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

Abstract

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. Single-center observational prospective cohort study. Outpatient pediatric rheumatology clinic at a tertiary care academic pediatric hospital. The study included 61 patients diagnosed with JIA who started therapy with standard-dose MTX 15mg/m2 /week. At 3months, treating physicians were given the option of maintaining the MTX dose, increasing the MTX dose, or adding etanercept (ETN), based on their clinical judgment. Patients were evaluated at baseline, 3months (51 patients), and 6months (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 3months (p=0.005). Reductions in JADAS by 6months 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. 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.