Syddansk Universitet. Det Sundhedsvidenskabelige Fakultet
Doi
Abstract
Kardiovaskulær sygdom (CVD) og -mortalitet er 1,5-2 gange hyppigere forekommende hos patienter med reumatoid artritis (RA) end hos baggrundsbefolkningen. Både traditionelle kardiovaskulære risikofaktorer og RA-associerede risikofaktorer er blevet forbundet med øget forekomst af aterosklerose og øget risiko for CVD hos RA patienter. Denne afhandling er baseret på sekundære analyser fra database og biobank fra Dansk multicenter OPERA studie, hvor 180 tidlig og behandlingsnaive RA patienter blev randomiseret til treat-to-target behandling med adalimumab plus methotrexat eller placebo plus methotrexat i et år. Afhandlingen undersøger lipider i plasma samt 92 kardiovaskulæreog inflammations-relaterede plasma proteiner i longitudinal og cross-sectional studie design.Artikel 1 Formålet var at undersøge effekten af et års behandling med adalimumab plus methotrexat sammenlignet med placebo plus methotrexat i ændringer af lipid koncentrationer hos tidlig og behandlingsnaive RA-patienter. Vi observerede signifikante stigninger i koncentrationer af LDL-kolesterol, totalt kolesterol, HDL-kolesterol og non-HDL-kolesterol i adalimumab plus methotrexat gruppen samt signifikante stigninger i koncentrationer af totalt kolesterol, HDL-kolesterol og VLDL-kolesterol i placebo plus methotrexat gruppen efter 1 års behandling. Vi fandt ingen forskel i ændringerne af lipiderne mellem behandlingsgrupperne. Artikel 2Formålet var at undersøge associationer mellem 92 kardiovaskulære- og inflammations-relaterede plasma proteiner målt ved OLINK CVD-III-panel og anti-CCP-status og sygdomsaktivitet hos tidlig og behandlingsnaive RA-patienter. Vi fandt en signifikant højere koncentration af chitotriosidase-1 og tyrosine-protein phosphatase non-receptor type substrate-1 og signifikant lavere koncentration af metalloproteinase inhibitor 4 i anti-CCP-negative gruppe sammenlignet med anti-CCP-positiv gruppe. Endvidere, den stærkeste association med sygdomsaktivitet i anti-CCPnegativ gruppe var mellem interleukin-2 receptor subunit alpha koncentrationer og antal af hævede led og mellem Eselectin og CRP, mens i anti-CCP-positive gruppe mellem C-C motif chemokine 16 og DAS28-CRP. Clusteranalyse baseret på koncentrationer af 92 proteiner viste to patient cluster i hver anti-CCP-gruppe. Fordeling af proteinkoncentrationerne i clustrene var sammenlignelige mellem anti-CCP-grupperne. Små forskelle på enkeltproteinniveauer mellem anti-CCP-grupper indikerer en proaterogen og proinflammatorisk profil hos anti-CCP-negative tidlige og behandlingsnaive RA-patienter. Clusteranalyse viste, at fordeling af kardiovaskulære og inflammationsrelaterede plasmaproteiner ikke var afhængig af anti-CCP-status.Artikel 3Formålet var at undersøge effekten af et års behandling med adalimumab plus methotrexat sammenlignet med placebo plus methotrexat på ændringer af 92 kardiovaskulære- og inflammations-relaterede plasma protein koncentrationer hos tidlig og behandlingsnaive RA-patienter. Endvidere, at sammenligne forskellen i ændringerne i proteinkoncentration i forhold til klinisk respons efter 1 år. Vi fandt, at koncentrationerne af E-selectin, tumor necrosis factor receptor superfamily member-10C, matrix metalloproteinase-9, platelet-derived growth factor subunit A og monocyte chemotactic protein-1 signifikant faldt samt, og at koncentrationerne af matrix extracellular phosphoglycoprotein signifikant steg i adalimumab plus methotrexat gruppe sammenlignet med placebo plus methotrexat gruppe. Responderne havde en større indflydelse på ændringerne i proteinkoncentrationerne end non-responderne.Cardiovascular disease (CVD) and mortality is 1.5 to 2-fold higher in patients with rheumatoid arthritis (RA) than in the general population. Traditional cardiovascular risk factors and RA-related risk factors are associated with the increased prevalence of atherosclerosis and the increased risk of CVD in RA. This thesis is based on secondary analyses of clinical and biochemical database and biobank samples from the Danish multicenter OPERA study, where 180 early, treatment-naïve RA patients were randomized to 1-year treat-to-target treatment with adalimumab plus methotrexate or placebo plus methotrexate. The three papers in this thesis examine plasma lipids and 92 cardiovascular- and inflammation-related plasma proteins in longitudinal and cross-sectional study design.Paper 1 The aim of this study was to investigate the effects of 1-year treatment with adalimumab plus methotrexate compared to placebo plus methotrexate on changes in lipid levels in early, treatment-naïve RA patients. We observed a significant increase in levels of LDL cholesterol, total cholesterol, HDL cholesterol, and non-HDL cholesterol in the adalimumab plus methotrexate group, as well as significant increase in levels of total cholesterol, HDL cholesterol, and VLDL cholesterol in the placebo plus methotrexate group after 1 year of treatment. We found no difference in the lipid level changes between the treatment groups.Paper 2The aim of this study was to investigate associations between 92 cardiovascular- and inflammation-related proteins measured by the OLINK CVD III panel and anti-CCP status and disease activity in early, treatment-naïve RA patients. We found significantly higher levels of chitotriosidase-1 and tyrosine-protein phosphatase non-receptor type substrate-1 and a significantly lower levels of metalloproteinase inhibitor 4 in the anti-CCP-negative group compared to the antiCCP-positive group. Furthermore, the strongest association with disease activity in the anti-CCP-negative group was between interleukin-2 receptor subunit alpha levels and number of swollen joints and between E-selectin and CRP, while in the anti-CCP-positive group it was between C-C motif chemokine 16 and DAS28-CRP. Cluster analysis based on the concentrations of 92 cardiovascular- and inflammation-related proteins showed two patient clusters in each antiCCP group. Distribution of the protein levels between clusters was comparable between the anti-CCP groups. Small differences in single protein levels between anti-CCP groups indicate a proatherogenic and proinflammatory profile in anti-CCP-negative early, treatment-naïve RA patients. However, cluster analysis showed similar effects of multiple cardiovascular- and inflammation-related plasma proteins, regardless of anti-CCP status.Paper 3The aim of this study was to investigate the effects of 1-year treatment with adalimumab plus methotrexate compared to placebo plus methotrexate on changes in levels of 92 cardiovascular- and inflammation-related proteins in early, treatment-naïve RA patients. Furthermore, the aim was to compare the differences in protein level changes in relation to clinical response after 1 year. We found that the concentrations of E-selectin, tumor necrosis factor receptor superfamily member-10C, matrix metalloproteinase-9, platelet-derived growth factor subunit A, and monocyte chemotactic protein1 significantly decreased and that the concentrations of matrix extra-cellular phosphoglycoprotein significantly increased in the adalimumab plus methotrexate group compared to the placebo plus methotrexate group. Changes in the protein levels were greater in responders than in non-responders.<br/
