The Scleroderma Association of NSW Inc. cannot offer direct advice on treatment or available therapies. It is up to each patient to make all relevant health decisionsIn consultation with their own doctor or health professional.|
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Science 31 October 2008: |
Although scleroderma affects as many as 300,000 Americans and kills roughly 10,000 every year, this autoimmune disease remains an enigma and far from the public's radar. Its cause--or causes--remains murky. Genetic and environmental studies have yielded few clues, as the disease seems to strike almost at random.
Scleroderma was formally discovered in 1754 by Carlo Curzio, an Italian doctor who described treating a woman with thick, stiff skin--the symptom from which scleroderma gets its name (from Greek meaning "hard skin"). This skin condition, along with the circulation problem that Lowe experienced, known as Raynaud syndrome, are the classic signs of the disease--and many people with scleroderma suffer from only these disabling, not deadly, symptoms.
Another hallmark of scleroderma is that patients suffer a diverse array of symptoms, leading many physicians to consider the condition a constellation of disorders. In bad cases of systemic scleroderma, the most severe form of the disease, inflammation and fibrotic scar tissue flare up in multiple organs, blood vessels narrow and harden, and traitorous immune cells attack a person's own flesh. The dizzying complexity of scleroderma has kept scientists both frustrated and fascinated for decades. "The problem is we don't really understand what the primary basis is of the disease," says Robert Lafyatis, a rheumatologist at Boston University (BU) School of Medicine. "We don't know if it's a vascular disease, a fibrotic disease, or an immune disease."At a recent meeting in Cambridge, U.K., Lafyatis and several hundred scleroderma investigators gathered* to compare notes and chart the field's progress. Despite continued bewilderment about what causes the disease, there was good news to report. In the 1980s, physicians began effectively treating the kidney problems that then killed most scleroderma patients. New insights into the disease's molecular underpinnings are helping to tackle other dangerous symptoms, too. Some researchers are even finding that "rebooting" a person's immune system with stem cell therapy may completely eliminate the systemic fibrosis that continues to kill many people. "There's been a change from nihilism to a bright light at the end of the tunnel,"says Alan Tyndall, a rheumatologist at the University of Basel in Switzerland. "As medical students [in the 1960s], we were told that scleroderma is a death sentence and there's no hope; now, that's changed"
Many suspects, little proof
Frozen fingers. Scleroderma is often marked by stiff, hardened skin that severely limits movement in victims' joints.
CREDIT: AP PHOTO/THE OAKLAND PRESS/PAULA ARTMAN
Fetal cells were another suspect. During pregnancy, such cells pass through the placental barrier and enter an expectant mother's circulation. Scientists found that these foreign cells could live for decades in a woman, and some theorized that the cells might trigger scleroderma. This theory could offer an explanation for one of scleroderma's puzzles: 80% of patients are women, most in their pospartum years. However, as more studies were done, some research suggested that fetal cells helped fight or prevent the disease in the mother, rather than cause it. The true role they play remains unresolved.
One solid scleroderma clue is the disease's link to genetics. Although the incidence in the U.S. general population is only about 14 people per million per year, the odds of a person developing the condition are more than 100 times greater if a family member does too, and more than 280 times greater if that member is your identical twin. Those rates indicate a genetic component to the disease, albeit a weak one because the great majority of family members or twins don't share the disease. "If you compare scleroderma to a traditional genetic disease, the genetic pattern in families is not that strong," says Xiaodong Zhou, a clinician who studies scleroderma genetics at the University of Texas Health Science Center in Houston. "But if you compare it to the [prevalence in] the general population, … it's very high."
The Choctaw Nation of Oklahoma, a Native American population, has a much higher prevalence of scleroderma--roughly three times higher than the general population, which has led to several studies surveying their DNA. Researchers pinpointed several DNA markers around the gene for fibrillin-1 that correlate with the Choctaw scleroderma cases--and the protein's presence in connective tissue makes sense, given the disease's symptoms. Still, fibrillin's exact role in the condition remains murky. Researchers have failed to link the fibrillin gene to other populations of scleroderma patients.
Other genetic studies of scleroderma have pointed to the major histocompatibility complex, an array of genes that controls immune cell function, but "it's a common region for autoimmune disease, "explains Zhou. "They've all been linked to that region."
More recently, Michael Whitfield, a geneticist with Dartmouth Medical School, has used genome-wide microarrays to screen all the gene activity within scleroderma skin and tissue samples. In July, Whitfield and colleagues reported in PLoS ONE that 17 out of 22 scleroderma patients had a genetic fingerprint, a distinct pattern of gene activity, differing from controls. Most of the overactive genes were the usual suspects for an auto-immune disorder--those involved in immune cell activation, including T, B, and macrophage cells--but others with altered activity were genes involved in fibrosis and collagen growth. Whitfield also found a cell proliferation signature--a group of cell-cycle genes that are expressed only when cells are dividing, which hints that scleroderma tissue has higher rates of DNA replication.
Whitfield says the most surprising outcome from the study is that even tissue from scleroderma patients that looks normal still has the distinctive genetic fingerprint of the disease. His group plans to repeat the experiment with a larger sample to see if it continues to hold true. If so, Whitfield hopes the multigene fingerprint could be turned into diagnostic or predictive tools for clinicians. "The limiting factor in terms of understanding scleroderma is getting large enough patient cohorts to do studies,"notes Whitfield. "And it's the heterogeneity that's really plagued us, from the molecular level and from the genetic level."
Whitfield says that his microarray approach isn't likely to yield one simple gene as an answer. "There's very likely to be multiple factors contributing to scleroderma,"he says."We're not going to find a single mutation. It's almost certainly going to be a combination."
Treating the symptoms
Although figuring out the root of scleroderma remains a
major research goal, the number-one priority has been to find treatments
that keep the symptoms at bay, a quest that has led to a game of cat and
mouse between drugs and the disease. The number-one killer of scleroderma
patients used to be kidney failure. Twenty percent of patients would die in
middle age as their kidneys' arteries became clogged and constricted with
smooth muscle cells. However, in 1979, scientists found a class of drugs,
angiotensin-converting enzyme (ACE) inhibitors, which relax the disease's
stranglehold on the kidney. Harrison Farber, director of the Pulmonary
Hypertension Center at BU, calls ACE-inhibitor therapy one of "the biggest
breakthroughs in scleroderma," noting that people are no longer dying of
renal failure.
Lungs then became the new battleground. Like the kidneys, the pulmonary arteries, the vessels that carry blood between the heart and the lungs, also tend to become occluded and constricted in scleroderma. But much to the frustration and puzzlement of doctors, ACE inhibitors don't help here. "Once people stopped dying of kidney failure, they now lived long enough to die from pulmonary problems," says Francesco Del Galdo, associate director of the Scleroderma Center at Jefferson University Hospitals in Philadelphia, Pennsylvania. One in seven scleroderma patients developed pulmonary hypertension, and it was inevitably deadly. By the late 1990s, however, researchers began employing a variety of drugs, including Viagra, which help to widen and relax the lung's arteries.
Although these treatments are touted as helping patients live longer, some clinicians remain unconvinced. Six different drugs have received approval from the U.S. Food and Drug Administration for treatment of lung problems in scleroderma, but all were largely tested using a simple approach: the 6-minute walk test. If a patient testing a new drug could complete this exercise with greater ease, the drug was considered to be effective. However, only one clinical trial has ever shown the drugs to improve a scleroderma patient's survival against a placebo. "These drugs can help the symptoms," says Lafyatis. "But it's not clear that it helps their mortality; … some patients benefit from it and some don't."
Scleroderma poses a further deadly challenge: fibrosis. In severe cases, fibroblasts, the cells that create and maintain the extracellular matrix, seem to be irreversibly activated, inducing an unwanted scarring process. Chris Denton, an experimental rheumatologist at University College London Medical School, notes that now "it's the fibrosis that causes the mortality of disease, because it's happening simultaneously in multiple organs." Yet the lungs remain the key battleground, as lung fibrosis can strike 70% of scleroderma patients, and scarring there leads to eventual suffocation.
Scientists at the Cambridge meeting agreed that eliminating the fibrosis problem should prevent scleroderma from being a killer and turn it into a more manageable chronic disease. How to thwart the process has been mostly a mystery, but there was new optimism at the conference. "We have a rich variety of potential molecular targets [for fibrosis], and for many of these, inhibitors are available and are being tested in clinical trials," says Oliver Distler, head of the scleroderma clinic at the University of Zurich, Switzerland.
Most of these inhibitors aim at a longtime suspect for fibrosis: TGF-
a so-called cytokine with multifarious pathways. One track stimulates both
collagen and scar-tissue formation, whereas other tracks stimulate cell
death via apoptosis or cell differentiation. Researchers have found elevated
levels of the receptors for TGF-
on fibroblasts from scleroderma patients, suggesting that the activated form
of the protein plays a role in their dysfunction. (When TGF-
is initially secreted, it's bound by other molecules and inactive.) But what
triggers the production and activation of TGF-
in scleroderma remains unknown.
Moreover, because TGF-'s
stimulation of scar and collagen tissue is normal and necessary in many
cases, completely disabling the cytokine pathway is not a good option for
treating scleroderma. "If you can't do fibrosis, you're in big trouble,"says Tyndall.
Scientists have therefore been teasing out how to selectively block the
TGF- route that
elicits overactive scar formation. Some believe that targeting the upstream
proteins that activate TGF-
may be the key to halting scleroderma's fibrosis while allowing normal wound
healing to continue. One such TGF--inhibiting
drug is Gleevec, which has previously earned fame for its successes treating
leukemia and other cancers. In recent years, physicians have reported cures
or near-cures of late-stage scleroderma patients after trying Gleevec, which
has motivated a number of phase II clinical trials of the drug for the
condition. Luke Evnin, chair of the board of directors at the Scleroderma
Research Foundation in San Francisco, California, cautions that the results
so far are by no means definitive."In larger case series, it is not clear
that [the drug] is broadly applicable," he says. "But still the enthusiasm
from the initial cases persists."
Many scleroderma scientists remain wary of overhyping Gleevec. "We had promising drugs 10 years ago that were very hopeful "says Distler. "But the clinical studies actually failed." Those drugs, he notes, were "rather unspecific immunosuppressive drugs." They had appeared to work in phase II studies, says Distler, but then failed in larger randomized controlled trials.
Tyndall believes that stem cell transplants could solve scleroderma's fibrosis and perhaps all its other symptoms, too. The approach mirrors a strategy used to treat leukemia: Stem cells from bone marrow that can give rise to new immune cells are taken out from a patient, and then physicians use drugs to purposely obliterate the patient's entire immune system, a strategy called immunoablation. After that, the preharvested stem cells are infused back into the patient, where they can create fresh bone marrow and, it is hoped, a new functioning immune system. Tyndall says some of his scleroderma patients went back to normal after receiving this aggressive immune rebooting. A multicenter randomized phase III trial with 150 patients is under way to confirm these findings.
Nonetheless, those at the conference in Cambridge seemed to reach a consensus that scleroderma would need more than just one solution. "No two scleroderma patients are alike. It's really amazing to me," says Farber. Each patient may need a tailor-made treatment: One requires an aggressive antifibrotic treatment whereas another demands an emphasis on fighting pulmonary hypertension, Farber and others suggested.
Still, Denton is increasingly optimistic. "I think we're in a stronger position now, because in the previous era, we were trying therapies with an unclear view of what the biology is,"he says. "Now we're in an era where treatments are having an impact on outcome, … and we're also starting to understand the very complex biology that links the different processes in scleroderma. "
The Scleroderma Association of NSW Inc. cannot offer direct advice on treatment or available therapies. It is up to each patient to make all relevant health decisionsIn consultation with their own doctor or health professional.
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is the shortest distance between two people." Victor Borge