Institutionen för medicin / Department of Medicine
Abstract
Rheumatoid Arthritis (RA) is a common chronic inflammatory disease
characterized by progressive bone destruction that leads to joint
deformity and physical disability. Even though several therapeutic drugs
are available, none have emerged as an ideal RA treatment that delays
joint destruction and halts disease progression. A new class of drugs,
tumor necrosis factor (TNF) antagonists, has recently been introduced in
clinical practice: infliximab (chimeric anti-TNF antibody), etanercept
(soluble TNF receptor) and adalimumab (fully human anti-TNF antibody).
The exact mechanisms of action of these drugs are still poorly
understood, even though the important role played by cytokines in RA
pathogenesis is the main rationale behind using them for treatment. This
thesis investigates the molecular mechanisms of action for TNF
antagonists in RA with a focus on synovial inflammation and bone
destruction.
A major feature of RA is synovial inflammation with local accumulation of
immune cells through increased cell influx and decreased clearance of
resident cells. We demonstrated that early RA, which is characterized by
important macrophage infiltration, is associated with low levels of
synovial apoptosis. We also identified macrophage infiltration and
synovial expression of the anti-apoptotic molecule FLIP (FLICE inhibitory
protein) as determinant factors of synovial apoptosis. As apoptosis is a
potential relevant mechanism for RA, we investigated if treatment with
TNF antagonists modulates this process. We demonstrated that therapy with
both infliximab and etanercept induces apoptosis of macrophages but not
of lymphocytes in RA joints. Blood-derived macrophages were less
susceptible to anti-TNF induced apoptosis, suggesting that induction of
apoptosis through TNF blockade is specific for an inflammatory milieu
such as the rheumatoid joint.
Synovial inflammation leads to bone destruction that is mediated through
either an indirect mechanism induced through cytokine-mediated release of
pro-destructive factors such as the matrix metalloproteinases
(MMP)-tissue inhibitors of MMPs (TIMPs) system or a direct mechanism
mediated through receptor activator of the nuclear factor-?B ligand
(RANKL)-osteoprotegerin (OPG) system. We demonstrated that etanercept is
able to decrease serum levels of MMPs and the ratio between MMPs and
TIMP, which represents a potential mechanism involved in prevention of
future development of joint damage. Moreover, baseline MMP-3 serum levels
could predict the changes in disease activity during therapy. The
RANKL/OPG system is considered to be the final denominator of bone
remodeling. We demonstrated that treatment with both etanercept and
infliximab increased synovial OPG expression without changes in RANKL
expression. The synovial RANKL/OPG ratio thus decreased following
therapy, the effect being more pronounced in the responders compared to
non-responders to therapy.
In conclusion, we have demonstrated that TNF antagonists modulate
important mechanisms implicated in synovial inflammation and bone
destruction. We propose that therapies which target synovial TNF
independent mechanisms, such as RANKL expression and lymphocyte
apoptosis, are also valuable candidates for adjuvant therapy in RA
