Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
14-3-3, a Novel Mediator Upregulated by TNF, Reflects Clinical Response to Anti-TNF Therapy.
Maksymowych1, Walter P., Marotta2, Anthony
TNFa targeted therapies are routinely used in the treatment of RA and despite their efficacy, patient response remains heterogeneous. This underscores the unmet need for biomarkers to assist in the identification of likely responders. 14-3-3 proteins are intracellular proteins mediating several key signalling pathways but one isoform, 14-3-3h, has been detected extracellularly in the joints and serum of patients with arthritis. It has been described as a specific RA serum marker and as a novel drug target based on its induction of key factors, including TNFa, that are involved in the pathogenesis of RA. We investigated the direct effects of TNFa on 14-3-3h and whether its clinical expression reflects response to anti-TNFa therapy.
To examine the stimulatory effects of TNFa on 14-3-3h, monocytic THP-1 cells were stimulated with 50ng/ml, for 18h and % induction was determined through densitometry. Serum 14-3-3h was measured in a cohort of 74 RA patients who were refractory to standard DMARDs and candidates for anti-TNF therapy at pre-treatment and approximately 15 weeks post-treatment using an investigational-grade 14-3-3h ELISA. EULAR classification criteria were used to define good, moderate or non-response. Two-tailed paired and unpaired t-tests and Mann-Whitney U-tests were used to determine group differences in 14-3-3h levels pre-treatment and its modifiability post-treatment. Correlations were calculated between 14-3-3h and clinical variables using the Pearson chi-square.
Stimulation of monocytes with TNFa resulted in a 30% increase in 14-3-3h transcripts. A good EULAR response was observed in 15 of the 74 patients (20%). The mean (SD) and median levels of 14-3-3h were higher in those who failed to achieve a good EULAR response [mean = 7.56 (8.28), median = 2.52ng/ml] compared to the good EULARresponders [mean = 4.23 (6.86), median = 0.72ng/ml], with median differences being statistically significant (p=0.015). Post-treatment 14-3-3h serum levels were significantly lower than pre-treatment (mean difference of 0.93ng/ml (95% CI 0.089 to 1.78, t=2.21, p=0.031) indicating that serum 14-3-3h levels are modifiable with anti-TNFa therapy. There were no significant correlations between pre-treatment clinical variables and serum levels of 14-3-3h. For the whole cohort, D14-3-3h correlated moderately with DESR (r=0.35, p=0.002), DHAQ (r=0.28, p=0.016) and DCRP (r=0.25, p=0.036). A subset analysis of good EULAR responders (15 patients, 10 females) versus non-responders (17 patients, 11 females) revealed no correlation in the D14-3-3h with the change in clinical variables in non-responders but a high correlation with DESR (r=0.89, p<0.00001), DCRP (r=0.68, p=0.006) and importantly DDAS (r=0.56, p=0.009) in good responders.
14-3-3h is up-regulated by TNFa in vitro and its serum levels are lower in patients who respond well to anti-TNFa therapy. Serum 14-3-3h expression is modifiable with anti-TNF therapy. In patients with good EULAR response, serum 14-3-3h levels correlate strongly with measures of clinical improvement. 14-3-3h should be further investigated as a promising candidate biomarker that predicts response to anti-TNF therapy.
To cite this abstract, please use the following information:
Maksymowych, Walter P., Marotta, Anthony; 14-3-3, a Novel Mediator Upregulated by TNF, Reflects Clinical Response to Anti-TNF Therapy. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :428