Espondilite Anquilosante: genética e mecanismos moleculares
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2015
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A Espondilite Anquilosante (EA) é uma doença reumática crónica rara, de natureza inflamatória e progressiva com características auto-imunes. A EA pertence ao grupo de doenças denominadas espondiloartropatias ou espondiloartrites.
É uma doença ainda sem cura, e desta forma, os tratamentos existentes combatem apenas os seus sintomas e não a doença em si.
A EA afecta indivíduos por todo o globo, afectando raças e etnias diferentes, em Portugal afecta entre 0,3 a 0,5% da população. A EA é uma doença que remonta aos primórdios da história da Humanidade.
Os doentes com esta patologia queixam-se principalmente de dor lombar e rigidez na coluna. Tais sintomas tendem, maioritariamente, a aparecer na adolescência ou no início da idade adulta, apresentando maior prevalência no sexo masculino. Suspeita-se de EA quando se está perante um indivíduo com menos de 40 anos, com dores de costas de características inflamatórias, que persistem há mais de três meses, associadas a rigidez matinal, que, no entanto, melhoram com a prática de exercício físico. Com o avançar da doença, o movimento lombar vai sendo cada vez mais limitado, à medida que as vértebras se fundem entre si.
A doença foi durante muito tempo considerada uma variação da artrite reumatóide. A EA é uma doença caracterizada por factores genéticos e de entre os mais importantes e conhecidos para esta patologia, está o gene Human Leucocyte Antigen-B27, também denominado HLA-B27, existindo diferentes teorias explicativas para a patogénese imunitária deste gene.
O sistema imunitário é um sistema complexo com uma quantidade diversificada de células e proteínas com diferentes funções. Entre as proteínas do sistema imunitário existem as citoquinas (glicoproteínas envolvidas e reguladoras da resposta imunitária e resposta inflamatória), que vão desempenhar um papel importante na Espondilite Tem-se correlacionado diferentes citoquinas inflamatórias com mecanismos patogénicos da EA.
O objectivo da presente dissertação é realizar uma revisão sobre a fisiopatologia e os mecanismos moleculares e genéticos da espondilite, demonstrando o que se sabe sobre a doença no presente e o que aguarda o futuro.
São apresentados estudos que apontam para determinados SNP´s como os principais responsáveis na protecção, susceptibilidade ou severidade da EA, explicando o porquê de diferentes indivíduos com o mesmo gene poderem ter maior ou menor risco de vir a desenvolver a doença. Posteriormente, são descritos os genes mais relevantes implicados. na doença (HLA-B27, ERAP1, IL1A, IL23R, RUNX3, KIF21B, TBKBP1 e PPARGC1B), bem como os seus mecanismos.
É dado enfoque às formas de tratamento da doença, onde são referenciados os novos avanços médicos, os tratamentos convencionais, como os AINES e os bloqueadores TNF, assim como as terapêuticas não convencionais. Por fim, são indicadas instituições nacionais e internacionais dedicadas ao suporte e melhoria da qualidade de vida dos pacientes com EA. Novas descobertas na área dos medicamentos biológicos como o ustekinumab e o secukinumab e o bloqueio de citoquinas inflamatórias chave no desenvolvimento da EA permitem antever novas e melhores formas para combater esta doença.
Ankylosing Spondylitis (AS) is a rare chronic rheumatic disease, with an inflammatory and progressive nature which shows autoimmune features. It belongs to a disease group called spondyloarthropathies or spondyloarthritis. It is a disease yet without a cure, and thus, the available treatments only fight its symptoms and not the disease itself. AS is a disease that dates back to the dawn of human history and it affects individuals across the globe with different racial and ethnic backgrounds. In Portugal, it affects approximately 0,3% to 0,5% of the population. Patients with this pathology complain mainly of lower back pain and spine stiffness. These symptoms tend, mostly, to appear during adolescence or young adulthood, showing a higher prevalence in males. One suspects of AS when is facing an individual under 40 years old that has a back pain with inflammatory characteristics, which persisted for more than three months, associated with early morning stiffness, which, however, is improved by physical activity. With the advance of the illness, the lumbar motion starts to be increasingly limited, as the spinal vertebrae are fused together. The disease has long been considered a variation of rheumatoid arthritis. AS is a disease characterized by genetic factors and amongst the most important, and well known for this disease, lays the Human Leukocyte Antigen-B27 gene, also known as HLA-B27. There are different theories to explain the immune pathogenesis of this gene. The immune system is a complex system with a diverse amount of cells and proteins that have different functions. Among the proteins of the immune system there are the cytokines (glycoproteins involved and regulating immune response and inflammatory response), which will play a major role in spondylitis. Various inflammatory cytokines have been correlated with pathogenic mechanisms of AS. The purpose of this work is to conduct a review, regarding the pathophysiology and the molecular and genetic mechanisms of spondylitis, demonstrating what is presently known about the disease and what the future holds. The SNP’s are also listed as the main factors responsible for the protection, susceptibility or severity of the AS. This theory explains why individuals that share the same gene may have higher or lower risk of developing this disease. The most relevant genes involved in the disease (HLA-B27, ERAP1, IL1A, IL23R, RUNX3, KIF21B, and TBKBP1 PPARGC1B) and its mechanisms are also described. A special focus on disease management is given, referencing new medical advances, conventional like NSAIDS and TNF-blockers and also alternative treatments. National and International Foundations dedicated to the support and improvement of the quality of life of AS patients are presented. New discoveries in the area of biological medicines, such as ustekinumab and secukinumab and the blockade of key inflammatory cytokines in the development of AS, creates a window for new and better drugs to combat this disease.
Ankylosing Spondylitis (AS) is a rare chronic rheumatic disease, with an inflammatory and progressive nature which shows autoimmune features. It belongs to a disease group called spondyloarthropathies or spondyloarthritis. It is a disease yet without a cure, and thus, the available treatments only fight its symptoms and not the disease itself. AS is a disease that dates back to the dawn of human history and it affects individuals across the globe with different racial and ethnic backgrounds. In Portugal, it affects approximately 0,3% to 0,5% of the population. Patients with this pathology complain mainly of lower back pain and spine stiffness. These symptoms tend, mostly, to appear during adolescence or young adulthood, showing a higher prevalence in males. One suspects of AS when is facing an individual under 40 years old that has a back pain with inflammatory characteristics, which persisted for more than three months, associated with early morning stiffness, which, however, is improved by physical activity. With the advance of the illness, the lumbar motion starts to be increasingly limited, as the spinal vertebrae are fused together. The disease has long been considered a variation of rheumatoid arthritis. AS is a disease characterized by genetic factors and amongst the most important, and well known for this disease, lays the Human Leukocyte Antigen-B27 gene, also known as HLA-B27. There are different theories to explain the immune pathogenesis of this gene. The immune system is a complex system with a diverse amount of cells and proteins that have different functions. Among the proteins of the immune system there are the cytokines (glycoproteins involved and regulating immune response and inflammatory response), which will play a major role in spondylitis. Various inflammatory cytokines have been correlated with pathogenic mechanisms of AS. The purpose of this work is to conduct a review, regarding the pathophysiology and the molecular and genetic mechanisms of spondylitis, demonstrating what is presently known about the disease and what the future holds. The SNP’s are also listed as the main factors responsible for the protection, susceptibility or severity of the AS. This theory explains why individuals that share the same gene may have higher or lower risk of developing this disease. The most relevant genes involved in the disease (HLA-B27, ERAP1, IL1A, IL23R, RUNX3, KIF21B, and TBKBP1 PPARGC1B) and its mechanisms are also described. A special focus on disease management is given, referencing new medical advances, conventional like NSAIDS and TNF-blockers and also alternative treatments. National and International Foundations dedicated to the support and improvement of the quality of life of AS patients are presented. New discoveries in the area of biological medicines, such as ustekinumab and secukinumab and the blockade of key inflammatory cytokines in the development of AS, creates a window for new and better drugs to combat this disease.
Descrição
Orientação: Isabel Ribeiro
Palavras-chave
MESTRADO INTEGRADO EM CIÊNCIAS FARMACÊUTICAS, ESPONDILITE ANQUILOSANTE, GENÉTICA, TRATAMENTOS MÉDICOS, ANKYLOSING SPONDYLITIS, GENETICS, MEDICAL TREATMENTS, CIÊNCIAS FARMACÊUTICAS, PHARMACEUTICAL SCIENCES