Latest News in Rheumatology
3/7/2003
FDA Committee Findings: The Risk of Lymphoma and
Congestive Heart Failure From TNF Inhibitors
Low Back Pain, Sacroiliitis, and the Relationship With
HLA-B27 in Crohn's Disease
New
Molecule Offers a More "Natural" Way to Encourage Sleep
Hibernating
Black Bears Shed Light on Osteoporosis Treatments
New
US Labeling to Eliminate Drug Confusion
New
Metal-on-Metal Hip Replacements
Silver Spring, MD -- The Food and Drug Administration's (FDA)
Arthritis Advisory Committee recommended Tuesday that no additional warning
information be required regarding the risk of lymphoma or other cancers in
rheumatoid arthritis (RA) patients treated with TNF inhibitors. The committee
was more concerned about data suggesting that these drugs might worsen heart
failure, even in patients with only mild cardiac problems.
The committee met to consider updated safety data on TNF blockers available
in the U.S.: infliximab (Remicade®, Centocor), etanercept (Enbrel®, Amgen),
and adalimumab (Humira®, Abbott). They examined data from clinical trials,
postmarketing surveillance, and patient registries.
According to the committee, the data presented by FDA analysts and
presentations from the three companies currently marketing TNF medications
indicate that these drugs do not increase cancer risk beyond the higher level
already associated with RA, which doubles lymphoma risk compared with the
general population.
Lymphoma risk became a concern for the FDA after several cases were
discovered in postmarketing surveillance. This week's hearing included analysis
of malignancy data from the three companies' clinical trials, from the MedWatch
adverse event reporting system (found at http://www.fda.gov/medwatch/articles.htm),
and from the extensive postmarketing surveillance that the FDA requires for
approval for these new medications. The total included approximately 10,000
patients, some who have been taking TNF medications for as long as six years.
No malignancies other than lymphomas occurred more often in patients taking
TNF inhibitors than in the general population, and the lymphoma rate was about
the same as in the population of RA patients not treated with the TNF
inhibitors. The fact that RA is associated with an increased risk of lymphoma is
not widely appreciated, and the committee concluded that it would likely create
more confusion by calling attention to a potential "nonproblem".
Committee oncology consultant Dr. Douglas W. Blayney (Lewis Family Cancer
Center, Pomona, CA) said, "I am most struck by what we don't see in these
cases. We don't see follicular lymphomas or Hodgkin's disease. We don't see
Kaposi's sarcoma or an excess of melanomas. We see lymphomas that seem to
reflect the background level of lymphomas seen in RA."
The committee also evaluated data from clinical trials of TNF inhibitors
studied for the treatment of congestive heart failure (CHF). TNF mediates some
aspects of heart disease pathology, so some people believed that blocking this
factor would be beneficial. But trials to test etanercept and infliximab for
that use were stopped early for safety reasons, and data from these trials
presented to the committee show that TNF medications appear to actually worsen
heart failure in some situations.
There was disagreement among committee members about how to approach the
heart failure warning. Some said they would avoid TNF medications in any
patients with heart failure, while others pointed out that the benefits from TNF
inhibitors are likely to outweigh risks in many patients with mild, treatable
CHF. The committee advised the FDA that since this appears to be an effect
common to this class of drugs, additional warning language should be added to
the prescribing information for all currently marketed TNF medications.
Resource: Safety Updated on TNF-alpha blocking agents, Food and
Drug Administration, Center for Drug Evaluation and Research, Arthritis Advisory
Committee. March 4, 2003. Available at http://www.fda.gov/cder/.
Researchers in the UK sought to determine the prevalence of sacroiliitis in
patients who have back pain in Crohn's disease (CD) using computer tomography
(CT) and to reassess the association of sacroiliitis in CD with HLA-B27.
S. Steer and colleagues from Guy's and St. Thomas' Hospitals NHS Trust in
London, England had 134 patients with CD completed complete a questionnaire
about musculoskeletal symptoms. Those reporting low back pain were assessed,
including radiographs and CT of the sacroiliac joints. HLA-B27 status was
determined in patients with and without back pain.
Results: There were 70 (52%) patients with low back pain, of whom 31
(45%) had CT evidence of sacrioiliitis. These were characterized by more frequent
spinal stiffness and positive sacroiliac compression tests even when
sacroiliitis was not suspected. Nine had previously recognized radiological and
clinical AS, and of these, 78% were HLA-B27 positive. Of those with newly
identified sacroiliitis, 14% were HLA-B27 positive. This frequency was not
statistically different to the 9% HLA-B27 positivity of those without back pain.
The researchers conclude that sacroiliitis defined by CT is a common cause of
low back pain in CD. They found that a relationship of sacroiliitis and HLA-B27
could be confirmed only for those with "classical AS". Their results
complement the possibility that sacroiliitis in CD is an isolated phenomenon,
unrelated to HLA-B27 and which may evolve into "classical AS" in
genetically susceptible people.
Resource: Low Back Pain, Sacroiliitis, and the Relationship With
HLA-B27 in Crohn's Disease, The Journal of Rheumatology, March 2003 (3);
518-22.
Chemists at the Scripps Research Institute in La Jolla, California, have
developed a new molecule that could induce "normal" sleep without the
unwelcome side effects of current sleeping pills, for which the side effects of
these pills can be very
severe. This article does not specifically mention any health conditions that
can result in problems with sleeping, although a number of spondylitis patients
report that they have difficulty getting a "good night's rest" for
various reasons. Results of this study are published in the Proceedings of
the National Academy of Sciences.
Sedatives used for sleeping disorders generally turn down activity in
the central nervous system, like throwing a blanket over the whole of the
brain's communication with the body. This brings sleep that is more like anesthesia
than normal "physiological" rest. It may leave the person completely
wiped out and unable to respond to the sort of disturbances that would wake up a
person receiving "normal" sleep. Oftentimes people are woken up from
sleep for a good reason, so this poses additional concerns. Some sleeping pills are potentially
addictive, perhaps leading to depression over prolonged periods. Some people
overdose on sleeping pills as a method of suicide.
Researchers think that normal sleep is triggered by sleep-inducing substances
in the brain. In 1995, Benjamin Cravatt and coworkers at the Scripps Institute
isolated a molecule called "oleamide" from sleep-deprived cats, which
could induce sleep in rats. Oleamide improves sleep by shortening the
"dropping off" period and promoting deep slumber without the deadening
effects of sedatives. Oleamide acculates in the brain when sleep approaches.
Yet using oleamide as
a sleep inducer in laboratory tests has produced mixed results. During sleep, an
enzyme called fatty acid amide hydrolase (FAAH) breaks down oleamide. The
Scripps team thought that the FAAH enzyme might make a better target because if
FAAH could be prevented from doing its job, then sleep should follow.
In 1996, Cavatt and colleagues developed molecules capable of blocking the
FAAH enzyme, but only up to a point. They now describe new molecules that are up
to a thousand times more potent, which allows for greater potential as sleep
aids.
On a side note, FAA also breaks down a related molecule in the brain that
appears to act as a pain suppressor. These researchers are hoping that FAAH
inhibitors could also provide pain-relieving drugs by protecting these molecules
in the brain that suppress pain.
Resource: http://www.nature.com
Unlike humans, bears seem to recover from bone loss caused by inactivity.
During hibernation each year, animals suffer from significant bone loss but seem
to have a unique ability to rebound. This may hold some secrets to preserving bone in humans, at least according to
researchers at Penn State Milton S. Hershey Medical Center and Michigan
Technological University. They show that wild black bears have a built-in coping
mechanism that ensures that yearly hibernation doesn't leave the bears' bones
too fragile.
In humans, disuse or immobilization as a result of bed rest or injury causes
rapid bone loss that can lead to weakness and fractures -- and the bone loss is
not always completely recoverable. So Henry J. Donahue, Ph.D., professor of
orthopedics and rehabilitation, Musculoskeletal Research Laboratory, Penn State
Milton S. Hershey Medical Center, and colleagues sought to determine how bears
recover from five to seven months of hibernation each year that causes them a significant
amount of bone loss due to disuse.
Blood samples were obtained from radio-collared wild bears during winter
hibernation and active summer periods. A total of 17 bears (seven males ages one
to seven years; six females ages one to 12 years with cubs; and four females
ages one to 17 years without cubs) were part of the study. The data suggested
that bears, like other animals, lose bone during extended periods of disuse.
However, humans and other animals tend to also decrease bone formation during
sedentary periods.
Seth Donahue, PhD, former post-doctoral fellow at Penn State College of
Medicine and assistant professor of biomedical engineering at Michigan Technological
University, explains, "These findings raise the possibility that
hibernating black bears may minimize bone loss during disuse by maintaining the
same level of bone formation as when they're active." He suggests that
because bones do not urinate or defecate during hibernation, it is likely that
the calcium freed in the body due to bone loss is reused in bone
formation.
S. Donahue also says that these bears may be able to make more rapid and
complete recoveries during remobilization (active) periods of the year than
other animals, since bone formation in humans and like animals takes longer than
bone loss. One possible mechanism for complete recovery is that bone cells in
bears are more sensitive to mechanical simulation and circulating hormone levels
during remobilization, so they tend to rebuild bone faster.
Resource: Clinical Orthopedics and Related Research, March 2003.
The Food and drug Administration (FDA) says that about 200,000 Americans are
harmed each year because they receive the wrong drug. In response, the FDA is
beginning a new program that uses upper- and lower-case letters, italics, and a
mix of colors to highlight drug names in an attempt to reduce the number of
medication errors caused by look-alike, sound-alike drug names.
For example, there is sometimes confusion between Lamictal (anti-epilepsy)
and Lamisal (anti-fungal). Under the FDA's new system, the "ictal"
portion of Lamictal will appear in red, italicized letters. To reduce confusion
between chlorproPAMIDE (anti-diabetic) and chlorproMAZINE (tranquilizer), the
last six letters of both will be capitalized.
FDA employees will write test prescriptions before new drugs enter the market
in order to test new names. Volunteer nurses and pharmacists will then try to
decipher them. Since the testing began, one-third of the new names have
been sent back to the manufacturer for refinement.
Ryan Baker, a FDA spokesperson, says a Health Canada working group is looking
at the issue too, and this department is leading a coalition to examine the
broader subject of adverse medical events. In the area of look-alike,
sound-alike names, he said Schering Canada Inc. agreed in December to remove
Peg-Intron from the market because it sounded similar to a new Schering product,
Pegetron. Both medications are used tot treat patients with chronic hepatitis C
infection.
Resource: New US labeling to eliminate drug conFUSION, P.
Sullivan, Canadian Medical Association Journal, March 4, 2003; 168 (5).
Vincent Santee's story is similar to what a number of people with AS have
experienced, but his
treatment is probably different. He recently underwent a new procedure -- metal-on-metal hip replacement surgery. Dr.
Terry Clyburn, assistant professor of orthopedic surgery at The University of
Texas Medical School at Houston, believes that a new generation of all-metal hip
replacements will lessen the possibility of repeated hip-replacement
surgeries.
Santee was a teenager when he began feeling symptoms of AS. By the time he
was 21, he says that he walked like a man three times his age and often had to
use a walker or crutches just to get from his living room to the kitchen. Other
times he couldn't move at all. AS destroyed the cartilage in both of his hips,
which caused pain when the bones scraped together. At the advice of doctors,
Santee eventually decided to replace his hips through surgery to hopefully
improve his quality of life.
In the past, patients Santee's age weren't considered good candidates for
total hip replacements because the device was only expected to last
approximately ten years. The plastic parts wear down over time and patients
would likely undergo at least one more surgery during their lifetime to replace
the device.
But Santee decided on a newly improved technology -- metal hip replacement.
He had both joints replaced at the same time due to the severity of his AS. Just
a few days after surgery, he was home, slowly walking around. He underwent a
four-week physical therapy program to help speed up his recovery. At the time of
this article, Santee was excited about the expected outcome, and stated
"I'm healing nicely."
The new device consists of a stem (designed to fit securely in the femur),
and at the top of the stem is a chrome ball that fits into the metal socket. The
surface of each part is porous so it allows surrounding bone to grow into the
device, making it stronger and eliminating the need for cement to hold it in
place.
Clyburn says that the new device offers numerous advantages for people with
hip arthritis. Preliminary results show that the new metal hip replacements
could last 30 years or more. The ball that fits into the metal socket is larger
than older-generation devices, which reduces the risk of hip dislocation and
provided for greater range of motion. He also says that experienced surgeons can
perform minimally-invasive surgery to implant the metal-on-metal device.
"In the past, we had to make very large incisions. With improved
technology, we can implant this device through a 3 1/4 inch incision."
The procedure takes less than two hours. The next day, the patient is up and
walking. Formal rehabilitation is not necessary for most patients with this new
procedure, according to Clyburn.
But as with any surgery, there are risks, so Clyburn advises patients to
consult with their doctors to fully understand potential complications, like
infection. And the metal-on-metal hip replacement may not be appropriate for all
patients.
Resource: http://www.healthleader.uthouston.edu