Risk of Lymphoma Following Exposure to Calcineurin Inhibitors and Topical Steroids in Patients with Atopic Dermatitis

Abstract

Systemic use of immunosuppressant agents increases the risk of lymphoma in transplantation. We performed a nested case-control study in the PharMetrics database to evaluate the association between topical immunosuppressants and lymphoma in a cohort of patients with atopic dermatitis. We identified cases of lymphoma and randomly selected four controls for each case, matched by length of follow-up. We used conditional logistic regression to calculate odds ratio (OR) and 95% confidence intervals (CIs) of the association between topical immunosuppressants and lymphoma. Two hundred and ninety-four cases of lymphoma occurred in 293,253 patients, 81 in patients younger than 20 years. The adjusted analysis yielded the following OR (95%CI) for: severity (OR 2.4; 95% CI 1.5-3.8), oral steroids 1.5 (1.0-2.4), "super potent" topical steroids 1.2 (0.8-1.8) , "low potency" topical steroids OR 1.1 (0.7-1.6); pimecrolimus 0.8(0.4-1.6), tacrolimus OR 0.8 (0.4-1.7), and concomitant topical steroids, pimecrolimus, and tacrolimus 1.0 (0.3-4.1). We did not find an increased risk of lymphoma in patients treated with topical calcineurin inhibitors. It is difficult to disentangle the effects of severity of disease on outcome versus the true effects of drugs. However, in the adjusted analysis, severity of AD was the main factor associated with an increased risk of lymphoma.

Study on Corticosteroids use Pattern in Dermatological Practice and Investigating Adverse Effect of Corticosteroids Including its Associated Factors

“…23,32 Topical corticosteroids, which are considered relatively safe, are also associated with various adverse effects as discussed above though they are preferred over systemic corticosteroids for dermatologic disorders. 7,[10][11][12] Our study revealed that adverse effects were significantly associated with the regular use of corticosteroids. This finding is in strong agreement with several other studies in which incidence of adverse effects were high with daily and long-term use of corticosteroids like increase in risk of bone fractures, restlessness, insomnia, mania, depression, cognitive defects, weight gain, thinning of skin etc.…”

“…Our finding is in consistence with several other studies where topical corticosteroids were preferred over systemic corticosteroids for dermatologic disorders. 7,[10][11][12] This might dose. Consistent with our findings, another study in patients with actinic keratosis reported higher levels of adherence to a once-a-day topical corticosteroid therapy, although rates of adherence declined over the treatment period.…”

Topical Calcineurin Inhibitors and Malignancy Risk

“…In the meta-analysis of the case-control studies the increased risk for lymphomas was insignificant (OR 1.18, 95% CI 0.94 -1.47) (43). Three of the studies involved in this meta-analysis indicated a significant association between severity of atopic dermatitis and lymphoma (21,22,45). In the cohort study by Margolis et al the RR of lymphoma in patients with severe AD was 1.95 (95% CI, 1.15 -3.12) (45) while in the two case control studies the adjusted OR varied from 2.4 (95% CI, 1.5 -3.8) to 3.72 (95% CI, 1.40 -9.87) (21,22).…”

“…Many opinion leaders and medical associations, including the American academy of allergy, asthma and immunology (AAAAI), American college of allergy, asthma and immunology (ACAAI), American academy of dermatology, canadian dermatology association (CDA), and Canadian society of allergy and clinical immunology (CSACI) released position statements, expressing disagreement about box warning, promoting the safety of the TCIs and demanding reconsideration of the alert (15)(16)(17)(18). In September 2010, the FDA released a comprehensive review of TCI safety summarizing data from six studies including more than 6 million patients (19)(20)(21)(22)(23)(24)(25)(26). Later on, in May, 2011 according to a total of 72 cases of malignancy that had been reported in children treated with TCI, the FDA issued an addendum (27,28).…”

Clinical correlations of recent developments in the pathogenesis of atopic dermatitis

“…176 A scientific consensus conference convened by the American Academy of Dermatology concluded there is no causal proof that topical calcineurin inhibitors cause lymphomas or nonmelanoma skin cancers. However, the prudent use of these agents is recommended, especially minimal use as second-line agents for recalcitrant AD.…”