Managed Care - April 2008 - (Page 56) TOMORROW’S MEDICINE In the World of Tomorrow’s Medicine, A Single Physician Makes a Difference Hal Hoffman’s work led to the discovery of the genetic basis of an autosomal dominant disease and to creation of a prototypical orphan drug Thomas Morrow, MD e seldom describe a single contemporary practicing physician in the United States as a pioneer, but that term would truly describe Hal Hoffman, MD, a pediatric allergist in San Diego who practices at the University of California–San Diego and at Children’s Hospital there. During his fellowship years he learned about a family that had an interesting and quite disabling condition called cryopyrin-associated periodic syndrome (CAPS), an inherited disease that affects about 300 people in the United States. CAPS consists of three syndromes caused by mutations in a gene that has been renamed recently from the cold-induced auto-inflammatory syndrome 1 (CIAS1) gene to the nucleotidebinding domain, leucine-rich family (NLR) and pyrin domain containing 3 (NLRP-3) gene. These three conditions are inherited as an autosomal dominant disease (think big B from the Punnett square) and can also occur from a spontaneous mutation of the NLRP-3 gene. There are about 75 different known mutations of this gene. These mutations bring about increased activity of cryopyrin, an inflammatory regulatory protein that in turn induces overproduction in interleukin-1β (IL-1β). Interleukins are one of several types of cytokines, a group of proteins that allow complex communications between the various cells of the immune system including lymphoid, inflammatory, and hematopoietic cells. Some interleukins have anti-inflammatory effects and others promote inflammatory actions. Specifically, IL-1β is known to promote endogenous fever, synthesis of acute phase proteins by the liver, increased vascular permeability, chemokine induction, and Band T- cell activation. The hallmark presentation of CAPS is recurrent attacks of fever of up to 103 degrees F, chills, rashes, joint pain, fatigue, and eye disor- W ders. The symptoms and signs are periodic and associated with stress, cold, and exercise as well as other less understood inducers. Even a mild cool breeze from an air-conditioned building or walking through the frozen food section of a grocery store can act as a trigger. Three types of CAPS The three specifically named types of CAPS in increasing severity are: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID). Each present early in life and can be associated with long term complications such as amyloidosis. Diagnosis is determined with a detailed history and physical exam and laboratory measurements of C-reactive protein and serum amyloid A. It is confirmed with genetic testing for the various mutations of the NLRP-3 gene. Occasionally this syndrome can exist without genetic confirmation. FCAS is also known as familial cold urticaria. Onset occurs during infancy and early childhood. Symptoms appear within hours of exposure to cold temperatures. The rash is the first symptom, followed by fever and joint pain. Episodes resolve within 24 hours if further cold exposure is avoided. MWS symptoms are first expressed in early childhood or adolescence and include hearing loss and amyloidosis in addition to all of the general symptoms described above. Acute symptoms last 24 to 48 hours. NOMID is also known as chronic infantile neurologic cutaneous articular syndrome. This version of CAPS is expressed shortly after birth Thomas Morrow, MD, is the immediate past president of the National Association of Managed Care Physicians. He has 23 years of managed care experience at the payer or health plan level. 56 MANAGED CARE / APRIL 2008
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