experimental antes y después. Resultados: El cumplimiento general con la higiene de manos aumentó de forma significativa en el período posterior a la implementación (82 a 89%, p = 0,007). El puntaje de conocimientos aumentó entre los dos períodos de tiempo (Mediana = 26, RIC = 22-28 vs Mediana = 30, RIC = 26-32; p = 0,001). El consumo de alcohol aumentó de 10,5 litros a 58,1 litros por 1.000 pacientes/día [razón de incidencias (RI) = 2,39; 95% CI = 1,99; 2,88]. Las tasas mensuales de IAAS no mostraron variaciones [RI = 0,90; 95% CI = 0,71; 1,13]. Discusión: Este estudio demuestra que la implementación de una estrategia multimodal para la higiene de manos aumenta significativamente el cumplimiento con esta medida, independientemente del tipo de trabajador y el servicio hospitalario. Conclusión: Con la estrategia multimodal se aumentó significativamente el cumplimiento con la higiene de manos.