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When George Martin, M.D., was doing his dermatology residency at UCLA in the mid-1980s, psoriasis was considered a disorder of keratinization.
“We treated patients' moderate-to-severe disease with topical steroids, tar preparations, sunlight and various forms of ultraviolet light-UVB boxes and photochemotherapy, or PUVA. It was pretty archaic by today’s treatment standards,” says Dr. Martin, who practices in Maui, Hawaii, is founder and program chairman of Maui Derm meetings and medical board member of the National Psoriasis Foundation.
While dermatologists at the time could effectively treat psoriasis patients’ skin, scientists would discover during the decades to follow that the disease and treatment were far more complicated.
Kreuger JG and Gottlieb AB at Rockefeller University in New York, NY, demonstrated in a paper published in 1990 that psoriasis was likely driven by inflammation, specifically T-cells,1 according to Dr. Martin.
Methotrexate was approved for the treatment of psoriasis in the 1970’s, but its widespread adoption for the treatment of severe psoriasis was slow to gain traction. The recognition of Krueger’s and Gottlieb’s findings spurred more widespread use of methotrexate, as well as the investigation of cyclosporine as a systemic therapy, leading to the FDA’s approval of cyclosporine for psoriasis treatment in 1997.
More than skin deep
Around 2006, researchers began to uncover that this inflammatory disorder was not confined to the skin. Rather, it’s a systemic disorder, with 20% to 30% of patients developing psoriatic arthritis. Psoriasis patients, according to Dr. Martin, are at higher risk for numerous comorbidities, including cardiovascular events, metabolic syndrome and kidney disease.
“The life expectancy of psoriasis patients is about five years shorter than cohorts,” Dr. Martin says.
Alefacept (Amevive, Biogen Idec) and efalizumab (Raptiva, Genentech), therapies that affected T-cell activation and T-cell migration, came onto the scene in the early 2000s but fell by the wayside, making room for the tumor necrosis factor (TNF) inhibitors-the next big wave in psoriasis therapy.
TNF inhibitors entered dermatology via impressive outcomes in rheumatology, according to Dr. Martin. The options include etanercept (Enbrel, Amgen, approved for psoriasis in 2004), infliximab (Remicade, Janssen, 2006) and adalimumab (Humira, Abbvie, 2008).
Last 15 years
Anti-TNF therapy paved the way for discovering the roles of other treatment targets, including the roles of interleukin (IL-) 23 and IL-17.
“The recognition of IL 17 was a major inflammatory driver in the skin led to the development of the IL-17 inhibitor family. Additionally, the recognition of the importance of IL-23, which is often referred to as the ‘master cytokine,’ in the pathogenesis of psoriasis, led to targeted therapy initially with ustekinumab [FDA approved for psoriasis in 2009], an IL 12/23 blocker,” Dr. Martin says.
Treatment continues to progress with the introduction and approval of three specific IL-23 blockers.
“What’s impressive about the IL-23 pathway is its long-term efficacy. Following loading doses, maintenance drugs can be administered every 8 to 12 weeks. And following cessation of the therapy, there’s a durability of response that last months after the last injection,” Dr. Martin says. “IL-23 inhibitors are also moderately effective in treating psoriatic arthritis.”
There’s more good news. Drugs that inhibit IL-17 not only treat psoriasis but also psoriatic arthritis.
Biologics weren’t the only big news in the last 15 years. In 2014, the FDA approved a breakthrough small molecule therapy apremilast, phosphodiesterase 4 (PDE4) inhibitor, for psoriasis and psoriatic arthritis.
“Apremilast doesn’t possess the same efficacy of the biologic agents in the treatment of psoriasis, but it’s a safe alternative as a therapeutic bridge that fits between topical therapy and a biologic agent,” he says.
Today: Enter JAK inhibitors
The psoriasis drug pipeline is also focused on small molecules, particularly the Janus kinase (JAK) inhibitors. While tofacitinib, approved for psoriatic arthritis, did not clear the FDA for psoriasis due to safety concerns, studies showed the 10mg twice daily dose had similar efficacy to etanercept, according to Dr. Martin.
“Recently phase 2 data for tyrosine kinase 2, or TYK2 inhibitors, has demonstrated remarkable efficacy. We’re waiting for phase 3 results,” he says. “TYK2 inhibitors are inhibitors of the JAK pathway that link the IL-12/23 pathway through gene transcription. TYK2 inhibitors block that critical pathway.”
From skin saving to potentially life saving
Dr. Martin says that dermatologists used to treat a systemic disease with topical therapies.
Sadly, many dermatologists still practice that way, he says.
Now, dermatologists have the knowledge and therapies to not only improve psoriasis and psoriatic arthritis symptoms, which leads to a better quality of life, but there’s hope that treating the disease systemically decreases the risk for cardiovascular and other comorbidities. Biologic agents might help improve overall survival.
That remains to be proven in large, prospective well controlled studies, Dr. Martin says. But research is strongly pointing in that direction.
1 Krueger JG, Krane JF, Carter DM, Gottlieb AB. Role of growth factors, cytokines, and their receptors in the pathogenesis of psoriasis. J Invest Dermatol. 1990;94(6 Suppl):135S-140S.
George Martin, M.D., founder and program chairman of Maui Derm meetings and medical board member of the National Psoriasis Foundation, practicing dermatologist, Maui, Hawaii.