UCSD researcher discovers new treatment for rare disease

By: RUTH MARVIN WEBSTER - For the North County Times | Saturday, January 29, 2005 9:41 PM PST ∞

They are called colds, even though doctors insist the temperature outside has nothing to doing with catching one. That is, for everyone except a handful of people ---- about 300 or so Americans ---- who have a rare hereditary disease called FCAS, or familial cold auto-inflammatory syndrome. For them, an air-conditioned room or fall breeze can send them to bed with a fever, achy joints and a painful rash.

Menifee resident Arlene Fowler, her mother, her two grown daughters and her 23-year-old granddaughter all have FCAS. Though not life-threatening, Fowler says their disorder has been considerably more than a mere nuisance.

"In grammar school, I was always being sent home from school because they thought I had the measles," remembers Fowler, who would catch a chill in the morning and regularly break out in a rash by lunch or run a fever.Ý

And for Fowler, who loves the beach and the outdoors, it was also embarrassing.Ý

"As a young girl, there were lots of times when I would have liked to go places, but because of this disease, I didn't," she said. "Now, my heart goes out to my granddaughter. I remember wanting to go out and wear sleeveless shirts and look pretty, but you had to stay inside or catch a chill and pay the price with a day in bed.

"Back then, it wasn't called FCAS," Fowler said. "We just called it names, none of which you can repeat."

For generations, Fowler family members had to simply endure days in bed wrapped up in a warm blanket with a hot water bottle when the temperature fluctuated. That was before Fowler's son-in-law read an article about Dr. Alan Wanderer, who was working with patients with cold urticaria, an allergy to cold substances such as ice cream or ice cubes.ÝÝÝÝÝÝÝÝ

Fowler decided to contact him.Ý

"We figured any doctor who would take pains to help a child eat ice cream might be able to help us," she said.Ý

At first, researchers thought the Fowlers' condition was one in the same. In cold urticaria, the hives are produced by a rapid release of histamine called mast cells, and the treatment involves taking antihistamines. But antihistamines weren't effective for patients with FCAS.Ý

Dr. Hal Hoffman, an assistant professor and pediatrician at UC San Diego, Childrens Hospital and the Ludwig Institute, began studying FCAS eight years ago at the urging of Wanderer, and worked to change its name from its previous name, familial cold urticaria, to familial cold auto-inflammatory syndrome ---- mostly, to make a clear delineation between the two conditions.

"Many patients got frustrated with the medical system, when all of their doctors would just send them home with antihistamines," Hoffman said.

Cold urticaria is more of a typical allergy, but FCAS is something quite different, he explained. Though patients with FCAS have rashes, mast cells and histamine are not involved, and their symptoms, such as fever and joint pain, are more common to a new group of conditions called auto-inflammatory disorders.

"Because FCAS was a hereditary disease, the first thing I wanted to do was find the gene that is involved," Hoffman said. Then with the help of the Fowlers and other FCAS families, the Human Genome Project and other researchers at UCSD, Hoffman was able to identify the gene that is mutated in these patients. His discovery was published in late 2001 in the journal Nature Genetics.

The gene contains a code for a protein, which Hoffman coined cryopyrin, meaning "icy fire." He also noted that the identification of cryopyrin has led to a better understanding of its role in the immune system and how it regulates the release of interleukins, important mediators of fever and systemic inflammation.

With the discovery of the gene and protein under his belt, Hoffman turned to finding a cure. To further understand the immune abnormalities involved in this condition, Hoffman and his team put Fowler and other members of her family in a 36-degree room for 45 minutes, and within an hour, she and the others with FCAS broke out in a rash and later that evening developed fever, joint swelling and red eyes. Hoffman found increased levels of interleukin-1 in the skin of the patients with FCAS after exposure to cold.

This finding prompted Hoffman to study a new drug called anakinra that blocks the effects of interleukin-1 and is used by some patients with rheumatoid arthritis. As reported in the medical journal The Lancet in November, the medication given before exposure to cold eliminated all of the FCAS symptoms ---- including the Fowlers'. While it is now being used to treat eight patients around the country with similar success, others like the Fowlers cannot afford it, and still others are not willing to risk a daily injection, which is not without its side effects.

Hoffman notes that though it is a relatively rare disease, understanding FCAS ---- and particularly the protein cryopyrin ---- could help to understand not only other immune diseases, but the innate immune system, as well.Ý

"On a scientific level, the investigation of uncommon disorders such as FCAS can provide important insights into the mechanisms of more common diseases," he said. "Inflammation has been shown in recent years to be important in many disorders from atherosclerosis to Alzheimer's."

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