Background Glucocorticoid-induced tumor necrosis factor receptor related protein (GITR) is a member of the tumor necrosis factor receptor superfamily that is activated by its specific ligand (GITRL). GITR is mainly expressed in immature and mature T cells especially regulatory (Treg) cells (CD4+ CD25+) and effector T cells (CD25–) . GITRL is mainly expressed in endothelial cells, dendritic cells, macrophages and B cells but not in T cells. GITR-GITRL system is known to have important regulatory role on inflammatory response and immune reactivity.
Objectives This study aimed to measure serum and synovial fluid (SF) levels of GITRL in patients with recent onset rheumatoid arthritis (RA) before and after initiation of therapy and to evaluate the relationship between GITRL and RA clinical and laboratory characteristics, disease activity and response to therapy.
Methods We measured GITRL in the serum (n=48) and SF samples (n=21) from 48 recent onset RA patients and in the serum from 20 healthy control (n=20) at baseline and 6 months after initiation therapy with non-biological disease modifying anti-rheumatic drugs (DMARDS). In the patients Disease activity was calculated by the 28 joint counts (DAS28) and musculoskeletal ultrasound examination (MSUS) was performed at baseline and after 6 months using a 12-joint score (bilateral elbow, wrist, 2nd metacarpophalangeal (MCP), 3rd MCP, knee, ankle) ; immunoglobulin-M rheumatoid factor (IgM-RF) titre, anti-cyclic citrullinated peptide (anti-CCP) antibodies titre and C-reactive protein (CRP) levels were measured and the health assessment questionnaire (HAQ) score were recorded.
Results Serum and SF GITRL levels were highly significantly increased in RA (39.38±16.78 ng/mL and 30.6±16.79 ng/mL respectively) compared to serum level in the healthy controls (10.3±5.46 ng/mL) (p<0.001). In RA patients, baseline serum and SF levels of GITRL significantly correlated with DAS28 (r=0.52 and 0.56 respectively, p<0.05), anti-CCP titres (r=0.46 and 0.51 respectively, p<0.05), grey scale (GS) (r=0.5 and 0.52 respectively, p<0.05) and power Doppler (PD) (r=0.65 and 0.68 respectively, p<0.001) synovitis scores. Also, serum and SF levels of GITRL at 6 months follow up significantly correlated with the DAS28 (r=0.42 and 0.48 respectively, p<0.05), GS score (r=0.46 and 0.51 respectively, p<0.05), PD signal (r=0.43 and 0.45 respectively, p<0.05). Logistic regression analysis showed that baseline serum levels of GITRL were predictive of follow up DAS 28 and PD synovitis score (p=0.009 and 0.03 respectively).
Conclusions Rheumatoid arthritis patients have significantly increased serum and synovial levels of GITRL that remarkably correlated with the DAS28 and MSUS parameters of inflammations suggesting that it could be a useful marker to reflect RA disease activity. GITRL could be a useful biomarker to predict treatment outcome in RA patients.
Kim SH, Youn J. Rheumatoid Fibroblast-like Synoviocytes Downregulate Foxp3 Expression by Regulatory T Cells Via GITRL/GITR Interaction. Immune Netw. 2012;12(5):217–21.
Naredo E, Rodríguez M, Campos C, Rodríguez-Heredia JM, Medina JA, Giner E, et al. Validity, reproducibility, and responsiveness of a twelve-joint simplified power Doppler ultrasonographic assessment of joint inflammation in rheumatoid arthritis. Arthritis Rheum 2008;59(4):515–22.
Disclosure of Interest None declared