Background and purpose: The p38 kinase regulates the release of proinflammatory cytokines including tumour-necrosis factor-a (TNFa) and is regarded as a potential therapeutic target in rheumatoid arthritis (RA). Using the novel p38 inhibitor Org 48762-0, we investigated the therapeutic potential of p38 inhibition and compared this to anti-mouse (m)TNFa antibody treatment in murine collagen-induced arthritis (CIA). Experimental approach: Pharmacological profiles of Org 48762-0 were characterized in kinase assays, cellular assays and in lipopolysaccharide (LPS)-induced inflammation in mice. The effects of Org 48762-0 and of mTNFa-neutralization on established arthritis were examined in murine CIA. Key results: Org 48762-0 potently inhibited p38a kinase with a high degree of kinase selectivity. In cellular assays, Org 48762-0 reduced LPS-induced TNFa release. Oral administration of Org 48762-0 in mice showed drug-like pharmacokinetic properties and inhibited LPS-induced cytokine production. These pharmacological characteristics of Org 48762-0 prompted a comparison of therapeutic efficacy with mTNFa-neutralization in CIA. Org 48762-0 and anti-mTNFa antibody treatment equally inhibited development of arthritis when evaluated macroscopically. Radiological analyses revealed protection against bone damage for both treatments, although statistical difference was reached with Org 48762-0 treatment only. Further, micro-computed tomographical and histopathological analyses confirmed the protective effects of Org 48762-0 on joint damage. Conclusions and implications: Pharmacological targeting of p38 kinase provided good protection against joint tissue damage in CIA. In our experiments, neutralization of mTNFa produced less prominent suppression of bone damage. Our data suggest a therapeutic potential for selective and potent p38 inhibitors in RA.
RESUMOApesar de terem revolucionado a prática reumatológica, o uso dos inibidores do fator de necrose tumoral (anti-TNFs) no tratamento da artrite reumatóide (AR) fez surgir um problema considerado solucionado em muitos países desenvolvidos: o risco elevado de reativação de infecção tuberculosa latente (ITBL). Desse modo, a identificação de casos de ITBL passou a ser obrigatória antes do início da terapêutica com anti-TNF. O teste cutâneo da tuberculina (PPD) não é um teste de screening ideal nesse grupo de pacientes em virtude de sua baixa especificidade, sua reação cruzada com antígenos vacinais e de outras micobactérias ambientais e, principalmente, por conta da incapacidade de o paciente com AR produzir uma resposta adequada ocasionada por uma anormalidade na responsividade das células T, característica da doença. Ensaios com base na detecção da produção de IFNγ in vitro por células mononucleares periféricas estimuladas por antíge-nos específicos (ESAT-6 e CFP-10), que não são encontrados na vacina BCG nem em outras micobactérias ambientais, parecem ser mais acurados que o PPD na detecção de ITBL em virtude de maior especificidade, melhor correlação com medidas indiretas de exposição ao Mycobacterium tuberculosis e menor reação cruzada com a vacinação por BCG e infecções por outras micobactérias.Palavras-chave: artrite reumatóide, tuberculose, anti-TNF. ABSTRACTDespite representing a major advance in rheumatology practice, the use of tumor necrosis factor blockade (anti-TNFs) in the treatment of rheumatoid arthritis (RA) has given rise to a problem that was considered solved in many developed countries, i.e. the heightened risk of reactivation of latent tuberculosis infection (LTBI). The identification of cases of LTBI has thus been made obligatory prior to starting any anti-TNF treatment. The cutaneous tuberculin test (PPD) is not the ideal screening test for this group of patients. Low specificity, cross-reactivity with vaccine antigens and other exogenous microorganisms coupled to a defect in the cell-mediated component of the immunological response account for the inadequacy of PPD as a screening tool in this subset of patients. Assays using the detection of in vitro IFNγ production by peripheral blood mononuclear cells stimulated by specific antigens (ESAT-6 and CFP-10), which are found neither in the BCG vaccine nor in other micro-organisms in the environment should perform better than the PPD, owing to a presumed higher specificity as well as to correlation with indirect measures of exposure to Mycobacterium tuberculosis besides decreased cross-reactivity determined by prior BCG vaccination and/or other infections.
Joaquim de Souza Cavalcanti was a pioneer among us - the Brazilian State of Pernambuco and North-Northeast region - in cardiac surgery in its initial phase (Blalock-Taussig surgery and mitral valvulotomy), in thoracic surgery (pneumectomy, lung lobectomy and segmentectomy, lung decortication, and mediastinal tumor resection), and in numerous techniques and operative tactics in general surgery.
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