The Autoimmune Epidemic: Bodies Gone Haywire in a World Out of Balance--and the Cutting-Edge Science that Promises Hope (No Series) (28 page)

Yet the precise ways in which sex hormones influence autoimmune disease remain largely unknown. What researchers do know is that sex hormone balance is a crucial factor in the optimum regulation of immune and inflammatory responses and that hormones such as estrogen that women produce modulate the activity of proteins in our bodies, leading in ways we do not yet fully understand to a more reactive autoimmune response.

At the Mayo Clinic in Rochester, Minnesota, researchers have made some headway in explaining how the genetic difference between the sexes plays a role in why women develop multiple sclerosis almost twice as often as men. Their findings suggest that how much of the protein interferon gamma—a cytokine that signals the immune system to start the immune response—a person produces appears to be a key variable in understanding who gets MS and who doesn’t and especially in explaining why women develop MS more often than men. If you have a gene that produces high levels of interferon-gamma, or signaling proteins that tell the immune system to get active fast, it may predispose you to developing MS. Under this scenario men get MS less often because men, in general, are less likely to have a gene variant that is related to higher secretion of these cytokines. Research by scientists at the Cleveland Clinic and elsewhere have also shown that women and men naturally produce different levels of interferon-gamma and that higher levels of interferon-gamma can intensify the MS damage processes and make the disease worse. The fact that men have a lower frequency of the interferon-gamma genetic variant may be part of the reason why men are generally protected from MS.

A PATIENT’S DIAGNOSTIC PORTRAIT

Scientific discovery is often made up of many, many dots that together create a pointillist picture. In the future a patient’s diagnostic portrait may consist of putting together a number of these dots, small glimmers of information that, when we step back to view them, create an impressionist portrait of a disease-in-the-making. In the next decade it is possible that clinicians will be able to examine a patient’s specific pattern of autoantibodies to see if he or she fits more precise, established predisease patterns; be attuned to the genes that predispose a patient to a particular autoimmune disease (taking into account gender); ascertain a patient’s viral load by testing for autoantibodies against viruses such as Epstein-Barr and cocksackie B that are known to be implicated in one’s risk of developing diseases such as lupus and diabetes; examine a patient’s diet to see if it is likely to be adding to the stress on the immune system because of the food choices a patient routinely makes; and test for the chemical and toxic “body burden” a patient is carrying by screening blood, hair samples, and urine (and, in breast-feeding women, their breast milk). This type of patient portrait is certainly likely to lead doctors to make what Hal Scofield calls “some good predictions” that a patient’s immune system is being triggered in the wrong way and that he or she totters on the verge of disease. Physicians can then warn patients about the adverse health course they are on and intervene with lifestyle changes and medications with the intention of averting an array of life-altering and debilitating diseases.

Think of LaShekia Chatman of Buffalo, New York. What if LaSheika had been able to go into a physician’s office and, as part of a routine adolescent checkup, be tested for all known autoantibodies for lupus with an eye toward seeing whether she was developing the specific “drum roll” pattern that precedes the disease; for Epstein-Barr autoantibodies to see if she might be experiencing a case of molecular mimicry; and for heavy metal and other environmental chemical levels through her blood, urine, and hair? With prior knowledge that her barrel already sat right at the brim with a telltale pattern of lupus autoantibodies, Epstein-Barr antibodies, and a plethora of chemicals and metals absorbed into her body from her Buffalo neighborhood, could treatment have been started to prevent lupus as well as scleroderma from doing such devastating damage to her by the age of twenty, stealing away her chance to live a normal life?

THE HIGH COST OF PREVENTIVE TREATMENTS

Such a scenario is still years off, of course. Indeed, Michelle Petri, clinical director of the Johns Hopkins Lupus Center, who is currently spearheading an international task force to revise clinicians’ criteria for diagnosing lupus, isn’t sure such pretesting will ever be truly viable. She cautions that this kind of antibody and genetic testing would pose a tremendous cost to our health-care system if we began to use it widely on patients who were not yet showing overt signs of illness, a cost our already overburdened health-care system certainly could not bear.

Meanwhile, there remain pressing ethical questions. Although a discussion of medical ethics falls outside the scope of this book—certainly whole books have been written on the topic by experts in the field—it’s important to consider the risks of preventive testing and treatments. For example, many of the drugs prescribed as preventive medicine come with dangerous side effects. A physician treating someone who shows all the signs of being on the verge of disease but who is still enjoying relatively good health in his or her day-to-day life would have to think twice before intervening with the sledgehammer treatments available today that damp down whole aspects of the immune system without discriminating between the good and the bad. Furthermore, if we can test for genetic predisposition and detect the earliest biomarkers of disease before patients fall ill, will health-and life-insurance companies cover such patients? Will companies hire them? When we consider that autoimmune disease may show up in individuals who are not genetically predisposed, the complexities surrounding any attempt to predict disease multiply.

Predicting who is going to be sick is a highly promising field of scientific inquiry, but deciding when to test for prediagnostic biomarkers and intervene with such patients promises to be dangerously tricky. The physicians’ creed is “First, do no harm.” Currently on the market for treatment of rheumatoid arthritis and Crohn’s disease are classes of drugs that remove or inactivate certain immune activity, such as tumor necrosis factor, or TNF. Tumor necrosis factor, which belongs to a group of proteins that communicate with cells, is essential in maintaining cell life and death decisions and control of T-cell populations. The thought has been that if you could prevent TNF from signaling the release of joint-damaging substances in diseases like rheumatoid arthritis, you could go a long way in treating the disease. These anti-TNF therapies go by names that consumers recognize as Remicade and Enbrel. Anti-TNF therapy, which has been used most broadly to treat rheumatoid arthritis with hopes that it would prove to be the bright new promise for suffering patients, has turned out to pack a nasty surprise. These drugs do help to stave off joint destruction, but in the process TNF blockers also cause rheumatoid arthritis and psoriasis patients to have several-fold-higher rates of lymphoma (a type of cancer). According to FDA officials, Remicade and Enbrel use have a “probable or possible” link to the development of lymphoma, and studies show that several patients’ lymphomas regressed once treatment with these medications was discontinued. In other rheumatoid arthritis patients, TNF therapy actually kick-starts new forms of autoimmunity that mimic multiple sclerosis, autoimmune hemolytic anemia, type 1 diabetes, lupus, and psoriasis. Also used in the treatment of Crohn’s, anti-TNF therapy has been linked to the development of other autoimmune diseases, such as lupus. Once we muck about with one aspect of the immune system, we may derail other important immune-cell functions. All too often the cure is worse than the disease.

A similar story arises with Tysabri, a drug used to treat multiple sclerosis that the U.S. Food and Drug Administration fast-tracked for approval in November 2004. Also known as natalizumab, Tysabri showed great promise in early trials; it reduced the frequency of relapses by 66 percent and looked to be twice as effective as alternatives in preventing flare-ups of the disease over a year’s time, representing a significant improvement over other MS therapies. It was certainly a far more attractive alternative than low-dose chemotherapy, which has often been used to treat MS in the past. The success of Tysabri, which was also being tested for efficacy in treating Crohn’s disease and rheumatoid arthritis, is based on its ability to bind to a protein on immune-system cells, preventing them from traveling to the brain, where they can then pass into the nervous system and cause the brain and spine lesions that lead to MS symptoms. The drug, which is administered intravenously once a month in a doctor’s office—making it a better alternative to drugs that require daily injections—appeared to be safe and well tolerated, although there was no information about long-term safety.

But within months of Tysabri’s approval it became clear that the drug posed rarely seen but potentially fatal side effects. Some patients taking the drug developed a rare infection—progressive multifocal leukoencephalopathy, or PML—and two patients died. Anita Louise Smith was one of these patients. Smith had enrolled in an experimental drug trial for treating multiple sclerosis with Tysabri in 2002 in Colorado. Although Smith had been diagnosed with MS, she had not yet developed debilitating symptoms. Tysabri was a promise that she could reduce the chances of being ravaged by the disease by keeping her MS from progressing. But in 2005, Smith died at the age of forty-six from PML, an infection that usually affects people whose immune systems are compromised. In Smith’s case, her infection was linked to her use of Tysabri in combination with another drug, Avonex, which also helps to prevent immune cells from entering the brain. It appeared that Tysabri’s mechanism of action—blocking the entry of immune cells into the nervous system by blocking their entry into the brain—might also make patients more vulnerable to infection. The FDA withdrew Tysabri only three months after its approval. By that time Tysabri had come to seem less impressive for other reasons as well: its ability to halt episodes of MS relapse, while notable, was generally not much better than what was seen, over time, with other available drugs. The risk of relapse dropped from an average of two relapses every three years using other approved MS drugs such as Copaxone, Rebif, Betaseron, and Avonex—all of which reduce flare-ups or minimize the appearance of lesions in the brain—to one every three years with Tysabri. The question was simple but grave: Would a physician want to expose someone to the risk of death for the sake of eliminating one relapse every three years? For some patients the answer might be yes, but for many others, like Anita Louise Smith’s family, the answer would certainly have been no.

Today, researchers are working to tease out whether the fatal brain infections associated with Tysabri might have something to do with the fact that the patients who experienced them were receiving Tysabri along with Avonex. There were no cases of PML among the five hundred patients who took Tysabri alone for multiple sclerosis or the two thousand who have taken it in clinical studies for Crohn’s disease or rheumatoid arthritis. On June 5, 2006, the U.S. Food and Drug Administration approved the reintroduction of Tysabri as treatment for relapsing forms of multiple sclerosis. Investigators suspect, for the time being, that it could be that the two drugs together had an additive effect preventing immune-system fighter cells from entering the brain—working in tandem to open the door to brain infection. Still, no one is sure. Which is the point: when working with the inscrutable immune system, investigators are often working partially blind: they don’t understand nearly enough about how one pathway of immune cell interactions impacts another to predict what will happen when they alter one of these pathways. Science tends to be murky that way, but as any immunologist will tell you, perhaps in no field is it messier than in autoimmune-disease drug research. When we attempt to develop therapies to keep the immune system from attacking itself, it is impossible to guess whether all other functioning parts of the immune system will remain uncompromised in the process—and only long-term clinical trials can provide the answer.

All of which leaves autoimmune-disease sufferers with dicey options. The multiple sclerosis drugs Avonex, Rebif, and Betaseron can lead to rare liver problems, Copaxone can lead to severe allergic reaction. For those with rheumatoid arthritis, Remicade and Enbrel can lead to a greatly elevated risk of lymphoma, serious infections, and tuberculosis; Celebrex and Vioxx are overwhelmingly linked to cardiac problems. Those suffering from Crohn’s disease can choose between methotrexate, which can be toxic to the liver, and prednisone, which can also lead to potentially fatal infections because it suppresses the entire immune system. Not a pretty picture.

Newer therapies are emerging as more promising, perhaps the most impressive of which is Rituxan, also known as rituximab, now being used to treat those with multiple sclerosis and other autoimmune diseases. Rituxan works by preventing signals from being transmitted that set B cells in motion to react against the body’s own tissue. So far, early studies in MS populations are promising, indicating that Rituxan does lead to rapid depletion of self-reactive B cells. The drug, which has been used for nine years as a cancer drug to treat non-Hodgkins lymphoma, can cause serious side effects in lymphoma patients, including liver problems, but these side effects do not seem prevalent in those with multiple sclerosis—at least not in the nearly two years in which Rituxan has been studied. Some studies show that Rituxan not only helps to stop MS disease progression, but helps patients to recover some of the neurological function that they lost due to MS in earlier months and years. Rheumatologists are also using rituximab (under the name MabThera) to treat patients with rheumatoid arthritis. In a study of 156 patients who had not responded to TNF inhibitors such as Enbrel (which works by tamping down T-cell activity), patients taking MabThera reported an improvement in their physical well-being and ability to perform daily tasks, as well as a slowing down of joint damage. For some patients, their disease went into remission.