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

• Published in: Arthritis and rheumatism 2006-04, Vol.54 (4), p.1122-1131
• Main Authors: Kirkham, Bruce W., Lassere, Marissa N., Edmonds, John P., Juhasz, Katherine M., Bird, Paul A., Lee, C. Soon, Shnier, Ron, Portek, Ian J.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Arthritis, Rheumatoid - diagnosis; Arthritis, Rheumatoid - immunology; Biological and medical sciences; Cytokines - biosynthesis; Cytokines - genetics; Disease Progression; Diseases of the osteoarticular system; Female; Humans; Inflammatory joint diseases; Magnetic Resonance Imaging; Male; Medical sciences; Middle Aged; Prognosis; Prospective Studies; RNA, Messenger - biosynthesis; Synovial Membrane - metabolism; Time Factors
• ISSN: 0004-3591; 1529-0131
• DOI: 10.1002/art.21749

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‐1β (IL‐1β), IL‐10, IL‐16, IL‐17, RANKL, tumor necrosis factor α (TNFα), and interferon‐γ (IFNγ) 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‐1β, TNFα, IL‐17, and IL‐10 were predictive of damage progression. IL‐17 was synergistic with TNFα. TNFα and IL‐17 effects were most pronounced with shorter disease duration, and IL‐1β effects were most pronounced with longer disease duration. IFNγ 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‐1β and TNFα are consistent with results of previous clinical research, but the protective role of IFNγ, 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.