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BioTech Navigator, August 1997
disease onset. It is estimated that the
current annual cost of treating RA is
$40 billion in the U.S. alone, which
includes medication as well as non-
medical costs associated with the dis-
ease. Current therapy for rheumatoid
arthritis is directed at suppression of
the later stages of the inflammatory
process to reduce symptoms and pre-
vent progressive damage to the joints.
RA can show an abrupt onset
(10% of cases), but more often the
disease has a slow and insidious
course. The gradual development of
symmetric polyarthritis of the small
joints in the hands and feet is com-
mon, although some patients develop
arthritis of one or more large joints.
The diagnosis of RA requires a com-
plete patient history and physical ex-
amination. Laboratory results and
radiographs are of only secondary im-
portance; some 25% of RA patients
will never test positive for rheumatoid
factor, yet these patients can be very
ill clinically. A history of symmetri-
cal, multiple small-joint disease, with
tenderness and swelling observed on
physical examination, indicates dis-
ease. The management of RA re-
quires a multidisciplinary approach.
Patients are treated initially with bed
rest, physical therapy, and typically
with products such as steroids and
nonsteroidal, anti-inflammatory
agents and with other therapies, all of
which are limited for several reasons,
including their lack of specificity and
ineffectiveness when used chronically.
Furthermore, steroids suppress the
immune system and make the patient
susceptible to infections while nons-
teroidal, anti-inflammatory agents
have been implicated in the formation
of gastro-intestinal ulcerations.
the association of RA with class II
major histocompatibility complex
(MHC) polymorphisms that control
antigen presentation to CD4+ T cells.
Further evidence is noted by the infil-
tration of synovial tissue with large
numbers of activated T cells, and the
development of several animal models
of RA that are dependent upon and
transmissible by antigen-specific
CD4+ T cells. Biological therapeu-
tics, such as monoclonal antibodies
(Mabs) against T cells have been used
successfully in some of these animal
models. This type of scientific evi-
dence has lead to the thinking that
anti-T cell Mabs may be useful for
RA.
The second involves three
cytokines [tumor necrosis factor-alpha
(TNF-
), interleukin-1 (IL-1), and
interleukin-6 (IL-6)]. All three cy-
tokines possess pro-inflammatory ac-
tivity and have been found to be pre-
sent in higher concentration than nor-
mal in affected joints. Cytokines are
proteins synthesized by many diverse
cell types (not just T cells), which
bind to receptors on several cells and
exert a variety of biologic effects.
One effect is the stimulation of
degradative enzymes such as, collage-
nase, which selectively destroys colla-
gen. Collagen is an intricate compo-
nent of all tissues, including cartilage.
The destruction of joints in RA is re-
lated to an imbalance of cartilage
breakdown and regeneration.
The precise role(s) of many
cytokines in autoimmune diseases is
still being investigated. IL-1 and
F
-
are two cytokines which there
is considerable information pertaining
to their role in RA. The association
of
F
-
with RA is strengthened by
studies in transgenic mice made to
express human
F
-
. These genet-
ically engineered mice develop a
chronic inflammatory arthritis which
resembles RA. Treatment with anti-
bodies against
F
-
or with soluble
F
-
receptors was shown to re-
lieve the inflammatory arthritis in
Molecular and cellular basis
of rheumatoid arthritis:
disease. The body normally distin-
guishes between self and non-self,
between proteins found in the body
and proteins carried by foreign in-
vaders (bacteria, viruses, fungi, and
protozoans). When an immune cell
(T or B lymphocyte) reacts to a self-
protein during its development in the
thymus or bone marrow, that cell is
usually killed or inactivated. But oc-
casionally a self-reactive immune cell
-- that is, a T cell or B cell pro-
grammed to attack a self-protein --
escapes destruction. Years later it can
be activated and trigger an immune
response. Activation is thought to
occur after infection with a common
bacteria or virus that contains a pro-
tein with a stretch of amino acids that
match a stretch on a tissue protein.
Researchers have shown that a match
between a foreign protein and a self-
protein need only be five amino acids
long to induce an autoimmune re-
sponse. In the case of RA, several
bacteria have been implicated in the
initiation of disease, including strep-
tococcus, mycoplasma, and borrelia
(the agent of Lyme disease). Retro-
viruses have also been implicated.
When the causative agent first gains
access to the joint, it causes an in-
flammatory response, with damage to
small blood vessels and the accumula-
tion of inflammatory cells
(macrophages, lymphocytes).
Macrophages process the pathogenic
material and present the antigen to
lymphocytes (B and T cells), which
respond by producing antibodies and
cytotoxic chemicals (B cells produce
antibodies, T cells produce cytokines
that activate B cells and cytotoxins
that attack tissues directly). The re-
sult is an extravascular immune com-
plex disease.
So how does this activated
immune response develop into RA?
There are two current viewpoints.
The first involves T cells, where there
is substantial evidence to indicate a
central role in the pathogenesis of
RA. One piece of evidence includes
The cause of RA is much the
same as the cause of any autoimmune
