Influence of safety warnings on the prescribing attitude of JAK 2inhibitors for rheumatoid arthritis in Italy

The Janus kinase inhibitors (JAKi) tofacitinib (TOFA), baricitinib (BARI), upadacitinib (UPA) and 74 filgotinib (FILGO) are effective drugs for the treatment of rheumatoid arthritis. However, the US 75 Food & Administration (FDA) raised concerns on the safety of TOFA after its approval. This 76 prompted the European Medicines Agency (EMA) to issue two safety warnings for limiting TOFA 77 use then extended in a third warning to all Jaki in patients at high risk of developing serious adverse 78 events (SAE). These included thrombosis, major adverse cardiac events (MACE) and cancer. Thepurpose of this work was to analyze how the first two safety warnings from EMA affected the pre- 80 scribing of Jaki by rheumatologists in Italy. All patients with rheumatoid arthritis who had been 81 prescribed JAKi for the first time in a 36-month period from July 1, 2019, to June 30, 2022 were con- 82 sidered. Data were obtained from the medical records of 29 Italian tertiary referral rheumatology 83 centers. Patients were divided into three groups of 4 months each, depending on whether the JAKi 84 prescription had occurred before the EMA's first safety alert (July 1-October 31, 2019, Group 1), 85 between the first and second alerts (November 1, 2019-February 29, 2020, Group 2), or between the 86 second and third alerts (March 1, 2021-June 30, 2021, Group 3). Percentage and absolute changes in 87 patients prescribed the individual JAKi were analyzed. Differences among the three Groups of pa- 88 tients in demographic and clinical characteristics were also assessed. A total of 864 patients were 89 prescribed a JAKi during the entire period considered. Of these, 343 were identified in Group 1, 233 90 in Group 2 and 288 in Group 3. An absolute reduction of 32% was observed in the number of patients 91 prescribed a JAKi between Group 1 and Group 2 and 16% between Group 1 and Group 3. In contrast, 92 there was a 19% increase in the prescription of a JAKi in patients between Group 2 and Group 3. In 93 the first Group, BARI was the most prescribed drug (227 prescriptions, 66.2% of the total), followed 94 by TOFA (115, 33.5%) and UPA (1, 0.3%). In the second Group, the most prescribed JAKi was BARI 95 (147, 63.1%), followed by TOFA (65, 27.9%) and UPA (33, 11.5%). In the third Group, BARI was still 96 the most prescribed JAKi (104 prescriptions, 36.1%), followed by UPA (89, 30.9%), FILGO (89, 21.5%) 97 and TOFA (33, 11.5%). The number of patients prescribed TOFA decreased significantly between 98 Group 1 and Group 2 and between Group 2 and Group 3 (p ˂ 0.01). Patients who were prescribed 99 BARI decreased significantly between Group 1 and Group 2 and between Group 2 and Group 3 (p 100 ˂ 0.01). In contrast, patients prescribed UPA increased between Group 2 and Group 3 (p ˂ 0.01). 101 These data suggest that the warnings issued for TOFA were followed by a reduction in total JAKi 102 prescriptions. However, the more selective JAKi (UPA and FILGO) were perceived by prescribers 103 as favorable in terms of risk/benefit ratio and their use gradually increased at the expense of the 104 other molecules

Composição morfológica da forragem consumida por bovinos de corte durante o rebaixamento do capim-marandu submetido a estratégias de pastejo rotativo Morphological composition of the herbage consumed by beef cattle during the grazing down process of marandu palisadegrass subjected to rotational strategies

O objetivo deste trabalho foi avaliar o efeito de estratégias de pastejo rotativo sobre a composição morfológica da forragem consumida por bovinos de corte em pastos de Brachiaria brizantha cv. Marandu. Os pastejos foram realizados sempre que o dossel atingia 95 ou 100% de intercepção luminosa (IL) até as alturas pós-pastejo de 10 e 15 cm. Foi avaliada a composição morfológica das extrusas coletadas de animais fistulados no esôfago em três etapas ao longo do rebaixamento dos pastos. À medida que o rebaixamento progrediu, a proporção de lâminas foliares na extrusa diminuiu e a de colmos e de material morto aumentou. Pastejos iniciados com 100% de IL ou realizados até a altura pós-pastejo de 10 cm resultaram em menor proporção de lâminas foliares e maior de colmos e de material morto. O tratamento 95/15 foi consistente entre os tratamentos que apresentaram as maiores proporções de lâminas foliares e menores de colmos e de material e, mesmo no final do rebaixamento, apresentou, ainda, mais de 50% de proporção de lâminas foliares na extrusa. Os resultados obtidos indicam que, durante o rebaixamento do dossel, pastejos mais freqüentes e menos severos proporcionam aos animais a obtenção de dietas com elevada proporção de lâminas foliares, o que deve aumentar o valor nutritivo da forragem consumida.<br>The objective of this work was to evaluate the effect of rotational grazing strategies on the morphological composition of the herbage consumed by beef cattle in Brachiaria brizantha cv. Marandu swards. Grazings were carried out when swards achieved 95 and 100% of light interception (LI) until postgrazing heights of 10 and 15 cm. Morphological composition of the herbage consumed was determined from extrusa samples harvested from oesophageal-fistulated animals in three occasions, during the grazing down process. As sward height decreased from the pre-grazing condition, the proportion of leaf laminae in the extrusa decreased, and that of stems and dead material increased. Grazing at 100% LI or at 10 cm postgrazing height resulted in lower proportion of leaf laminae and higher proportion of stems and dead material than grazing at 95% LI or 15 cm postgrazing height. The treatment 95/15 ranked consistently among those with the highest proportions of leaf laminae, lowest proportions of stems and dead material; and, at the end of the grazing session, it still had 50% of leaf laminae in the extrusa. In general, the results indicate that more frequent and less severe grazings favour animal to feed on forage with a high proportion of leaf laminae, which increases diet nutritive value

West Nile virus surveillance, Brazil, 2008-2010

Background West Nile virus (WNV) is an emergent pathogen that is widely distributed in North and Central America. The recent introduction in South America has focused attention on the spread of WNV across Southern American countries. The transmission network involves mosquitoes, birds, horses and humans. Methods The serological evaluation of sera from 678 equids and 478 birds was performed using a WNV-specific blocking ELISA, and only the positive results were confirmed by plaque reduction neutralisation tests (PRNTs). Molecular analysis was performed on sera from 992 healthy equids and on 63 macerates of brains from equids that died of encephalitis and had previously tested negative for other pathogens. We also tested swabs from 928 birds. The samples analysed were collected in different biomes of Brazil. Results We identified WNV antibodies by ELISA in thirteen equids and five birds, and PRNT90 confirmed WNV positivity in four equid samples collected in 2009 in an area between the Amazon and the Pantanal. None of the ELISA positive bird samples were confirmed by PRNT90, and all samples tested by RT-PCR were negative. Conclusion WNV circulation is confirmed by this large scale survey even in the absence of detection of clinical cases. (Résumé d'auteur

Analysis of survival rate and persistence predictors of baricitinib in real-world data from a large cohort of rheumatoid arthritis patients

Objectives: The persistence in therapy of rheumatoid arthritis drugs and particularly bDMARD is a limiting factor for their long-term use. The randomized controlled trials (RCTs) may not reflect real-world contexts due to strict inclusion and exclusion criteria. Baricitinib, which targets both JAK1 and JAK2, has been used in Italy for several years. The aim of this multi-center study is to assess the real world persistence on therapy of baricitinib in RA patients and to identify predictive factors of baricitinib's survival rate. Methods: This is a retrospective, multicentric, Italian, longitudinal study. All patients were enrolled according to the following criteria: a) age ≥ 18 years old; b) diagnosed with RA according 2010 ACR/EULAR classification criteria; c) treated with baricitinib. In order to describe baricitinib clinical efficacy, the survival rate was evaluated by The Kaplan–Meier curve. Then, predictive factors of drug retention rate were assessed by performing the Cox analysis, identifying which risk factors influenced treatment persistence. Results: Overall, we included 478 patients treated with baricitinib. Among them, 380 (79.5%) were females. Baricitinib's survival rate was 94.6% at 6 months, 87.9% at 12 months, 81.7% at 24 months and 53.4% at 48 months. The Cox analysis regression showed that a higher bDMARDs/tsDMARD line of therapy seems to be a negative prognostic factor for the drug retention rate (HR 1.26 CI 95% 1.07–1.49, p = 0.006. Conclusion: Real-life study confirms baricitinib effectiveness up to 4 years, but previous treatment with bDMARDs was a negative prognostic factor for its survival rate

Long-Term Retention Rate of Tofacitinib in Rheumatoid Arthritis: An Italian Multicenter Retrospective Cohort Study

Background: Tofacitinib (TOFA) was the first Janus kinase inhibitor (JAKi) to be approved for the treatment of rheumatoid arthritis (RA). However, data on the retention rate of TOFA therapy are still far from definitive. Objective: The goal of this study is to add new real-world data on the TOFA retention rate in a cohort of RA patients followed for a long period of time. Methods: A multicenter retrospective study of RA subjects treated with TOFA as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) was conducted in 23 Italian tertiary rheumatology centers. The study considered a treatment period of up to 48 months for all included patients. The TOFA retention rate was assessed with the Kaplan–Meier method. Hazard ratios (HRs) for TOFA discontinuation were obtained using Cox regression analysis. Results: We enrolled a total of 213 patients. Data analysis revealed that the TOFA retention rate was 86.5% (95% CI: 81.8–91.5%) at month 12, 78.8% (95% CI: 78.8–85.2%) at month 24, 63.8% (95% CI: 55.1–73.8%) at month 36, and 59.9% (95% CI: 55.1–73.8%) at month 48 after starting treatment. None of the factors analyzed, including the number of previous treatments received, disease activity or duration, presence of rheumatoid factor and/or anti-citrullinated protein antibody, and presence of comorbidities, were predictive of the TOFA retention rate. Safety data were comparable to those reported in the registration studies. Conclusions: TOFA demonstrated a long retention rate in RA in a real-world setting. This result, together with the safety data obtained, underscores that TOFA is a viable alternative for patients who have failed treatment with csDMARD and/or biologic DMARDs (bDMARDs). Further large, long-term observational studies are urgently needed to confirm these results