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Panic has swept through millions of women with silicone implants in the last
few years – and not without reason. Dozens of recipients have been diagnosed
with autoimmune disorders, the US government has recently banned most
implants because of doubts over their safety, and manufacturers are now
swamped with lawsuits. But despite the legal brouhaha, crucial medical
questions remain unanswered. Do silicone implants really cause immune
disorders as the anecdotal reports fuelling the lawsuits suggest? And if so,
how?

Three decades after breast implants came into use, scientists are now
starting the kinds of studies that could provide answers. In clinics across
the US, tens of thousands of women, mostly those who already have implants,
are being asked to participate in formal medical trials. These could take
years to complete but are probably the only route to a definitive verdict on
the alleged link between silicone implants and autoimmune disease.

In the meantime, detailed laboratory studies of the biological effects of
silicone are giving little grounds for optimism. Most immunologists have
come to believe that there is no such thing as a biologically inert
substance. Contrary to the advice given to thousands of women by plastic
surgeons, it seems that silicone does react with the human body, stimulating
the immune system to produce antibodies and, in some cases, inflammatory
responses. The crucial question now is whether such responses can lead to
more serious immune disorders.

Lack of regulation

Many consider it scandalous that such studies were not done years ago. ‘If
one is going to implant something into the body one ought to do safety
studies first,’ says John Naim, an immunologist at Rochester General
Hospital in New York. ‘We’re working backwards on this issue.’ Critics’
targets include not only implant manufacturers but the US Food and Drug
Administration, which allowed plastic surgeons in the US to insert an
estimated 2 million silicone gel implants without asking manufacturers to
prove their safety. One reason for the lack of regulation is that by 1976,
when the FDA first acquired authority over medical devices, breast implants
had been on the market for more than a decade.

The earliest breast augmentations, attempted by plastic surgeons in Japan
and the US in the 1950s and 1960s, involved injections of paraffin or
silicone oil. Today’s implants are made from silicone gel or saline solution
contained in a silicone rubber capsule. Until now, women have preferred
silicone gel implants because they look and feel more natural. Saline
implants are also especially prone to leaking and can foster bacterial
colonies.

Japanese researchers first reported the possible adverse effects of silicone
on the immune system as early as the 1970s. Women who had been given
injections of silicone suffered the most severe cases of inflammation and
other problems (a fact that explains why silicone injections were never
approved in the US). Then in the early 1980s several reports emerged
associating silicone implants with autoimmune diseases. But plastic
surgeons, manufacturers and some women fought to defend their use, and only
in 1988 did the FDA finally request safety data. As late as 1990, more than
100 000 women each year in the US were still receiving breast implants for
purely cosmetic reasons.

The rush for implants finally ended in 1991, when a US federal court found
that the biggest manufacturer, Dow Corning, had concealed evidence linking
ruptured implants to immune disorders. The claimant in that case was awarded
$7.3 million in damages and Dow Corning now faces thousands of
further lawsuits. Last year, the FDA banned silicone gel implants, limiting
them primarily to women having reconstructive surgery after mastectomies who
enrol in safety studies. The FDA is also asking manufacturers to prove the
safety of saline implants, although they remain on the market.

Nobody can say exactly how often silicone implants rupture, but it is clear
they don’t last a lifetime. What’s more, the FDA advises women that implants
may leak even without rupturing. And not all reports of symptoms such as
pain, swelling, rashes and fatigue involve detectable leaking.

Over the past year, researchers have published dozens of anecdotal reports
describing autoimmune disorders in women with silicone implants. The
disorders include scleroderma, a disfiguring thickening of the skin which
can be fatal when it affects internal organs, rheumatoid arthritis and
systemic lupus erythematosus, a debilitating condition that affects the
skin, joints, lungs or kidneys. All three diseases involve chronic,
widespread inflammation – the end result of the immune system mistakenly
turning against the body’s own tissues.

Proving that silicone implants can trigger such diseases is difficult, not
least because their causes in the general population are still a mystery.
Nonetheless, there is some tantalising circumstantial evidence. In the
population as a whole, for instance, lupus and rheumatoid arthritis are far
more common than scleroderma. If silicone had nothing to do with autoimmune
disease, the same trend would be seen in women with silicone implants. But
it isn’t: scleroderma seems to be more common than lupus or rheumatoid
arthritis in women with implants. And some women who have had their implants
removed have reported remarkable recoveries, although others have remained
ill.

Silicone is a synthetic polymer made of molecules which have a backbone of
silicone and oxygen and organic side chains. Manufacturers use elastomer,
silicone rubber, to make the outer capsules of both saline and silicone gel
breast implants and other implants including those for many joints, the eye,
and the penis. Researchers have known for at least two decades that
macrophages – scavenger cells which normally engulf and devour damaged or
infected cells – tend to swarm around silicone implants and fuse into what
are called foreign-body granulomas. These giant cells have many nuclei and
may also contain particles of engulfed silicone. Granulomas containing
silicone have come to light in lymph nodes, the central organs of the
immune system, and some women with implants occasionally suffer from swollen
lymph nodes. But whether the granulomas adversely affect the immune system
and cause disease is unclear.

The best researchers can do at the moment is suggest how silicone implants
might trigger an immune disorder. The most obvious mechanism would be that
the immune system treats silicone as foreign and forms specific antibodies
to attack gel leaking from an implant. The formation of such antibodies
could signal the early stages of a widespread immune reaction. This
explanation became less speculative last year, when researchers led by
Randall Goldblum and John Heggers at the University of Texas Medical Branch
in Galveston detected what appeared to be specific antisilicone antibodies
in two children who developed severe reactions to hard silicone shunts.

Another theory suggests that the immune system is provoked not by silicone
itself but by proteins interacting with silicone. When proteins come into
contact with a silicone surface, they tend to uncoil and spread out over the
silicone. Such denatured proteins might appear foreign to the immune system,
leading to the production of antibodies. This, in turn, could provoke the
immune system into attacking the denatured proteins. If the antibodies
could react with normal proteins, too, then the immune system’s ability to
distinguish between foreign and self might break down, leading to the
development of autoimmune diseases. ‘Our immune system is in a dynamic
equilibrium. We have to ward off invaders but not attack ourselves,’ says
Naim. ‘It’s a delicate balance.’

Yet another possibility is that the silicone is not the primary cause of
autoimmune reactions but a cofactor. It is possible, for instance, that
silicone could be an adjuvant, an ingredient that boosts the response of
antibodies to particular antigens (substances that stimulate the immune
system in a specific manner). Naim compares an adjuvant to lighter fluid
sprayed on charcoal to make it catch fire. No one is sure how adjuvants
work. The traditional theory is that they act as a depot, pinning down
antigens so that antibody-producing cells have a chance to gather and
react. Another possibility is that the adjuvant acts as a ‘chemotactic’
agent, signalling immune cells to gather.

Evidence for the adjuvant hypothesis appeared earlier this year in a study
published in Immunological Investigations. Naim and his colleagues found
that after they injected silicone into rats, the rats produced a stronger
immune response to an injected protein from cows – a result which has been
replicated by researchers at Dow Corning. Naim’s team concluded that
silicone gel is ‘a potent immunological adjuvant’. Neal Rose, head of
immunology at Johns Hopkins University in Baltimore, says that the study
‘creates some interesting scenarios’ but fails to prove that silicone’s
adjuvant properties could provoke an autoimmune disorder. To do that, says
Rose, the researchers would have to establish that silicone boosts the rat’s
immune responses to its own proteins, not just to cow proteins. Naim and
his colleagues hope to clinch the issue by injecting silicone into a strain
of mouse that is predisposed to a disease similar to rheumatoid arthritis.
In rheumatoid arthritis, the immune system attacks tissues that are rich in
the protein collagen. So by injecting the animal with a mixture of collagen
and silicone, the researchers should be able to test whether silicone
stimulates the development of autoimmune arthritis.

Another explanation centres on the chronic inflammation that some women
experience around the site of the implant. Like most forms of inflammation,
this involves only localised immune responses, not the wide-ranging
responses that are seen throughout the immune system in autoimmune
disorders. But what if chronic, localised inflammation could, over several
years or more, trigger a systemic immune disorder? Rose, who remains
sceptical about the connection between autoimmune disorders and implants,
thinks this may be the most likely explanation, if there is indeed a link.
‘If I were a betting man I’d be willing to make a small wager on it,’ he
says.

Distress signals

According to this theory, immune cells near the implant release massive
quantities of cytokines into the bloodstream – the hormones immune cells use
to send out distress signals and communicate with other cells. These of
cytokines provoke an immune response throughout the body. ‘There’s nothing
wrong with inflammation. It’s essential for life,’ says Rose. ‘But what
happens when you have it day in and day out for ten years?’

Doctors have also seen chronic local inflammation around hard silicone
implants, especially in the wrist. Yet this inflammation, which can cause
pain and degrade the bone around the implant, does not seem to trigger the
systemic autoimmune reactions reported with breast implants. Rose
speculates that this could be either because silicone gel is more mobile
and reactive than hard silicone, or because of the location of breast
implants.

Many women with breast implants develop symptoms such as aching joints,
fatigue, rashes and swollen lymph nodes but do not have a specific immune
disorder such as lupus or scleroderma. Last year, a group led by Eng Tan at
the Scripps Research Institute in La Jolla, California, tested 24 women
with such symptoms and found that 17 had antinuclear antibodies, a type of
antibody associated with autoimmune disorders. Seven of the patients had
scleroderma, a disease found in only 9 out of every million people in the
general population. Of 13 patients with immune complaints but no diagnosable
autoimmune disorder, seven had the autoantibodies. In another study, some
women with implants had high levels of antinuclear antibodies but no
symptoms.

One possible interpretation of Tan’s study is that the autoantibodies are an
early warning signal, or serum marker, indicating that these women may later
develop a full-blown autoimmune disease. Or they may indicate that the
silicone is causing clusters of symptoms, a sort of silicone autoimmune
syndrome. Tan’s team also found that women who had ruptured implants seemed
to develop symptoms more quickly.

In a study soon to be published in the Journal of Autoimmunity, researchers
found another type of antibody acting against the body’s own tissues in
women with breast implants. Suzanne Teuber and Eric Gershwin of the
University of California at Davis studied 46 women who reported concerns
about their implants or complaints such as fatigue or pain. They found that
35 per cent had anticollagen antibodies. Some 26 per cent had antibodies
against Type I collagen, the type associated with the fibrous scar tissue
that normally forms around the implant. Only one woman from a control group
without implants had such antibodies. ‘The hypothesis is that if implants
trigger autoimmune disease, one of the first places you would see that
would be in an autoimmune response to the environment immediately around
the implant,’ says Teuber.

‘An important issue is to try to identify that fraction of people who are at
risk,’ says Tan. If researchers could prove that autoantibodies are an early
marker for autoimmune disease, women with these antibodies could have their
implants removed. Another way to identify those at risk might be to take
magnetic resonance or ultrasound images of the implants to try to spot leaks
of silicone gel. Tan points out that some of the elastomer capsules are
bound to leak because no manufacturer has perfect quality control. Last
year, Dow Corning admitted ‘faking’ some of its quality-control records.

Eventually, researchers may find that some women have a genetic
predisposition to autoimmune disease and that its development is acclerated
by the implant. In this case too, women with a known predisposition could
have implants removed.

The ideal trial of breast implants would follow a group of women who have
the surgery and a group of controls from the time of implantation through
the decade or more that it takes for symptoms to develop. But with a million
or more women living in fear, epidemiologists may have to settle for
retrospective studies that try to reconstruct a decade of history in women
who already have symptoms. ‘I don’t think the world is going to wait for a
really good prospective study,’ says Rose.

In the meantime, even those researchers who are convinced that autoimmune
disorders can be caused by the implants are trying to reassure women who
feel torn between keeping their implants and risking debilitating disease.
Says Naim: ‘My opinion is, if a woman is not having any symptoms, the risk
of going through a second surgery is still greater than the risk of leaving
the implants in.’ Nevertheless, tens of thousands of women with implants are
rushing to have them removed, providing steady business for the same plastic
surgeons who once made a living augmenting breasts.