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. 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-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.

[1]  J. Edmonds,et al.  Documenting damage progression in a two-year longitudinal study of rheumatoid arthritis patients with established disease (the DAMAGE study cohort): is there an advantage in the use of magnetic resonance imaging as compared with plain radiography? , 2004, Arthritis and rheumatism.

[2]  F. Breedveld,et al.  Association of the -2849 interleukin-10 promoter polymorphism with autoantibody production and joint destruction in rheumatoid arthritis. , 2003, Arthritis and rheumatism.

[3]  P. Tak,et al.  Comparison of synovial tissues from the knee joints and the small joints of rheumatoid arthritis patients: Implications for pathogenesis and evaluation of treatment. , 2002, Arthritis and rheumatism.

[4]  F. Loo,et al.  Gene therapy for rheumatoid arthritis. Lessons from animal models, including studies on interleukin-4, interleukin-10, and interleukin-1 receptor antagonist as potential disease modulators. , 2002 .

[5]  I. Frazer,et al.  Association of clinical, radiological and synovial immunopathological responses to anti-rheumatic treatment in rheumatoid arthritis. , 2001, Rheumatology.

[6]  L. Kiemeney,et al.  The relationship between disease activity, joint destruction, and functional capacity over the course of rheumatoid arthritis. , 2001, Arthritis and rheumatism.

[7]  P. Miossec,et al.  The combination of tumor necrosis factor alpha blockade with interleukin-1 and interleukin-17 blockade is more effective for controlling synovial inflammation and bone resorption in an ex vivo model. , 2001, Arthritis and rheumatism.

[8]  H. Genant,et al.  Magnetic resonance imaging in rheumatoid arthritis: summary of OMERACT activities, current status, and plans. , 2001, The Journal of rheumatology.

[9]  C. S. Lee,et al.  Cytokine expression and synovial pathology in the initiation and spontaneous resolution phases of adjuvant arthritis: Interleukin‐17 expression is upregulated in early disease , 2001, Clinical and experimental immunology.

[10]  B. Bresnihan,et al.  The pathogenesis and prevention of joint damage in rheumatoid arthritis: advances from synovial biopsy and tissue analysis. , 2000, Arthritis and rheumatism.

[11]  Hiroshi Takayanagi,et al.  T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ , 2000, Nature.

[12]  P. Duray,et al.  Active synovial matrix metalloproteinase-2 is associated with radiographic erosions in patients with early synovitis , 2000, Arthritis research.

[13]  Josef M. Penninger,et al.  Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand , 1999, Nature.

[14]  L. Joosten,et al.  IL-1 alpha beta blockade prevents cartilage and bone destruction in murine type II collagen-induced arthritis, whereas TNF-alpha blockade only ameliorates joint inflammation. , 1999, Journal of immunology.

[15]  A. Zwinderman,et al.  Long-term course and outcome of functional capacity in rheumatoid arthritis: the effect of disease activity and radiologic damage over time. , 1999, Arthritis and rheumatism.

[16]  J. Edmonds,et al.  Intraarticular variability of synovial membrane histology, immunohistology, and cytokine mRNA expression in patients with rheumatoid arthritis. , 1999, The Journal of rheumatology.

[17]  D. Furst,et al.  Etanercept Therapy in Rheumatoid Arthritis , 1999, Annals of Internal Medicine.

[18]  A. Saudan,et al.  Introduction to reading radiographs by the Scott modification of the Larsen method. , 1999, The Journal of rheumatology.

[19]  E. Sercarz,et al.  Induction or protection from experimental autoimmune encephalomyelitis depends on the cytokine secretion profile of TCR peptide-specific regulatory CD4 T cells. , 1998, Journal of immunology.

[20]  F. Wolfe,et al.  Radiographic outcome of recent-onset rheumatoid arthritis: a 19-year study of radiographic progression. , 1998, Arthritis and rheumatism.

[21]  R. Beckenbaugh,et al.  Tissue cytokine patterns distinguish variants of rheumatoid synovitis. , 1997, The American journal of pathology.

[22]  J. Edmonds,et al.  Reference curves of radiographic damage in patients with rheumatoid arthritis: application of quantile regression and fractional polynomials. , 1997, Journal of Rheumatology.

[23]  L. Joosten,et al.  Role of interleukin-4 and interleukin-10 in murine collagen-induced arthritis. Protective effect of interleukin-4 and interleukin-10 treatment on cartilage destruction. , 1997, Arthritis and rheumatism.

[24]  R. Badolato,et al.  Role of cytokines, acute-phase proteins, and chemokines in the progression of rheumatoid arthritis. , 1996, Seminars in arthritis and rheumatism.

[25]  M. Feldmann,et al.  Immunoregulatory role of interleukin 10 in rheumatoid arthritis , 1994, The Journal of experimental medicine.

[26]  B. Bresnihan,et al.  Synovial tissue macrophages and joint erosion in rheumatoid arthritis. , 1994, Annals of the rheumatic diseases.

[27]  Douglas G. Altman,et al.  Practical statistics for medical research , 1990 .

[28]  F. Arnett.  Revised criteria for the classification of rheumatoid arthritis. , 1990, Orthopedic nursing.

[29]  B. Bresnihan,et al.  Analysis of the histologic variation of synovitis in rheumatoid arthritis. , 1988, Arthritis and rheumatism.

[30]  M. Liang,et al.  The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. , 1988, Arthritis and rheumatism.

[31]  T. Pincus,et al.  Severe functional declines, work disability, and increased mortality in seventy-five rheumatoid arthritis patients studied over nine years. , 1984, Arthritis and rheumatism.

[32]  A. Larsen,et al.  Radiographic Evaluation of Rheumatoid Arthritis and Related Conditions by Standard Reference Films , 1977, Acta radiologica: diagnosis.

[33]  Malcolm D. Smith,et al.  Reduced chemokine and matrix metalloproteinase expression in patients with rheumatoid arthritis achieving remission. , 2003, The Journal of rheumatology.

[34]  Tx Station.  Stata Statistical Software: Release 7. , 2001 .

[35]  B. Bresnihan,et al.  Synovial tissue macrophage populations and articular damage in rheumatoid arthritis. , 1996, Arthritis and rheumatism.

[36]  L. Hamilton.  How Robust is Robust Regression , 1992 .

[37]  H. Holman,et al.  Measurement of patient outcome in arthritis. , 1980, Arthritis and rheumatism.

[38]  Olof Safwenberg.  ZWEI RÖNTGENOLOGISCH DIAGNOSTIZIERTE FÄLLE VON MILZARTERIENANEURYSMA , 1937 .