Base teórica: A artrite reumatoide (AR) é uma doença autoimune sistêmica onde a inflamação crônica da sinóvia articular e a subsequente erosão óssea e da cartilagem resultam em destruição articular, dor e incapacidade funcional. Apesar dos recentes progressos no tratamento da AR, estes ainda apresentam limitações e significativos efeitos adversos, salientando a necessidade de novas estratégias terapêuticas. Plantas da família das Amarilidáceas apresentam em seus bulbos um conjunto de alcaloides muito característicos e exclusivos com atividades farmacológicas, tais como atividade antiviral, anti-inflamatória e atividade anticolinérgica. A montanina é um alcaloide isolado da Rhodophiala bífida, uma planta da família das amarilidáceas utilizada na medicina popular, mas nunca antes testada como terapia para doenças inflamatórias. Objetivo: Avaliar o efeito da montanina como uma terapia anti-inflamatória in vivo em dois modelos de artrite e in vitro sobre a proliferação de linfócitos e sobre a invasão de fibroblastos sinoviais (FLS). Métodos: Artrite induzida por antígeno (AIA) foi realizada em camundongos Balb/C com albumina bovina sérica metilada e a nocicepção e a migração de leucócitos para a articulação do joelho foram os parâmetros avaliados. Artrite induzida por colágeno (CIA) foi realizada em camundongos DBA/1J e o desenvolvimento e severidade da artrite foi avaliado através de escore clínico, nocicepção articular e escore histológico. Montanina foi administrada via intraperitoneal, duas vezes ao dia. A proliferação de linfócitos estimulados por concanavalina A (conA) foi realizada pelo método de MTT e invasão de FLS em 24 horas foi avaliada em um sistema de insertos de Matrigel. Resutados: A administração de montanina diminuiu a migração articular de leucócitos (p0,001) e a nocicepção (p0,01) em camundongos com AIA. Em camundongos com CIA, o tratamento com montanina reduziu a severidade da artrite e o dano articular avaliado pelos escores clínico (p0,01) e histológico (p0,05) e melhorou a nocicepção articular (p0,05), sem causar nenhum dano hepático. Além disso, montanina inibiu in vitro a proliferação de linfócitos estimulados com conA (p0,01) e diminuiu a invasão de FLS (p0,05) em 54%, com uma ação independente de citotoxicidade. Conclusão: Esses resultados indicam que a montanina pode ser explorada para se tornar um possível fármaco para o tratamento de doenças inflamatórias e autoimunes, como a AR. / Background: Rheumatoid arthritis (RA) is an autoimmune and systemic disease where the chronic inflammation of articular synovia and the subsequent bone and cartilage erosion results in joint destruction, pain and functional disability. Despite recent progress in RA treatments, its still have limitations and significant side effects, emphasizing the need of new therapeutic strategies. Amaryllidaceae plants presenting at its bulbs a set of very characteristics and exclusives alkaloids with pharmacological activities such as antiviral, anti-inflammatory and anticholinergic activity. Montanine is an alkaloid isolated from the Rhodophiala bifida, an Amaryllidaceae plant used in alternative medicine but never before tested as a therapy for inflammatory diseases. Objective: To evaluate the effect of montanine as an in vivo anti-inflammatory therapy in two arthritis models and in vitro on lymphocytes proliferation and fibroblast-like synoviocytes (FLS) invasion. Methods: Antigen-induced arthritis (AIA) was performed in Balb/C mice with methylated bovine serum albumin and nociception and leukocytes migration into the knee joint were evaluated. Collagen-induced arthritis (CIA) was performed in DBA/1J mice and arthritis development and severity were assessed by clinical scoring, articular nociception and histological scoring. Montanine was administered intraperitoneally twice a day. Lymphocyte proliferation stimulated by concanavalin A in 48 hours was performed with MTT assay and FLS invasion in 24 hours was assayed in a Matrigel-coated transwell system. Results: Administration of montanine decreased leukocyte articular migration (p0.001) and nociception (p0.01) in mice with AIA. In mice with CIA, treatment with montanine reduced severity of arthritis and joint damage assessed by clinical (p0.01) and histological score (p0.05) and ameliorates articular nociception (p0.05), without causing any hepatic damage. Moreover, montanine inhibited in vitro lymphocyte proliferation stimulated with ConA (p0.01) and decreased FLS invasion by 54% (p0.05), with an action independent of cytotoxicity. Conclusion: These findings suggest that montanine can be explored to become a possible medicament to treat inflammatory and autoimmune diseases such as arthritis.

No description available.

Background: Rheumatoid arthritis (RA) is an inflammatory disease associated with an increased risk of cardiovascular morbidity and mortality. Methotrexate is a widely used RA medication that has encouraging results for being protective from RA cardiovascular related complications. In a published meta-analysis, MTX showed a 21% reduction in cardiovascular mortality; however, this meta-analysis had multiple limitations. Arterial stiffness is considered to be one of RA's extra-articular manifestations. As a common medication, could MTX have a beneficial effect on traditional cardiovascular risk factors and arterial stiffness parameters? Aims: The aim of this thesis is to assess the effect of MTX on cardiovascular morbidity and mortality using meta-analysis and a cross sectional and longitudinal study to determine whether MTX therapy is associated with reduced blood pressure, AS parameters (measured by pulse wave velocity (PWV), augmentation index (AIX)) and other traditional cardiovascular risk factors (glucose, lipids) in rheumatoid arthritis patients in Saudi Arabia. Methods: Meta-analysis of cohort study design was conducted using combined reporting guidelines. Studies were selected using a systematic search in five databases. Meta-analysis of the effect estimate of the cohort study design was done using a fixed effect model. Another part of the thesis is a cross sectional and longitudinal study of RA patients attending the rheumatology clinic at the university hospital in Saudi Arabia that were classified into three groups: 'current-MTX', which were patients that took MTX for at least three months; 'no-MTX', which were patients that were not on MTX for at least one year; and 'new-MTX', which were patients that were due to commence MTX directly after recruitment. Arterial stiffness and central 2 blood pressure parameters were assessed in RA patients using a validated non-invasive Mobil-O-Graph device. Other cardiovascular and non-cardiovascular parameters were also assessed during patient recruitment from patient interviews, medical records and the laboratory database. Patients were followed-up with two times. Linear regression analysis was performed; a mixed model for repeated measures was done to evaluate the effect of time on differences in blood pressure and arterial stiffness between groups. Results: Nine studies were included in the meta-analysis, and MTX showed a 46% reduction in cardiovascular events. Non-significant heterogeneity was documented between studies. A total of 353 patients (mean age 49 years, female 89%, median RA duration 10 years) were recruited at baseline (March 2013 to January 2014); with 117 reassessed over 3-6 months of follow-up. Augmentation index of the 'current-MTX' group was reduced compared to the 'no-MTX' group by 1.1 (95% CI -4.7 to 2.6) %; and systolic blood pressure was increased by 2.5 (95% CI -2.3 to 7.4) mmHg in 'current-MTX', but results were not statistically significant. During follow-up, no difference was found between treatment groups or within each individual group in the longitudinal analysis. Conclusion: Methotrexate is associated with reduced cardiovascular events on meta-analysis of cohort studies. In the cross sectional setting and longitudinal analysis, methotrexate did not prove to be beneficial in reducing arterial stiffness and blood pressure parameters and other cardiovascular risk factors in rheumatoid arthritis patients in Saudi Arabia.

published_or_final_version / Medicine / Master / Master of Philosophy

published_or_final_version / Pathology / Doctoral / Doctor of Philosophy

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