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Imunoterapia na artrite reumatóide em Portugal : avanços terapêuticos, riscos e benefícios
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A AR é uma doença inflamatória crónica, de causa desconhecida, abrange geralmente as articulações, podendo afectar qualquer órgão provocando as mais diversas manifestações clínicas. Neste tipo de patologia há uma desregulação do sistema imunitário, constituindo fonte de dor e incapacidade que pode ser temporária ou definitiva, apresentando graves repercussões a nível de Saúde Pública, a nível económico e social.
A presente dissertação, pretende abordar de forma concisa as diversas formas de tratamento desta patologia com especial enfoque na utilização da Imunoterapia. Tem sido demonstrado que os DMARDs reduzem a actividade da doença, retardando a sua progressão, reduzindo a taxa de novas erosões articulares e melhorando a qualidade de vida. No entanto, a maioria dos doentes sentem apenas benefícios parciais com os DMARDs “tradicionais” e muitos não toleram o uso destes fármacos a longo prazo. Embora uma oportunidade única para intervenção possa existir no início do curso da doença, acredita-se que os DMARDs devam ser introduzidos em todas as fases da doença, mesmo em fases posteriores, com o objectivo claro na redução de sinais e sintomas, melhoria da função articular e progressão estrutural da doença.
Durante os últimos anos, verificou-se um grande progresso no conhecimento da imunopatogénese das diferentes doenças inflamatórias. O avanço da Biotecnologia, novas técnicas de Biologia Molecular e Imunopatologia permitiu o desenvolvimento de agentes biológicos, conhecimento dos mecanismos específicos da patologia, levando à produção de moléculas (ex. proteínas altamente purificadas) capazes de estimular o sistema imunitário de modo a criar uma resposta imunitária capaz de retardar ou eliminar a progressão da doença. Em consequência, observámos a expansão de novas opções terapêuticas na AR com o desenvolvimento de terapias direccionadas especificamente para factores determinantes da inflamação, os medicamentos biológicos.
A eficácia e segurança dos agentes biológicos e a janela de oportunidade que estes agentes terapêuticos proporcionam não invalindam no entanto a constante monitorização de efeitos adversos e ocorrências imprevistas. As diferenças entre agentes biológicos requerem per si pesquisa considerável, considerando diferentes populações, estadios da doença e melhoria da adequação para um ou outro agente em monoterapia ou em combinação com outros agentes terapêuticos. De futuro, são expectáveis melhorias nas abordagens combinadas, incluindo combinações de diferentes agentes biológicos. Até à data, as abordagens biológicas combinadas conduziram a um maior risco de infecção, no entanto,atingindo os alvos corretos ou adequando as doses administradas, esse risco aumentado poderá ser superado (1).
O crescente número de dados dá credibilidade à crença de que o diagnóstico e início do tratamento precoce na AR são necessários para maximizar os benefícios a curto e longo prazo para o doente, proporcionando uma janela de oportunidade para uma modificação de fundo no curso da doença. Além da crescente ênfase na intervenção precoce, actualmente em Reumatologia preconiza-se um esforço continuo na melhoria das taxas de resposta global em doentes actuais e expansão da intervenção em populações não tratadas. O objectivo a longo prazo da intervenção terapêutica é atingir a remissão da doença (2).
Tecnologias emergentes para a quantificação de auto-anticorpos e confirmação de sua utilidade clínica indicam e expandem o papel de marcadores sorológicos no diagnóstico da AR. O valor de diagnóstico predictivo do anti-CCP combinado com isoformas do FR sugere que a AR pode potencialmente ser identificada com base na sorologia. Considerando que esses auto-anticorpos estão presentes em indivíduos em fases anteriores ao desenvolvimento da doença, isso sugere um papel causal na patogênese da AR. A detecção de auto-anticorpos específicos pode assegurar a chave para o diagnóstico muito precoce da AR e assim a intervenção terapêutica pode ser instituída antes do desenvolvimento de erosões substanciais nas articulações. Já são claros os benefícios da terapia iniciada no período que antecede as manifestações clínicas da doença, uma vez que a detecção precoce da AR e a intervenção terapêutica são elementos chave na prevenção de danos nas articulações, inclusive nos doentes que apresentam FR negativo. Neste contexto, a especificidade dos anticorpos anti-CCP para o diagnóstico da AR, inclusive nos estadios inicias da doença e como marcador sorológico, aliado ao FR e PCR, constitui uma ferramenta útil como indicador de resposta a tratamento instituído no seguimento farmacoterapêutico de doentes com AR em combinação com dados clínicos nos diversos períodos de desenvolvimento da doença.
RA is a chronic inflammatory disease of unknown cause, usually covers the joints and can affect any organ causing the most diverse clinical manifestations. In this type of pathology there is a dysregulation of the immune system, providing a source of pain and disability that can be temporary or permanent, with serious repercussions for public health, economic and social. This dissertation aims to address concisely the various forms of treatment of this pathology with special focus on the use of immunotherapy. It has been demonstrated that the disease modifying antirheumatic drugs (DMARDs) reduce disease activity, delaying its progression, reducing the rate of new articular erosions and improving quality of life. However, most patients experience only partial benefits with "traditional" DMARDs and many do not tolerate long-term use of these drugs. Although a unique opportunity for intervention may exist early in the course of the disease, it is believed that DMARDs should be made at all stages of the disease, even in later phases, with a clear reduction of signs and symptoms, improvement of articular function and structural progression.During the last years, there was great progress in the knowledge of the immunopathogenesis of various inflammatory diseases. Advances in Biotechnology, new techniques in molecular biology and Immunology allowed the development of biological agents, knowledge of the specific mechanisms of the disease, leading to the production of molecules (eg highly purified proteins) capable of stimulating the immune system to create immune responses capables of retarding or eliminating the progression of RA. The efficacy and safety of biological agents and the window of opportunity provided by these therapeutic agents, doesn´t invalidate however, constant monitoring of adverse events .The differences between biological agents require considerable research per se, considering different populations and stages of disease, improvement suitability for either agent alone or in combination with other therapeutic agents. In the future, improvements are expected in the combined approaches, including different combinations of biological agents. To date, the combined biological approaches have led to an increased risk of infection, however, reaching the correct targets and adjusting the administered dosages; this increased risk may be overcome. The increasing number of data lends to the belief that early diagnosis and early treatment in RA are needed to maximize short and long term benefits for patients, providing a window of opportunity for a substantive modification in the course of the disease. Besides the growing emphasis on early intervention, currently in Rheumatology there is an effort to keep on improving overall response rates in diagnosed patients and expansion of current interventions in untreated populations. The long-term goal of therapeutic intervention is to achieve disease remission. Emerging technologies for quantification of autoantibodies and their clinical usefulness of confirmation indicates and expands the role of serum markers for the diagnosis of RA. The diagnostic predictive value of anti-CCP combined with FR isoforms suggests that RA can potentially be identified with bases in serology. Whereas these autoantibodies are present in patients at earlier stages of disease development, this suggests a causal role in the pathogenesis of RA. The detection of specific autoantibodies may provide the key for very early diagnosis of RA and thus a therapeutic intervention can be instituted before the development of substantial erosion in joints. There are already clear benefits of therapy initiated in the period preceding the clinical manifestations of the disease, since early detection of RA and therapeutic intervention are key elements in the prevention of joint damage, even in patients with negative FR. In this context, the specificity of anti-CCP antibodies for the diagnosis of RA, including the initial stages of the disease and as a serological marker, combined with RF and CRP, is a useful tool as an indicator of response to treatment administered, pharmacotherapeuthical follow-up of patients with RA in conjunction with clinical data in various periods of disease development.
RA is a chronic inflammatory disease of unknown cause, usually covers the joints and can affect any organ causing the most diverse clinical manifestations. In this type of pathology there is a dysregulation of the immune system, providing a source of pain and disability that can be temporary or permanent, with serious repercussions for public health, economic and social. This dissertation aims to address concisely the various forms of treatment of this pathology with special focus on the use of immunotherapy. It has been demonstrated that the disease modifying antirheumatic drugs (DMARDs) reduce disease activity, delaying its progression, reducing the rate of new articular erosions and improving quality of life. However, most patients experience only partial benefits with "traditional" DMARDs and many do not tolerate long-term use of these drugs. Although a unique opportunity for intervention may exist early in the course of the disease, it is believed that DMARDs should be made at all stages of the disease, even in later phases, with a clear reduction of signs and symptoms, improvement of articular function and structural progression.During the last years, there was great progress in the knowledge of the immunopathogenesis of various inflammatory diseases. Advances in Biotechnology, new techniques in molecular biology and Immunology allowed the development of biological agents, knowledge of the specific mechanisms of the disease, leading to the production of molecules (eg highly purified proteins) capable of stimulating the immune system to create immune responses capables of retarding or eliminating the progression of RA. The efficacy and safety of biological agents and the window of opportunity provided by these therapeutic agents, doesn´t invalidate however, constant monitoring of adverse events .The differences between biological agents require considerable research per se, considering different populations and stages of disease, improvement suitability for either agent alone or in combination with other therapeutic agents. In the future, improvements are expected in the combined approaches, including different combinations of biological agents. To date, the combined biological approaches have led to an increased risk of infection, however, reaching the correct targets and adjusting the administered dosages; this increased risk may be overcome. The increasing number of data lends to the belief that early diagnosis and early treatment in RA are needed to maximize short and long term benefits for patients, providing a window of opportunity for a substantive modification in the course of the disease. Besides the growing emphasis on early intervention, currently in Rheumatology there is an effort to keep on improving overall response rates in diagnosed patients and expansion of current interventions in untreated populations. The long-term goal of therapeutic intervention is to achieve disease remission. Emerging technologies for quantification of autoantibodies and their clinical usefulness of confirmation indicates and expands the role of serum markers for the diagnosis of RA. The diagnostic predictive value of anti-CCP combined with FR isoforms suggests that RA can potentially be identified with bases in serology. Whereas these autoantibodies are present in patients at earlier stages of disease development, this suggests a causal role in the pathogenesis of RA. The detection of specific autoantibodies may provide the key for very early diagnosis of RA and thus a therapeutic intervention can be instituted before the development of substantial erosion in joints. There are already clear benefits of therapy initiated in the period preceding the clinical manifestations of the disease, since early detection of RA and therapeutic intervention are key elements in the prevention of joint damage, even in patients with negative FR. In this context, the specificity of anti-CCP antibodies for the diagnosis of RA, including the initial stages of the disease and as a serological marker, combined with RF and CRP, is a useful tool as an indicator of response to treatment administered, pharmacotherapeuthical follow-up of patients with RA in conjunction with clinical data in various periods of disease development.
Descrição
Tese de mestrado, Cuidados Farmacêuticos, Universidade de Lisboa, Faculdade de Farmácia, 2013
Palavras-chave
Imunoterapia Artrite Reumatóide Agentes Biológicos Teses de mestrado - 2013