Background/Purpose:   Despite a poor understanding of its biochemical role in the inflammatory process, nicotinamide phosphoribosyltransferase (NAMPT) has been implicated in a number of autoimmune conditions, and its inhibition has resulted in the reduction of pro-inflammatory cytokines.  This study evaluates pre- and post-treatment plasma levels of NAMPT and other inflammatory biomarkers in response to initiation of low-dose methotrexate (MTX) in JIA.

Methods:   Plasma samples from thirty-two JIA patients between 3 and 17 years of age were evaluated.  Samples were collected prior to and 3 months after the initiation of MTX therapy, with twenty-six patients providing samples for both sampling periods.  Plasma levels of IL-1α, IL-1β, IL-1RA, IL-6 and TNFα were determined by multiplex analysis (Milliplex MAP, Millipore).  Plasma NAMPT levels were determined by competitive EIA.  Therapeutic response was determined by Peds ACR and JADAS-71 scoring at 3 months on therapy.  Statistical analyses were conducted by Spearman’s rank correlation, simple linear regression, Wilcoxon signed rank, and Wilcoxon rank-sum tests, as appropriate.

Results:   Plasma levels of Nampt were found to correlate with IL-1α (ρ=0.45, p<0.001), IL-1β (ρ=0.31, p<0.05), IL-1ra (ρ=0.49, p<0.001), IL-6 (ρ=0.34, p<0.01) and CRP (ρ=0.28, p<0.05).  At 3 months on MTX, significant reductions in IL-1α (p<0.05), IL-1β (p<0.05), IL-1RA (p<0.001) and TNFα (p<0.05) were observed, however IL-6 and NAMPT did not decrease significantly.  Patients achieving Peds ACR 30 had lower plasma IL-1α levels at 3 months than non-responders (4.2±7.7 vs. 17.5±14.3 pg/mL, p < 0.05), and JADAS-71 scores were associated with 3 month IL-6 (p<0.01) and TNFα (p<0.05) concentrations.

Pre-treatment NAMPT concentrations were lower in patients achieving a Peds ACR 50 response at 3 months (11.9±2.1 vs. 16.7±4.1 ng/mL, p< 0.01).  In addition, an inverse relationship was observed between pre-treatment NAMPT concentrations and the change in active joint count (p<0.01) and change in JADAS-71 (p=0.06) from baseline to 3 months on MTX therapy.

Conclusion:   Plasma NAMPT correlates with several cytokines observed in inflammatory arthritis, and although NAMPT concentrations did not significantly change over the treatment period, pre-treatment NAMPT concentrations were lower in JIA responders at 3 months.  Therefore, NAMPT may provide a novel predictive biomarker of early therapeutic response in JIA patients treated with low-dose MTX.