Remember when Grandma used to say, "don’t go out in the cold; you’ll get sick”? It turns out that she was right for a small number of people who have a condition called familial cold autoinflammatory syndrome (FCAS), in which individuals are afflicted by rash, fever, joint pain and flu-like symptoms after exposure to cold conditions as mild as an air-conditioned room or fall breeze.
The disorder became a hot protocol for research labs in 2001 after investigators at the University of California, San Diego (UCSD) School of Medicine discovered the mutated gene that caused FCAS*. Now, the same UCSD team reports in the November 13, 2004 issue of the journal Lancet, that they’ve found an effective treatment – one that inhibits an abnormal immune response that leads to symptoms in FCAS-affected patients.
Dr. Hoffman examines the arm of FCAS patient Arlene Fowler, while her daughters Cathy and Cinda look on. All three women suffer from familial cold autoinflammatory syndrome (FCAS).
“We witnessed a truly remarkable response and a life-changing therapy for these patients,” said Hal M. Hoffman, M.D., a UCSD assistant professor of medicine and pediatrics, and the lead author of the study in Lancet. “On a scientific level, the investigation of uncommon disorders such as FCAS can provide important insights into the mechanisms of more common diseases. For example, inflammation has been shown in recent years to be important in many disorders from arteriosclerosis to Alzheimer’s disease.”
Because cold triggers fever in FCAS patients, in 2001 the UCSD team named the disease-causing protein they discovered “cryopyrin,” which means icy fire. In their new studies with seven individuals, four afflicted with FCAS and three normal subjects, the investigators determined that cryopyrin regulates the release of interleukin-1 (IL-1), an important mediator of fever and systemic inflammation during the body’s initial immune response. After finding increased levels of IL-1 in the skin of the FCAS patients following an experimental cold challenge, the researchers administered a recombinant IL-1 receptor antagonist, a drug called anakinra, which inhibits the action of IL-1 and thus prevents acute inflammation, fever and flu-like symptoms. The treatment prior to cold exposure prevented the clinical and laboratory manifestations of the disease in the FCAS patients. Anakinra is currently approved by the Food and Drug Administration for treatment of rheumatoid arthritis.
FCAS is a hereditary disorder thought to affect nearly 300 Americans, with 90 percent of them tracing their ancestry to a man from Northern Europe who migrated to the U.S. in the 1600s. FCAS is one of a family of seven distinct, single-gene defects that are considered to be hereditary periodic fever disorders**, characterized by recurrent bouts of systemic inflammation involving several tissues, including joints and skin.
Over the past seven years, Hoffman has studied FCAS by drawing blood samples at different family reunions held throughout the United States, from Georgia, Ohio, Illinois and Missouri, to Utah and California. Frequently, the individuals with FCAS didn’t know they had distant relatives in other states with the same condition. Interviewing hundreds of patients in divergent regions of the country, Hoffman said he found a similar story that had been passed along through the years.
“One older family member told me that the disease started with his great-great-great-great grandfather who was working on a farm during a hot day, and he fell into cold water,” Hoffman said. “Then, at another reunion, someone else would tell me that the problem started with a man who got shipwrecked and was in cold water for a long period of time. The common thread was always cold water.”
In actuality, the common thread was exposure to cold. When individuals with FCAS get cold, within an hour or so they develop fever, chills, joint pain, red eyes, achy muscles and rash. In severe cases, patients develop kidney failure related to the disorder.
A typical FCAS patient is 77-year-old Arlene Fowler of Menifee in Southern California California. “I’ve had this all my life,” she said. “My Mom, who had it, told me that some long-distant cousin caused the problem by daring our relative to jump in ice water.”
“I couldn’t live back east; it’s far too cold,” Fowler noted. “Even a slight change of temperature causes a rash, swollen joints, chills, a headache and painful red eyes. It’s hard for me to breathe when I get out in the cold air. I feel miserable, but I’ve learned to live with it. Having a hot tub to warm up helps!”
In addition to the three women, who suffer from FCAS, their husbands were "normal controls" in the UCSD study. Dr. Hoffman is pictured in the back row, third from the left.