Limits...
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.

Show MeSH

Related in: MedlinePlus

Peripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMC) from patients with chronic rheumatoid arthritis (cRA) (n = 15) and mononuclear cells from PBMC fromearly rheumatoid arthritis (eRA) (n =5) and healthy volunteers (HV) (n = 10) were examined by flow cytometry for expression of CD4, CD14, CD19, CD45RO, OX40, and OX40L. Closed squares = peripheral blood from patients with cRA; semi-solid squares = peripheral blood from patients with eRA; gray squares = synovial fluid from patients with cRA; white squares = peripheral blood from healthy volunteers. We observed an increased percentage of OX40- and OX40L-expressing cells in the synovial fluid, with CD4 + CD45RO + T-cells being more positive for OX40 and CD19+ B cells and monocytes being more positive for OX40L. Paired data (PBMC and SFMC) were analyzed by Wilcoxon signed-rank test, non-paired data were analyzed by the Mann-Whitney U-test. Solid lines represent median with interquartile range and whiskers represent the 5th to 95th percentiles. *P <0.05 and **P <0.01, ***P <0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig3: Peripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMC) from patients with chronic rheumatoid arthritis (cRA) (n = 15) and mononuclear cells from PBMC fromearly rheumatoid arthritis (eRA) (n =5) and healthy volunteers (HV) (n = 10) were examined by flow cytometry for expression of CD4, CD14, CD19, CD45RO, OX40, and OX40L. Closed squares = peripheral blood from patients with cRA; semi-solid squares = peripheral blood from patients with eRA; gray squares = synovial fluid from patients with cRA; white squares = peripheral blood from healthy volunteers. We observed an increased percentage of OX40- and OX40L-expressing cells in the synovial fluid, with CD4 + CD45RO + T-cells being more positive for OX40 and CD19+ B cells and monocytes being more positive for OX40L. Paired data (PBMC and SFMC) were analyzed by Wilcoxon signed-rank test, non-paired data were analyzed by the Mann-Whitney U-test. Solid lines represent median with interquartile range and whiskers represent the 5th to 95th percentiles. *P <0.05 and **P <0.01, ***P <0.001.

Mentions: We investigated which cells express the membrane-bound isoforms. PBMC from eRA (n = 5), and paired SFMC and PBMC from cRA (n = 15) were examined for expression of OX40 and OX40L by T cells, B cells, and monocytes. As expected, OX40 was mainly expressed by CD4 + CD45RO + T cells in the inflamed joint compared with peripheral blood (Figure 3). The highest percent of OX40-expressing cells, was seen on CD4 + CD45RO + T cells of cRA SFMC (37.5% (27.1% to 44.2%)) compared with cRA PBMC (22.9% (14.3% to 30.7%)), eRA PBMC (18.3% (13.8% to 22.65%)) and HV PBMC (13.7% (11.2 to 18.1%)) (all P <0.001). OX40+ cells were significantly higher on CD4 + CD45RO + T cells of cRA PBMC compared with HV PBMCs (P <0.05). OX40+ B cells and monocytes were only present in low numbers.Figure 3


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)

Peripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMC) from patients with chronic rheumatoid arthritis (cRA) (n = 15) and mononuclear cells from PBMC fromearly rheumatoid arthritis (eRA) (n =5) and healthy volunteers (HV) (n = 10) were examined by flow cytometry for expression of CD4, CD14, CD19, CD45RO, OX40, and OX40L. Closed squares = peripheral blood from patients with cRA; semi-solid squares = peripheral blood from patients with eRA; gray squares = synovial fluid from patients with cRA; white squares = peripheral blood from healthy volunteers. We observed an increased percentage of OX40- and OX40L-expressing cells in the synovial fluid, with CD4 + CD45RO + T-cells being more positive for OX40 and CD19+ B cells and monocytes being more positive for OX40L. Paired data (PBMC and SFMC) were analyzed by Wilcoxon signed-rank test, non-paired data were analyzed by the Mann-Whitney U-test. Solid lines represent median with interquartile range and whiskers represent the 5th to 95th percentiles. *P <0.05 and **P <0.01, ***P <0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig3: Peripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMC) from patients with chronic rheumatoid arthritis (cRA) (n = 15) and mononuclear cells from PBMC fromearly rheumatoid arthritis (eRA) (n =5) and healthy volunteers (HV) (n = 10) were examined by flow cytometry for expression of CD4, CD14, CD19, CD45RO, OX40, and OX40L. Closed squares = peripheral blood from patients with cRA; semi-solid squares = peripheral blood from patients with eRA; gray squares = synovial fluid from patients with cRA; white squares = peripheral blood from healthy volunteers. We observed an increased percentage of OX40- and OX40L-expressing cells in the synovial fluid, with CD4 + CD45RO + T-cells being more positive for OX40 and CD19+ B cells and monocytes being more positive for OX40L. Paired data (PBMC and SFMC) were analyzed by Wilcoxon signed-rank test, non-paired data were analyzed by the Mann-Whitney U-test. Solid lines represent median with interquartile range and whiskers represent the 5th to 95th percentiles. *P <0.05 and **P <0.01, ***P <0.001.
Mentions: We investigated which cells express the membrane-bound isoforms. PBMC from eRA (n = 5), and paired SFMC and PBMC from cRA (n = 15) were examined for expression of OX40 and OX40L by T cells, B cells, and monocytes. As expected, OX40 was mainly expressed by CD4 + CD45RO + T cells in the inflamed joint compared with peripheral blood (Figure 3). The highest percent of OX40-expressing cells, was seen on CD4 + CD45RO + T cells of cRA SFMC (37.5% (27.1% to 44.2%)) compared with cRA PBMC (22.9% (14.3% to 30.7%)), eRA PBMC (18.3% (13.8% to 22.65%)) and HV PBMC (13.7% (11.2 to 18.1%)) (all P <0.001). OX40+ cells were significantly higher on CD4 + CD45RO + T cells of cRA PBMC compared with HV PBMCs (P <0.05). OX40+ B cells and monocytes were only present in low numbers.Figure 3

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