ARUBA, DUTCH CARIBBEAN – Calcineurin inhibitors – used largely off label for dermatologic conditions – should become a better-known part of the armamentarium, said Dr. Charles Ellis.
Calcineurin inhibitors work by preventing T-cell activation by blocking calcineurin through its inhibitor immunophilin, said Dr. Ellis, of the University of Michigan, Ann Arbor. Among the drugs in this class are cyclosporine, pimecrolimus, tacrolimus, and a therapy in development, voclosporin. Only pimecrolimus and tacrolimus are available in topical forms.
In the United States, oral cyclosporine is approved for psoriasis but is generally not marketed for the indication, he said. All of the other therapies are used off label, although oral tacrolimus and oral pimecrolimus have been shown to be effective against psoriasis in small studies. The drugs have proved useful for atopic dermatitis, pyoderma gangrenosum, lichen planus, and alopecia areata.
Cyclosporine should not be used for longer than 1 year because it can cause kidney dysfunction, so it is not recommended for psoriasis. And in alopecia, it usually stops working, so he said he generally will not start patients on the drug for this condition.
Voclosporin is being developed for psoriasis by the Canadian company Isotechnika. A phase III trial showed about a 50% improvement in Psoriasis Area and Severity Index (PASI-75) score by week 12; the effect continued through week 24 (Lancet 2008;371:1337-42).
However, patients taking voclosporin had double the rate of headache and gastrointestinal problems as did those on placebo, said Dr. Ellis.
The drug was to be reviewed by a Food and Drug Administration advisory panel in 2010, but the agency cancelled the meeting. In the United States, Isotechnika is seeking approval to treat infectious uveitis; the psoriasis indication is being pursued in Canada. The drug is also in development for prevention of kidney transplant rejection.
Topical calcineurin inhibitors offer a distinct advantage because they do not have the same systemic side effects seen with the oral formulations, said Dr. Ellis.
Pimecrolimus cream and tacrolimus ointment are approved as second-line therapies for short-term chronic treatment of moderate to severe dermatitis in nonimmunocompromised adults and children. They can be used in a standard regimen, with applications up to a week after clearing, or in a proactive regimen, using the topicals until there is clearance, and then applying twice weekly to all affected areas for a year.
Topical calcineurin inhibitors were initially embraced as a potentially safe alternative to topical steroids. But animal data has linked high exposure to lymphoma.
There are no human data to support this as a potential risk, but the FDA, in 2006, added a boxed warning for rare cases of malignancy, he said. "It’s a theoretical problem," but has nonetheless dampened enthusiasm for the drugs, said Dr. Ellis.
Even so, he said, in his practice, topical calcineurin inhibitors are not considered anathema. He uses them off label for psoriasis of the face, groin, and genitals; seborrheic dermatitis; pyoderma gangrenosum; mucosal lichen planus; and vitiligo, among other conditions.
When considering use, weigh the potency, the cost, and how long it takes to discuss the potential risks with patients, said Dr. Ellis.
Astellas Pharma, which markets tacrolimus ointment (Protopic) in the United States, is conducting a very long-term safety study of the therapy in children with atopic dermatitis, which might provide answers on the cancer risk, he said.
He disclosed serving as a consultant to Allergan and Ferndale Laboratories.