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Soluble OX40L is associated with presence of autoantibodies in early rheumatoid arthritis.

Laustsen JK, Rasmussen TK, Stengaard-Pedersen K, Hørslev-Petersen K, Hetland ML, Østergaard M, Junker P, Hvid M, Deleuran B - Arthritis Res. Ther. (2014)

Bottom Line: Soluble OX40 plasma levels of eRA patients were not different at the time of treatment initiation, but were significantly higher after 12 months of treatment, compared with HV or cRA patients.Soluble OX40L was significantly elevated throughout the first 12 months of treatment compared with HVs and patients with cRA.The sOX40/sOX40L ratio was decreased in eRA, and a low ratio at the time of adalimumab discontinuation was associated with increased DAS28CRP and risk of flare the following year.

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: OX40 and its ligand OX40L are key components in the generation of adaptive memory response and provide necessary co-stimulatory signals for activated effector T cells. Here we investigate the dual roles of the membrane and soluble (s) forms of OX40 and OX40L in plasma and synovial fluid and their association with autoantibodies and disease activity in rheumatoid arthritis (RA).

Methods: Soluble OX40 and sOX40L plasma levels were measured in treatment-naïve early RA patients (eRA) at baseline and after 3, 6, and 12 months of treatment with methotrexate and adalimumab (n = 39) and with methotrexate alone (n = 37). Adalimumab was discontinued after the first year, and patients were followed for additional 12 months. For comparison, sOX40 and sOX40L were measured in patients with chronic RA (cRA, n = 15) and healthy volunteers (HV, n = 34). Membrane-bound OX40 and OX40L expression on T cells, B cells and monocytes were quantified.

Results: Soluble OX40 plasma levels of eRA patients were not different at the time of treatment initiation, but were significantly higher after 12 months of treatment, compared with HV or cRA patients. Soluble OX40L was significantly elevated throughout the first 12 months of treatment compared with HVs and patients with cRA. Adalimumab treatment did not influence sOX40 or sOX40L plasma levels. At baseline, sOX40L levels were strongly associated with the presence of anti-citrullinated protein antibodies (ACPA) (P <0.001) and IgM-RF (P <0.0001). The sOX40/sOX40L ratio was decreased in eRA, and a low ratio at the time of adalimumab discontinuation was associated with increased DAS28CRP and risk of flare the following year. T cells in the synovial fluid had the highest expression of OX40, while monocytes and B cells were the main expressers of OX40L in the joint.

Conclusions: Plasma levels of sOX40 and sOX40L were increased in eRA and sOX40L was correlated with ACPA and IgM-RF. Further, expression of membrane-bound OX40 and OX40L was increased in eRA and cRA. Combined, these findings could reflect that increased activity in the OX40 systems facilitate to drive disease activity and autoantibody production in RA.

Trial registration: Clincaltrials.gov NCT00660647, 10 April 2008.

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Related in: MedlinePlus

Comparison of plasma sOX40 (A) and sOX40L (B) from patients with early rheumatoid arthritis (eRA) (n =76), chronic rheumatoid arthritis (cRA) (n = 15), and healthy volunteers (HV) (n = 34). Plasma samples from patients with eRA were obtained at treatment initiation (0), and after 3 and 12 months of treatment. Patients with cRA had all had disease for more than 8 years. Paired data (within the eRA group) were analyzed by Wilcoxon signed-rank test, non-paired data were analyzed by Mann-Whitney U-test. Boxes represent median with interquartile range, and whiskers represent the 5th to 95th percentile: *P <0.05; **P <0.01; ***P <0.001. ELISA cutoff is indicated by the dotted line.
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Fig1: Comparison of plasma sOX40 (A) and sOX40L (B) from patients with early rheumatoid arthritis (eRA) (n =76), chronic rheumatoid arthritis (cRA) (n = 15), and healthy volunteers (HV) (n = 34). Plasma samples from patients with eRA were obtained at treatment initiation (0), and after 3 and 12 months of treatment. Patients with cRA had all had disease for more than 8 years. Paired data (within the eRA group) were analyzed by Wilcoxon signed-rank test, non-paired data were analyzed by Mann-Whitney U-test. Boxes represent median with interquartile range, and whiskers represent the 5th to 95th percentile: *P <0.05; **P <0.01; ***P <0.001. ELISA cutoff is indicated by the dotted line.

Mentions: In the initial experiments, we wanted to determine the plasma level of sOX40 in eRA patients and to compare this level with the corresponding levels in cRA patients and HV. At the time of treatment initiation, eRA patients’ sOX40 levels were similar to those of cRA and HV. During the first treatment year sOX40 levels increased from 5.97 pg/ml (5.97 pg/ml to 7.14 pg/ml) at baseline to 11.47 pg/ml (7.69 pg/ml to 13.68 pg/ml) at 12 months (P <0.001), and sOX40 levels at 12 months were also significantly higher than those of cRA patients (5.97 pg/ml (5.97 pg/ml to 10.03 pg/ml) and HV (5.97 pg/ml (5.97 pg/ml to 17.34 pg/ml)) (both P <0.01, Figure 1A).Figure 1


Soluble OX40L is associated with presence of autoantibodies in early rheumatoid arthritis.

Laustsen JK, Rasmussen TK, Stengaard-Pedersen K, Hørslev-Petersen K, Hetland ML, Østergaard M, Junker P, Hvid M, Deleuran B - Arthritis Res. Ther. (2014)

Comparison of plasma sOX40 (A) and sOX40L (B) from patients with early rheumatoid arthritis (eRA) (n =76), chronic rheumatoid arthritis (cRA) (n = 15), and healthy volunteers (HV) (n = 34). Plasma samples from patients with eRA were obtained at treatment initiation (0), and after 3 and 12 months of treatment. Patients with cRA had all had disease for more than 8 years. Paired data (within the eRA group) were analyzed by Wilcoxon signed-rank test, non-paired data were analyzed by Mann-Whitney U-test. Boxes represent median with interquartile range, and whiskers represent the 5th to 95th percentile: *P <0.05; **P <0.01; ***P <0.001. ELISA cutoff is indicated by the dotted line.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4230735&req=5

Fig1: Comparison of plasma sOX40 (A) and sOX40L (B) from patients with early rheumatoid arthritis (eRA) (n =76), chronic rheumatoid arthritis (cRA) (n = 15), and healthy volunteers (HV) (n = 34). Plasma samples from patients with eRA were obtained at treatment initiation (0), and after 3 and 12 months of treatment. Patients with cRA had all had disease for more than 8 years. Paired data (within the eRA group) were analyzed by Wilcoxon signed-rank test, non-paired data were analyzed by Mann-Whitney U-test. Boxes represent median with interquartile range, and whiskers represent the 5th to 95th percentile: *P <0.05; **P <0.01; ***P <0.001. ELISA cutoff is indicated by the dotted line.
Mentions: In the initial experiments, we wanted to determine the plasma level of sOX40 in eRA patients and to compare this level with the corresponding levels in cRA patients and HV. At the time of treatment initiation, eRA patients’ sOX40 levels were similar to those of cRA and HV. During the first treatment year sOX40 levels increased from 5.97 pg/ml (5.97 pg/ml to 7.14 pg/ml) at baseline to 11.47 pg/ml (7.69 pg/ml to 13.68 pg/ml) at 12 months (P <0.001), and sOX40 levels at 12 months were also significantly higher than those of cRA patients (5.97 pg/ml (5.97 pg/ml to 10.03 pg/ml) and HV (5.97 pg/ml (5.97 pg/ml to 17.34 pg/ml)) (both P <0.01, Figure 1A).Figure 1

Bottom Line: Soluble OX40 plasma levels of eRA patients were not different at the time of treatment initiation, but were significantly higher after 12 months of treatment, compared with HV or cRA patients.Soluble OX40L was significantly elevated throughout the first 12 months of treatment compared with HVs and patients with cRA.The sOX40/sOX40L ratio was decreased in eRA, and a low ratio at the time of adalimumab discontinuation was associated with increased DAS28CRP and risk of flare the following year.

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: OX40 and its ligand OX40L are key components in the generation of adaptive memory response and provide necessary co-stimulatory signals for activated effector T cells. Here we investigate the dual roles of the membrane and soluble (s) forms of OX40 and OX40L in plasma and synovial fluid and their association with autoantibodies and disease activity in rheumatoid arthritis (RA).

Methods: Soluble OX40 and sOX40L plasma levels were measured in treatment-naïve early RA patients (eRA) at baseline and after 3, 6, and 12 months of treatment with methotrexate and adalimumab (n = 39) and with methotrexate alone (n = 37). Adalimumab was discontinued after the first year, and patients were followed for additional 12 months. For comparison, sOX40 and sOX40L were measured in patients with chronic RA (cRA, n = 15) and healthy volunteers (HV, n = 34). Membrane-bound OX40 and OX40L expression on T cells, B cells and monocytes were quantified.

Results: Soluble OX40 plasma levels of eRA patients were not different at the time of treatment initiation, but were significantly higher after 12 months of treatment, compared with HV or cRA patients. Soluble OX40L was significantly elevated throughout the first 12 months of treatment compared with HVs and patients with cRA. Adalimumab treatment did not influence sOX40 or sOX40L plasma levels. At baseline, sOX40L levels were strongly associated with the presence of anti-citrullinated protein antibodies (ACPA) (P <0.001) and IgM-RF (P <0.0001). The sOX40/sOX40L ratio was decreased in eRA, and a low ratio at the time of adalimumab discontinuation was associated with increased DAS28CRP and risk of flare the following year. T cells in the synovial fluid had the highest expression of OX40, while monocytes and B cells were the main expressers of OX40L in the joint.

Conclusions: Plasma levels of sOX40 and sOX40L were increased in eRA and sOX40L was correlated with ACPA and IgM-RF. Further, expression of membrane-bound OX40 and OX40L was increased in eRA and cRA. Combined, these findings could reflect that increased activity in the OX40 systems facilitate to drive disease activity and autoantibody production in RA.

Trial registration: Clincaltrials.gov NCT00660647, 10 April 2008.

Show MeSH
Related in: MedlinePlus