Increased Plasma Levels of IL17F in Rheumatoid Arthritis Download

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Increased Plasma Levels of IL17F in Rheumatoid Arthritis Patients are Reduced by Methotrexate and Biologic Agents
J. Greenberg 1,*, V. Furer 1, J. Todd 2, Q. A. Lu 2, R. Ramirez 2, S. Abramson, 1 M. Attur 1
1NYU
HOSPITAL FOR JOINT DISEASES, New York, 2Singulex, Alameda CA, United States
Introduction
A pivotal role of Th17 cells and related cytokines have
been recognized in RA.
Multiple isoforms of IL17 have
Figure 1.
IL-17 Levels in OA vs DMARD-naïve RA Patients
10000
< 0.0001
but have not been well characterized in RA patients (pts).
< 0.0001
Abatacept Etanercept Adalimumab Infliximab
0.0040
1000
Biomarker concentration
Objectives
Table 1. Treatment groups demographics and baseline characteristics
OA vs RA
been discovered, including IL17A, IL17F and IL17AF,
1. To compare levels of inflammatory mediators
100
10
1
0.1
including IL17A and IL17F in RA patients versus
0.01
OA
RA
OA
IL-17A
pg/mL
controls (OA patients).
RA
OA
IL-17F
pg/mL
RA
Number of
Subjects, N
Female (%)
27
18
11
4
23 (85)
15 (83)
11 (100)
3 (75)
Age, years,
mean (SD)
DAS28,
mean (SD)
49.5 (13)
54.5 (12)
54 (13)
52 (6)
5.64 (1.34)
5.7 (1.7)
5.57 (1.28)
5.66 (1.89)
IL-17A/F
pg/mL
2. To compare the effects of anti-TNF biologics
(infliximab, adalimumab, and etanercept) and T-cell
Figure 2. Comparison of Plasma Biomarkers Levels in
OA vs DMARD-naïve RA Patients
costimulatory modulation (abatacept) on IL17A and
Table 2. Ratio of week 12 to Baseline Biomarker Values
OA vs RA
IL17 F levels.
Abatacept
1000000
< 0.0001
< 0.0001
< 0.0001
0.0010
0.0002
< 0.0001
0.3562
Median
Wk12/Wk0
Ratio
Biomarker
100000
Biomarker concentration
10000
Methods
Median
Wk12/Wk0
Ratio
p-value
p-value
DAS28
0.94
0.0626
0.90
0.00225
CRP
0.88
0.435
0.75
0.00863
ESR
1.08
0.820
0.82
0.00448
VEGF
0.82
0.0195
0.64
0.0863
IL-17A
1.15
0.576
0.86
0.120
1000
100
10
1
We examined a panel of plasma biomarkers in DMARD-
Anti-TNF
0.1588
0.1
naïve RA patients versus knee OA patients. We also
0.69
< 0.001
0.85
IL-17 A/F
0.97
0.899
0.76
0.163
IL-6
0.92
0.556
0.83
0.0417
IL-6 R alpha
OA
RA
CRP
ng/mL
compared the effects of RA drugs on the panel of
IL-17F
OA
RA
OA
OA
RA
IL-6
pg/mL
IL-6R alpha
ng/mL
RA
IL-1 RA
pg/mL
OA
RA
VEGF
pg/mL
OA
RA
TNF-RII
pg/mL
OA
RA
TNF alpha
pg/mL
OA
RA
IL-1beta
pg/mL
0.0159
1.03
0.160
0.98
Total MMP9
0.85
0.095
0.70
0.0966
pro MMP9
0.69
0.040
0.80
0.192
0.292
sTNF RII
0.90
0.0098
1.17
0.0293
biomarkers at baseline and at 3-month follow-up from an
observational cohort of RA patients. Biomarker assays
were performed using a fluorescence based, highly
Figure 3. Comparison of MMP-9 Levels in
OA vs DMARD-naïve RA Patients
Figure 4. Effect of Methotrexate on IL17
Levels in Treated RA Patients
Pre- vs Post-Methotrexate
OA vs RA
100000
10000
sensitive Erenna Immunoassay system (Singulex, Inc).
< 0.0001
1000
Biomarker concentration
Clinical assessments included DAS28-ESR. Change in
each biomarker was assessed as the ratio of the post-drug
to the pre-drug value using the Wilcoxon signed rank test
0.0039
0.9971
10000
biomarker concentration
0.3592
100
10
1000
100
10
1
0.1
1
0.01
for the overall cohort, as well as the anti-TNF and
0.1
OA
RA
tMMP-9
ng/mL
abatacept groups separately.
OA
RA
pMMP-9
ng/mL
OA
RA
pre
IL-17A
pg/mL
post
pre
post
IL-17F
pg/mL
pre
post
IL-17A/F
pg/mL
MMP-2
ng/mL
Conclusions
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.
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