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Research: Improved understanding of the pathogenesis of RA has led to the development of the biologic DMARDs, antibodies,
soluble receptors, and receptor antagonists that target TNF-alpha and IL-1 at the cell surface level.
Research has begun to focus on downstream intracellular targets at the cytoplasmic and nuclear levels. Among the best
understood are the mitogen-activated protein kinase (MAPK) pathways. MAPK cascades consist of multitiered pathways in which
MAPK is activated in turn by a MAPK kinase (MAPKK or MEK).
MAPK pathways directly regulate activator protein 1 (AP-1)dependent transcription through the synthesis of the AP-1 proteins
fos and jun. Transcription of AP-1 is in turn regulated by three genes that control posttranslational modification, JNK1,
JNK2, and JNK3.
The p38 pathway is also thought to play a critical role in cytokine production and apoptosis. To date, the greatest progress
has been made in the development of p38 MAPK inhibitors.
Pharmacogenetics can be defined as the variability of drug response due to inherited characteristics in individuals.
The availability of whole-genome single-nucleotide polymorphism (SNP) maps will soon make it possible to create an SNP profile
for patients who do or do not respond clinically to a given medication.
Whole-genome SNP mapping analyses aimed at determining linkage disequilibrium profiles along an ordered human genome
backbone are in progress. SNP fingerprints will be used to identify patients with a greater chance of responding to a medicine.
Standardized pharmacogenetic maps for drug registration and post-marketing surveillance will result in safer, more effective,
and more cost-efficient medicines.
Pharmacogenetic evidence-based treatment strategies will have major implications for all aspects of the product pipeline,
including drug discovery, high throughput target screening protocols, lead optimization, and drug formulation, to produce
series of medicines for a particular disease that will meet the efficacy needs of the majority of patients
A second major pathway is the NF-kappa beta pathway, also activated by extracellular stimuli, including TNF-alpha and
IL-1. To date, few specific NF-kappa beta inhibitors have been identified.
Cytokines have a very wide range of functions relevant to the pathophysiology of RA. Functions relevant to RA; Regulation
of the inflammatory respomse;
a) Proinflammatory: TNF-alpha,IL-1,IL-6.IL-7,chemokines (Il-8,MIP-1alpha/beta,Rantes) b) Anti-inflammatory: IL-10,TGF-beta,IL-4,IL-1Ra,sTNFR
I/II,IL-1R II
Modulation of the immune response; I) Modify Th1/Th2 bias ;a) Th1:IL-12,IL-18,IFN-y ;b) Th2:IL-4,Il-13,IL-10,chemokines
II) Mediate activation/apoptosis: IL-2,IL-15,IFN-y,IL-3,IL-5,IL-7,
Remodel tissue; I) Bone and cartilage destruction: IL-1,TNF-alpha,OPG/RANKL (TRANCE) ;II) Angiogenesis/growth factors:
TNF-alpha,TGF-beta,VEGF
These molecules are key regulators of inflammatory responses, having actions that are either proinflammatory (TNF-alpha,
IL -1, IL-6, IL-7, chemokines, IL-8, MIP-1alpha/beta, and regulated upon activation, normal T cell expressed and secreted
[RANTES]) or anti-inflammatory (IL-10, transforming growth factor [TGF]-beta, IL-4; IL-1 receptor antagonist [Ra], soluble
TNF receptor [sTNFR] type I/II, and type II IL-1 receptor [IL-1R II]).
Cytokines can also modulate immune responses. IL-12, IL-18, and interferon (IFN)-y promote a Th1 bias and IL-4, IL-13,
IL-10, and chemokines promote a Th2 bias. Activation and/or apoptosis are mediated by IL-2, IL-15, IFN-y, IL-3, IL-5, and
IL-7.
Cytokines are also involved in regulation of tissue remodeling. IL-1, TNF-alpha, and OPG (osteoprotegerin) /RANKL (receptor
activator of nuclear factor-kappa b ligand) (TRANCE, TNF-related activator-induced cytokine) have been implicated in bone
and cartilage destruction, and TNF-alpha, TNF-beta, and vascular endothelial growth factor (VEGF) have been shown to have
trophic/angiogenic effects.
CD4+ T cells might initiate the disease process in RA. Activated by antigens, these cells stimulate monocytes, synovial
fibroblasts, and macrophages to produce the key proinflammatory cytokines TNF-alpha, IL-1, and IL-6 as well as to release
MMPs, enzymes that degrade connective tissue matrix.1 TNF-alpha and IL-1 also inhibit synovial fibroblasts from producing
tissue inhibitors of MMPs. These two actions by TNF-alpha and IL-1, among others, are believed to result in the joint damage
that occurs in RA.
Activated CD4+ T cells also contribute to joint damage by stimulating the development of osteoclasts by expressing osteoprotegrin
ligands (OPGLs) and by stimulating B cells to produce immunoglobulins such as rheumatoid factor.
Activated macrophages, lymphocytes, and fibroblasts and their products can stimulate angiogenesis, a fact that may account
for the increased vascularity of the synovium in rheumatoid joints.
Other cytokines involved in the complex cellular interactions that occur as part of the inflammatory process include
IL-4, IL-10, IL-12, and IFN-g. In addition, CD11 and CD69 cells are involved in the cell-surface signaling that leads to the
production of cytokines.
Progressive joint damage occurs in unchecked RA. In the early stages of the disease, cartilage destruction begins, and
neutrophils, T cells, and B cells are recruited into the synovial cavity. The synovial membrane exhibits hyperplasia, and
hypertrophic synoviocytes and capillaries are starting to form.
In a joint with established RA,the greatly thickened, inflamed synovium (pannus) invades and erodes adjacent bone and
cartilage. Activated macrophages, lymphocytes, and fibroblasts and their products stimulate extensive angiogenesis, a central
feature in synovial inflammation and pannus formation. Synovial villi become evident.
TNF-alpha is one of the most potent osteoclastogenic cytokines produced in inflammation, and it is pivotal in the pathogenesis
of RA. Production of TNF-alpha and other proinflammatory cytokines in RA is largely T-cell dependent. Activated synovial T
cells express both membrane-bound and soluble forms of RANKL. In the RA synovium, fibroblasts also provide an abundant source
of RANKL and macrophage colony-stimulating factor (M-CSF).
TNF-a and IL-1 target stromal-osteoblastic cells to increase expression of RANKL. In the presence of permissive levels
of RANKL, TNF-alpha acts directly to stimulate osteoclast differentiation of macrophages and myeloid progenitor cells.
In addition, TNF-alpha induces IL-1 release by synovial fibroblasts and macrophages, and IL-1, together with RANKL, is a major
survival and activation signal for nascent osteoclasts. Thus, TNF-alpha and IL-1, acting in concert with RANKL, can
powerfully promote osteoclast recruitment, activation, and osteolysis in RA.
Cytokines exert their damaging effects by binding to specific receptors, and there are several potential approaches that
can be employed to block these effects.
Cytokines can be neutralized through the use of antibodies or soluble receptors. With this approach, the cytokine never
reaches the receptor on the cell of interest. This avenue for the treatment of RA has been taken with soluble TNF-alpha receptor
fusion proteins, soluble IL receptors, monoclonal antibodies against TNF-alpha, and monoclonal antibodies against IL-6.
Receptor antagonists or antibodies can bind to cytokine receptors on cells and prevent cytokines from binding. This blocks
their actions on the cell in question. This approach to the treatment of RA has been taken with recombinant IL-1Ra and an
antibody against the IL-6 receptor.
Administration of anti-inflammatory cytokines can inhibit expression of inflammatory cytokines. This approach has been
taken with IL-4 and IL-10.
Autoimmune diseases, including RA, result when an imbalance in the cytokine network develops, either from excess production
of proinflammatory cytokines or from inadequate presence of natural anti-inflammatory mechanisms.
A key step in the treatment of rheumatoid synovitis is restoring the balance between proinflammatory cytokines (TNF-alpha,
granulocyte-macrophage colony stimulating factor [GM-CSF], IFN-gamma, IL-1, IL-6, IL-8, IL-15, IL-16, IL-17, and IL-18) and
anti-inflammatory cytokines (IL-4, IL-10, IL-11, IL-13).
TGF-bets, tissue inhibitors of metalloproteinases (TIMPs), and matrix metalloproteinases (MMPs) may all play critical
roles in shifting the cytokine equilibrium between proinflammatory and anti-inflammatory.
TNF-alpha released by macrophages interacts with multiple receptors, most notably the p55 (55 kD) TNF receptor (CD120a)
and the p75 (75 kD) TNF receptor (CD120b), on many cell types to control a wide range of innate and adaptive immune response
functions.
Events associated with activation of these receptors include apoptosis, tumor cell lysis, hemorrhagic necrosis of tumors,
shock, tissue damage, T-cell proliferation, dermal necrosis, insulin resistance, and bone resorption
It is now generally accepted that many cytokines are involved in the pathogenesis of autoimmune disease (eg, RA, Crohn's
disease, psoriasis, ankylosing spondylitis), either directly by causing tissue destruction or indirectly through the activation
of T cells.
Proinflammatory cytokines that have been shown to be elevated in patients with autoimmune disease include IL-18, IL-15,
IFN-gamma, and TNF-alpha.
The cytokine cascade involving IL-12 and IL-18 activation of T cells, leukotrienes (LTs), IL-2, and IFN-gamma ultimately
results in the recruitment of activated macrophages that promote tissue destruction by further release of IL-1alpha and beta
and TNF-alpha.
The most recent additions to the anti-arthritis armamentarium are drugs known as biologic DMARDs. Currently available
biologic DMARDs include etanercept, infliximab, adalimumab, and anakinra. Their mechanism of action is to inhibit the actions
of the cytokines interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha).
Etanercept is a recombinant human TNF receptor fusion protein. It is given by twice-weekly sc administration with or
without MTX.
Infliximab is a chimeric (human and murine) anti-TNF monoclonal antibody approved for reducing signs and symptoms in
patients with moderate to severe RA who have failed MTX therapy. Infliximab has a long half-life and may be administered iv
every 4 to 8 weeks in combination with MTX.
Adalimumab is a fully-human monoclonal anti-TNF-alpha antibody. It is administered by subcutaneous injection. It has
a long half-life and can be given once every 2 weeks as monotherapy or in combination with MTX.
Anakinra is a recombinant human form of IL-1Ra, a specific inhibitor of IL-1 that blocks the binding of IL-1 to its receptors.
It is given by sc injection every 24 hours.
According to results from a Phase II study presented recently at the American College of Rheumatology (ACR) scientific
meeting, the novel investigational biologic agent, CTLA4Ig, may have potential for treating rheumatoid arthritis patients
who do not respond adequately to etanercept (Enbrel) alone. CTLA4Ig is the first in a new class of treatments
called costimulation blockers and is being developed by Bristol-Myers Squibb Company. Researchers found that people who inadequately
responded to etanercept alone showed significant improvement from baseline in ACR 20 and 70 response rates with the addition
of once monthly infusions of CTLA4Ig compared with placebo plus etanercept over a six-month period. The primary
endpoint of the study was the proportion of patients meeting the ACR 20 criteria, a way of measuring patient improvement using
American College of Rheumatology (ACR) guidelines. By achieving ACR 20, a patient has at least a 20 percent improvement
in multiple measures of disease activity. In this study of people with active rheumatoid arthritis despite treatment with
etanercept, 85 people received a once-monthly infusion of a 2 milligram per kilogram (mg/kg) dose of CTLA4Ig and twice-weekly
injections of etanercept. Another 36 people studied received a placebo in addition to the twice-weekly etanercept injections. Of
the 85 patients receiving CTLA4Ig 2 mg/kg plus etanercept, 41 (48.2 percent) achieved ACR 20. Of the 36 patients receiving
placebo and etanercept, only 10 (27.8 percent) achieved ACR 20. Also, researchers found that 9 of the 85 patients (10.6 percent)
receiving CTLA4Ig 2 mg/kg achieved ACR 70 -- a 70 percent improvement in symptoms. No patient receiving placebo plus etanercept
achieved ACR 70. Bristol-Myers Squibb plans to initiate CTLA4Ig phase III development in rheumatoid arthritis
later this year.
Researchers at Stanford University Medical Center have found that selective COX-2 inhibitors a class of medications
widely prescribed for painful inflammatory conditions such as osteoarthritis and rheumatoid arthritis - interfere with the
healing process after a bone fracture or cementless joint implant surgery.
Their findings, published in the November issue of the Journal of Orthopaedic Research, suggest that patients who regularly
take COX-2 inhibitors should switch to a different medication, such as acetaminophen or codeine derivatives, following a bone
fracture or cementless implant.
The study, conducted in rabbits, also suggests that physicians should consider changing prescribing patterns since many
doctors commonly prescribe anti-inflammatory drugs including COX-2 inhibitors under the very circumstances in which the drugs
should be avoided.
"It's very common. You break a bone and go to the ER. The doctor sets it in a splint and prescribes one of these anti-inflammatory
drugs (including COX-2 inhibitors) for pain," said Dr. Stuart Goodman, professor of orthopaedic surgery at the Stanford School
of Medicine and lead author of the study. "We now know that could actually delay healing."
According to a Stanford release, researchers confirmed years ago that nonspecific NSAIDS inhibited bone growth and healing,
but the Stanford study is among the first to show that COX-2 inhibitors have the same effect.
In tests with rabbits, the researchers found that while the tissue in the control group contained 24.8 percent and 29.9
percent new bone growth, the tissue harvested after the rabbits consumed naproxen and rofecoxib contained significantly less
15.9 percent and 18.5 percent respectively. The difference in new bone growth associated with the two drugs was statistically
insignificant; suggesting the COX-2 inhibitor impeded new bone growth as much as the nonspecific NSAID.
While acknowledging the limitations of animal research, Goodman said this study "has great applicability to humans, because
the healing process is virtually the same" for rabbit and human bones. Goodman is having his own patients avoid COX-2 inhibitors
for six weeks after a fracture or joint implant, and he recommends other physicians do the same. "This research has very practical
applications."
Goodman said his recommended six-week "time-out" period is an educated guess, because his study didn't address how long
the bone-growth-suppressing effects of COX-2 inhibitors last. To answer that question, Goodman and his colleagues recently
began a follow-up study
The U.S. Food and Drug Adminisration (FDA) and Pharmacia are advising health care professionals in the U.S. about new
warnings and information in the product labeling of the drug Bextra (valdecoxib), a drug approved for treatment of osteoarthritis,
rheumatoid arthritis and dysmenorrhea (menstrual pain).
According to the FDA, the labeling is being updated with
new warnings following postmarketing reports of serious adverse effects including life-threatening risks related to skin reactions
-- including Stevens Johnson Syndrome, and anaphylactoid reactions (serious allergic reactions). In addition, the labeling
will state that the drug is contraindicated -- not to be used -- in patients allergic to sulfa containing products.
On
November 13, 2002, Pharmacia, the manufacturer of Bextra sent letters to health care professionals advising them of postmarketing
reports and new warnings that will be included in the drug label. Since the firm began marketing the drug in March of 2002,
cases of the serious skin and hypersensitivity reactions have been reported. These included cases of Stevens Johnson syndrome,
toxic epidermal necrolysis, exfoliative dermatitis and erythema multiforme. Although these adverse events are rare, some of
these patients required hospitalization. Based on these reports, FDA has approved labeling changes for Bextra that include
a warning for serious skin reactions. As these reactions can be life threatening, people who start Bextra and experience a
rash should discontinue the drug immediately.
Health care professionals are encouraged to report any unexpected
adverse or serious events associated with the use of Bextra directly to Pharmacia Corporation.
In an open label phase I/II study of 15 patients with active rheumatoid arthritis (RA), multiple
infusions of a humanized monoclonal antibody to interleukin-6 (MRA) normalized acute phase reactants associated with the disease,
led to clinical improvement, and was well tolerated
This is the first study of repetitive dosing with MRA for the treatment of active RA, Dr. Norihiro Nishimoto of Osaka University
and colleagues note in The Journal of Rheumatology for July.
In a previous study, a single intravenous dose of MRA improved the signs and symptoms RA and normalized acute phase reactants.
In the current study, 15 patients with active RA were given three intravenous doses of MRA (2, 4, or 8 mg/kg) biweekly for
6 weeks with treatment continuing for 24 weeks. None were taking immunosuppressive agents such as methotrexate.
Repetitive dosing with up to 8 mg/kg biweekly was well tolerated, the team reports. A total of 70 adverse reactions were
reported, but none were severe and there were few infectious complications. Most patients experienced an increase in total
serum cholesterol and long-term follow up is needed to determine the significance of this finding, according to the researchers.
None of the patients developed anti-MRA antibodies and there were no new observations of antinuclear antibody or anti-DNA
antibody.
MRA completely normalized acute-phase reactants erythrocyte sedimentation rate, C-reactive peptide and serum amyloid A,
as well as fibrinogen in 12 of 15 of patients who maintained detectable serum MRA concentrations.
The improvement rate for American College of Rheumatology (ACR) 20 and ACR 50 of >80% and 33%, respectively, demonstrates
the "strong therapeutic efficacy" of MRA for established RA, the team writes. There was no statistically significant difference
in efficacy between the three doses.
The efficacy of MRA in preventing joint damage is a subject for future trials, Dr. Nishimoto and colleagues write. Chugai
Pharmaceutical Company, Ltd. In Japan, which sponsored the study, is developing MRA.
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