Genetic and pharmacogenomic research has resulted in targeted treatments for diseases affecting the skin, ranging from Marfan syndrome to melanoma, said an expert Friday at the 74th Annual Meeting of the American Academy of Dermatology, in Washington D.C.
Stephen I. Katz, M.D., Ph.D."In the area of pharmacogenomics, we now know a lot about how one's genetic makeup affects how we respond to certain medications," said Stephen I. Katz, M.D., Ph.D. "The best example involves toxic epidermal necrolysis/Stevens-Johnson syndrome (TEN/SJS): the Han Chinese face a 1,000-fold to 10,000-fold greater risk of developing TEN/SJS as a reaction to certain medications if they have the human leukocyte antigen allele HLA-B*1502. "In some countries, regulators have mandated that people must be tested for this allele before taking certain drugs." Dr. Katz is director of the National Institutes of Health’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS).
Regarding rare diseases, he adds, "It's astounding — we never thought we could biochemically influence some diseases involving the skin structure. Now we know what genes are involved in Marfan syndrome, for example. A mutation in the fibrillin-1 gene affects the transforming growth factor beta (TGF-β) pathway, making people much more sensitive to the effects of TGF-β. As a consequence, drugs that inhibit TGF-β binding have been developed or were already on the market. Angiotensin inhibitors have an effect on TGF-β and can prevent aortic dilatation, which predisposes patients to aortic coarctation."
Over the past decade, researchers also have discovered how microbial flora in the human microbiome impact health and disease. "We've known for many years that superinfection exacerbates atopic dermatitis (AD). Investigators are now studying how microbial flora on the skin and in the gut may be affecting disease. Does the gut flora have anything to do with AD expression? And is there a way to replenish the normal flora in AD?"
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The microbiome also influences human physiology, determining whether a person is fat or thin, Dr. Katz says. It can also be manipulated to prevent or treat Clostridium difficile infections by performing fecal transplants in patients with recalcitrant disease.
Autoinflammatory diseases defined by NIH experts in the past 15 years include familial Mediterranean fever (FMF), neonatal-onset multi-system inflammatory disease (NOMID), deficiency of the interleukin (IL)-1 receptor antagonist (DIRA) and others.
"These diseases are characterized by neutrophilic inflammatory infiltrates in the skin. Not only have the genes responsible for these diseases been defined, but most have been shown to involve the IL-1 pathway. We also have treatments for many of these diseases." These treatments work by inhibiting the IL-1β pathway, Dr. Katz says.
In psoriasis, elucidation of the IL-12 and -23 pathways has driven the development of several new biologic drugs.
"Understanding the inflammatory and immunological pathways has led pharmaceutical companies to develop highly specific drugs that are beneficial and, so far, relatively safe." However, Dr. Katz says, one company had to halt development of an antibody that targeted the IL-17A pathway when the company identified an association with depression and suicide. This association is still being scrutinized, he says.
"Five years ago," he adds, "metastatic melanoma was a death sentence. Nowadays, if we know the mutation in the metastatic melanoma, there are currently three drugs on the market that will interfere with certain transcriptional pathways such as the BRAF pathway and the MEK pathway. In addition, we have checkpoint inhibitors, which are humanized monoclonal antibodies used to enhance the immune response to melanoma."
Examples include anti-cytotoxic T-lymphocyte associated protein 4 (CTLA4), which enhances the presentation of tumor-associated antigens to T cells by dendritic cells. Similarly, anti-programmed cell death protein 1 (PD1) blocks the inhibition of T cells' killing of tumors, thereby enhancing the immune response, he says.
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Thanks to combinations of drugs and monoclonal antibodies, he says, "We in medicine have been able to make outcomes for patients with melanoma a little brighter. People are living significantly longer than the six to 10 months that was previously typical after a diagnosis of metastatic melanoma."