AD and lymphoma: Meds not the culprit

Toulouse, France - Treatments used to control acute flares of atopic dermatitis include topical and oral corticosteroids as well as the topical calcineurin inhibitors pimecrolimus and tacrolimus, which now carry a "black box" label warning mandated by the Food and Drug Administration because of possible cancer risks.

However, according to a recent study, it appears that severe atopic dermatitis (AD) itself - and not necessarily the use of oral corticosteroids - seems to be associated with an increased risk of lymphoma.

Atopic dermatitis affects approximately 20 percent of children and 1 percent to 3 percent of adults in developed countries. Though a childhood disease, atopic dermatitis persists through adulthood in up to 50 percent of cases. Intermittent treatment with topical steroids or topical calcineurin inhibitors is necessary to control acute flares of the disease.

"As the systemic use of these immunosuppressant agents is associated with an increased risk of lymphoma in transplantation patients, we wanted to determine if there was a risk of lymphoma following exposure to topical calcineurin and topical steroids in patients with atopic dermatitis," says Carle F. Paul, M.D., professor and chairman of the department of dermatology at Purpan University Hospital, Toulouse, France.

Dr. Paul says tacrolimus ointment and pimecrolimus cream have been available in the United States for the treatment of atopic dermatitis since December 2000 and 2001, respectively. Studies have shown that the long-term application of these topicals in mice skin was associated with the development of lymphoma.

"The clinical relevance of the animal findings is uncertain because the skin of mice is more permeable than that of humans and high systemic exposure following topical application in rodents has been documented, whereas exposure in humans after topical application of calcineurin inhibitors is minimal. Furthermore, cases of lymphoma have been reported in patients with topical calcineurin inhibitors used alone or in combination with topical corticosteroids," Dr. Paul tells Dermatology Times.

Dr. Paul and colleagues conducted a case-control study by using the PharMetrics database to determine lymphoma risk in atopic dermatitis patients using topical immunosuppressants. After identifying established cases of lymphoma, Dr. Paul matched each case by length and follow-up to four randomly selected controls. A univariate analysis was done (odds ratio and 95 percent confidence interval), as well as a multivariate analysis, which was adjusted for age, sex, comorbidities, specialty of the treating physician, severity of AD and the treatment used (tacrolimus, pimecrolimus, topical and oral corticosteroids).

Lymphoma risk linked to AD severity

"We found that there was no increased risk of lymphoma in patients treated with topical calcineurin inhibitors.

"However, this finding should be confirmed when longer exposures to these drugs are available. We did see, though, that the severity of atopic dermatitis was the main factor associated with an increased risk of lymphoma," Dr. Paul says.

In the study, 25 percent of the patients used topical steroids at AD index date compared to 3 percent and 1.5 percent using pimecrolimus and tacrolimus, respectively. During the follow-up period, approximately 50 percent of the patients used no medication, 40 percent only used topical steroids, 7.4 percent and 3.7 percent used pimecrolimus and tacrolimus, respectively, and 0.9 percent of patients were exposed to both calcineurin inhibitors.

Of the 293,253 patients (58.6 percent <20 years of age) included in the study, 294 cases of lymphoma were identified after the index date, 81 of which were in patients younger than 20 years of age. Dr. Paul says the number of lymphoma cases exposed to pimecrolimus, tacrolimus and both were 14, 11 and 5, respectively.

The type of lymphoma could not be identified in 66 percent of the cases, but in those that could be identified, 11.2 percent showed Hodgkin's disease and 22.8 percent, non-Hodgkin's lymphoma (B-cell, 4.4 percent and T-cell, 18.4 percent). All T-cell non-Hodgkin's lymphoma cases were mycosis fungoides except for one case of zary syndrome.