Rheumatoid arthritis (RA) is a chronic, progressive, autoimmune
disease for which there is no current cure. However, the advent
of biologic therapy has made it possible to induce remission in
the majority of patients.
However, in order to effect remission, research suggests that a
critical therapeutic window may exist within the first two years
of disease onset when the rate of x-ray progression of the
disease- which correlates directly with potential disability-
can be slowed. X-ray changes occur within two years of disease
onset in 50-70 percent of RA patients.
Many experts have suggested control of disease progression
should start early to limit joint damage in RA. RA is associated
with substantial disability and economic losses.
Most studies have shown that a combination of methotrexate and
TNF-inhibitors work effectively to slow x-ray progression and
improve daily functioning. TNF-inhibors include drugs such as
etanercept (Enbrel), infliximab (Remicade), and adalimumab
(Humira). A second generation of biologics has become available
for use in patients who fail first line treatment. These include
drugs such as abatacept (Orencia) and rituximab (Rituxan).
Newer biologic drugs are currently under study. One such drug
is golimumab. Golimumab (Centocor, Schering-Plough) is a
fully-human TNF-inhibitor monoclonal antibody that targets and
neutralizes both the soluble and the membrane-bound form of
TNF-alpha. Golimumab is being investigated for administration by
subcutaneous (SC) injection and intravenous (IV) infusion.
In RA clinical trials in the U.S., patient responses to
treatment are measured using the American College of
Rheumatology (ACR) response of 20% (ACR 20), 40% (ACR 50), and
70% (ACR 70). In other words, if a patient has a 20 percent
response to treatment, they have an ACR 20 response. If they
have a 50 percent response to treatment they have reached ACR
50… and so on. The greater the number of patients reaching a
higher ACR level the more effective the treatment.
The greater the number of patients responding at a given ACR
level, the better the drug.
For instance, a drug that gives an ACR 70 response of 40
percent is much better than a drug that gives an ACR 70 response
of 20 percent.
According to new findings presented from a double-blind,
placebo-controlled, dose-ranging Phase 2 study, nearly 75
percent of patients with moderately to severely active
rheumatoid arthritis (RA) receiving golimumab (CNTO 148) and
methotrexate experienced at least 20 percent improvement in
arthritis symptoms (ACR 20) at one year.
Investigators also reported that more than one-third of
patients treated with golimumab and methotrexate achieved
remission at one year.
In this preliminary study of the effects of golimumab in RA,
172 adults with active RA for at least three months' duration
despite methotrexate therapy were randomized to one of five
treatment groups: placebo every two weeks or golimumab 50 or 100
mg every two weeks or every four weeks.
All patients received stable doses of methotrexate of at least
10 mg/week. At week 16, 62 percent, 31 percent and 12 percent of
all patients receiving golimumab (combined golimumab treatment
groups) plus methotrexate experienced ACR 20, ACR 50 and ACR 70
improvements, respectively, compared with 37 percent, 6 percent
and zero percent of patients receiving placebo plus
methotrexate, respectively.
At week 52 of the study, ACR 20, ACR 50 and ACR 70 scores
improved to 74 percent, 45 percent and 22 percent respectively,
among patients receiving golimumab plus methotrexate (combined
golimumab treatment groups). Moreover, patients receiving 50 mg
every two weeks and 100 mg every two weeks maintained efficacy
through week 52, even after converting to every four weeks
administration at week 20.
Patients receiving golimumab plus methotrexate also achieved
remission, as assessed by the abbreviated disease activity scale
(DAS 28), which measures tender and swollen joints, inflammation
and overall disease activity including measurement of
erythrocyte sedimentation rate (ESR). A DAS 28 of less than 2.6
indicates remission.
After 16 weeks of treatment, 27 percent of patients in the
golimumab (combined golimumab treatment groups) plus
methotrexate group achieved remission as assessed by DAS28 (DAS
< 2.6) compared with six percent of patients receiving placebo
plus methotrexate. Similar remission rates were reported at week
52, with 34 percent of patients receiving golimumab plus
methotrexate achieving remission at that time point. All of
these results were statistically significant.
Golimumab was generally well tolerated in the study through
week 52. Serious adverse events (AEs) reported were eight
percent for the combined golimumab groups compared with six
percent for the placebo group. No deaths, cases of tuberculosis
or other opportunistic infections were reported through 52
weeks, and serious infections were uncommon. The most common
clinically relevant serious AEs through week 52 were pneumonia
(three patients), lung cancer (one patient), cardiac tamponade
(one patient), and cardiac failure (one patient). One patient
died from coronary artery disease approximately four months
after completing 52 weeks of the study.
While these adverse events appear serious (and they are), they
are not worse than what is usually seen in clinical trials
involving RA. RA is not a benign disease and patients will
develop medical problems that are not necessarily related to the
medication being studied. However, all adverse events have to be
reported.
The results from this early (phase 2) study shows promise.
Through the development of new drugs and through the further
investigation of mechanisms of disease, a cure for RA will be
found, hopefully, in the now too distant future.
About The Author: Nathan Wei, MD FACP FACR is a rheumatologist
and Director of the Arthritis and Osteoporosis Center of
Maryland. He is a Clinical Assistant Professor of Medicine at
the University of Maryland School of Medicine. For more info:
http://www.arthriti
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