Cost-minimization analysis of biological disease-modifying antirheumatic drugs in the Brazilian public health system (SUS) considering patients' weight / Análise de custo-minimização de medicamentos modificadores de curso da doença biológicos no Sistema Único de Saúde (SUS) no Brasil considerando o peso dos pacientes

Objective: To perform a cost-minimization analysis comparing the cohort with the current average patient weight of 70 kg (MoH current assumption). Since most rheumatoid arthritis (RA) patients in Brazil are women (60 kg or less), we also aimed to define this percentage at Brazilian public healthcare system (SUS). Methods: Treatment-naïve RA patients using biologics from January 2008 to November 2018 were retrieved from Datasus as well as the number of patients ≤ 60 kg and their drug use distribution. Data on drug costs were assessed from the last payment reported by MoH and then recalculated using the weighted average of 60 kg and a 52-weeks a year to assess cost-minimization. Results: In the studied cohort, 33,646 patients (33.3%) were classified as ≤ 60 kg. Annual cost per patient, considering an average weight of 60 kg, ranged from 2,872,29 USD to 4,223.93 USD. Tocilizumab 80 mg was the only drug demonstrating a reduction in annual cost per patient (-526.79 USD). Conclusion: Cost-minimization analysis based on weight-dependent dosage showed that tocilizumab could reduce MoH costs with RA treatment in 14.28%. By adopting weight-dependent dose of 60 kg, the Brazilian government could save up to 916,651.31 USD per year using tocilizumab versus other biological disease-modifying antirheumatic drugs (DMARDs). In ten years, it represents an accumulative saving of 9,166,513.57 USD.

Objetivo: Realizar uma análise de custo-minimização comparando a coorte com o peso médio de pacientes de 70 kg (atual premissa do Ministério da Saúde ­ MS). Como a maioria dos pacientes são mulheres (≤ 60 kg), também se objetivou definir esse percentual no sistema público de saúde brasileiro (SUS). Métodos: Pacientes com artrite reumatoide (AR) virgens de tratamento utilizando biológicos de janeiro/2008 a novembro/2018 foram retirados do Datasus, assim como o número de pacientes com ≤ 60 kg e a distribuição de uso das drogas. Os custos dos medicamentos foram avaliados a partir do último pagamento relatado pelo MS e recalculados utilizando a média de 60 kg e um ano de 52 semanas para estimar a custo-minimização. Resultados: Na coorte estudada, 33.646 pacientes (33,3%) foram classificados com ≤ 60 kg. O custo anual por paciente, considerando o peso médio de 60 kg, variou de 2.872.29 a 4.223,93 USD. Tocilizumabe 80 mg foi o único que demonstrou redução no custo anual por paciente (-526,79 USD). Conclusão: A custo-minimização baseada em dose peso-dependente mostrou que o tocilizumabe poderia reduzir os custos do MS no tratamento de AR em 14,28%. Ao adotar o peso de 60 kg, o governo poderia economizar até 916.651,31 USD ao ano utilizando tocilizumabe vs. outros medicamentos modificadores do curso da doença biológicos (MMCDb). Em 10 anos, isso representa uma economia acumulada de 9.166.513,57 USD.

A novel pathway for inducible nitric-oxide synthase activation through inflammasomes.

Innate immune recognition of flagellin is shared by transmembrane TLR5 and cytosolic Nlrc4 (NOD-like receptor family CARD (caspase activation recruitment domain) domain containing 4)/Naip5 (neuronal apoptosis inhibitory protein 5). TLR5 activates inflammatory genes through MYD88 pathway, whereas Nlrc4 and Naip5 assemble multiprotein complexes called inflammasomes, culminating in caspase-1 activation, IL-1ß/IL-18 secretion, and pyroptosis. Although both TLR5 and Naip5/Nlrc4 pathways cooperate to clear infections, little is known about the relative anti-pathogen effector mechanisms operating through each of them. Here we show that the cytosolic flagellin (FLA-BSDot) was able to activate iNOS, an enzyme previously associated with TLR5 pathway. Using Nlrc4- or Naip5-deficient macrophages, we found that both receptors are involved in iNOS activation by FLA-BSDot. Moreover, distinct from extracellular flagellin (FLA-BS), iNOS activation by intracellular flagellin is completely abrogated in the absence of caspase-1. Interestingly, IL-1ß and IL-18 do not seem to be important for FLA-BSDot-mediated iNOS production. Together, our data defined an additional anti-pathogen effector mechanism operated through Naip5 and Nlrc4 inflammasomes and illustrated a novel signaling transduction pathway that activates iNOS.