In early rheumatoid arthritis, elevated serum levels of ifn-regulated chemokines are associated with disease activity, autoantibody secretion and radiographic progression
Résumé
Background: The interferon (IFN) signature has mainly been studied in established rheumatoid arthritis (RA), and was associated with poor response to rituximab. Serum CCL2, CXCL10 and CCL19 levels are associated with an interferon (IFN) gene signature and disease activity in systemic lupus. The objectives were to assess the IFN serum signature, and its association with features of early RA
Methods: The ESPOIR cohort has enrolled 813 patients with early arthritis (more than 6 weeks and less than 6 months) not treated with steroid or DMARD. RA was defined according to ACR/EULAR 2010 criteria. Serum CXC10, CCL19 and CCL2 levels were assessed in 806, 805 and 748 patients at enrollment and in 88 sex and age-matched controls. An elevated level of each chemokine was defined as a value greater than the mean + 2DS value of the control population. Patients with at least 2 elevated serum levels among these 3 IFN-regulated chemokines were defined to have an INF-high score.
Results: Among the 813 patients included in the ESPOIR cohort, 694 (78% female, mean age 48.5±12.3, mean DAS28 5.3±1.2) had RA according to ACR/EULAR 2010 criteria. Elevated levels of CCL2, CXCL10, CCL19 were observed in 1.7% of early RA patients vs 0.09% of patients with other early arthritides (P=0.9), 48.5 vs 38.1% (P=0.04) and 21.8 vs 8.5% (P= 0.006), respectively. An IFN-high score was observed in 14.1% of RA patients vs 3.4% of patients with other early arthritides (P= 0.006) and had a greater positive predictive value (96.0%) for RA diagnosis than any individual chemokine. The level of anti-PG antibodies did not significantly differ between patients with/without an IFN-high score (2.9 [2.1-4.9] vs 3.2[2.2-4.9], P= 0.8). Females and ever smokers did not have a more frequent IFN-high score (11.7 and 12.5%, respectively) than males and never smokers (15.5 and 12.6%, P=0.2 and P=1, respectively). Among the 694 patients with RA according to ACR/EULAR 2010. CXCL10 and CCL19 were significantly correlated with DAS28 at enrollment (r= 0.2, P< 0.0001 for both) whereas CCL2 was not. Patients with RF or anti-CCP autoantibodies had elevated CCL19 (342.1[157.2-724.1] vs 212.7 [93.1-423.4] pg/ml, P<0.0001 and 332.6 [161.8-650.1] vs 207.1 [85.6-420.7] pg/ml, P<0.0001) whereas they had similar CCL2 and CXCL10 levels. Radiographic progression at 2 years (increase of total Sharp score greater than 1 or than 5) was associated with a significant increase in CCL2 (P= 0.03 and P= 0.002, respectively) and CCL19(P= 0.02 and P= 0.008, respectively), but not in CXCL10.
Conclusions: Assessment of 3 IFN-regulated chemokines allowed identifying a serum IFN signature in 14% of patients with early RA. This signature is probably genetically determined given the absence of association with environmental factors and the known role of IFN gene polymorphisms in RA. CCL19, involved in germinal center formation, was associated with autoantibody secretion, disease activity and radiographic progression, CXCL10, involved in leucocyte homing, with disease activity and CCL2, which stimulates osteoclastogenesis, with radiographic progression. This suggests the potential therapeutic interest of targeting IFN in early RA.