Gloria E. Grubbs, a Vietnam Vet from Dorchester, is 50 now, has “raised two kids up” and made a life for herself, despite a 19-year struggle with scleroderma, the disfiguring disease that can turn the body into a mass of stiff, scar-like tissue, inside and out.
It started with a tightening and thickening in her skin, then moved on to her joints and internal organs. Her heart is now so rigidly encased that she needs an operation, and fibrous tissue is threatening her lungs and kidneys, too.
Grubbs keeps her spirits up by getting out of bed as often as she can to “mess with my plants” and do the washing, ironing and babysitting she must do to supplement her disability check.
She wouldn’t wish scleroderma “on my worst enemy,” she says. “It’s a very depressing disease.”
It’s also “the most frustrating disease in rheumatology,” says Dr. Don Goldenberg, chief of rheumatology at Newton-Wellesley Hospital. “That’s because of the lack of effective treatment, the difficult lifestyle and cosmetic issues people face, and the fact that we still don’t know why it happens.”
There’s no cure in sight for Grubbs or 300,000 other Americans with scleroderma, a disease that chiefly strikes women of childbearing age. In its virulent form, it kills half its victims within five years. But researchers are finally on the trail of its causes – and of new treatments.
Acting on a tip about the high rate of scleroderma among Choctaw Indians in Oklahoma, for instance, researchers at the University of Texas-Houston Medical School have discovered a region on chromosome 15 that may contain a scleroderma gene.
Back in 1830, the US government seized the land of the Choctaw, who then lived in Mississippi, giving them a cruel choice: stay behind on small plots or migrate to Oklahoma.
Roughly 20,000 trudged to Oklahoma in what became known as the “trail of tears.” There, they became a kind of genetic laboratory – a small, intermarrying population in which any mutation that popped up would spread through the group.
The fact that researchers are closing in on just such a mutation means they can now look for similar genes in others with scleroderma – and perhaps understand its origins.
In Seattle, researchers from the Fred Hutchinson Cancer Research Center and the Virginia Mason Research Center are chasing another theory. They’ve found that women with scleroderma have higher levels of fetal cells from past pregnancies in their blood than other women, even decades later.
Since a fetus has genetic material from its father and mother, says rheumatologist Dr. J. Lee Nelson, any fetal cells that get into the mother’s bloodstream may be seen by her immune system as “non-self,” triggering an immune disruption that can lead to scleroderma.
Still other researchers, are trying to sort out the physiological steps that lead to scleroderma.
The initial problem, some think, is microscopic damage to small blood vessels, usually in the extremities, causing periods of reduced blood flow, followed by a restoration of normal flow.
This cycle causes normal proteins in the blood and tissues to break apart, says Dr. Frederick Wigley, director of the scleroderma research center at Johns Hopkins School of Medicine.
The newly-exposed protein fragments, or antigens, are then spotted by the immune system, which treats them as foreign and begins making antibodies against them.
A second wave of the immune response is then thought to cause cells called fibroblasts to start pumping out excessive amounts of collagen, a fibrous protein that helps hold body tissues together. At the same time, the cells begin making too little collagenase, the enzyme that destroys excess collagen.
Other researchers believe immune problems come first – perhaps from a genetic mutation, renegade fetal cells or some other stimulus – and that the blood vessel damage comes second.
Whatever the sequence, researchers agree that a key warning sign is Reynaud’s phenomenon, in which blood vessels in the fingers bcome severely constricted in response to cold or stress. About 95 percent of people with scleroderma have Reynaud’s, though half of those with Reynaud’s never get scleroderma.
Until recently, treating the underlying process of scleroderma has proved difficult. “There are no proven efficacious therapies,” says Dr. James Siebold of the Robert Wood Johnson Medical School in New Brunswick, N.J.
But doctors are getting better at treating the damage it does, organ-by-organ. The cancer drugs Cytoxan and methotrexate, for instance, often combat scarring in the lungs.
Drugs called ACE inhibitors can reverse kidney damage. The once-reviled sedative thalidomide, expected to be approved soon for limited use in the United States, may retard scarring. And some researchers are trying photopheresis – pumping blood out of the body and exposing it to ultraviolet light to destroy immune cells.
Some approaches have proved disappointing. Prednisone, a powerful steroid, helps with joint pain but can make high blood pressure and kidney problems worse. Another once-promising drug, d-pencillamine, has also been a letdown.
On the other hand, some treatments in the pipeline show considerable promise, notably a drug called Relaxin, made by the Connetics Corp. in Palo Alto, Calif.
A genetically engineered version of a hormone secreted in pregnancy that allows a woman’s skin to stretch, Relaxin works by boosting collagenase and decreasing collagen.
In studies, 70 percent of patients taking low doses have shown improvement, including a 30 percent softening of the skin. Other symptoms improved, too, like patients’ ability to open their mouths wider and stretch their hands. Curiously, though, higher doses did not work.
Another ray of hope comes from stem cell transplants, a variant of bone marrow transplants. The idea is to remove stem cells (immature immune cells from which other immune cells grow), then blast the patient with drugs and radiation to destroy the immune system, including “memory” cells that contribute to auto-immune problems.
Then, the stem cells are infused back into the body to regenerate a new immune system that, hopefully, has lost the memory of its auto-immune attacks, says Dr. Daniel Furst, a Seattle rheumatologist who is spearheading this effort.
Furst has transplanted three patients with early aggressive scleroderma and says the results look promising, which suggests that stem cell transplants might help with other auto-immune diseases such as lupus, multiple sclerosis and arthritis.
In research to be presented at a conference next month, Dr. David Trentham, a rheumatologist at Beth Israel Deaconess Medical Center, has gotten encouraging results using an antibiotic called minocycline in 11 people with scleroderma.
As of now, none of these options appears miraculous. But they do represent the kind of progress Gloria Grubbs is rooting for.
“I really want them to find a cure,” she says. In the meantime, she tries to “dwell on positive things. And when you think you hit the lowest point, remember there is somebody out there worse than you that you can help.”
Where to learn more
For more information, call The Scleroderma Foundation: 800-722-HOPE (or 4673). On the Web, it’s www.scleroderma.com