Limits...
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 RANKL and ACPA associate with bone destruction. Graphs show the results of ELISA measurement of total serum RANKL concentrations in RF-negative RA patients grouped by bone erosion status (a). ACPA-positive and anti-cit-vim-positive patients observed higher prevalence of bone destructions than ACPA-negative or anti-cit-vim-negative patients in both early RA cohorts (b). Horizontal lines represent median values, *p <0.05; ns: p >0.05. VC denotes validation cohort. ACPA anti-citrullinated protein antibodies, cit citrullinated, ELISA enzyme-linked immunosorbent assay, RA rheumatoid arthritis, RANKL receptor activator of nuclear factor kappa B ligand, RF rheumatoid factor, vim vimentin
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig2: Serum RANKL and ACPA associate with bone destruction. Graphs show the results of ELISA measurement of total serum RANKL concentrations in RF-negative RA patients grouped by bone erosion status (a). ACPA-positive and anti-cit-vim-positive patients observed higher prevalence of bone destructions than ACPA-negative or anti-cit-vim-negative patients in both early RA cohorts (b). Horizontal lines represent median values, *p <0.05; ns: p >0.05. VC denotes validation cohort. ACPA anti-citrullinated protein antibodies, cit citrullinated, ELISA enzyme-linked immunosorbent assay, RA rheumatoid arthritis, RANKL receptor activator of nuclear factor kappa B ligand, RF rheumatoid factor, vim vimentin

Mentions: RANKL serum concentrations were significantly elevated (p <0.05) in patients with evidence of bone erosions at baseline (median 243 pmol/l, IQR 194–284, n = 9) compared with those without bone erosions (151 pmol/l, IQR 91–216, n = 50) (Fig. 2a). Baseline bone erosions were numerically more prevalent in ACPA-positive than ACPA-negative patients (24 vs. 16 %, p >0.05) and significantly more prevalent in anti-cit-vim (amino acids 60–75) -positive than anti-cit-vim-negative patients (32 vs. 15 %, p <0.05) (Fig. 2b), while no such differences were observed for anti-cit-enolase (amino acids 5–21) or anti-cit-fib (amino acids 563–583) antibodies. Interestingly, this association appear to be independent of ACPA levels as far as anti-cit vim (amino acids 60–75) -positive patients had a median ACPA titer of 533 AU/ml (IQR 190–1742), while anti-cit-fib (amino acids 563–583) -positive patients had a significant higher median ACPA titer of 2286 AU/ml (IQR 1580–5885).Fig. 2


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 RANKL and ACPA associate with bone destruction. Graphs show the results of ELISA measurement of total serum RANKL concentrations in RF-negative RA patients grouped by bone erosion status (a). ACPA-positive and anti-cit-vim-positive patients observed higher prevalence of bone destructions than ACPA-negative or anti-cit-vim-negative patients in both early RA cohorts (b). Horizontal lines represent median values, *p <0.05; ns: p >0.05. VC denotes validation cohort. ACPA anti-citrullinated protein antibodies, cit citrullinated, ELISA enzyme-linked immunosorbent assay, RA rheumatoid arthritis, RANKL receptor activator of nuclear factor kappa B ligand, RF rheumatoid factor, vim vimentin
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig2: Serum RANKL and ACPA associate with bone destruction. Graphs show the results of ELISA measurement of total serum RANKL concentrations in RF-negative RA patients grouped by bone erosion status (a). ACPA-positive and anti-cit-vim-positive patients observed higher prevalence of bone destructions than ACPA-negative or anti-cit-vim-negative patients in both early RA cohorts (b). Horizontal lines represent median values, *p <0.05; ns: p >0.05. VC denotes validation cohort. ACPA anti-citrullinated protein antibodies, cit citrullinated, ELISA enzyme-linked immunosorbent assay, RA rheumatoid arthritis, RANKL receptor activator of nuclear factor kappa B ligand, RF rheumatoid factor, vim vimentin
Mentions: RANKL serum concentrations were significantly elevated (p <0.05) in patients with evidence of bone erosions at baseline (median 243 pmol/l, IQR 194–284, n = 9) compared with those without bone erosions (151 pmol/l, IQR 91–216, n = 50) (Fig. 2a). Baseline bone erosions were numerically more prevalent in ACPA-positive than ACPA-negative patients (24 vs. 16 %, p >0.05) and significantly more prevalent in anti-cit-vim (amino acids 60–75) -positive than anti-cit-vim-negative patients (32 vs. 15 %, p <0.05) (Fig. 2b), while no such differences were observed for anti-cit-enolase (amino acids 5–21) or anti-cit-fib (amino acids 563–583) antibodies. Interestingly, this association appear to be independent of ACPA levels as far as anti-cit vim (amino acids 60–75) -positive patients had a median ACPA titer of 533 AU/ml (IQR 190–1742), while anti-cit-fib (amino acids 563–583) -positive patients had a significant higher median ACPA titer of 2286 AU/ml (IQR 1580–5885).Fig. 2

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