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Receptor activator of nuclear factor kappa-B ligand (RANKL) but not sclerostin or gene polymorphisms is related to joint destruction in early rheumatoid arthritis
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
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2017 (English)In: Clinical Rheumatology, ISSN 0770-3198, E-ISSN 1434-9949, Vol. 35, no 5, p. 1005-1012Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to analyze relationships between receptor activator of nuclear factor kappa-B (RANKL), sclerostin and their gene polymorphisms with radiological progression in patients with early rheumatoid arthritis (RA). Patients with early RA (n = 407, symptomatic <1 year) (ARA criteria) examined radiologically at inclusion and after 24 months were consecutively included. Disease activity score and C-reactive protein were regularly recorded. Sclerostin, RANKL, and anti-CCP2 antibodies were analyzed in plasma at baseline using ELISAs. Data on gene polymorphism for sclerostin and RANKL were extracted from Immunochip analysis. Sex- and age-matched controls (n = 71) were identified from the Medical Biobank of Northern Sweden. The concentration of RANKL was significantly higher in patients compared with controls, median (IQR) 0.56 (0.9) nmol/L and 0.20 (0.25) nmol/L (p < 0.001), and in anti-CCP2-positive patients compared with sero-negative individuals. Sclerostin was significantly increased in female patients 0.59 (0.47-0.65) ng/mL compared with female controls 0.49 (0.4-0.65) ng/mL (p < 0.02). RANKL concentration was related to the Larsen score at baseline (p < 0.01), after 24 months (p < 0.001), and to radiological progression at 24 months (p < 0.001). Positivity of RANKL and anti-CCP2 yielded significant risk for progression with negativity for both as reference. No single nucleotide polymorphism encoding TNFSF11 or SOST was associated with increased concentrations of the factors. The concentration of RANKL was related to the Larsen score at baseline, at 24 months, and radiological progression at 24 months particularly in anti-CCP2-positive patients, while the concentration of sclerostin was unrelated to radiological findings.

Place, publisher, year, edition, pages
2017. Vol. 35, no 5, p. 1005-1012
Keywords [en]
Early rheumatoid arthritis, Radiological progression, Receptor activator of nuclear factor kappa-B ligand, Sclerostin, Single nucleotide polymorphism
National Category
Rheumatology and Autoimmunity
Identifiers
URN: urn:nbn:se:umu:diva-133357DOI: 10.1007/s10067-017-3570-4ISI: 000399879000004PubMedID: 28190118Scopus ID: 2-s2.0-85012180651OAI: oai:DiVA.org:umu-133357DiVA, id: diva2:1094927
Funder
Swedish Research Council, K2013-52X-20307-07-3Available from: 2017-05-11 Created: 2017-05-11 Last updated: 2023-03-23Bibliographically approved
In thesis
1. Early rheumatoid arthritis: biomarkers and hormonal factors in relation to disease progression
Open this publication in new window or tab >>Early rheumatoid arthritis: biomarkers and hormonal factors in relation to disease progression
2021 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Tidig reumatoid artrit : biomarkörer och hormonella faktorer i relation till sjukdomsprogress
Abstract [en]

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease, affecting approximately 0.5 to 1% of the adult population. Although the aetiology is not fully known, a complex interaction between genetic, environmental and stochastic factors is thought to trigger the pathogenic mechanisms. A distinguishing feature of RA is the presence of disease associated autoantibodies, mainly rheumatoid factor (RF) and anti-cyclic citrullinated antibodies (ACPA), which are important in both diagnostic and prognostic purpose. The disease is systemic but primarily affects the joints, and can cause irreversible destructions of cartilage and bone, eventually leading to functional disabilities. Moreover, extra-articular features (i.e., symptoms outside the joints) can occur and the patients have an increased risk for comorbidities, predominantly cardiovascular disease. Since the disease is heterogenous, varying from mild to more severe forms, the prognosis can be difficult to predict. Improvements in early diagnosis and identification of patients at risk of a more severe disease course can lead to better outcomes for the patients. The overall aim of this thesis was to evaluate prognostic biomarkers, and to evaluate hormonal and reproductive factors in relation to cardiovascular events (CVE) in patients with newly diagnosed RA (symptoms <12 months).

Methods: The patients were included in a prospective inception cohort from the years of 1996 to 2017 and followed-up regularly at the early RA clinics in the northern region of Sweden. Clinical and laboratory parameters, and treatment were regularly recorded in the Swedish Rheumatology Quality Register (SRQ). Enzyme-linked immunosorbent assays (ELISA) and a multiplex assay were used to analyse bone remodelling factors and ACPA reactivities, respectively. Questionnaires regarding hormonal and reproductive factors were sent out to female patients ≤80 years. Information of CVE was extracted from the Swedish National Health Register and Cause of Death Register. Potential markers for disease progression i.e., bone remodelling factors and autoantibodies were analysed in relation to disease progression. Hormonal and reproductive factors were analysed in relation to CVE. 

Results: In paper I we found associations between receptor activator of nuclear factor kappa-B (RANKL), a central molecule of bone metabolism, and radiological findings at baseline, 24 months, and radiological progression analysed in 407 RA patients. The combination of RANKL and anti-CCP positivity indicated a more severe disease course in terms of joint destruction. Sclerostin was not associated with radiological outcome. Polymorphisms of the genes for sclerostin (SOST) and RANKL (TNFSF11) did not show significant associations with radiological outcome or with the concentrations, respectively. In paper II, we found that even though antibody status is considered in clinical practice and modern treatment reduces disease activity, the radiographic joint damage remained increased among anti-CCP positive patients. In paper III, 22 different ACPA reactivities were analysed in relation to disease courses of RA. The presence of a higher number of different ACPA reactivities, and different ACPA subtypes could provide prognostic information of disease activity and radiological destruction. In paper IV, we found that hormonal and reproductive factors were associated with CVE in female patients. A higher number of childbirths increased the risk for CVE, whilst oral contraceptives decreased the risk. The majority of patients with later CVE had their RA disease onset after menopause and had a longer duration from menopause until RA onset.

Conclusion: RANKL can function as a prognostic marker for the disease course of RA. Even though anti-CCP antibodies are taken into account in clinical practice and treatment reduce disease activity, the joint damage can progress, supporting the direct bone degrading effects by ACPA. The number of, and different subtypes of ACPA, can predict different disease progression. These markers can be valuable to identify patients at need for more aggressive treatment and careful radiographic monitoring, even if disease activity is under control. Finally, hormonal factors such as childbirths, oral contraceptives and the timing of RA onset in relation to hormonal status can add value for the evaluation of CVE risk in female RA patients. 

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2021. p. 93
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2142
Keywords
Early rheumatoid arthritis, biomarker, ACPA, RANKL, disease activity, radiological destruction, cardiovascular events, hormonal factors
National Category
Rheumatology and Autoimmunity
Research subject
rheumatology
Identifiers
urn:nbn:se:umu:diva-187172 (URN)978-91-7855-583-3 (ISBN)978-91-7855-582-6 (ISBN)
Public defence
2021-09-30, Bergasalen, Målpunkt Q, Norrlands Universitetssjukhus, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2021-09-09 Created: 2021-09-06 Last updated: 2021-09-09Bibliographically approved

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Boman, AntoniaKokkonen, HeidiÄrlestig, LisbethBerglin, EwaRantapää-Dahlqvist, Solbritt

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