Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation of the
synovial membrane that can lead to joint deformity and physical disability. Despite recent progress
in the therapeutic field of RA, the exact molecular mechanisms responsible for chronic joint
inflammation are not yet completely understood. The overall aim of this thesis was to identify new
molecular mechanisms responsible for inflammation in the rheumatoid joint and to understand how
distinct anti rheumatic drugs act upon these mechanisms.
I first focused on validating arthroscopy as a research tool for better understanding of the
molecular mechanisms of action of anti rheumatic drugs, demonstrating that rheumatologic
arthroscopy is a safe method, with very few complications and allowing retrieval of representative
tissue in clinical longitudinal studies. We also propose an easy to perform way to quantitate
macroscopic joint changes based on photos acquired during arthroscopies.
Based on our validation study we then used this method to perform several mechanisms of action
studies. We first investigated the effect of etanercept on synovial expression of lymphotoxin-α
(LT-α) and tumor necrosis factor-α (ΤΝF-α). As predicted from previous in vitro studies
etanercept was able to decrease synovial expression of both LT-α and TNF-α. The effect was
however limited to good clinical responders. We propose LT-α modulation as an additional but not
essential mechanism to explain the clinical efficacy observed with this drug in clinical practice.
Defective apoptosis of lymphocytes is linked to pathogenesis of RA and glucocorticoids are good
in vitro inducers of lymphocyte apoptosis. We therefore investigated the effect of intra articular
glucocorticoids on synovial apoptosis demonstrating that in the complex milieu of rheumatoid joint
glucocorticoids actually fail to induce lymphocyte apoptosis. We further demonstrate that
monocytes are essential in rescuing synovial T cells from glucocorticoid-induced apoptosis
through a soluble factor mediated mechanism, a feature that is specific for RA-derived synovial
lymphocytes.
LL-37 is an anti microbial peptide belonging to the cathelicidin family with important functions in
innate immune response but recently also implicated as a modulator of acquired immune
responses. We therefore investigated a potential role for LL-37 in RA pathogenesis, demonstrating
that the peptide is present at low levels in healthy synovium, but up regulated in the context of
inflammation. We also identified synovial neutrophils and to a lesser extent macrophages as the
main cell types expressing LL-37. Distinct modulation patterns of LL-37 by some but not all anti
rheumatic drugs and correlation with local levels of inflammation suggest a potential direct
contribution of LL-37 to synovial pathology in RA.
In conclusion, we demonstrated that arthroscopy is a safe and reliable research tool for studies on
mechanisms of action of anti rheumatic drugs and pathogenic traits of the inflamed rheumatoid
joint