San Diego, CA (11/12/98)- New classes of immunomodulatory and anti-inflammatory
drugs represent a new era is the treatment of arthritis, according to researchers
at the American College of Rheumatology's 62nd National Meeting.
"These
new drugs are on a level with the three major breakthroughs of the past century
in this field: the discovery that aspirin could improve the symptoms of arthritis;
that corticosteroid benefit patients with rheumatoid arthritis and that methotrexate
can improve the outlook for arthritis patients. This is a very exciting time
for patients, physicians and researchers, said Michael Weinblatt, M.D., Brigham
and Women's Hospital, Boston, MA.
Overproduction
of TNFa may cause inflammation in patients with arthritis
Weinblatt was the lead investigator in a series of studies involving etanercept,
one of a new class of immunomodulatory agents. He reported the results of
a large clinical trial of etanercept in combination with methotrexate, a standard
treatment for rheumatoid arthritis. Significant improvements were seen in
signs and symptoms among patients receiving etanercept compared with placebo.
More than half of patients receiving etanercept showed an improvement of at
least 50% compared with only three percent of the placebo group.
Etanercept, also known as TNF receptor P75 Fc fusion protein, or Enbrel,
is a biological response modifier that regulates production of the inflammatory
protein TNF (tumor necrosis factor) by inhibiting the binding of TNF to TNF-receptor
sites. TNF is known to be involved in the inflammatory process that characterizes
rheumatoid arthritis.
Similar results were reported with another immunomodulator that also interferes
with the actions of TNF, but by a different mechanism. The drug, called infliximab
(or Remicade), is a chimeric monoclonal anti-TNF alpha antibody. The antibody
binds with TNF, interrupting the inflammatory process. Treatment benefit was
observed within the first week of treatment, and persisted throughout a long-term
trial.
"We saw a 50% response rate in treated patients, regardless of dose. This
appears to be a very effective and well tolerated therapy for patients with
aggressive disease. An extra benefit is that the patients will only need treatment
once every eight weeks," said Dr. Peter Lipsky, M.D., University of Texas
Southwestern Medical Center.
The new drugs fall under a broad category known as disease-modifying anti-rheumatic
drugs (DMARDs). Another DMARD recently approved by the FDA is leflunomide,
also called Arava. Leflunomide interferes with the rheumatoid inflammatory
process by inhibiting an enzyme in the immune system, dihydroorotate dehydrogenase,
an enzyme involved in de novo pyrimidine synthesis. A 12 month study showed
that the drug improved patients' symptoms and slowed the progression of rheumatoid
arthritis, reported Arthur Weaver, M.D., medical director, Arthritis Center
of Nebraska.
A fourth new DMARD, mycophenolate mofetil or CellCept, also improved patients'
symptoms during the course of a nine-month clinical study. The drug was well
tolerated and appeared to prevent flare-up of disease even after it had been
discontinued for more than a month, reported Michael Schiff, M.D., Director,
Denver Arthritis Clinic.
"This is a time of extraordinary excitement among rheumatology researchers.
We are beginning an era of rational, target-specific treatment of rheumatoid
arthritis. These new drugs provide options for treatment of early and late
disease for symptoms ranging from moderate to severe," said Schiff.
The new drugs are a welcome addition to the current armamentarium against
rheumatic disease, representing new hope for patients who cannot tolerate
or do not respond fully to current treatments. The researchers cautioned that
a number of questions about the long-term use of the new immunomodulatory
drugs remain. There is concern that treatment with immunomodulatory agents
may make some patients vulnerable to serious infection, malignancy and autoimmune
disease. While there is little indication of risk at this point, only long-term
studies can clear up these concerns, said Schiff.
COX-2 in the Spotlight
Non-steroidal anti-inflammatory drugs such as aspiring and ibuprofen are
a mainstay of treatment for arthritis. However, these drugs often produce
side-effects, the most common of which is gastric ulcer. COX-2 specific inhibitors
are a new class of anti-inflammatory medications that are being studied to
determine whether they produce fewer serious GI side effects than NSAIDs.
There are two types of cyclooxygenase in the body. Cyclooxygenase-1 (COX-1)
produces prostaglandins that are believed to be responsible for maintaining
important day-to-day normal body functions, including the protection of the
lining of the stomach. Cyclooxygenase-2 (COX- 2) is responsible for producing
prostaglandins that are believed to be primarily responsible for pain and
inflammation. Currently available medicines used to treat arthritis and pain,
known as nonsteroidal anti-inflammatory drugs (NSAIDs), inhibit both COX-1
and COX-2. COX-2 specific inhibitors work by inhibiting COX-2 without significantly
inhibiting COX-1.
Researchers reviewed the results of clinical trials with two new COX-2 inhibitors-
celecoxib (Celebra) and rofecoxib (Vioxx). Both drugs appear to be as effective
as NSAIDs, while sparing patients the gastrointestinal side-effects seen with
those drugs.
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