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Serum RANKL levels associate with anti- citrullinated protein antibodies in early untreated rheumatoid arthritis and are modulated following methotrexate.

Hensvold AH, Joshua V, Li W, Larkin M, Qureshi F, Israelsson L, Padyukov L, Lundberg K, Defranoux N, Saevarsdottir S, Catrina AI - Arthritis Res. Ther. (2015)

Bottom Line: Patients with newly diagnosed untreated RA (n = 183) were analyzed at baseline and 3 months after initiating methotrexate (MTX) treatment.Pearson's chi-square test, Wilcoxon rank sum test, Wilcoxon signed rank test and linear regression models were used.Among ACPA specificites, anti-cit-vimentin (amino acids 60-75) was associated with higher RANKL concentration and higher prevalence of bone erosion (p <0.05).

View Article: PubMed Central - PubMed

Affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, L8:04 CMM, 171 76, Stockholm, Sweden. aase.hensvold@ki.se.

ABSTRACT

Introduction: Receptor activator of nuclear factor kappa B ligand (RANKL) is a key regulator of bone metabolism. Anti-citrullinated protein antibodies (ACPA) have been suggested to cause bone destruction by osteoclast activation. We investigated the relationship between RANKL and ACPA in patients with early untreated rheumatoid arthritis (RA).

Methods: Patients with newly diagnosed untreated RA (n = 183) were analyzed at baseline and 3 months after initiating methotrexate (MTX) treatment. Serum RANKL (total RANKL), ACPA (anti-CCP2) and ACPA specificities (anti-citrullinated (cit)-vimentin, anti-cit-enolase and anti-cit-fibrinogen) were determined by enzyme-linked immunosorbent assay (ELISA). Synovial RANKL expression was evaluated by immunohistochemistry in a small group of patients (n = 15). The relationship between anti-cit-vim antibodies and bone destruction was further validated in 1116 RA patients included in the EIRA cohort. Pearson's chi-square test, Wilcoxon rank sum test, Wilcoxon signed rank test and linear regression models were used.

Results: Serum RANKL concentration was significantly higher (p <0.05) in ACPA-positive (median: 689 pmol/L, IQR 342-1253) compared with ACPA-negative (median: 159 pmol/L, IQR 96-243) patients and this difference was also seen for synovial RANKL expression. Serum RANKL associated with ACPA (p <0.05) and bone erosions in rheumatoid factor (RF)-negative patients (n = 59). Among ACPA specificites, anti-cit-vimentin (amino acids 60-75) was associated with higher RANKL concentration and higher prevalence of bone erosion (p <0.05). Significant reductions in both serum RANKL and ACPA levels were observed after 3 months of MTX treatment (p <0.05).

Conclusions: RANKL was elevated in ACPA-positive and in anti-cit-vimentin-positive patients with early untreated RA and associated with bone erosions. These findings give further support for an early direct pathogenic link between ACPA and bone destruction in RA.

No MeSH data available.


Related in: MedlinePlus

Serum and synovial RANKL is increased in ACPA-positive as compared to ACPA-negative rheumatoid arthritis (RA). Graphs illustrate the results of ELISA measurement of total serum RANKL concentrations in RA (a) and in RF-negative RA (e) grouped by ACPA status. Immunohistochemistry staining shows expression of synovial RANKL in one ACPA-positive (b) and one ACPA-negative RA patient (c) and the graph illustrate the results of image analysis in 15 patients (d). Horizontal lines represent median values, *p <0.05. ACPA anti-citrullinated protein antibodies, ELISA enzyme-linked immunosorbent assay, RANKL receptor activator of nuclear factor kappa B ligand, RF rheumatoid factor
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Fig1: Serum and synovial RANKL is increased in ACPA-positive as compared to ACPA-negative rheumatoid arthritis (RA). Graphs illustrate the results of ELISA measurement of total serum RANKL concentrations in RA (a) and in RF-negative RA (e) grouped by ACPA status. Immunohistochemistry staining shows expression of synovial RANKL in one ACPA-positive (b) and one ACPA-negative RA patient (c) and the graph illustrate the results of image analysis in 15 patients (d). Horizontal lines represent median values, *p <0.05. ACPA anti-citrullinated protein antibodies, ELISA enzyme-linked immunosorbent assay, RANKL receptor activator of nuclear factor kappa B ligand, RF rheumatoid factor

Mentions: Serum concentration of RANKL (Fig. 1a) was significantly higher in ACPA-positive (689 pmol/L, IQR 342–1253) than in ACPA-negative patients (159 pmol/L, IQR 96–243, p <0.05). Similarly, median synovial expression of RANKL (Fig. 1b-d) was significantly higher in ACPA-positive than in ACPA-negative patients.Fig. 1


Serum RANKL levels associate with anti- citrullinated protein antibodies in early untreated rheumatoid arthritis and are modulated following methotrexate.

Hensvold AH, Joshua V, Li W, Larkin M, Qureshi F, Israelsson L, Padyukov L, Lundberg K, Defranoux N, Saevarsdottir S, Catrina AI - Arthritis Res. Ther. (2015)

Serum and synovial RANKL is increased in ACPA-positive as compared to ACPA-negative rheumatoid arthritis (RA). Graphs illustrate the results of ELISA measurement of total serum RANKL concentrations in RA (a) and in RF-negative RA (e) grouped by ACPA status. Immunohistochemistry staining shows expression of synovial RANKL in one ACPA-positive (b) and one ACPA-negative RA patient (c) and the graph illustrate the results of image analysis in 15 patients (d). Horizontal lines represent median values, *p <0.05. ACPA anti-citrullinated protein antibodies, ELISA enzyme-linked immunosorbent assay, RANKL receptor activator of nuclear factor kappa B ligand, RF rheumatoid factor
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4559929&req=5

Fig1: Serum and synovial RANKL is increased in ACPA-positive as compared to ACPA-negative rheumatoid arthritis (RA). Graphs illustrate the results of ELISA measurement of total serum RANKL concentrations in RA (a) and in RF-negative RA (e) grouped by ACPA status. Immunohistochemistry staining shows expression of synovial RANKL in one ACPA-positive (b) and one ACPA-negative RA patient (c) and the graph illustrate the results of image analysis in 15 patients (d). Horizontal lines represent median values, *p <0.05. ACPA anti-citrullinated protein antibodies, ELISA enzyme-linked immunosorbent assay, RANKL receptor activator of nuclear factor kappa B ligand, RF rheumatoid factor
Mentions: Serum concentration of RANKL (Fig. 1a) was significantly higher in ACPA-positive (689 pmol/L, IQR 342–1253) than in ACPA-negative patients (159 pmol/L, IQR 96–243, p <0.05). Similarly, median synovial expression of RANKL (Fig. 1b-d) was significantly higher in ACPA-positive than in ACPA-negative patients.Fig. 1

Bottom Line: Patients with newly diagnosed untreated RA (n = 183) were analyzed at baseline and 3 months after initiating methotrexate (MTX) treatment.Pearson's chi-square test, Wilcoxon rank sum test, Wilcoxon signed rank test and linear regression models were used.Among ACPA specificites, anti-cit-vimentin (amino acids 60-75) was associated with higher RANKL concentration and higher prevalence of bone erosion (p <0.05).

View Article: PubMed Central - PubMed

Affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, L8:04 CMM, 171 76, Stockholm, Sweden. aase.hensvold@ki.se.

ABSTRACT

Introduction: Receptor activator of nuclear factor kappa B ligand (RANKL) is a key regulator of bone metabolism. Anti-citrullinated protein antibodies (ACPA) have been suggested to cause bone destruction by osteoclast activation. We investigated the relationship between RANKL and ACPA in patients with early untreated rheumatoid arthritis (RA).

Methods: Patients with newly diagnosed untreated RA (n = 183) were analyzed at baseline and 3 months after initiating methotrexate (MTX) treatment. Serum RANKL (total RANKL), ACPA (anti-CCP2) and ACPA specificities (anti-citrullinated (cit)-vimentin, anti-cit-enolase and anti-cit-fibrinogen) were determined by enzyme-linked immunosorbent assay (ELISA). Synovial RANKL expression was evaluated by immunohistochemistry in a small group of patients (n = 15). The relationship between anti-cit-vim antibodies and bone destruction was further validated in 1116 RA patients included in the EIRA cohort. Pearson's chi-square test, Wilcoxon rank sum test, Wilcoxon signed rank test and linear regression models were used.

Results: Serum RANKL concentration was significantly higher (p <0.05) in ACPA-positive (median: 689 pmol/L, IQR 342-1253) compared with ACPA-negative (median: 159 pmol/L, IQR 96-243) patients and this difference was also seen for synovial RANKL expression. Serum RANKL associated with ACPA (p <0.05) and bone erosions in rheumatoid factor (RF)-negative patients (n = 59). Among ACPA specificites, anti-cit-vimentin (amino acids 60-75) was associated with higher RANKL concentration and higher prevalence of bone erosion (p <0.05). Significant reductions in both serum RANKL and ACPA levels were observed after 3 months of MTX treatment (p <0.05).

Conclusions: RANKL was elevated in ACPA-positive and in anti-cit-vimentin-positive patients with early untreated RA and associated with bone erosions. These findings give further support for an early direct pathogenic link between ACPA and bone destruction in RA.

No MeSH data available.


Related in: MedlinePlus