Nature Biotechnology
18, IT12 - IT14 (2000)
doi:10.1038/80045
ArthritisThe aging populations of developed countries are likely to present
a growing market for arthritis therapies.Arthritis (from the Greek word for joint) is a chronic multifactorial disease
induced when the immune system attacks and begins degrading the body's
joints. The disease knows no racial boundaries and comes in many forms, including
calcific periarthritis, enteropathic arthritis, chronic, gouty, and hand osteoarthritis,
hip and knee osteoarthritis, thumb, Jaccoud's, and juvenile osteoarthritis,
oligoarthritis, polyarthritis, and peripheral, psoriatic, rheumatoid, and
septic arthritis. Rheumatoid arthritis (RA) alone is estimated to affect 1%
of the world's population and is twice as prevalent in women as in men.
In the US, arthritis and other rheumatic conditions affect about 43 million
people, or about 15% of the population, at a total disease burden close to
$65 billion. Prescription sales of the various drugs used to control the disease
are in excess of $3.5 billion, growing at about 11% annually1.
With such a massive economic and societal burden, it is not surprising that
arthritis is a disease in which there is a tremendous amount of research to
find effective drugs that focus not only on the symptoms, but also on the
causes themselves.
Historical perspective
Some of the most effective treatments against arthritis have been the anti-inflammatories
known as glucocorticoids that have been in use for about 50 years2.
However, the disease itself began having its histological and molecular characteristics
investigated systematically only from the mid-1960s onward. For example, electron
microscopic studies of tissues in RA began showing in detail the extent of
tissue damage in joints, but also corollary effects such as angiopathies3. Serological analyses in the late 1960s focused on developing correlations
between the disease and known macromolecules, such as the deficiency in  1-A-globulin
that occurs sometimes in RA4. These analyses were complemented
by studies that focused on the effects of medications used at the time, such
as anti-inflammatories, on joint or synovial tissue5. At the
same time, initial efforts toward hip surgery, including endoprosthesis, were
also being developed6.
The early 1970s saw the development of cell cultures from rheumatic tissues
that would later form the basis of in vitro assays used for drug discovery7, as well as the application of nonsteroid and non−anti-inflammatory
drugs in RA treatment, such as therapy using gold suspensions, which is used
even today8. Later came the initial characterizations of autoantibodies
against ubiquitous tissue antigens in RA9, setting the stage
for today's approaches that focus on inhibiting the immune autorecognition
events that cause the disease. Also in the late 1970s, immunosuppressants
such as cyclosporin-A began to be used for treatment.
Diagnostics based on bone density measurements began to be validated in
the case of postmenopausal osteoarthritis in the mid-1980s10,
heralding the growing importance of diagnostic monitoring that aims to begin
treatment as early as possible. There were also increasing efforts to characterize
the cytotoxic T-cell response in arthritis, based initially on correlations
with viral infections, such as Epstein−Barr infection11.
In the past 15 years, there has been a veritable explosion in the number of
treatment options available, based on an increasing understanding of some
of the key symptoms of the disease. Most of these therapies, however, focus
on addressing the symptoms, rather than the underlying causes, of the disease.
Current state
The market for arthritis drugs is huge; therefore, it is not surprising
that many companies, including some of the largest pharmaceutical companies,
have R&D programs aimed at characterizing the self-antigens involved in
the disease, or key enzymes that participate in the inflammatory response,
in an effort to develop new or better drugs. A selection of these companies
and their efforts against arthritis are listed in Table 1
.
Key to the development of current therapies is the characterization of
the variety of self-antigens that are the focus of the immune response. This
is the subject of concerted efforts by many academic and corporate groups.
One example of a recent autoantigen implicated in the disease is leukocyte
function-associated antigen (LFA-1) in treatment-resistant Lyme arthritis12.
Reducing inflammation is the most commonly used treatment option in arthritis,
and glucocorticosteroids, such as prednisolone and methylprednisolone, are
some typical choices. However, there is still much that is uncertain about
their real efficacy and tolerance profiles, even though they have been in
use for some time13. For example, they often need to be used
in combination with calcitriol or bisphosphonates to reduce the risk of developing
osteoporosis, which may occur as a result of the long-term administration
of glucocorticosteroids.
At present, a great deal of attention is being focused on nonsteroidal
anti-inflammatory drugs (NSAIDs) based on inhibiting the cyclooxygenase (COX)
enzymes. The two isoforms, COX-1 and COX-2, are central to the production
of prostaglandins, produced in excess at sites of inflammation. COX-1 synthesizes
prostaglandins that are involved in the regulation of normal cell activity,
whereas COX-2 produces prostaglandins mainly where inflammation occurs. Thus,
selective inhibition of COX-2 in particular is sufficient to limit inflammation
significantly, and COX-2 inhibitors, such as G.D. Searle's Celebrex,
are heavily prescribed. There are still some concerns about side effects arising
from the inhibition of a key enzyme in tissues and organs other than the ones
affected by the disease, such as the kidney and the brain14.
Finally, there is emerging recognition that synovial tissues in arthritis
may be under attack not just from antibodies or cytotoxic T-cells that recognize
self-antigens, but also from the complement system. This critical molecular
cascade goes awry in a number of conditions, including arthritis, and is the
subject of intense R&D15.
Clinical progress
Arthritis is the subject of numerous clinical trials investigating new
agents or ones already in use for side effects. For example, even though Celebrex
(celecoxib) is prescribed, clinical trials are ongoing to refine its side-effect
profile and determine additional uses. For example, a recent report describes
the effects of the drug on the gastrointestinal mucosal surface, and on platelet
function in comparison to naproxen, a COX-1 inhibiting NSAID16.
The small-scale trials showed that no ulcers occurred in patients receiving
celecoxib in comparison to 19% of patients who received naproxen. Also, there
was no statistically significant effect on platelet aggregation or bleeding
time with celecoxib, whereas such effects were observed with naproxen. The
results of these trials confirm the advantage of COX-2 selectivity in terms
of reducing side effects in arthritis treatment. Indeed, COX-2 is the target
for several inhibitors, in addition to celecoxib, that are under development
with the goal of improving efficacy and reducing side effects17.
In addition to single-drug clinical trials focusing on new targets, there
are other trials that aim to optimize current approaches, specifically comparing
various regimens of combination therapy in arthritis. One recent trial involved
199 patients in a multicenter, randomized study with a two-year follow-up,
comparing combination therapy (sulfasalazine, methotrexate, hydroxychloroquine,
and prednisolone) with a single antirheumatic drug (sulfasalazine or methotrexate)
with or without prednisolone, in early RA18. Here, combination
therapy was found to be better in causing initial remission in at least a
proportion of the patients studied.
Finally, other types of trials aim to determine the effects of antiarthritis
drugs on various molecular responses, such as the production and subsequent
effect of cytokines. For example, a recent trial linked the immune suppressive
effect of dexamethasone on interleukin-10 (IL-10) production and on the type
1 (T1)/type 2 (T2) T-cell balance found in RA19. Dexamethasone
therapy in RA patients leads to a rapid, clinically beneficial effect, and
the upregulation of IL-10 production observed after administration may be
involved in the prolonged clinical benefit. At the same time, there is an
immunosuppressive effect accompanied by a relative shift toward T2-cell activity.
Such results offer significant insights into the individual mechanisms that
affect the progression and outcome of the disease.
Industry challenges
Arthritis is now a disease that is fought with many drugs. On the whole,
these drugs treat inflammation as a symptom, but do not address the actual
cause of the disease. Thus, the industry's main challenge is to tackle
the cause head-on—a task that is complex and difficult. For example,
exactly why does the immune system turn against the host it is supposed to
protect? This question is at the heart of all autoimmune disease, of which
arthritis is one.
Several hypotheses can offer some insight, and some interesting approaches
are emerging that attempt to enhance our understanding of the underlying causes,
thus helping to design better drugs. For example, recent work focuses on gene
variations that themselves correlate with arthritis. A good example is the
variation observed in the estrogen receptor gene that has been linked to the
age of onset of RA in women, but not in men20. This correlation
potentially links the serum concentrations of estrogen and the actual timing
of onset of the disease, offering a novel set of targets as well as potential
reasons for why and how the disease develops.
In addition to trying to get to the root cause of the disease, the industry
faces the challenge of refining its understanding of the multiple molecular
mechanisms involved. For example, in addition to COX-2 inhibitors, there is
a great deal of excitement caused by the emerging importance of matrix metalloproteinases
(MMPs) in the disease. Enzymes that degrade the extracellular matrix, MMPs
are controlled normally by a set of tissue inhibitors that, if disrupted,
will allow the enzymes to work unchecked, degrading the matrix and promoting
not only arthritis, but also tumor growth and metastasis.
Increasing understanding of this process has led to the validation of MMPs
as targets for the development of inhibitors and has prompted efforts aimed
at finding out why the inhibitors went out of balance in the first place.
With respect to MMP inhibitors, there has been considerable progress recently
in obtaining three-dimensional structures of the enzymes alone and in combination
with their inhibitors, which will help in the design of novel inhibitors with
clinical potential21.
Future directions
Future efforts against arthritis will center on the identification of what
causes the immune system go awry, and also the identification of candidate
self-antigens targeted in arthritis. Ongoing research will be helped by animal
studies and in vitro models of arthritis based on tissue culture of rheumatoid
synovial fibroblasts. The latter are being used increasingly to study specific
signal transduction mechanisms in the disease. It was found recently that
once the thrombin receptor is activated in these cells, they subsequently
produce interleukin-6 and granulocyte colony-stimulating factor, both of which
lead to inflammation22. Any suppression in the production of
inflammation-causing signals in joints could help alleviate the symptoms,
thus offering new avenues for drug targeting.
In the future, increasing attention will be directed toward by-products
of molecular events that have gone wrong in arthritis and on their synergistic
effect in promoting the disease. A good example, nitric oxide, is produced
in excess in rheumatoid tissues and is now being investigated for its effects
in cartilage damage in arthritic joints23. Another good example
is tumor necrosis factor  (TNF), an inflammation-promoting cytokine
associated with multiple inflammatory events, including arthritis. Anti-TNF
therapies are the subject of intense research, and first-generation therapies
are already on the market24.
Although a lot is already known about certain molecular pathways involved
in specific aspects of arthritis, as well as the effects of drugs, the future
will see increased efforts to refine our understanding of the mode of action
of new drugs. Hopefully, this will lead to the design of even better drugs
with more specific benefits and fewer side effects. For example, a recent
study reports on the novel actions of the NSAID aceclofenac, prescribed for
rheumatoid arthritis and osteoarthritis. The study showed that the therapeutic
effects of aceclofenac are due, to a certain degree, to a newly decribed chondroprotective
effect of a metabolite of the drug, which supresses promatrix metalloproteinase
production and proteoglycan release and therefore reduces arthritic symptoms25. This and other studies of this type on mode of action issues will
no doubt lead to optimized drug design efforts as well as to the validation
of novel targets for de novo drug design, via the elucidation of specific
pathways involved in the disease. Specific examples of novel targets for anti-arthritis
drugs include vascular adhesion protein-1 (VAP-1), which mediates leukocyte-endothelial
cell interactions and can also be used as a potential target for imaging inflammation
itself26, vascular endothelial growth factor (VEGF) isoforms
and VEGF receptors, Flt-1, KDR and neuropilin-1, all of which are involved
in angiogenesis which itself is central to the development of rheumatoid arthritis27.
It should also be pointed out that diagnostic methods for arthritis continue
to improve and evolve. For example, a recent study shows how synovial fluid
has certain physical characteristics that enable the distinction between inflammatory
and degenerative arthritis using non-invasive analysis by spin echo diffusion,
which is an analytical method for determining flow characteristics and differences
among viscous fluids. This observation can potentially lead to a better prediction
of the nature of arthritis early on in patients who have inflamed joints28.
Finally, the future will also see the increasing application of gene therapy
as a front-line defense against the disease, aiming at long-term corrective
treatment. A variety of genes that code for antiarthritic proteins are under
investigation, including IL-1Ra, IL-1sR, TNFsR, transforming growth factor 
(TGF), IL-13, Fas L, IL-10, and vIL-10, as are the vectors that will
carry them to arthritic tissues29. Already, two human arthritis
gene therapy protocols are underway in the US and Germany, with ex vivo transfer
of an IL-1Ra cDNA to the metacarpophalangeal joints of patients with RA.
Conclusions
Arthritis presents a major socioeconomic burden that has and will continue
to attract major research and development efforts aimed at elucidating the
basis of the disease as well as developing effective therapies. Increasing
understanding of the molecular cascades involved are already producing significantly
better drugs than in the past with increased selectivity and fewer side effects,
and this will continue into the foreseeable future as arthritis is a multifactorial
disease that is unlikely to be solved with a magic bullet-type approach.
Reprinted from Nature Biotechnology 17, 726−727
(1999).
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