Background Rheumatoid arthritis (RA) is an autoimmune disease characterised by the presence of autoantibodies and autoreactive T cells, leading to synovitis and progressive destruction of the joints. The TNF-family members OX40 and OX40L are crucial for the generation of memory T cells, which can lead to persistence of immunity, if the T cells are autoreactive (1), Both molecules exist in a soluble form (s), and have previously been connected to autoimmune diseases (2). Furthermore, sOX40 have been suggested to be antagonistic to the membrane bound form, and thereby have an anti-inflammatory function (3).
Objectives To investigate the presence and bioactivity of sOX40 and sOX40L and their association with disease activity and progression in RA
Methods Plasma samples from early RA patients (eRA, n=76) randomised to conventional DMARD treatment with or without 12 months of adalimumab treatment were obtained from the OPERA study. Correlations between plasma levels of sOX40 and sOX40L (analysed by ELISA; detection limits 5.97 pg/ml and 1.16 ng/ml, respectively) at 0, 3, and 12 months after treatment initiation and DAS28, HAQ, IgM-RF, and anti-CCP were calculated. The results were compared with a transverse sample set of chronic RA patients (cRA, n=12, disease duration > 8 years) and with healthy volunteers (HV, n=32). All data are expressed as median.
Results eRA had a low amount of sOX40 at baseline (5.97 pg/ml), which increased to 11.47 pg/ml at 12 months (p<0.0001). The level at 12 months was also significantly increased compared with both HV and cRA (all p<0.005). Soluble OX40L was significantly elevated (18.30 ng/ml) compared with HV (1.16 ng/ml, p<0.0001) and cRA (1.59 ng/ml, p<0.01), and remained elevated at 12 months (15.10 ng/ml, p=0.7). Soluble OX40 and sOX40L levels were unaffected by addition of adalimumab treatment. The levels of sOX40L were strongly associated with presence of IgM-RF and anti-CCP at 0 months (rho=0.5 and 0.4, respectively, p<0.0001). The sOX40/sOX40L ratio was significantly decreased in eRA compared with HV and cRA (all p<0.0001). The sOX40/sOX40L ratio at adalimumab discontinuation (12 months) correlated with disease flare in the following 6 months (p=0.007)
Conclusions The findings of this study showed, that sOX40L was markedly elevated in eRA compared with HV and cRA, suggesting that sOX40L plays a key role in early RA. The level of sOX40L remained high despite adalimumab treatment, and sOX40 levels increased, indicating that anti-TNFα treatment does not affect memory generation. Combined with the predictive values of the sOX40L/sOX40 ratio to risk of disease flare this dysfunction in the OX40 system could explain why many patients experience relapse after anti-TNF discontinuation
: Ishii et al., OX40-OX40L interaction in T-cell mediated immunity and immunopathology, Advances in immunology, chapter 3, 2010
M. Croft, Control of immunity by the TNFR-Related molecule OX40 (CD134), Annu. Rev. Immunol 2010, 28. 57-78
R Sibliano et al., Technical advance: soluble OX40 molecule mimics regulatory T cell modulatory activity on FCεRI-dependent mast cell degranulation, J Leukoc Biol. 2011
Disclosure of Interest None Declared