umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Association between marginal jawbone loss and the onset of rheumatoid arhtritis and relationship to plasma levels of RANKL
Umeå University, Faculty of Medicine, Department of Odontology.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
Umeå University, Faculty of Medicine, Department of Odontology.
Umeå University, Faculty of Medicine, Department of Odontology.
Show others and affiliations
2018 (English)In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 70, no 4, p. 508-515Article in journal (Refereed) Published
Abstract [en]

Objective: To investigate whether periodontitis, characterized by marginal jawbone loss, precedes the onset of symptoms of rheumatoid arthritis (RA), and to analyze plasma levels of RANKL (a cytokine that is crucial for bone resorption) and anti–citrullinated peptide antibodies (ACPAs) in presymptomatic individuals compared with matched referent controls.

Methods: Marginal jawbone loss was measured on dental radiographs of the premolar/molar regions in the jaws in 176 subjects, 93 of whom subsequently developed RA. Among these participating subjects, 46 had documented radiographs predating symptom onset, and 45 cases could be matched to controls, according to sex, age, and smoking status. Plasma RANKL concentrations were analyzed using enzyme‐linked immunosorbent assay. A receiver operating characteristic curve was used to define the cutoff value for RANKL positivity.

Results: Bone loss was significantly greater in presymptomatic subjects classified as never smokers compared with that in controls, and increasing levels of bone loss were associated with a higher risk of the subsequent development of RA (hazard ratio 1.03, 95% confidence interval 1.01–1.05). No association between jawbone loss and RA was observed in smokers. A significantly greater extent of marginal jawbone loss was detected in RANKL‐positive presymptomatic subjects, and even more pronounced jawbone loss was observed in those who were positive for both RANKL and ACPA.

Conclusion: Marginal jawbone loss preceded the clinical onset of RA symptoms, but this was observed only in nonsmokers. Moreover, marginal jawbone loss was significantly greater in RANKL‐positive presymptomatic subjects compared with RANKL‐negative presymptomatic subjects and was highest in presymptomatic subjects positive for both ACPA and RANKL.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2018. Vol. 70, no 4, p. 508-515
National Category
Rheumatology and Autoimmunity
Research subject
Medicine, rheumatology; Odontology
Identifiers
URN: urn:nbn:se:umu:diva-146131DOI: 10.1002/art.40394PubMedID: 29195021OAI: oai:DiVA.org:umu-146131DiVA, id: diva2:1194440
Available from: 2018-04-03 Created: 2018-04-03 Last updated: 2018-06-09Bibliographically approved
In thesis
1. Insights into the processes preceding the onset of rheumatoid arthritis
Open this publication in new window or tab >>Insights into the processes preceding the onset of rheumatoid arthritis
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Rheumatoid arthritis (RA) is a chronic inflammatory disease, characterized by the production of anti-citrullinated protein antibodies (ACPA) in the majority of all patients and a persistent inflammation in the synovial tissue leading to joint destruction. The aetiology of RA remains to a large extent unknown but is believed to be a complex interplay between genetic, environmental and stochastic factors. Recently, several infectious agents have been shown to have the capacity to induce citrullination of both endogenous and exogenous antigens e.g., Epstein-Barr virus (EBV) and Porphyromonas gingivalis (P.gingivalis). Disease progression in patients with RA is suggested to be a longstanding process that begins several years before symptom onset of RA. This hypothesis is supported by studies showing increased antibody levels against ACPA and disease related cytokines/chemokines several years before symptom onset of RA. The presence of ACPA is highly specific for RA and is already used as an indicator of progression and prognosis of the disease. This thesis is aimed to further investigate the origin and role of ACPA and the processes preceding the development of RA. New insights into these processes are of importance in order to be able to prevent the disease onset, achieve better diagnostic methods and treatments in the future.

All of the individuals included in these papers, had attended to the Department of Rheumatology at Umeå University to receive their diagnosis of RA. The register of the patients were thereafter co-analysed with the register of the Medical Biobank of Northern Sweden. Plasma/sera samples were analysed for antibodies and receptor activator of nuclear factor kappa-B ligand (RANKL) using different ELISA techniques from individuals before symptom onset (pre-symptomatic individuals) and at disease onset (patients). Cytokines/chemokines were analysed using Meso Scale Discovery methods. Levels of marginal jawbone loss were measured using dental radiographs from premolar/molar regions. The Larsen score at disease onset was used to grade radiographs of hands and feet.

In Paper I antibodies against Epstein-Barr virus nuclear antigen (EBNA) 1 and 2 (VCP1 and VCP2) and histone 4 (H4) derived citrullinated peptides (HCP1 and HCP2) were found to predate symptom onset of RA. In Paper II, antibodies against anti-P.gingivalis (anti-CPP3 and -RgpB IgG) were significantly increased in pre-symptomatic individuals and were detectable several years before symptom onset of RA. In Paper III the concentration of RANKL was shown to be increased several years before symptom onset of RA, especially in ACPA/rheumatoid factor (RF)/anti-carbamylated (CarP) antibody positive individuals. Positivity for RANKL was found to appear later in time than both positivity for ACPA, RF and anti-CarP antibodies. The highest Larsen score at disease onset was yielded when combining positivity for RANKL and anti-CarPivantibodies. In Paper IV periodontitis, defined as marginal jawbone loss was significantly higher in pre-symptomatic individuals who never smoked, compared with matched controls. RANKL positive individuals particularly those that were also ACPA positive, had a significantly greater extent of jawbone loss in comparison to those individuals who were RANKL negative.

Antibodies against citrullinated exogenous and endogenous peptides were found to be associated with the symptom onset of RA. No hierarchy among the citrullinated epitopes could be identified. RANKL levels were particular increased in ACPA-positive individuals, and RANKL positivity appeared later in time than the general ACPA response. Periodontitis, defined as marginal jawbone loss was significantly higher in pre-symptomatic individuals, who never smoked.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2018. p. 62
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1954
Keywords
rheumatoid arthritis, pre-symptomatic individuals, autoantibodies, anti-citrullinated protein/peptides antibodies, Epstein-barr virus, neutrophil extracellular traps, periodontitis, Porphyromonas gingivalis, receptor activator of nuclear factor kappa-B ligand
National Category
Rheumatology and Autoimmunity
Research subject
Medicine, rheumatology
Identifiers
urn:nbn:se:umu:diva-146293 (URN)978-91-7601-863-7 (ISBN)
Public defence
2018-04-27, Sal D, Målpunkt T, våning 9, Norrlands Universitetsjukhus, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2018-04-06 Created: 2018-04-04 Last updated: 2018-06-09Bibliographically approved

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full textPubMed

Authority records BETA

Kindstedt, ElinJohansson, LindaPalmqvist, PyKoskinen Holm, CeciliaKokkonen, HeidiJohansson, IngegerdRantapää-Dahlqvist, SolbrittLundberg, Pernilla

Search in DiVA

By author/editor
Kindstedt, ElinJohansson, LindaPalmqvist, PyKoskinen Holm, CeciliaKokkonen, HeidiJohansson, IngegerdRantapää-Dahlqvist, SolbrittLundberg, Pernilla
By organisation
Department of OdontologyDepartment of Public Health and Clinical Medicine
In the same journal
Arthritis & Rheumatology
Rheumatology and Autoimmunity

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 103 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf