Science Space
Linking Biomechanics, Inflammation and Bone Formation in Early Psoriatic Arthritis
Study rationale
Psoriatic arthritis (PsA) is a pleomorphic chronic inflammatory arthritis of unknown aetiology.
Enthesis have recently been recognized as a central anatomical and functional “target” organ in PsA, linking many of the disease manifestations, such as new bone formation, dactylitis and nail disease. Enthesis aim to resist and dissipate stress during mechanical loading. Mechanical stress has therefore been hypothesized as an important trigger of enthesitis but increased mechanical stress at enthesis in PsA patients has not been demonstrated. Not surprisingly feet are preferentially involved, with enthesitis and synovitis being detected by ultrasound and magnetic resonance imaging (MRI), even in patients with psoriasis without musculoskeletal clinical manifestations. This suggests that inflammatory changes at the synovio-entheseal complex comprise part of the early pathogenesis of PsA. The factors that contribute to increased mechanical load at enthesis can be dependent of biomechanical parameters such as feet ground reaction forces, inter-segmental angles and ankle joint moment, which can be nowadays, assessed using tridimensional multi-segment models.
At the molecular level, recent insights into the regulation of Wnt/ß-catenin pathway in inflammatory arthritis field have revealed distinct behaviors of its two major inhibitors: Dickkopf (DKK)-1 and sclerostin (SOST) in ankylosing spondylitis (characterized by predominantly bone anabolism at enthesis) and rheumatoid arthritis (where catabolic events predominate). In PsA ankylosing enthesitis and severe erosive arthritis can coexist, suggesting the existence of opposite bone regulation mechanisms and raising the question on the pattern of DKK-1 and SOST expression in this disease.
Aim The aim of this project is to test the hypothesis that induced mechanical stress leads to inflammation and bone formation at the synovio-entheseal complex.
Specific objectives 1) To identify biomechanical parameters of foot function that can predict the development of enthesitis in early PsA patients as detected by MRI.
2) To characterize serum biomarkers of bone metabolism related to Wnt signaling that can differentiate between axial and peripheral PsA and can be used as biomarkers of prediction of different PsA subtypes.
Methodology A cohort with all consecutive patients with early PsA, less than one year disease duration, naïve of DMARDs therapy, followed at Psoriatic Arthritis Clinics of Santa Maria Hospital, will be included. Feet and ankle MRI using a dynamic contrast enhancement 1.5 Tesla protocol will be performed for assessment of primary outcome – the development of enthesitis. Patients gait will be characterized using a three dimensional six-segment model for feet biomechanics based in the application of spherical reflective markers tracked by a camera motion analysis system. Biomechanics assessment and feet and ankle MRI will be performed at baseline, 12 months and 24 months. MRI due to its high sensitivity for subtle inflammatory changes will allow identification of bone marrow edema, enthesitis, enthesophytes, synovitis, tenossinovitis, erosions and soft tissue edema, at early phases of disease. Kinematics and kinetics parameters will be the main predictors of the development of enthesitis. Other covariates include demographic, clinical and laboratorial variables. A blood sample will be collected before treatment, 3 months after NSAIDs and after starting any DMARDs for determination of circulating natural inhibitors of the Wnt/ß-catenin pathway. These will be correlated with primary outcome, disease phenotypes and concomitant treatment. The total follow up will be 2 years and management strategy according to standard care. Written informed consent and local ethical approval will be obtained prior to any study procedure.
Statistical analysis: Primary analysis: T student test will be used to determine association between kinematics and kinetics parameters and the development of enthesitis. Clinical and laboratorial variables will be examined to find predictors of enthesis in a stepwise approach using primarily a univariate analysis and later a multivariate analysis if adequate. Secondary analysis: serum biomarkers measurements will be compared across PsA subtypes using GLM models and significant differences assessed by Bonferroni multicomparison tests. We expect that the inclusion of 45 patients will allow us to have a power>80% to assess differences in biomechanics parameters between patients that achieve primary endpoint and those who don´t.
Elsa Vieira Sousa
Estudante De Doutoramento
Psoriatic arthritis (PsA) is a pleomorphic chronic inflammatory arthritis of unknown aetiology.
Enthesis have recently been recognized as a central anatomical and functional “target” organ in PsA, linking many of the disease manifestations, such as new bone formation, dactylitis and nail disease. Enthesis aim to resist and dissipate stress during mechanical loading. Mechanical stress has therefore been hypothesized as an important trigger of enthesitis but increased mechanical stress at enthesis in PsA patients has not been demonstrated. Not surprisingly feet are preferentially involved, with enthesitis and synovitis being detected by ultrasound and magnetic resonance imaging (MRI), even in patients with psoriasis without musculoskeletal clinical manifestations. This suggests that inflammatory changes at the synovio-entheseal complex comprise part of the early pathogenesis of PsA. The factors that contribute to increased mechanical load at enthesis can be dependent of biomechanical parameters such as feet ground reaction forces, inter-segmental angles and ankle joint moment, which can be nowadays, assessed using tridimensional multi-segment models.
At the molecular level, recent insights into the regulation of Wnt/ß-catenin pathway in inflammatory arthritis field have revealed distinct behaviors of its two major inhibitors: Dickkopf (DKK)-1 and sclerostin (SOST) in ankylosing spondylitis (characterized by predominantly bone anabolism at enthesis) and rheumatoid arthritis (where catabolic events predominate). In PsA ankylosing enthesitis and severe erosive arthritis can coexist, suggesting the existence of opposite bone regulation mechanisms and raising the question on the pattern of DKK-1 and SOST expression in this disease.
Aim The aim of this project is to test the hypothesis that induced mechanical stress leads to inflammation and bone formation at the synovio-entheseal complex.
Specific objectives 1) To identify biomechanical parameters of foot function that can predict the development of enthesitis in early PsA patients as detected by MRI.
2) To characterize serum biomarkers of bone metabolism related to Wnt signaling that can differentiate between axial and peripheral PsA and can be used as biomarkers of prediction of different PsA subtypes.
Methodology A cohort with all consecutive patients with early PsA, less than one year disease duration, naïve of DMARDs therapy, followed at Psoriatic Arthritis Clinics of Santa Maria Hospital, will be included. Feet and ankle MRI using a dynamic contrast enhancement 1.5 Tesla protocol will be performed for assessment of primary outcome – the development of enthesitis. Patients gait will be characterized using a three dimensional six-segment model for feet biomechanics based in the application of spherical reflective markers tracked by a camera motion analysis system. Biomechanics assessment and feet and ankle MRI will be performed at baseline, 12 months and 24 months. MRI due to its high sensitivity for subtle inflammatory changes will allow identification of bone marrow edema, enthesitis, enthesophytes, synovitis, tenossinovitis, erosions and soft tissue edema, at early phases of disease. Kinematics and kinetics parameters will be the main predictors of the development of enthesitis. Other covariates include demographic, clinical and laboratorial variables. A blood sample will be collected before treatment, 3 months after NSAIDs and after starting any DMARDs for determination of circulating natural inhibitors of the Wnt/ß-catenin pathway. These will be correlated with primary outcome, disease phenotypes and concomitant treatment. The total follow up will be 2 years and management strategy according to standard care. Written informed consent and local ethical approval will be obtained prior to any study procedure.
Statistical analysis: Primary analysis: T student test will be used to determine association between kinematics and kinetics parameters and the development of enthesitis. Clinical and laboratorial variables will be examined to find predictors of enthesis in a stepwise approach using primarily a univariate analysis and later a multivariate analysis if adequate. Secondary analysis: serum biomarkers measurements will be compared across PsA subtypes using GLM models and significant differences assessed by Bonferroni multicomparison tests. We expect that the inclusion of 45 patients will allow us to have a power>80% to assess differences in biomechanics parameters between patients that achieve primary endpoint and those who don´t.
Elsa Vieira Sousa
Estudante De Doutoramento
