Cytokine Biomarkers of Disease Activity and Therapeutic Response after Initiating Methotrexate Therapy in Patients with Juvenile Idiopathic Arthritis

Abstract

Study objective: To evaluate the relationship between plasma cytokine levels with disease activity and therapeutic response in patients with juvenile idiopathic arthritis (JIA) after initiating methotrexate (MTX) therapy.

Design: Single-center observational prospective cohort study.

Setting: Outpatient pediatric rheumatology clinic at a tertiary care academic pediatric hospital.

Patients: The study included 61 patients diagnosed with JIA who started therapy with standard-dose MTX 15 mg/m² /week. At 3 months, treating physicians were given the option of maintaining the MTX dose, increasing the MTX dose, or adding etanercept (ETN), based on their clinical judgment.

Measurements and main results: Patients were evaluated at baseline, 3 months (51 patients), and 6 months (35 patients). Plasma samples from each visit were analyzed for interleukin (IL)-1α, IL-1β, IL-1Ra, IL-6, and tumor necrosis factor-α (TNF-α). Cytokine concentrations were evaluated for relationships with disease activity using the 71-joint count Juvenile Arthritis Disease Activity Score (JADAS). Therapeutic response was assessed by changes in JADAS. Failure to respond to standard-dose MTX was defined as the need for the addition of ETN or a MTX dose increase at or before the 3-month visit. Increased disease severity at baseline was associated with increased IL-6 (p=0.01) and TNF-α (p=0.008) levels. Initiation of MTX was associated with reductions in IL-1α (p=0.009), IL-1β (p=0.01), IL-1Ra (p=0.007), and IL-6 (p=0.03) levels; however, reductions in JADAS were only associated with reductions in IL-6 (p=0.009) and TNF-α levels (p=0.02). Compared with responders, patients failing to respond to standard-dose MTX had increased TNF-α levels at baseline (p=0.02) and at 3 months (p=0.005). Reductions in JADAS by 6 months were observed following either the addition of ETN (p=0.009) or an increase in MTX dose (p=0.007), but the addition of ETN was associated with a median 7-fold increase in TNF-α levels (p=0.003) that corresponded with clinical response.

Conclusion: Plasma cytokine levels were responsive to MTX therapy in patients with JIA, but only TNF-α and IL-6 levels were consistently associated with disease activity and therapeutic response. Increased TNF-α levels at baseline were associated with failure to respond to standard-dose MTX and the need for more aggressive drug therapy. Initiation of ETN resulted in increased TNF-α levels that corresponded with therapeutic response, suggesting a potential clinical benefit of monitoring TNF-α levels as a pharmacodynamic marker of etanercept activity.

Keywords: biomarkers; cytokines; etanercept; juvenile idiopathic arthritis; methotrexate.