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Arthritis: Modern Treatments for That Old Pain in the Joints
by Ricki Lewis, Ph.D.
The human skeleton and muscles help to make possible the graceful
gyrations of the dancer and the prowess of the athlete, as well as the many
more mundane movements of our everyday lives. We tend to take for granted
the normally smooth sliding motion of our joints--until it is hampered. One
of the most common ills--arthritis--affects this vital function. Arthritis
is a disorder of the joints, the junctions between bones.
About 50 million people in the United States have arthritis. Although
many suffer only intermittently, according to the National Institute of
Arthritis and Musculoskeletal and Skin Diseases, the condition interferes
with day-to-day activities for 4.4 million people, and causes partial
disability in 1.5 million and complete disability in another 1.5 million
individuals. The Arthritis Foundation estimates that 70 million person-days
of missed work can be chalked up to arthritis in the United States each
year, as can 500 million days of restricted activity.
Symptoms of the more than 100 types of arthritis range from minor
stiffness to grave disability and deformity. Although arthritis cannot be
cured, its course can be slowed and symptoms relieved. And, with increasing
understanding of the disease process underlying at least some forms of the
illness, the outlook for new, more effective drugs is promising.
The Synovial Joint
Arthritis affects the synovial joint, a liquid-filled capsule built of
fibrous bands of connective tissue--the ligaments--that attach adjoining
movable bones. The capsule is lined on the inside with a membrane that
secretes the cushioning synovial fluid, which is stored in membrane-lined
packets called bursae. In healthy joints between movable bones, only a thin
film of synovial fluid covers the surfaces. A decrease in synovial fluid is
associated with the joint stiffness that we normally feel as we age. In
arthritis, the amount of synovial fluid increases, swelling the joint.
Opposing bones facing a joint are capped by cartilage, a flexible,
bloodless tissue. In a healthy synovial joint, the slipperiness of the
cartilage tips and the fluid in the joint allow the bones to move nearly
friction-free.
Joint deterioration can be hereditary or can result from injury,
infection, autoimmune disease (attack by the individual's own immune
system), or even a drug reaction. Although the physical changes behind some
forms of arthritis are well understood, we know relatively little about how
those changes begin.
Of the more than 100 types of arthritis, by far the most prevalent are
osteoarthritis (with nearly 16 million sufferers) and rheumatoid arthritis
(with nearly 3 million sufferers). (See accompanying article.) It is not
surprising that the rarer forms of arthritis may initially be misdiagnosed
as one of these more prevalent two.
This was the case with 10-year-old Christopher Green, of Scotia, N.Y.,
who had a fever for two weeks and then rapidly developed near-crippling
arthritis in his legs and hips. Chris's condition was first diagnosed as
juvenile rheumatoid arthritis, but the appearance of other symptoms (see
chart) soon led his physicians to suspect Kawasaki disease, a condition
first identified in Japan in 1974, where several epidemics have occurred.
Kawasaki disease includes arthritis 15 percent of the time. Chris fully
recovered the use of his joints after three weeks, and his doctors do not
expect the arthritis to recur--although the condition is so recently
identified that they cannot be certain.
Another rare form of arthritis is on the rise. It begins with infection
by Streptococcus pyogenes, also known as strep A. The incidence is 4 to 5
cases per 100,000 people, and the death rate is a whopping 20 to 25 percent.
From the initial symptoms of a sore throat and pneumonia, the illness can
progress to meningitis (inflammation of the membrane covering the brain). If
the patient survives, arthritis may develop.
Setting Therapy Goals
Arthritis therapy aims to protect the affected joints, maintain as much
mobility as possible, and strengthen neighboring muscles to minimize loss of
function. These goals can be approached by lifestyle changes, use of support
devices and drugs, and, finally, by surgery.
Eating fish (such as salmon and other deep sea fish) rich in the oils
eicosapentaenoic acid and ocosahexanoic acid improves symptoms of rheumatoid
arthritis, says Charles Dinarello, M.D., at the Tufts University School of
Medicine. "Our work on the mechanism of fish oil action suggests that its
anti-inflammatory properties are at least partly due to lowering tumor
necrosis factor," Dinarello says, referring to one of the immune system
biochemicals that collects in rheumatoid arthritis joints.
Over the past decade, more and more rheumatologists have suggested that
their patients exercise. Regular activity that does not place weight on
affected joints, but strengthens surrounding bones, muscles and ligaments,
can be valuable for many types of arthritis. With the help of a physical
therapist, isometric and isotonic exercises and massaging can be tailored to
the specific affected joints. For example, exercise that rotates the neck
can relieve stiffness and pain and improve mobility in a person with an
arthritic spine.
Devices and Drugs
An "activities of daily living" evaluation can help an arthritic patient
identify painful movements, which will assist in the development of devices
that can be used at home or in the work place. A person with arthritic hands
might use extensions--long handles--on utensils and pens. Shelves can be
rearranged so that the most frequently used items are within easy reach of
someone with arthritic shoulders. Crutches and canes can help those with
arthritic knees or hips. Special thumb, hand or wrist splints and gloves can
temporarily restore hand function. Wearing loose-fitting clothes that avoid
putting pressure on sensitive joints and avoiding obesity make life for the
arthritic patient a little easier.
In the 1940s, it was discovered that crude extracts from adrenal glands
of animals could rapidly relieve the inflammation of arthritis. In the
1950s, drug companies developed the anti-inflammatory agents cortisone and
hydrocortisone. These potent drugs resemble the human adrenal hormone
cortisol. But their use is limited today.
"Cortisone has adverse effects that were originally discovered in the
early 1950s. It is an immune suppressant, weakening the body's defense
against infections," says Dottie Pease, consumer safety officer at FDA's
pilot drug evaluation department. Cortisone taken by mouth can lead to
osteoporosis, and direct injection into joints can damage the cartilage.
Further, it can cause cataracts, skin thinning, diabetes, fluid retention,
poor wound healing, and increased susceptibility to infection. Still,
cortisone can offer great, albeit temporary, relief.
Today, the first pharmaceutical line of defense against arthritis is the
NSAIDs (nonsteroidal anti-inflammatory drugs), which include the
salicylates, such as aspirin, prescribed at higher than usual doses. Coated
and timed-release preparations can lessen the risk of gastrointestinal
bleeding, the major side effect of these drugs.
The NSAIDs block release of prostaglandins, which trigger inflammation.
Some more commonly used NSAIDs include ibuprofen, flurbiprofen,
indomethacin, and naproxen. Currently, 15 NSAIDs are available.
Drugs called disease modifiers are used in rheumatoid arthritis patients
who have had symptoms for at least six months and for whom NSAIDs no longer
control swelling of joints. One such treatment is gold injected into a
joint, which helps about 50 percent of patients, but unfortunately remains
effective in only 5 to 15 percent of them after five years of use.
"No one knows how it works, but it is not an anti-inflammatory," says
Pease. The physical presence of gold in the joint may reduce swelling, or
the metal may chemically react with a biochemical in some as yet unknown way.
Another disease modifier is methotrexate, an anti-cancer drug that
tempers the runaway cell division in the synovial joint. If these disease
modifiers do not work, agents that suppress the immune response, such as
cyclophosphamide, may be tried.
Biologics Block Cytokines
Unraveling the immune imbalances that underlie some forms of arthritis,
and investigating how drugs alter immune function to quell inflammation are
opening up an entirely new avenue to treating arthritis--the use of
"biologics," or body chemicals. A prime target for new arthritis drugs is
blocking cytokine production, a different approach to halting prostaglandin
synthesis, which is the mechanism of most existing arthritis drugs.
Innovative approaches under way include work at Nova Pharmaceuticals in
Baltimore with unusual amino acids that, in test animals, block the release
of inflammation-provoking cytokines from activated T cells (a specialized
type of white blood cell). Laboratory research at Immunex Corporation in
Seattle, Synergen Corporation in Boulder, Colo., and Hoffmann-La Roche in
Nutley, N.J., focuses on using interleukin-1 to prevent inflammation.
Interleukin-1 is an immune system chemical that must bind to the lining
inside joints to start the inflammatory process.
Joint Replacement
For advanced arthritis, joints can be replaced with synthetic materials,
usually metals like cobalt-chrome and titanium alloys in the larger joints
and polymers (long-chained molecules) such as silicone in the smaller
joints, such as in the fingers. The devices must be durable and must not
stimulate attack by the already overactive immune system, interfere with
healing, or push surrounding structures out of their normal position.
Before the advent of implants, surgeons would remove joint surfaces,
hoping that the scar tissue filling in the area would allow more mobility
than the arthritic joint. This type of surgery often failed. Implants proved
far more successful. They were pioneered by an army surgeon from Grand
Rapids, Mich., Alfred Swanson, M.D. He fashioned the first such devices in
the late 1950s out of silicone elastomers, polymers made from the element
silicone, which is found in quartz.
Research to fine-tune the implants continued in the 1960s, and in 1969,
the first silicone-based joint implants came on the market. These implants
provided a flexible hinge for the joints of the fingers, wrists and toes.
Since then, more than two dozen models have been developed, several by
Swanson, who is now a professor of surgery at Michigan State University.
More than a million people have received joint replacements--mostly in the
hip--and they are still based on silicone.
During implant surgery, technically called "implant resection
arthroplasty," the surgeon first removes the surface of the joint bones as
well as excess cartilage. The centers of the tips of abutting bones are
hollowed out, and the stems of the implant are inserted here. Between the
bones lies the hinge part of the implant, which both aligns the bones and
allows them to bend at the joint. The implant is "fixed," or held in place,
with bone cement and, finally, the tendons, muscles and ligaments are
repaired. As the site heals, the patient must exercise, but it can take a
year of physical therapy to achieve maximum rehabilitation.
A new type of hand surgery replaces joints and realigns fingers at the
same time. "All rheumatoid arthritis patients who have a severe deviation of
their fingers away from the thumb are candidates for this procedure," says
Robert Pearl, M.D., associate professor of plastic surgery at Stanford
University Medical Center.
He recently introduced an operation that repositions the tendon at the
base of the little finger. He finds that holding the pinky in place forces
the other fingers to align properly. Pearl's patients start moving the hand
the night after the operation, and wear a splint-like support device for the
next three weeks. "By six weeks after the operation, patients are able to do
most of their usual activities, especially the simple tasks that most of us
take for granted, but were virtually impossible for these individuals," he
says.
Newer joint replacements use materials that resemble body components.
"Recent hip implants have been coated with calcium phosphate materials, like
hydroxylapatite, which interact with bone. The aim is to enhance the
attachment of the implant to the bone with a biologically active material,"
says Tom Callahan, Ph.D., of FDA's Center for Devices and Radiological
Health. Rather than filling in the spaces with cement, investigators are
testing a variety of porous coatings that allow "biological fixation," in
which bone can grow into the implant area.
Hope, but No Miracles
Arthritis treatment seems to attract charlatans peddling "miracle
cures," folk remedies, and superstition. Over the years, people with
arthritis have been advised to cover themselves with horse manure, wear
copper bracelets, sit in abandoned radium mines, and swallow any number of
magic elixirs.
Although we still do not know precisely what causes this collection of
disorders, nor in most cases how to halt its course, modern medicine has an
arsenal of treatments available that attempt to make life easier. With
better understanding of the immune system's role in the spectrum of
arthritis, more treatment options may become available.n
Ricki Lewis is the author of Beginnings of Life and teaches biology at SUNY
Albany. She was diagnosed as having osteoarthritis while writing this
article.
Common Types of Arthritis
The result of any arthritis is painful joints, but the conditions have a
variety of symptoms that make them distinguishable from one another.
Osteoarthritis
This most common form of arthritis is also known as degenerative joint
disease, or simply the "wear-and-tear" disease, because it tends to affect
older people. Even so, osteoarthritis can appear earlier as the result of a
metabolic disorder, congenital or hereditary disorders, or injury or trauma.
Triathlete Jay Lehr attributes his arthritic knees to old football injuries.
However, findings in a variety of studies that relate osteoarthritis to
prolonged occupational or sports-related stress have been inconsistent.
In osteoarthritis, the smooth cartilage on facing bone ends wears away,
and new bone forms on the exposed ends. This bony overgrowth is a criterion
for diagnosis, along with pain when joints move and a grating sensation
called "joint crepitus" when the dry, exposed bone ends rub against each
other. Osteoarthritis is not usually associated with inflammation.
Darwin J. Prockop, M.D., and his co-workers at Jefferson Medical College
in Philadelphia recently uncovered a clue to the underlying cause of
osteoarthritis. They examined an extended family of 19, spanning three
generations, in which nine members developed osteoarthritis in the fingers,
elbows, hips, and knees by their 20s or 30s--far younger than the usual
onset of the disorder after age 40 or 50.
The researchers zeroed in on a protein called type II pro-collagen. This
protein forms coils that intertwine in groups of three to build the
cartilage that protects bone ends and reduces the friction in joints.
Because of a glitch in the gene that instructs cartilage cells to
manufacture collagen, the triple fibrils in the arthritis sufferers in this
family unravel after 20 to 30 years. As a result, the cartilage wears down
and no longer offers its protective cushion.
Rheumatoid Arthritis
In rheumatoid arthritis, the immune system attacks the joints as if they
were an enemy to be vanquished. This autoimmune response is a chain reaction
of sorts, for as the synovial joints themselves become inflamed, the
swelling weakens ligaments, pushes fingers away from thumbs, and throws
muscles out of alignment. This can lead to deformity and disability. Holding
a pencil, opening a can or bottle, and even shaking hands become monumental
tasks requiring the person to use both hands, often in awkward positions.
Rheumatoid arthritis can progressively worsen or stay the same for years
before worsening.
Rheumatoid arthritis progresses through five distinct stages.
Stage 1 generally has no symptoms, but deep in certain joints, the cells
forming the synovial membrane begin to attract T cells, a specialized type
of white blood cell. The T cells and synovial lining cells stick to each
other when proteins on their surfaces fit together like interlocking puzzle
pieces. Once attached to the joint lining cells, the T cells turn on B cells
(another type of white blood cell that makes antibodies that attack the
joint) and release small proteins called cytokines. In rheumatoid arthritis,
cytokines called interleukin-1, tumor necrosis factor, and gamma interferon
are released. Inflammation is detectable by lab results showing elevated
numbers of white blood cells in the synovial fluid.
In stage 2, the immune assault gears up. The cytokines attract more
white blood cells to the joints, and cause the malaise and fatigue, mild
joint stiffness, and swelling that are the earliest signs of the disease. At
this stage, more than a billion white blood cells a day collect in a knee
joint. The joint capsule begins to fill with scaffolds built of new blood
vessels. By stage 3, in response to all this activity, the cells forming the
synovial membrane begin to proliferate. Symptoms intensify, and drug therapy
must start now to prevent irreversible cartilage loss and joint deformity.
In stage 4, the disease process extends to the cartilage, tendons, and,
finally, the bone. Joint swelling is far more pronounced. As a result of
increased cell numbers and connective tissue, the synovial membrane can
weigh 100 times its normal weight. However, the destruction of the
cartilage, tendon and bone is by far the most important consequence of the
inflammatory process at this stage.
By stage 5, overgrowth of cartilage and destruction of bone are so great
that the ligaments surrounding the joint are thrown out of position. The
destruction that results is irreversible.
The diagnosis of rheumatoid arthritis is based on the presence of all of
the following four symptoms, for six or more weeks:
- joint stiffness upon awakening that lasts an hour or longer
- swelling in specific finger joints or wrist joints
- swelling in the soft tissue around three or more joints
- swelling of both sides of the joint. The swelling can occur with or
without pain. Additional diagnostic signs include x-ray evidence of bone
erosion, nodules under the skin, a blood test that reveals a "rheumatoid
factor" antibody (found in 80 percent of sufferers), or other key signs of
the disease.
Spondyloarthropathies
The spondyloarthropathies are a collection of disorders that tend to
affect the spine and include: Reiter's syndrome, psoriatic arthritis,
intestinal arthropathy, juvenile ankylosing spondylitis, reactive
arthropathy, and the most common type, ankylosing spondylitis, in which the
spinal bones fuse. Of the 2.5 million people with these ailments in this
country, 75 percent are male.
This particular form of arthritis has been under intense scrutiny since
1973, when researchers in the United States and Great Britain found that 90
percent of patients with ankylosing spondylitis have a protein on their cell
surfaces called HLA-B27. The HLA proteins are controlled by a group of genes
that oversees immune system function. The HLA protein so common among those
with ankylosing spondylitis is found in only 7 percent of the general
population, suggesting that there might be a link between HLA-B27 and the
arthritis. HLA-B27 is also found in the other spondyloarthropathies to a
greater extent than is seen in the general population.
Although the nature of the link between HLA-B27 and the
spondyloarthropathies is still elusive, researchers at the Harold C. Simmons
Arthritis Research Center at the University of Texas Southwest Medical
Center in Dallas recently came a giant step closer to explaining it by
introducing into rats through genetic engineering the human HLA-B27 gene.
The rats developed symptoms remarkably like their human
counterparts--persistent diarrhea, skin and hair scaliness, and joint
inflammation. The rats with arthritis in their genes will be raised in a
germ-free environment from birth. If they fail to develop symptoms, it will
mean that an environmental trigger is required to start the disease process.
Commenting on this research, James O. Mason, M.D., assistant secretary
for health in the U.S. Department of Health and Human Services, says, "This
important work, which could only be performed in animals, holds great
promise for helping us to better diagnose and treat these diseases in
humans." n
Lyme Disease
Bacterial infection was added to the list of causes behind arthritis in
1974, when 30 neighbors in the rural town of Lyme, Conn., came down with a
baffling illness. It began with flu-like symptoms and a rash resembling a
bull's-eye. This would happen 3 to 32 days following a tick bite, although
the person might be unaware of the bite. A few weeks after the initial
symptoms, about half of the people developed joint, tendon, muscle, and bone
pain, without swelling. In a few, swelling developed, mimicking juvenile
rheumatoid arthritis or rheumatoid arthritis.
The first clue that the illness was not juvenile rheumatoid arthritis
was that the cases appeared in clusters. In Lyme and two neighboring towns,
39 youngsters and 12 adults, in a population of 12,000, had the mysterious
illness. Normally, juvenile rheumatoid arthritis affects only 1 in 100,000
children. If the illness was juvenile rheumatoid arthritis, the incidence in
this area would be 100 times greater than normal. In heavily wooded areas,
the incidence was even more striking--1 in 10 children, or 10,000 times
greater than normal.
The people with what would become identified as Lyme disease were
brought to the attention of Allen Steere, M.D., then a rheumatologist at
Yale University in New Haven, Conn., and now affiliated with New England
Medical Center in Boston. He eventually put together the pieces to find the
culprit--a tick. "The initial challenge was to evaluate the clusters of
children and adults in Lyme with the unusual form of arthritis. What
suggested that it was arthropod- [tick] transmitted was the rural setting,
the onset in early summer through fall, and the fact that multiple family
members were affected yet had onset of symptoms in different years," Steere
recalls.
Today we know that Lyme disease is actually caused by a spiral-shaped
bacterium (spirochete) harbored in the deer tick, which spends part of its
life cycle in mice and deer. Since its identification, the locations and the
number of cases of Lyme disease have continued to increase. In 1983, 48
cases were reported to the national Centers for Disease Control in Atlanta,
and by 1986, the number had risen to 439. In 1989, 7,400 cases were reported
in 46 states, a 15-fold increase over the incidence in 1982, when national
surveillance began.
Antibiotics administered promptly can halt the course of Lyme disease.
With later disease and involvement of the heart, brain or joints, antibiotic
therapy is not as effective. Once arthritis appears, the joint pain and
stiffness can come and go, recurring even years later. Ten percent of those
with Lyme disease arthritis are left with permanently stiffened joints.
Researchers are optimistic that understanding how joints are affected by
Lyme disease may have wide-ranging benefits. "We're hoping that the lessons
we learn from Lyme disease will provide helpful clues in studying other
types of arthritis," says Steere. (For more on Lyme disease, see "Ticks
Carry Lyme Disease Across U.S." in the July-August 1988 FDA Consumer.) n
Some Less Common Forms of Arthritis
Type Incidence in U.S. Age of Onset Symptoms
gout 1.6 million >40 sudden onset of
(85% male) extreme pain
and swelling of
a large joint
juvenile 250,000 <18 joint stiffness, rheumatoid often in knee arthritis scleroderma 300,000 30?50 skin hardens and thickens systemic 300,000 teens?50s fever, weakness, lupus (>90% female) upper body rash,
erythematosus joint pain
Kawasaki hundreds of cases 6 months? fever, joint
disease in local outbreaks 11 years pain, red rash
on palms and
soles,
heart
complications
strep A 100,000 any age confusion, body
infection aches, shock, low
blood pressure,
dizziness,
arthritis,
pneumonia
Some More Common Forms of Arthritis
Type Incidence in U.S.
osteoarthritis 15.8 million
rheumatoid arthritis 2.9 million
spondyloarthropathies 2.5 million
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