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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 the ratio between sOX40 and sOX40L in early rheumatoid arthritis (eRA) and chronic rheumatoid arthritis (cRA). The ratio was significantly lower in patients with eRA than in patients with cRA. Healthy volunteers are not included as many of the measurements for both sOX40 and sOX40L were below the level of detection. Paired data (within the eRA group) were analyzed by the Wilcoxon signed-rank test and non-paired data were analyzed by the Mann-Whitney U-test. Boxes represent median with interquartile range and whiskers represent the 5th to 95th percentiles. *P <0.05, ***P <0.001.
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Fig2: Comparison of the ratio between sOX40 and sOX40L in early rheumatoid arthritis (eRA) and chronic rheumatoid arthritis (cRA). The ratio was significantly lower in patients with eRA than in patients with cRA. Healthy volunteers are not included as many of the measurements for both sOX40 and sOX40L were below the level of detection. Paired data (within the eRA group) were analyzed by the Wilcoxon signed-rank test and non-paired data were analyzed by the Mann-Whitney U-test. Boxes represent median with interquartile range and whiskers represent the 5th to 95th percentiles. *P <0.05, ***P <0.001.

Mentions: It has been suggested that like other members of the TNF superfamily, sOX40 and sOX40L function antagonistically to their membrane-bound forms. We therefore calculated the sOX40/sOX40L ratio to determine this axis in our cohort of eRA patients and correlated it with core disease parameters. Because sOX40 was measured in pg/ml and sOX40L was measured in ng/ml, the ratio was multiplied by a factor of 1,000. The sOX40/sOX40L ratio was significantly decreased in eRA compared with cRA throughout the study period (all P <0.001, Figure 2). We did not calculate a ratio for the HV, as many of the measurements for both sOX40 and sOX40L were below the detection limit. Adalimumab was discontinued after the first 12 month of treatment after which time patients underwent clinical examination at 3-months intervals for an additional year. Neither sOX40 nor sOX40L plasma levels were associated with change in disease activity (data not shown). However, patients with a high sOX40/sOX40L ratio at the time of adalimumab discontinuation had a significantly lower DAS28CRP after 3 months of follow up (P <0.05, data not shown). We did not observe the same correlation in the Placebo group (P = 0.9, data not shown). We also examined any association with disease flare and identified four patients with flare. They had a significantly decreased sOX40/sOX40L ratio compared with patients without flare (P <0.05, data not shown).Figure 2


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 the ratio between sOX40 and sOX40L in early rheumatoid arthritis (eRA) and chronic rheumatoid arthritis (cRA). The ratio was significantly lower in patients with eRA than in patients with cRA. Healthy volunteers are not included as many of the measurements for both sOX40 and sOX40L were below the level of detection. Paired data (within the eRA group) were analyzed by the Wilcoxon signed-rank test and non-paired data were analyzed by the Mann-Whitney U-test. Boxes represent median with interquartile range and whiskers represent the 5th to 95th percentiles. *P <0.05, ***P <0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: Comparison of the ratio between sOX40 and sOX40L in early rheumatoid arthritis (eRA) and chronic rheumatoid arthritis (cRA). The ratio was significantly lower in patients with eRA than in patients with cRA. Healthy volunteers are not included as many of the measurements for both sOX40 and sOX40L were below the level of detection. Paired data (within the eRA group) were analyzed by the Wilcoxon signed-rank test and non-paired data were analyzed by the Mann-Whitney U-test. Boxes represent median with interquartile range and whiskers represent the 5th to 95th percentiles. *P <0.05, ***P <0.001.
Mentions: It has been suggested that like other members of the TNF superfamily, sOX40 and sOX40L function antagonistically to their membrane-bound forms. We therefore calculated the sOX40/sOX40L ratio to determine this axis in our cohort of eRA patients and correlated it with core disease parameters. Because sOX40 was measured in pg/ml and sOX40L was measured in ng/ml, the ratio was multiplied by a factor of 1,000. The sOX40/sOX40L ratio was significantly decreased in eRA compared with cRA throughout the study period (all P <0.001, Figure 2). We did not calculate a ratio for the HV, as many of the measurements for both sOX40 and sOX40L were below the detection limit. Adalimumab was discontinued after the first 12 month of treatment after which time patients underwent clinical examination at 3-months intervals for an additional year. Neither sOX40 nor sOX40L plasma levels were associated with change in disease activity (data not shown). However, patients with a high sOX40/sOX40L ratio at the time of adalimumab discontinuation had a significantly lower DAS28CRP after 3 months of follow up (P <0.05, data not shown). We did not observe the same correlation in the Placebo group (P = 0.9, data not shown). We also examined any association with disease flare and identified four patients with flare. They had a significantly decreased sOX40/sOX40L ratio compared with patients without flare (P <0.05, data not shown).Figure 2

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