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Advisor(s)
Abstract(s)
A artrite reumatoide (AR) é uma doença autoimune sistémica, que se caracteriza pela inflamação crónica do tecido sinovial, o que resulta na perda da integridade e função da articulação. Não existe ainda cura para a doença principalmente em consequência da sua fisiopatologia demasiado complexa e não totalmente compreendida. De uma forma geral, a inflamação a nível sinovial envolve células apresentadoras de antigénio, macrófagos, fibroblastos, e células B e T, que, em conjunto com mediadores inflamatórios e complexos imunes, provocam a destruição das articulações através da erosão das cartilagens e dos ossos. Tal mecanismo resulta com consequente dor, inchaço e perda de função física das articulações. A AR caracteriza-se ainda pela presença de auto-anticorpos, fator reumatoide (FR) e anticorpo anti-péptido cirtrulinado (ACPA), tanto dentro como fora das articulações, sendo estes importantes marcadores do diagnóstico. Esta doença é fortemente influenciada por fatores ambientais e genéticos, existindo uma sequência de aminoácidos comum partilhada pelos alelos do locus do DRB1 do complexo leucocitário humano (HLA-DRB1), que confere suscetibilidade à doença. O ideal seria iniciar o tratamento quando ainda é possível evitar a destruição da articulação, no entanto é difícil realizar ensais clínicos para tratamento para da AR, quando faltam critérios uniformes e válidos para identificar indivíduos com doença precoce. O diagnóstico feito nos dias de hoje tem por base a avaliação articular, testes serológicos, pesquisa de agentes de fase aguda e duração dos sintomas que são avaliados, por meio de scores, permitindo posteriormente que os médicos encontrem o tratamento mais adequado para o doente. A presente monografia foca-se nos tratamentos disponíveis para a AR, cujo principal objetivo é atingir a remissão da doença, evento que ainda não é possível atingir pela maior parte dos doentes, especialmente a longo prazo. A era dos fármacos biológicos veio revolucionar o tratamento da AR, surgindo fármacos direcionados para diferentes alvos moleculares envolvidos no processo inflamatório, que vieram mudar notavelmente o prognóstico dos doentes. Entre eles, os inibidores do TNF, a classe com mais fármacos atualmente disponíveis, um inibidor da IL-1, inibidores do recetor IL-6, e agentes direcionados contra linfócitos B e T. Para além de mostrarem diferenças ao nível do mecanismo de ação, os vários biológicos apresentam esquemas e doses terapêuticas muito distintas, sendo possível adaptar a terapêutica ao doente em específico. Em geral, as principais reações adversas a estes medicamentos prendem-se com infeções graves e reações no local da administração. As primeiras podem ser amenizadas com a vacinação influenza, pneumococos e herpes zoster, sempre que seja possível. Finalmente, foi feita uma abordagem sobre os fármacos biossimilares, terapêuticas alternativas e novos potencias alvos terapêuticos que se encontram em fases de estudo.
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the synovial tissue, resulting in loss of joint integrity and function. There is still no cure for the disease, mainly as a result of its complexity and unclear pathophysiology. Inflammation at the synovial level generally involves antigen presenting cells, macrophages, fibroblasts, and B and T cells, which, together with inflammatory mediators and immune complexes, cause joint destruction through the erosion of the cartilage and bone. Such mechanism results in joint swelling, pain and loss of its physical function. RA is also characterized by the presence of rheumatoid factor (RF) and anti-citrullinated peptide antibody (ACPA) autoantibodies, both inside and outside the joints, which are important diagnostic markers. This disease is strongly influenced by environmental and genetic factors, existing a common amino acid sequence shared by alleles of the DRB1 locus of the human leucocyte complex (HLA-DRB1) that confers susceptibility to the disease. Ideally, the treatment should be initiated when joint destruction can still be avoided, however it is difficult to conduct clinical trials for the treatment of RA since uniform and valid criteria for identifying individuals with early disease are lacking. Nowadays, the diagnosis is based on joint evaluation, serological tests, research of acute phase agents and duration of the symptoms, which are evaluated by means of scores, allowing doctors to find the most appropriate treatment for the patient. The present monograph focuses on the available treatments for RA, which main goal is to achieve disease remission, an event that is not yet possible for most patients, especially in the long term. The era of biologic drugs has revolutionized the treatment of RA and being that the emerging drugs are directed to different molecular targets involved in the inflammation process, they have markedly changed the prognosis of patients. These drugs include TNF inhibitors, the class that includes the most drugs currently available, an IL-1 inhibitor, IL-6 receptor inhibitors, and agents targeting B and T lymphocytes. Besides the differences in the mechanism of action, the multiple biologicals have very different therapeutic strategies and doses, being, therefore, possible to adapt the therapy to a specific patient. In general, the main adverse reactions to these medicines are severe infections and reactions at the administration site. The former can be mitigated with influenza, pneumococcal and herpes zoster vaccination, whenever possible. Finally, an approach was taken on biosimilar drugs, alternative therapies and new potential therapeutic targets that are still under study.
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the synovial tissue, resulting in loss of joint integrity and function. There is still no cure for the disease, mainly as a result of its complexity and unclear pathophysiology. Inflammation at the synovial level generally involves antigen presenting cells, macrophages, fibroblasts, and B and T cells, which, together with inflammatory mediators and immune complexes, cause joint destruction through the erosion of the cartilage and bone. Such mechanism results in joint swelling, pain and loss of its physical function. RA is also characterized by the presence of rheumatoid factor (RF) and anti-citrullinated peptide antibody (ACPA) autoantibodies, both inside and outside the joints, which are important diagnostic markers. This disease is strongly influenced by environmental and genetic factors, existing a common amino acid sequence shared by alleles of the DRB1 locus of the human leucocyte complex (HLA-DRB1) that confers susceptibility to the disease. Ideally, the treatment should be initiated when joint destruction can still be avoided, however it is difficult to conduct clinical trials for the treatment of RA since uniform and valid criteria for identifying individuals with early disease are lacking. Nowadays, the diagnosis is based on joint evaluation, serological tests, research of acute phase agents and duration of the symptoms, which are evaluated by means of scores, allowing doctors to find the most appropriate treatment for the patient. The present monograph focuses on the available treatments for RA, which main goal is to achieve disease remission, an event that is not yet possible for most patients, especially in the long term. The era of biologic drugs has revolutionized the treatment of RA and being that the emerging drugs are directed to different molecular targets involved in the inflammation process, they have markedly changed the prognosis of patients. These drugs include TNF inhibitors, the class that includes the most drugs currently available, an IL-1 inhibitor, IL-6 receptor inhibitors, and agents targeting B and T lymphocytes. Besides the differences in the mechanism of action, the multiple biologicals have very different therapeutic strategies and doses, being, therefore, possible to adapt the therapy to a specific patient. In general, the main adverse reactions to these medicines are severe infections and reactions at the administration site. The former can be mitigated with influenza, pneumococcal and herpes zoster vaccination, whenever possible. Finally, an approach was taken on biosimilar drugs, alternative therapies and new potential therapeutic targets that are still under study.
Description
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2019
Keywords
Artrite Reumatoide Sinovite Fármacos Anti-Reumáticos Modificadores da Doença Agentes Biológicos Mestrado Integrado - 2019