© 2003 Massachusetts Medical Society
Psoriatic skin and an immune synapse (Inset). (From T.S. Kupper, N Eng J Med, 349:1987–90, 2003.)
The red, cracked, and bleeding scales of psoriasis appear on the scalps, knees, elbows, and trunks of 2% of the global population. Psoriasis is more than the annoying skin condition portrayed in the 1960s-era advertisements bemoaning "the heartbreak of psoriasis." Understanding the immunological underpinnings of the disease has spawned new treatments and, in turn, response to treatments is revealing more about the pathology.
Although skin cells pile up abnormally in psoriasis, the root cause lies in an overzealous immune response. The telltale scales are not the cause, but the effect. "For years it was thought that in psoriasis, epidermal skin cell hyperproliferation was the key step. In the last decade, psoriasis has been recognized as due to overactive T cells," says Joel M. Gelfand, professor of dermatology at the...
THE MANY LAYERS OF PSORIASIS
BIOLOGIC DRUGS USED TO TREAT PSORIASIS
Drug
Amevive (alefacept)
Mechanism
Recombinant fusion protein; binds CD2 receptors on T cells
Psoriatic plaques are piles of keratinocytes that divide seven times too fast. Normally, cells in the basal layer divide and rise in 30 days. "In psoriasis, it can be 3 or 4 days," explains Ivor Caro, medical director of dermatology at Genentech in South San Francisco.
Past treatments have been either too harsh or too tame. Circa 1950, patients receiving the treatment of choice, arsenic, unwittingly provided data on poisoning. Various ointments soothed but didn't treat. In the 1970s, PUVA (ultraviolet) therapy declined in popularity because of skin cancer risk. Then the systemic and ultimately toxic agents, methotrexate and cyclosporine, treatments for cancer and organ transplant rejection, respectively, were tried. But the secrets of their success at first were elusive.1
"Methotrexate was thought to work because it is an anticancer drug that prevents cellular turnover. No one thought that it might work as an immunosuppressant," Caro says. The effectiveness of cyclosporine as an antirejection drug in the 1980s provided the first clue implicating deranged immunity. "That's when the whole paradigm changed," recalls Caro. Soon researchers discovered excess tumor necrosis factor α (TNF-α) and activated T cells in psoriatic plaques.
From this researchers could start developing a new model. Psoriasis arises from the skin's role as an immune system outpost. In the presence of a foreign antigen or autoantigen, skin cells secrete TNF-α, which stimulates maturation of dendritic cells. Naïve T cells encounter the antigen-presenting cells in a lymph node. Activated memory T cells return to the circulation. Should the antigen that provoked the cascade appear again, the T cells become reactivated and home to the skin where they release TNF-α.
LYMPHOMA LURKING
But as investigators pursue optimal drug protocols, a red flag looms: a proclivity for lymphoma in patients with psoriasis or rheumatoid arthritis. Gelfand and coworkers detected 276 lymphomas among 2,718 patients with psoriasis in a UK population,2 nearly triple normal risk. Other studies reveal an even higher lymphoma risk in patients with psoriasis who use systemic treatments such as cyclosporine or methotrexate. "The problem is to tease out whether the disease or the treatment increases the risk of lymphoma," says Gelfand. Dermatologists hope that the new drugs will have a lower lymphoma risk, Caro adds.
And so even with an expanded and more targeted antipsoriasis arsenal, the story continues. Sums up Gelfand: "Understanding the pathology of psoriasis is the reverse of the usual direction of bench to bedside. By studying the clinical outcomes associated with psoriasis, we may better understand the impact of immune dysregulation on health."
Ricki Lewis
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