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.


Increased Plasma Levels of IL17F in Rheumatoid Arthritis Patients Are Reduced by Methotrexate and Biologic Agents.

Greenberg1,  Jeffrey D., Furer1,  Victoria, Todd2,  John, Lu2,  Quynh Ann, Ramirez2,  Renita, Lock2,  Michael, Abramson1,  Steven B.

NYU Hospital for Joint Diseases, New York, NY
Singulex, Alameda, California, Alameda, CA

Background/Purpose:

A pivotal role of Th17 cells and related cytokines have been recognized in RA. Multiple isoforms of IL17 have been discovered, including IL17A, IL17F and IL17AF, but have not been well characterized in RA patients (pts).

Methods:

Using plasma samples from cohorts of RA pts (N= 149) and a knee osteoarthritis (OA) pts (N= 128) serving as controls, we assayed IL17A, IL17F, IL17A/F and a panel including IL1Ra, IL6, IL6R, TNF, sTNFRII, pro-MMP9, MMP9, VEGF, and CRP. The RA cohorts consisted of 78 RA pts off any DMARDs and 71 RA pts with pre/post samples including 33 anti-TNF starts, 27 abatacept starts and 11 methotrexate (MTX) starts.Assays were performed using a fluorescence based, highly sensitive Erenna Immunoassay system (Singulex, Inc). Clinical assessments included DAS28-ESR. Median values between RA vs OA patients were compared using the Wilcoxon rank sum test and adjusted comparisons for age and gender were made using multivariate linear models. Correlations of markers were assessed using Spearman rank correlations. The change in marker value with treatment was assessed by the ratio of the post-drug value to the pre-drug value. Marker and ratio values were log-transformed.

Results: RA vs OA (Control) Disease Comparisons:

Plasma levels of IL17A, IL17A/F and IL17F were all significantly increased in RA vs OA patients, but the magnitude of differences varied. Median IL17F levels in RA (78.0 pg) were approximately 18-fold higher than OA patients (4.4 pg), p<0.001 in unadjusted comparisons, and remained significant (p<0.001) in adjusted comparisons. The difference between cohorts in IL17A and IL17AF was smaller in magnitude (0.3 vs 0.2 pg, p<0.001 and 2.6 vs 2.1 pg, p=0.004, respectively), although the latter difference was not significant in adjusted models. Within the RA cohort, correlation between DAS28 and IL17F was weak (rho = 0.32) and almost nonexistent between DAS28 and IL17A (rho = 0.11). RA pts also exhibited statistically significantly higher levels of the following proteins: IL1Ra, IL6, IL6R, pro-MMP9, VEGF, sTNFRII and CRP.

Pre and Post Drug Cohorts: Significant reductions were observed for multiple biomarkers across drug categories (Table), including a consistent reduction of IL17F across drug classes for abatacept (p<0.001), anti-TNFs (p=0.02) and MTX (p=0.006). Neither IL17A nor IL17AF was significant reduced with abatacept, anti-TNFs or MTX.

Table. Change in Plasma Biomarkers with DMARD Interventions

BiomarkerAbatacept (N=27)Anti-TNF (N=33)Methotrexate (N=11)   
Post/Pre Treatment Ratio (Median)p-valuePost/Pre Treatment Ratio (Median)p-valuePost/Pre Treatment Ratio (Median)p-value 
CRP0.88NS0.750.0090.56NS
VEGF0.820.020.64NS1.05NS
IL-17A1.15NS0.86NS0.77NS
IL-17F0.69<0.0010.850.020.470.006
IL-17 A/F0.97NS0.76NS0.77NS
IL-60.92NS0.830.040.380.007
IL-6 R alpha1.03NS0.98NS1.06NS
Total MMP90.85NS0.70NS1.1NS
pro MMP90.690.040.80NS1.22NS
TNF-alpha0.91NS1.96<0.0010.61NS
sTNF RII0.900.011.170.031.02NS

Conclusion:

1. Although both IL17A and IL17F plasma levels are increased in RA patients, the magnitude of elevation for IL17F in RA patients was much higher than IL17A.

2. Plasma levels of IL17F but not IL17A were consistently reduced by 3 efficacious drug classes, suggesting that inhibiting IL17F, in addition to IL17A, may relate to RA drug efficacy. Further mechanistic studies are required.

To cite this abstract, please use the following information:
Greenberg, Jeffrey D., Furer, Victoria, Todd, John, Lu, Quynh Ann, Ramirez, Renita, Lock, Michael, et al; Increased Plasma Levels of IL17F in Rheumatoid Arthritis Patients Are Reduced by Methotrexate and Biologic Agents. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :52
DOI:

Abstract Supplement

Meeting Menu

2011 ACR/ARHP