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The pathophysiology and treatment of rheumatoid arthritis.

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ARTHRITIS & RHEUMATISM
Vol. 40, No. 4, April 1997, pp 595-597
0 1997, American College of Rheumatology
Arthritis & Rheumatism
Official Journal of the American College of Rheumatology
EDITORIAL
THE PATHOPHYSIOLOGY AND TREATMENT OF
RHEUMATOID ARTHRITIS
WILLIAM P. AREND
No area in rheumatology research has undergone
such extensive evolution over the last 10 years as the
pathophysiology of rheumatoid arthritis (RA). Dramatic
new therapeutic approaches have been developed, rapidly following advances in knowledge about cellular
events in the rheumatoid synovium. However, the widely
publicized promise of these new therapeutic agents has
often been dampened by the initial results of clinical
trials, which appeared less exciting than anticipated.
Arthritis & Rheumatism has published 5 review articles
about the pathophysiology and treatment of RA over the
last 14 months (1-5), the last one, in this issue, on T
cells. The objective of this editorial is to provide some
perspective and commentary on this area of basic and
clinical research.
The current concept is that inflammation and
tissue destruction in the rheumatoid synovium result
from complex cell-cell interactions. These events are
thought to be initiated by an interaction between
antigen-presenting cells (APC) and CD4+ T cells; APC
display complexes of class I1 major histocompatibility
complex (MHC) molecules and peptide antigen(s) that
bind to specific receptors on the T cells. Macrophage
activation ensues, with secretion of proinflammatory
cytokines such as interleukin-1 (IL-1) and tumor necrosis factor a (TNFa). These cytokines stimulate synovial
fibroblasts and chondrocytes in the nearby articular
cartilage to secrete enzymes that degrade proteoglycans
and collagen, leading to tissue destruction. However,
this simplified scheme is based on many tenuous assumptions that are continuously being challenged.
The role and importance of APC in the initiation
and perpetuation of rheumatoid synovitis remains an
area of controversy. The established dogma has been
that unknown exogenous antigens, perhaps derived from
infectious agents, must be responsible for inducing the
disease. After uptake and processing by APC, peptides
are coupled to class I1 MHC molecules inside the cell,
followed by placement of this complex on the cell
surface. However, in spite of exhaustive studies over
many decades, there is no solid evidence to prove the
presence of protein or messenger RNA for any infectious agent in the chronic rheumatoid synovium. Therefore, the belief that rheumatoid synovitis is initiated by
specific exogenous antigens must be questioned.
The recent review article by Thomas and Lipsky
on dendritic cells (DC) in the rheumatoid synovium (1)
presents some alternative hypotheses on how APC may
function in RA pathophysiology. Those authors argue
that the initiating event in RA may be a slowlydeveloping differentiation of DC under the influence of
cytokines released by synovial macrophages in response
to nonspecific stimulation by minor trauma, infections,
allergic reactions, immunologic materials, etc. These DC
would eventually present autologous antigens to T cells:
perhaps degraded self-MHC molecules in the beginning
of the disease process and altered tissue components
later on. This scenario does not require T cells for the
initial stage of DC differentiation, or the presence of
exogenous material for antigen presentation. In addition
to DC, many other cell types may function as APC in the
rheumatoid synovium, including macrophages, B cells,
fibroblasts, and chondrocytes.
The association of RA with HLA-DR4/1 alleles
has suggested the possible importance of presentation of
a common arthritogenic peptide to T cells as an initiat-
William P. Arend, MD: University of Colorado Health Sciences Center, Denver, Editor, Arthn'tzs & Rheumatism.
Address correspondence to William P. Arend, MD, University of Colorado Health Sciences Center, 4200 East Ninth Avenue,
Denver, CO 80262.
595
596
ing event. However, this reasoning may be inverted to
suggest that a peptide derived from the diseaseassociated HLA-DR4/1 allele, perhaps the QKRAA
“shared epitope” itself, is initially presented by APC to
T cells as a self antigen (1,2). During thymic programming, the shared epitope could function to positively
select low-avidityT cells that then migrate to the periphery (6). In a multistep molecular mimicry hypothesis,
later in life these T cells could be activated by crossreactive antigens that display the shared epitope, leading
to inflammation (6). Since multiple infectious agents
possess potentially cross-reactive peptides, this mechanism would allow for reactivation of RA by presumably
common and ubiquitous organisms. Alternatively, perhaps the shared epitope increases the risk for RA by
failing to present a protective epitope, rather than by
presenting a disease-inducing epitope (5). RA appears
to be a multigenic disease, and the MHC region itself
may contribute fewer than 50% of the genetic influences, either predisposing to or protective against
disease.
The review by Fox on the role of T cells in the
immunopathogenesis of RA ( 5 ) summarizes the arguments both for and against the importance of these cells
in initiating or perpetuating the disease process (5).
Extensive work by many investigators to examine for the
presence of clonally restricted alp T cell receptors
(TCR) in the rheumatoid synovium has resulted in
contradictory and confusing findings. However, these
results should not be taken as conclusive evidence
against the role of an antigen-driven process since
antigen-specific T cells may comprise <1% of the total
tissue T cells in an immune-mediated disease. In addition, the paucity of T cell cytokines such as IL-2 and
interferon- y in the rheumatoid synovium may be secondary to the inhibitory effects of IL-10, and only a few
activated T cells may be necessary to drive the disease
process. Recently published data indicate that JL-15
may function to attract and activate T cells in the
rheumatoid synovium (7). Ongoing studies on T cell
subsets, the function of y/S T cells, the role of accessory
molecules in T cell activation, and possible defects in T
cell apoptosis may clarify the role and importance of T
cells in rheumatoid synovitis.
At the same time as basic research on APC and T
cells in FL4 has been carried out, clinical research studies
designed to intervene at the level of these cells have
been pursued. As summarized in a review by Moreland
et a1 (4), the initial studies in this area still hold some
hope, but the results generally have been somewhat
disappointing. Treatment of RA with murine, chimeric,
or humanized monoclonal antibodies (MAb) directed
AREND
against molecules on the surface of various subsets of T
cells has not yielded more than modest clinical benefits.
A recent review by Epstein (8) summarizes how expectation bias may have led to overly optimistic interpretations of the results of open trials of anti-CD4 MAb in
RA, which were not borne out in subsequent placebocontrolled and randomized trials. Studies using newer
anti-CD4 MAb that block function without depletion of
T cells are in progress. In addition, current trials also are
examining different therapeutic approaches designed to
nonspecifically or specifically block MHC or TCR function (4). Another current approach is the induction of
bystander tolerance by oral administration of small
amounts of chicken type I1 collagen. The findings of
initial clinical trials of this treatment were somewhat
mixed, but the results of a larger trial should be reported
soon. However, the validity of all of these therapeutic
efforts directed at APC or T cells rests upon the
assumption that these cells are key to the disease
process, either in initiation or perpetuation, an assumption that must be questioned.
Another area that has received considerable attention in basic and clinical research is the role of
macrophages and their cytokines in rheumatoid synovitis. A review by Burmester et a1 ( 3 ) asks whether these
cells are the “mastermind or the workhorse in arthritis.”
It is generally accepted, through the results of studies in
animal models of inflammatory arthritis, as well as in
patients with RA, that macrophage cytokines, particularly IL-1 and TNFa, are important mediators of pathophysiologic events (9). However, it remains unclear what
are the mechanisms stimulating synovial macrophages to
produce an abundance of proinflammatory cytokines, or
whether in the chronic rheumatoid synovium these cells
may become autonomous. Possible stimulatory influences include soluble T cell factors, direct contact with T
cells, other cytokines themselves, immunologic materials, or components of damaged tissue. Furthermore,
monocytes may be activated in the peripheral blood in
RA, influencing their localization to the joint and subsequent pathogenic potential.
The results of extensive studies in animal models
of arthritis indicate the efficacy of therapeutic approaches designed to interfere with the production,
levels, or effects of IL-1 and TNFa. Unfortunately, one
lesson learned with some difficulty over the last 5 years
is that the human disease RA is more complex than any
animal model. However, the initial results of clinical
trials in which RA patients were treated with MAb
against TNFa, soluble TNF receptors, or a specific IL-1
receptor antagonist have been modestly encouraging (4).
These results are important for establishing the concept
EDITORIAL
that interfering with cytokines in RA is feasible and
possibly beneficial, although more long-term studies are
necessary to prove the safety of these agents as well as
their capacity to prevent cartilage and bone destruction.
Fibroblast-like synoviocytes (FLS) represent another exciting area of research that has received increasing attention in the last 5 years. A review by Firestein on
the characteristics and function of these cells (2) discusses FLS as transformed and autonomous aggressors.
Firestein argues that FLS respond to their environment
but evolve into transformed cells that demonstrate
anchorage-independent growth, oncogene expression,
and loss of contact inhibition. FLS predominate in the
rheumatoid pannus, express abundant adhesion molecules such as vascular cell adhesion molecule 1, and, in
response to proinflammatory cytokines, secrete enzymes
that destroy nearby tissues. Rheumatoid FLS exhibit
autonomous invasive behavior when placed on normal
human cartilage engrafted into SCID mice, further
demonstrating the importance of this T cellindependent mechanism of tissue destruction (10). How
FLS become transformed into autonomous aggressors
remains unknown, two possibilities being somatic mutation or DNA disruption by retroviruses. Firestein suggests that in addition to enhanced proliferation from
synovial lining cells, the accumulation of FLS in the
rheumatoid joint must derive in part from defective
removal by apoptosis (2).
Therapeutic approaches to RA that interfere
with the function of FLS include the use of nonsteroidal
antiinflammatory drugs, inhibitors of metalloproteinases, cyclooxygenase 2 inhibitors, and leukotriene inhibitors (2). More theoretical approaches would include
efforts to enhance apoptosis of FLS by agents that
crosslink cell surface Fas molecules, or correction of
defective apoptosis by gene therapy. Other potential
new treatments for RA utilizing biologic agents include
MAb against adhesion molecules or against costimulatory molecules for T cell activation, and gene therapy
with anticytokine agents (4). These innovative approaches all hold theoretical promise, but may suffer
from a lack of specificity as well as adverse consequences
to normal biologic functions.
Are changes in thinking necessary to redirect
basic and clinical research efforts in RA? Possibly the
paradigm that this is a T cell-directed process throughout the chronic disease course needs to be questioned.
Moreover, RA may be multiple diseases, currently defined by some common clinical manifestations, and there
may not be a single predominant mechanism of initiation or perpetuation. Perhaps it will become possible to
define subsets of RA by genetic or serologic markers,
597
and to individualize therapy more appropriately. Partial
responses to current and new therapeutic agents may
become more complete when used in combination in
specific subsets of patients (11).
What areas of basic research are likely to yield
the most important new information regarding the
pathophysiology and treatment of RA? I suspect that a
definition of the multiple predisposing or protective
genetic factors, and a clarification of the mechanisms
whereby genetic influences alter cell functions, may lead
us in new directions. A further elucidation of the mechanisms of apparent autonomous function of rheumatoid
synovial fibroblasts, and what exogenous or endogenous
influences caused these cells to become so aggressive,
also might provide important insights into the disease
process. Will more complete knowledge about the
pathophysiology of RA move beyond the current dilemma and lead to a single curative therapeutic approach? The answer to this question remains unknown
as the mysteries about this enigmatic disease continue to
slowly unfold.
REFERENCES
1. Thomas R, Lipsky PE: Presentation of self peptides by dendritic
cells: possible implications for the pathogenesis of rheumatoid
arthritis. Arthritis Rheum 39:183-190, 1996
2. Firestein GS: Invasive fibroblast-like synoviocytes in rheumatoid
arthritis: passive responders or transformed aggressors? Arthritis
Rheum 39:1781-1790, 1996
3. Burmester GR, Stuhmuller B, Keyszer G, Kinne RW: Mononuclear phagocytes and rheumatoid synovitis: mastermind or workhorse in arthritis? Arthritis Rheum 4 0 5 1 8 , 1997
4. Moreland LW, Heck LW Jr, Koopman WJ: Biologic agents for
treating rheumatoid arthritis: concepts and progress. Arthritis
Rheum 40:397-409, 1997
5. Fox DA: The role of T cells in the immunopathogenesis of
rheumatoid arthritis: new perspectives. Arthritis Rheum 40598609, 1997
6. Albani S , Carson DA: A multistep molecular mimicry hypothesis
for the pathogenesis of rheumatoid arthritis. Immunol Today
17:466-470, 1996
7. McInnes IB, Leung BP, Sturrock RD, Liew FY: Interleukin-15
mediates T cell-dependent regulation of tumor necrosis factor-a
production in rheumatoid arthritis. Nature Med 3:189-195, 1997
8. Epstein WV: Expectation bias in rheumatoid arthritis clinical
trials: the anti-CD4 monoclonal antibody experience. Arthritis
Rheum 39:1773-1780, 1996
9. Arend WP, Dayer J-M: Inhibition of the production and effects of
interleukin-1 and tumor necrosis factor a in rheumatoid arthritis.
Arthritis Rheum 38:151-160, 1995
10. Muller-Ladner U, Kriegsmann J, Franklin BN, Matsumoto S,
Geiler T, Gay RE, Gay S: Synovial fibroblasts of patients with
rheumatoid arthritis attach to and invade normal human cartilage
when engrafted into SCID mice. Am J Pathol149:1607-1615,1996
11. O’Dell JR, Haire CE, Erikson N, Drymalski W, Palmer W,
Eckhoff PJ, Ganvood V, Maloley P, Klassen LW, Wees S, Klein H,
Moore GF: Treatment of rheumatoid arthritis with methotrexate
alone, sulfasalazine and hydroxychloroquine, or a combination of
all three medications. N Engl J Med 1334:1287-1291, 1996
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