High serum levels of CXCL13 predict lower response to csDMARDs in both ACPA-positive and ACPA-negative early rheumatoid arthritis

Objectives: Increased circulating levels of CXCL13 reflect synovial production and indicate immune dysregulation in patients with rheumatoid arthritis (RA). Here we tested whether CXCL13 predicts response to first-line treatment with methotrexate (MTX) in patients with early RA, independently and in association with anti-citrullinated protein antibodies (ACPA) and IgM-rheumatoid factor (RF). Methods: A prospective cohort of 243 early RA patients undergoing treat-to-target with MTX was evaluated. CXCL13, ACPA and IgM-RF were determined on baseline sera. Short-term variations of CXCL13 were measured after 2 months. The association of high CXCL13 (>= 100 pg/ml) with disease remission after 6 months and escalation to second-line therapies within year 2 was evaluated in the total population and in ACPA-subgroups separately. Results: High levels of CXCL13 were found in 53.6% of ACPA-positive and 31.5% of ACPA-negative patients, with minimal association with disease activity and RF. Serum CXCL13 remained stable after 2 months. High baseline CXCL13 independently predicted failure to achieve remission and more frequent requirement of second-line treatment in ACPA-positive patients, with adjusted ORs in the range of 0.17-0.49 for remission and 6.75 for second-line treatment. In ACPA-negative patients with high CXCL13, remission occurred at the expense of higher doses of MTX, and levels of CXCL13 predicted MTX escalations with an adjusted OR (95% CI) of 2.69 (1.35-5.34). Conclusions: High serum levels of CXCL13 identify a subgroup of RA patients who are more refractory to first-line treatment with MTX. CXCL13 appears a promising biomarker of response to MTX in both ACPA-positive and -negative early RA.