Background/Purpose:
TNF inhibitors have
been used as a treatment for moderate to severe RA patients. However, reliable
biomarkers that predict therapeutic response to TNF inhibitors are lacking.  In
RA, Th1 cells stimulate macrophage activation via IFNγ and lead to secretion
of TNF. Th17 cells are another pro-inflammatory Th subset which secrete IL17
and have also been involved in the pathogenesis of RA. In this study, we
investigated whether Th1- and Th17- associated chemokines may represent useful
prognostic biomarkers for TNF inhibitor treatment in RA. 

Methods:   We recruited RA patients from the
Cooper University Hospital Rheumatology Clinic. The inclusion criteria for this
study were: 1. diagnosis of RA by ACR criteria, 2. active RA defined by DAS
>4.4, 3. clinical indication for initiating adalimumab or etanercept
treatment. The exclusion criteria were: 1. diagnosis of other connective tissue
diseases, 2. diagnosis of chronic infection. We obtained complete medical
history and physical exam, demographic information, medications and laboratory
data. At baseline and 14 weeks after TNF inhibitor therapy, we assessed DAS28
ESR and measured serum levels of Th1-associated chemokines (CXCL9, 10, 11) and
Th17-associated chemokine (CCL20) using commercial ELISA kits. Responders
and non-responders were defined as patients who had good/moderate response and
no response at week 14 by EULAR response criteria. Wilcoxon two sample test was
performed to compare chemokine levels.

Results: We assessed 16 RA patients who
started either adalimumab or etanercept. Their baseline characteristics,
summarized in Table 1, show no significant differences between responders (n=9)
and non-responders (n=7).  Responders showed a trend toward higher levels of baseline
Th1 chemokines compared to non- responders (Fig 1). CXCL10 levels were
significantly higher in responders (437 ± 354 vs 144 ± 45 pg/ml, p=0.04) while
CXCL9 (2266 ± 1517 vs 1126 ± 452 pg/ml, p=0.16),and CXCL11 (887 ± 1114 vs 515 ±
853 pg/ml, p=0.25) differences did not reach statistical significance. There were
significant correlations between CXCL9 and CXCL10 (r =0.61, p=0.01) and between
CXCL9 and CXCL11 (r=0.66, p=0.01). CCL20 levels were lower in responders but were
not significantly different (15.6 ± 12.0 vs 33.8 ± 41.8 pg/ml, p=0.63).

Conclusion: Elevated baseline levels of Th1
cytokines including CXCL9, 10 and 11 appear to be associated with favorable
responses to TNF inhibitors whereas Th17 chemokine, CCL20, may be associated
with unfavorable responses.

Table 1. Baseline characteristics of RA patients

Figure 1. Baseline Th1 chemokine level in responders (R) and
non-responders (NR)