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Increased Plasma IL-17F Levels in Rheumatoid Arthritis Patients Are Responsive to Methotrexate, Anti-TNF, and T Cell Costimulatory Modulation

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Abstract

The aims of this study are to compare plasma levels of IL17A, A/F, and F biomarkers in RA patients versus controls, and to determine responsiveness to methotrexate (MTX), anti-TNFs, and abatacept. We selected plasma samples from RA cohorts consisting of a cross-sectional RA cohort (N = 78) not receiving DMARDs at the time of sampling, as well as from longitudinal drug start cohorts (N = 71 patients) with pre/post samples including anti-TNF, abatacept, and MTX-treated patients. We assayed IL-17A, IL-17F, and IL17-A/F using a highly sensitive immunoassay system. Plasma levels of IL-17A, IL-17A/F, and IL-17F were all significantly increased in RA versus controls. The difference was largest in IL-17F, with median IL-17F levels in RA patients being approximately 18-fold higher than controls (81 pg/mL in RA vs. 4.4 pg/mL in controls, p < 0.001). Among the forms of IL-17, only IL-17F was decreased after therapy in the MTX cohort (p = 0.006), abatacept cohort (p < 0.001), and anti-TNF cohorts (p = 0.02), whereas IL-17A and IL-17A/F were not significantly decreased for any of the three drug cohorts. Synovial fluid analysis demonstrated higher IL-17F levels in RA (p = 0.016) than healthy controls. These results suggest a specific role for IL-17F in human RA pathogenesis and as a therapeutic target.

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Abbreviations

hsCRP:

High sensitivity C-reactive protein

DMARD:

Disease-modifying antirheumatic drug

ELISA:

Enzyme-linked immunosorbent assay

ESR:

Erythrocyte sedimentation rate

IL-1 IL-1B:

Interleukin-1

IL-1B:

Interleukin-1 beta

IL-17:

Interleukin-17

IL-6:

Interleukin-6

IL-6R alpha:

Interleukin 6 receptor alpha

MMP:

Matrix metalloproteinase

MTX:

Methotrexate

OA:

Osteoarthritis

RA:

Rheumatoid arthritis

RANKL:

Receptor activator of nuclear factor kappa-B ligand

sTNFRII:

Soluble tumor necrosis factor receptor 2

TNF:

Tumor necrosis factor

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Acknowledgments

This work is supported in part by US National Institutes of Health grant R01-AR054817 (S.B.A.). Dr Greenberg received salary support from the NIH (K23AR054412).

Contributions

MJ carried out data analysis, interpretation, and supervised manuscript drafting/revision.

MA supervised data acquisition, interpretation, and manuscript revision.

VF carried out data acquisition.

JT supervised data acquisition, interpretation, and manuscript drafting/revision.

ML carried out data analysis and manuscript drafting/revision.

QL carried out data analysis.

RR generated biomarker results and carried out data analysis.

SA supervised data analysis, interpretation, and manuscript revision.

JG supervised data acquisition, analysis, interpretation, and manuscript revision.

Conflict of Interest

JT, RR, and QL are employees of Singulex, the manufacturer of the assays used in the study. The other authors declare that they have no competing interests.

Author information

Authors and Affiliations

  1. Department of Rheumatology, New York University Hospital for Joint Diseases, 301 East 17th Street, suite 1410, New York, NY, 10003, USA

    Manish Jain, Mukundan Attur, Vika Furer, Steven B. Abramson & Jeffrey D. Greenberg

  2. Singulex, Alameda, CA, USA

    John Todd, Renita Ramirez & Quynh A. Lu

  3. Independent Statistical Consultant, Mountain View, CA, USA

    Michael Lock

Authors
  1. Manish Jain
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  2. Mukundan Attur
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  3. Vika Furer
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  4. John Todd
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  5. Renita Ramirez
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  6. Michael Lock
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  7. Quynh A. Lu
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  8. Steven B. Abramson
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  9. Jeffrey D. Greenberg
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Corresponding author

Correspondence to Jeffrey D. Greenberg.

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Jain, M., Attur, M., Furer, V. et al. Increased Plasma IL-17F Levels in Rheumatoid Arthritis Patients Are Responsive to Methotrexate, Anti-TNF, and T Cell Costimulatory Modulation. Inflammation 38, 180–186 (2015). https://doi.org/10.1007/s10753-014-0020-1

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  • DOI: https://doi.org/10.1007/s10753-014-0020-1

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