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-1beta (IL-1beta), IL-10, IL-16, IL-17, RANKL, tumor necrosis factor alpha (TNFalpha), and interferon-gamma (IFNgamma) 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-1beta, TNFalpha, IL-17, and IL-10 were predictive of damage progression. IL-17 was synergistic with TNFalpha. TNFalpha and IL-17 effects were most pronounced with shorter disease duration, and IL-1beta effects were most pronounced with longer disease duration. IFNgamma was protective. These factors explained 57% of the MRI joint damage progression over 2 years.


CONCLUSIONS
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-1beta and TNFalpha are consistent with results of previous clinical research, but the protective role of IFNgamma, 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.
Department of Rheumatology, Guy's and St. Thomas' Hospital, London, UK. bruce.kirkham@gstt.sthames.nhs.uk
Bruce W
BW
Kirkham
Marissa N
MN
Lassere
John P
JP
Edmonds
Katherine M
KM
Juhasz
Paul A
PA
Bird
C Soon
CS
Lee
Ron
R
Shnier
Ian J
IJ
Portek
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000175:diagnosis / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D018450:Disease Progression; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011446:Prospective Studies; D012333:RNA, Messenger / Q000096:biosynthesis; D013583:Synovial Membrane / Q000378:metabolism*; D013997:Time Factors
D016207:Cytokines; D012333:RNA, Messenger