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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 concentration of ACPA and ACPA specificities. Graphs show the results of ELISA measurements of the antibody concentrations for patients being positive at baseline or at 3 months for the corresponding antibody: ACPA n = 120 (a), anti-cit-enolase (amino acids 5–21) n = 71 (b), anti-citrullinated (cit)-vimentin (vim) (amino acids 60–75) n = 67 (c), anti-cit-fibrinogen (fib) (amino acids 563–583) antibodies n = 42 (d). Horizontal lines represent median values, *p <0.05. Dotted lines delineate ELISA cutoff values for each antibody. ACPA anti-citrullinated protein antibodies, ELISA enzyme-linked immunosorbent assay
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Fig3: Serum concentration of ACPA and ACPA specificities. Graphs show the results of ELISA measurements of the antibody concentrations for patients being positive at baseline or at 3 months for the corresponding antibody: ACPA n = 120 (a), anti-cit-enolase (amino acids 5–21) n = 71 (b), anti-citrullinated (cit)-vimentin (vim) (amino acids 60–75) n = 67 (c), anti-cit-fibrinogen (fib) (amino acids 563–583) antibodies n = 42 (d). Horizontal lines represent median values, *p <0.05. Dotted lines delineate ELISA cutoff values for each antibody. ACPA anti-citrullinated protein antibodies, ELISA enzyme-linked immunosorbent assay

Mentions: ACPA concentration decreased from 780 AU/ml (IRQ 273–2197) at baseline to 556 (IRQ 197–1920) at 3 months (p <0.05), for the patients that were ACPA-positive at baseline and/or at 3 months (n = 120) (Fig. 3a). ACPA levels decreased in a large majority of the patients (89 %, Table 3).Fig. 3


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 concentration of ACPA and ACPA specificities. Graphs show the results of ELISA measurements of the antibody concentrations for patients being positive at baseline or at 3 months for the corresponding antibody: ACPA n = 120 (a), anti-cit-enolase (amino acids 5–21) n = 71 (b), anti-citrullinated (cit)-vimentin (vim) (amino acids 60–75) n = 67 (c), anti-cit-fibrinogen (fib) (amino acids 563–583) antibodies n = 42 (d). Horizontal lines represent median values, *p <0.05. Dotted lines delineate ELISA cutoff values for each antibody. ACPA anti-citrullinated protein antibodies, ELISA enzyme-linked immunosorbent assay
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: Serum concentration of ACPA and ACPA specificities. Graphs show the results of ELISA measurements of the antibody concentrations for patients being positive at baseline or at 3 months for the corresponding antibody: ACPA n = 120 (a), anti-cit-enolase (amino acids 5–21) n = 71 (b), anti-citrullinated (cit)-vimentin (vim) (amino acids 60–75) n = 67 (c), anti-cit-fibrinogen (fib) (amino acids 563–583) antibodies n = 42 (d). Horizontal lines represent median values, *p <0.05. Dotted lines delineate ELISA cutoff values for each antibody. ACPA anti-citrullinated protein antibodies, ELISA enzyme-linked immunosorbent assay
Mentions: ACPA concentration decreased from 780 AU/ml (IRQ 273–2197) at baseline to 556 (IRQ 197–1920) at 3 months (p <0.05), for the patients that were ACPA-positive at baseline and/or at 3 months (n = 120) (Fig. 3a). ACPA levels decreased in a large majority of the patients (89 %, Table 3).Fig. 3

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