RELATED ITEMS  Web resources Scleroderma Research Foundation The National Institutes of Health on scleroderma Jason Alexander teams up to fight scleroderma Bob Saget raising awareness about scleroderma

		Famed comedian Robin Williams continues the fight against scleroderma.

"You can make up a joke about almost anything," says Williams. "But to tell you the truth, there isn't even one tiny aspect of this disease which lends itself to humor. Scleroderma is a horrible disease with nothing to recommend it, other than the incredible courage which its victims muster in the face of overwhelming odds and terrible suffering."

But Williams and fellow comedians Dana Carvey, Lily Tomlin, and Bob Saget brought laughter to the nearly 800 people attending the 12th Cool Comedy – Hot Cuisine benefit for the Scleroderma Research Foundation (SRF) last weekend at the Regent Beverly Wilshire Hotel in Beverly Hills.

"It's a tremendous and appreciative audience because they want to laugh and need to laugh – the disease is incurable," says the Oscar-winning Williams. "But in the six years I've been at this event, we've come a long way. Now we know that there are specific areas that hold great promise in finding a cure."

Scleroderma resisted scientific research for decades. The complex, degenerative disease can present a variety of symptoms, has two distinct forms, and 80% of cases attack women in their childbearing years.

"It robs these women of not only their own lives in many cases, but robs their families which include countless children" notes actress Dana Delany, star of Presidio Med and a SRF board member.

That terrible fact was underscored earlier this year when SRF founder, chair, and mom Sharon Monsky died after a 16-year battle with the disease. "There simply wasn't a braver and more determined human being on the face of the planet," says Williams.

"We lost an invaluable resource and my best friend," says Saget, whose sister Gay died from scleroderma eight years ago. "But we're fortunate in that Luke Evnin is now chairman."

Evnin is a well-known researcher and shares a deep bond with Monsky. "He too has the disease," says Saget. "We all know that his commitment is both deep and personal as well, and for a disease like this killer those are real assets."

Deconstructing scleroderma

Scleroderma can affect blood vessels and circulation, prompt tissue loss, and creates overproduction of collagen in connective tissue. Many patients experience changes in their skin due to this collagen overproduction, often leaving their faces with a tight leathered look.

In about half of patients the disease is confined to the skin or muscles and called localized scleroderma. Although it may be disabling, localized scleroderma does not progress to generalized (systemic) scleroderma.

The remaining half of the 300,000 estimated to have the disease develop systemic scleroderma, which can cause extensive and fatal damage to organs in the digestive, respiratory, circulatory, and immune systems.

Characteristic symptoms may include:

·Bone and joint problems — Arthritis, aching joints, and stiffness in hands and feet.

·Run down feeling — Weight loss, fatigue, and shortness of breath.

·Skin abnormalities — Thickening, tightening, discoloration, swelling, and puffiness.

·Raynaud's phenomenon — The hands or feet change to red and blue and become painful as blood flow changes in response to cold, heat, or stress

Other symptoms may include hair loss, difficulty swallowing, heartburn, and dry mucus membranes.

Complicating matters, each of the two types of scleroderma have distinct subsets. These share a variety of symptoms with other diseases, often making diagnosis difficult and delaying treatment. Timely diagnosis can be a challenge – one standard test can yield early false negatives, delaying treatment even longer.

While early recognition and treatment of scleroderma continue to improve, the origin of this autoimmune disease remains unknown. Genetic and environmental factors may both be involved. Thankfully, an increasing body of research, largely driven by the SRF, reflects a growing consensus that it will be cured.

"Sharon's work literally convinced researchers that there was hope in finding a cure," says Delany. "Before research can begin researchers have to be convinced there is a light at the end of the tunnel. Now we know it's a solvable problem held back only by research resources."

What dreams may come

Current research areas supported by the SRF include:

·Collagen production — Fibrosis or skin hardening is the most visible characteristic of the disease. SRF-sponsored researchers at Duke University discovered that an essential messenger protein that regulates collagen production known as Smad7 is missing in scleroderma cells. Follow-up work now centers on ways to regulate collagen production by correcting this in order to stop this disfiguring effect of the disease.

·Antibody abnormalities — Work at Johns Hopkins University continues after their discoveries reported last year: antibodies found only in scleroderma patients also form unique clusters at the same cellular locations. Understanding how and why these antibodies form may lead to scleroderma's causes.

·Vascular dynamics — "This branch of research is the subject of well-deserved excitement and attention," says Delany. "What we thought might be byproducts of the disease may actually be very involved in its development and progression."

For example, the visible vascular effects of Raynaud's phenomenon are the first sign of scleroderma for 90-95% of patients, according to the SRF. But only 5-20% of those with Raynaud's — which causes nearly complete cessation of blow flow to affected areas — go on to develop scleroderma.

New research from Ohio State University shows that overabundance of a specific protein is tied to constriction of the blood vessel walls and that the micro lesions formed in response can contribute to the larger tissue death and organ failure that fells patients. If that protein expression can be controlled, the progression of the disease might be arrested or even prevented.

Endothelial antagonists — chemicals that interfere with the lining (endothelium) of vessels — are a promising research subset here. These prevent narrowing of blood vessels and have wider applications for hypertension.

"There are really two vascular components — finding out why people with scleroderma lose microvasculature and creating new blood vessels," explains Evnin. "Both hold promise."

Some other areas remain of interest as well. The role of environmental triggers for people who may have a genetic predisposition to the disease has yet to be unraveled. Viral infections and various industrial coatings, adhesives, and organic solvents such as the trichloroethylene used extensively in dry-cleaning are suspected triggers.

Because women with scleroderma outnumber men four-to-one, it's also thought that factors tied to gender, such as estrogen, may play a role. During the middle and late childbearing years, ages 30-55, women develop the disease between 7-12 times more often than men.

"There are a variety of promising pathways in research," notes Evnin. "At this point what delays research for us is simply more funding. We could responsibly and effectively utilize about three times what we have now."

"It's pretty much black and white," says Williams, who co-founded Comic Relief. "More attention and research funding needs to be put into scleroderma. There's just no joke about it — this disease and its rampage is a continuing tragedy."