PHILADELPHIA – New findings that show T-cell activation plays a critical role in the development of alopecia areata has opened new doors to treatment.
A report last year from a genome-wide association study involving 1,054 patients with alopecia areata (AA) and more than 3,000 controls, identified eight genes strongly linked to the disease ( Nature 2010;466:113-7 ). One of the gene’s codes for a ligand, ULBP3, appears in the dermal sheath of hair follicles in patients with AA. The ULBP3 ligand appears responsible for attracting the cluster of T cells that produce the characteristic histopathology of affected hair follicles, Angela M. Christiano, Ph.D., said at the meeting.
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New research into the genes that are linked to alopecia areata will lead to planned trials and a different approach to treatment.
"Normally the hair follicle is immune privileged, but when the ULBP3 ligand is increased, T cells attack" the follicle and cause its destruction and the hair loss that is pathognomonic for AA, said Dr. Christiano, professor of dermatology and of genetics and development at Columbia University Medical Center in New York.
The ULBP3 finding led to a search for possible treatments that could interfere with the T-cell attack, guiding Dr. Christiano and her associates to the drug abatacept (Orencia). The agent suppresses T-cell activation and activity and is approved for treating rheumatoid arthritis (RA) and juvenile idiopathic arthritis. Study results reported almost a decade ago showed that abatacept worked in a mouse model of AA, she said.
Testing of a drug such as abatacept represents a new direction for AA treatment, which until now has usually been treated with agents developed for psoriasis, a strategy that has been unsuccessful.
Dr. Christiano and her coinvestigators designed a pilot study to test the efficacy of abatacept in patients with moderately severe AA, 6-12 months after diagnosis. They set these parameters because the patients will have established disease that is unlikely to spontaneously remit, but not so severe as to be too advanced to respond to T-cell based treatment.
Their planned study will randomize 56 patients to either a subcutaneous injection of abatacept or placebo at baseline, weeks 2 and 4, and then every 4 weeks for five cycles for a total treatment duration of 6 months. The study’s primary endpoint will be a 30%-40% improvement on the severity of alopecia tool after the first 6 months of treatment, and then after an additional 6 months of untreated follow-up, she said in an interview.
Dr. Angela M. Christiano
"I don’t think we could have been more shocked by what we found" in the genetic study, said Dr. Christiano at the meeting, sponsored by the Drug Information Association. "We fully expected to be aligned with other skin autoimmune diseases, like psoriasis." Instead, the eight genes linked to AA closely overlapped with type 1 diabetes, RA, and celiac disease, disorders that "we never considered."
But like the ULBP3 ligand found in the hair-follicle dermal sheaths of patients with AA, these autoimmune diseases also feature upregulated ligands that attract T cells to cellular targets and cause the disease: synoviocytes in RA, gut epithelial cells in celiac disease, and pancreatic islet cells in a mouse model of type 1 diabetes.
Dr. Christiano said that she had no disclosures.