Synovial membrane cytokine expression is predictive of joint damage progression in rheumatoid arthritis - A two-year prospective study (the DAMAGE study cohort)

Objective. The primary aim of this prospective 2-year study was to explain the wide variability in joint damage progression in patients with rheumatoid arthritis (RA) from measures of pathologic changes in the synovial membrane. Methods. Patients underwent clinical measurements and joint damage assessments by magnetic resonance imaging (MRI) and radiography at enrollment and at year 2. Synovial membrane was obtained by knee biopsy and assessed histologically by hematoxylin and eosin staining. Interleukin-1 beta (IL-1 beta), IL-10, IL-16, IL-17, RANKL, tumor necrosis factor alpha (TNF alpha), and interferon-gamma (IFN gamma) messenger RNA (mRNA) expression was determined by quantitative reverse transcription-polymerase chain reaction. The relationship of synovial measurements to joint damage progression was determined by multivariate analysis. Results. Sixty patients were enrolled. Histologic features had no relationship to damage progression Multivariate analysis by several different methods consistently demonstrated that synovial membrane mRNA levels of IL-1 beta, TNF alpha, IL-17, and IL-10 were predictive of damage progression. IL-17 was synergistic with TNFa. TNFa and IL-17 effects were most pronounced with shorter disease duration, and IL-1 beta effects were most pronounced with longer disease duration. IFN gamma was protective. These factors explained 57% of the MRI joint damage progression over 2 years. Conclusion. We have demonstrated for the first time in a prospective study that synovial membrane cytokine mRNA expression is predictive of joint damage progression in RA. The findings for IL-1 beta and TNF alpha are consistent with results of previous clinical research, but the protective role of IFN gamma, the differing effects of disease duration, and IL-17-cytokine interactions had only been demonstrated previously by animal and in vitro research. These findings explain some of the variability of joint damage in RA and identify new targets for therapy.