Chapter 1 Introduction & aim of the thesis

Marcel D. Posthumus

Chapter 1

INTRODUCTION & AIM OF THE THESIS Rheumatoid arthritis (RA) is a complex inflammatory auto-immune disease associated with considerable disability, morbidity, and mortality 1,2. Early identification of patients with aggressive destructive disease is important, not only for prognostic, but also for therapeutic reasons 3. Novel, more aggressive therapies are currently developed 4 and the need for clinically feasible means for assessing the prognosis in the individual patients is becoming increasingly important 5. Cytokines play a major role in local inflammation and destruction, as well as in the systemic acute phase response 1. The relationship between acute phase proteins such as C-reactive protein (CRP) on the one hand, and disease activity and radiological progression on the other, has been demonstrated in several studies 6,7. Although CRP appears to be a good marker for prognostic purposes and for monitoring treatment effects, it is an indicator of inflammation in general which may be influenced by other stimuli of the acute phase response 8. The matrix metalloproteinases (MMPs), which are locally produced and activated within the affected joint as a result of cytokine mediated stimulation 9 could be more specific markers for joint inflammation and especially destruction in rheumatic diseases. In RA matrix metalloproteinase 3 (MMP-3=stromelysin 1) is of interest because it is thought to play a prominent role in the pathogenesis of matrix destruction in the inflamed joints 10. MMP-3 is capable of degrading many components of the matrix in the synovial joint 11, and has been localized in fibroblast-like synoviocytes of rheumatoid synovium 12,13 and in RA cartilage 14. The enzyme is secreted as a latent pro-enzyme resulting in elevated levels in local tissue and synovial fluid 15. In RA, serum MMP-3 is thought to originate from the inflamed joint because there are significant correlations between MMP3 levels in synovial fluid and in serum 16, and between serum MMP-3 levels and the number of clinically active inflamed joints 16,17. Furthermore local therapies, such as intra-articular corticosteroid injections, cause significant reductions in serum MMP-3 levels in synovial fluid and in the systemic circulation of patients with RA 8,18. The relative balance between activated MMPs and their inhibitors such as the tissue inhibitors of matrix metalloproteinases (TIMPs) and 2-macroglobulin (2-M) eventually determines the fate of the matrix. In synovial fluid the levels of activated MMP-3 are increased but measurement of activated MMP-3 in the systemic circulation is very difficult, if not impossible, because of the high levels of 2-M in the systemic circulation which encloses the activated enzyme completely 19.
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Introduction & aim of the thesis

Elevated systemic levels of MMP-3 (probably mainly pro-MMP-3) have been found in several other rheumatic diseases such as SLE, systemic sclerosis, ankylosing spondylitis, crystal induced arthritis, and psoriatic arthritis 20,21. Nevertheless, in RA the systemic levels of MMP-3 are considered to be a direct reflection of local synthesis and as such, serum MMP-3 could be a useful marker of disease activity and destruction in early RA. The aim of the thesis was to investigate the significance of serum MMP-3 in relation to disease activity, and in particular in relation to radiological progression, in patients with early RA. The data were derived from a prospective follow-up study in patients with recent onset RA (disease symptoms < 1 year). In chapter 2 a general review is provided on matrix metalloproteinases, in particular in rheumatoid arthritis. In chapter 3 the significance of serum MMP-3 in relation to the development of radiological damage in early RA is evaluated and in particular its prognostic value at an early time-point. In chapter 4 the clinical significance of serial measurements of serum MMP-3 levels in relation to markers of disease activity and radiological progression in early RA is analyzed, during a follow-up of three years. In chapter 5 the effects of treatment with sulphasalazine, or the combination methotrexate and sulphasalazine, on the serum MMP-3 levels in patients with early RA is investigated. Changes in serum MMP-3 were also compared to changes in CRP levels In chapter 6 serum MMP-3 levels in periods with and without progression of radiological damage in patients with early RA are evaluated and compared to CRP. In chapter 7 functional (at least in in vitro experiments 22) promoter polymorphisms in MMP genes are evaluated. In this study the significance of MMP-1 and MMP-3 promoter polymorphisms in relation to disease activity and radiological damage in patients with early rheumatoid arthritis is analyzed. In chapter 8 & 9 a summary, the general conclusions and future perspectives are given.

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Chapter 1

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1. 2. Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 2001;344(12):907-16. Navarro-Cano G, Del R, I, Pogosian S, Roldan JF, Escalante A. Association of mortality with disease severity in rheumatoid arthritis, independent of comorbidity. Arthritis Rheum 2003;48(9):2425-33. Emery P, Breedveld FC, Dougados M, Kalden JR, Schiff MH, Smolen JS. Early referral recommendation for newly diagnosed rheumatoid arthritis: evidence based development of a clinical guide. Ann Rheum Dis 2002;61(4):290-7. Smolen JS, Steiner G. Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov 2003; 2(6):473-88. Combe B, Dougados M, Goupille P, Cantagrel A, Eliaou JF, Sibilia J et al. Prognostic factors for radiographic damage in early rheumatoid arthritis: a multiparameter prospective study. Arthritis Rheum 2001;44(8):1736-43. van Leeuwen MA, van der Heijde DM, van Rijswijk MH, Houtman PM, van Riel PL, van de Putte LB et al. Interrelationship of outcome measures and process variables in early rheumatoid arthritis. A comparison of radiologic damage, physical disability, joint counts, and acute phase reactants. J Rheumatol 1994;21(3):425-9. van Leeuwen MA, van Rijswijk MH, van der Heijde DM, Te Meerman G, van Riel PL, Houtman PM et al. The acute-phase response in relation to radiographic progression in early rheumatoid arthritis: a prospective study during the first three years of the disease. Br J Rheumatol 1993;32 Suppl 3:9-13. Taylor DJ, Cheung NT, Dawes PT. Increased serum proMMP-3 in inflammatory arthritides: a potential indicator of synovial inflammatory monokine activity. Ann Rheum Dis 1994;53(11):76872. Vincenti MP, Brinckerhoff CE. Transcriptional regulation of collagenase (MMP-1, MMP-13) genes in arthritis: integration of complex signaling pathways for the recruitment of gene-specific transcription factors. Arthritis Res 2002;4(3):157-64. Hasty KA, Reife RA, Kang AH, Stuart JM. The role of stromelysin in the cartilage destruction that accompanies inflammatory arthritis. Arthritis Rheum 1990;33(3):388-97. Murphy G, Knauper V, Atkinson S, Butler G, English W, Hutton M et al. Matrix metalloproteinases in arthritic disease. Arthritis Res 2002; 4 Suppl 3:S39-S49. Okada Y, Takeuchi N, Tomita K, Nakanishi I, Nagase H. Immunolocalization of matrix metalloproteinase 3 (stromelysin) in rheumatoid synovioblasts (B cells): correlation with rheumatoid arthritis. Ann Rheum Dis 1989;48(8):645-53. Tetlow LC, Lees M, Woolley DE. Comparative studies of collagenase and stromelysin-1 expression by rheumatoid synoviocytes in vitro. Virchows Arch 1995;425(6):569-76. Martel Pelletier J, McCollum R, Fujimoto N, Obata K, Cloutier JM, Pelletier JP. Excess of metalloproteases over tissue inhibitor of metalloprotease may contribute to cartilage degradation in osteoarthritis and rheumatoid arthritis. Lab Invest 1994;70(6):807-15. Yoshihara Y, Nakamura H, Obata K, Yamada H, Hayakawa T, Fujikawa K et al. Matrix metalloproteinases and tissue inhibitors of metalloproteinases in synovial fluids from patients with rheumatoid arthritis or osteoarthritis. Ann Rheum Dis 2000;59(6):455-61. Yoshihara Y, Obata K, Fujimoto N, Yamashita K, Hayakawa T, Shimmei M. Increased levels of stromelysin-1 and tissue inhibitor of metalloproteinases-1 in sera from patients with rheumatoid arthritis. Arthritis Rheum 1995;38(7):969-75. Sasaki S, Iwata H, Ishiguro N, Obata K, Miura T. Detection of stromelysin in synovial fluid and serum from patients with rheumatoid arthritis and osteoarthritis. Clin Rheumatol 1994;13(2):22833.

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Introduction & aim of the thesis 18. Cheung NT, Mattey DL, Dawes PT, Taylor DJ. Serum pro-matrix metalloproteinase 3 in rheumatoid arthritis: a reflection of local or systemic inflammation? Arthritis Rheum 1996;39(5):884-6. Barrett AJ. Alpha 2-macroglobulin. Methods Enzymol 1981; 80:737-754. Keyszer G, Lambiri I, Nagel R, Keysser C, Keysser M, Gromnica-Ihle E et al. Circulating levels of matrix metalloproteinases MMP-3 and MMP-1, tissue inhibitor metalloproteinases 1 (TIMP-1), and MMP-1/TIMP-1 complex in rheumatic disease. Correlation with clinical activity of rheumatoid arthritis versus other surrogate markers. J Rheumatol 1999;26:251-8. Zucker S, Lysik RM, Zarrabi MH, Greenwald RA, Gruber B, Tickle SP et al. Elevated plasma stromelysin levels in arthritis. J Rheumatol 1994;21(12):2329-33. Ye S. Polymorphism in matrix metalloproteinase gene promoters: implication in regulation of gene expression and susceptibility of various diseases. Matrix Biol 2000;19(7):623-9.

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