Selective involvement of ERK and JNK mitogen-activated protein kinases in early rheumatoid arthritis (1987 ACR criteria compared to 2010 ACR/EULAR criteria): a prospective study aimed at identification of diagnostic and prognostic biomarkers as well as therapeutic targets
- Daphne de Launay,
- Marleen GH van de Sande,
- Maria JH de Hair,
- Aleksander M Grabiec,
- Gijs PM van de Sande,
- K Aad Lehmann,
- Carla A Wijbrandts,
- Lisa GM van Baarsen,
- Danielle M Gerlag,
- Paul P Tak,
- Kris A Reedquist
- Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Correspondence to Dr Kris A Reedquist, Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands;
- Received 20 September 2010
- Accepted 14 August 2011
- Published Online First 27 September 2011
Objectives To investigate the expression and activation of mitogen-activated protein kinases in patients with early arthritis who are disease-modifying antirheumatic drug (DMARD) naïve.
Methods A total of 50 patients with early arthritis who were DMARD naïve (disease duration <1 year) were prospectively followed and diagnosed at baseline and after 2 years for undifferentiated arthritis (UA), rheumatoid arthritis (RA) (1987 American College of Rheumatology (ACR) and 2010 ACR/European League Against Rheumatism (EULAR) criteria), or spondyloarthritis (SpA). Synovial biopsies obtained at baseline were examined for expression and phosphorylation of p38, extracellular signal regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) by immunohistochemistry and digital analysis. Synovial tissue mRNA expression was measured by quantitative PCR (qPCR).
Results ERK and JNK activation was enhanced at inclusion in patients meeting RA criteria compared to other diagnoses. JNK activation was enhanced in patients diagnosed as having UA at baseline who eventually fulfilled 1987 ACR RA criteria compared to those who remained UA, and in patients with RA fulfilling 2010 ACR/EULAR criteria at baseline. ERK and JNK activation was enhanced in patients with RA developing progressive joint destruction. JNK activation in UA predicted 1987 ACR RA classification criteria fulfilment (R2=0.59, p=0.02) after follow-up, and disease progression in early arthritis (R2=0.16, p<0.05). Enhanced JNK activation in patients with persistent disease was associated with altered synovial expression of extracellular matrix components and CD44.
Conclusions JNK activation is elevated in RA before 1987 ACR RA classification criteria are met and predicts development of erosive disease in early arthritis, suggesting JNK may represent an attractive target in treating RA early in the disease process.
DdL and MGHvdS contributed equally to this manuscript.
PPT and KAR contributed equally to this manuscript.
Funding This research was supported by the Dutch Arthritis Association (NR 04-1-301). Funding was also provided by the European Community's FP6 funding (Autocure). This publication reflects only the views of the authors and the European Community is not liable for any use that may be made of the information herein.
Provenance and peer review Not commissioned; externally peer reviewed.
This paper is freely available online under the BMJ Journals unlocked scheme, see http://ard.bmj.com/info/unlocked.dtl