Biologics signal new psoriasis strategies

Singapore - Recent clinical experience with biologic response modifiers suggests that chronic plaque psoriasis may not be represented by a single disease, but by several, and treating it effectively could require combinations of older and newer therapies.

"One of the problems we've had in treating psoriasis over the years is that we have systemic therapies for severe disease which can clear psoriasis, but not without some elements of risk. The Holy Grail is finding a treatment for psoriasis that's both effective and safe. With biologic treatments, we have an opportunity to come close to reaching that goal," says Christopher E. M. Griffiths, M.D., professor of dermatology and chair of the Dermatology Centre at the University of Manchester.

Current treatmentsAlefacept, efalizumabCurrent biologic treatments for psoriasis fall into two broad categories - those that target T-cells, namely alefacept (Amevive, Biogen Idec) and efalizumab (Raptiva, Genentech) and those that target TNF-alpha, namely infliximab (Remicade, Centocor) and etanercept (Enbrel, Amgen/Wyeth)."Alefacept is the first biologic which was specifically developed for treatment of psoriasis to have been approved by the FDA," Dr. Griffiths says. "The data so far looks good, but only about one in five patients have a significant clinical improvement" as a result of treatment.

"The side effect profile looks very good, and it appears as though efalizumab could be used for up to two or more years. So if it works for a patient, it could provide a long-term, relatively safe treatment," he says.

Etanercept, infliximabMore clinical data exists for TNF antagonists, as these drugs began as treatments for rheumatoid arthritis. Among TNF inhibitors, only etanercept has been approved for use with psoriasis in both the United States and Europe.

"Depending on the dose," Dr. Griffiths says, "between 30 percent and 50 percent of patients on etanercept can achieve significant clinical improvement. It seems to work a little better than (T-cell-targeting drugs). It also looks as though it can be used relatively safely over the long term."

Infliximab requires intravenous infusion, with loading doses of 5 mg/kg given three times over six weeks, followed by treatment every eight weeks thereafter.

"Compared with the other three drugs, it's much more effective. About 80 percent of patients have a very significant clinical improvement. And it works very quickly," he says.

However, concerns with TNF antagonists include the possibility that some patients can develop antibodies to infliximab, as well as infusion reactions.

"For rheumatoid arthritis, infliximab is often given concurrently with methotrexate," Dr. Griffiths says. "The reason for that is that methotrexate reduces the chance of developing antibodies to infliximab. And there are probably about 20 to 30 cases in the literature of demyelination, a multiple sclerosis-like syndrome, occurring with these drugs. But that's extremely rare. It's just a reflection of the fact that there's so much clinical experience with TNF antagonists."

Nevertheless, all biologic agents raise long-term concerns over increased risks for cancer, especially lymphoma and infections.

Integrating biologics"But there's very little doubt that the biologics are revolutionizing the way we manage psoriasis. Our goal is to work out what is the best way of integrating biologics, which are very expensive treatments, into our current practice and determining which patients will benefit most from biologics. One of the interesting insights that these drugs bring, particularly the two T-cell-targeting drugs, is that there's little knowledge as to whether a patient who doesn't respond to alefacept would respond to efalizumab and vice versa. It could well be that what these drugs are doing with their specificity of action is telling us that what we currently call psoriasis is probably several different, very clinically similar, related inflammatory skin diseases, and that these drugs are pulling out the different subsets," Dr. Griffiths says.

At the same time, there have been no controlled trials comparing biologics to each other or to systemic treatments such as methotrexate or cyclosporine.

For such reasons, he says, "biologic treatments are an exciting introduction to the world of biotechnology. They're going to make a difference in the way we treat psoriasis. But we shouldn't lose sight of the fact that we already have some pretty good treatments for psoriasis. It's a matter of trying to identify which patients are going to benefit most from using biologic therapy."

Pharmacogenetics attempts to do just that.