The use of topical calcineurin inhibitors (TCIs) was associated with an increased risk of developing lymphoma, but not cancer overall or skin cancer, according to the results of a meta-analysis published in JAMA Dermatology.

The U.S. Food and Drug Administration issued a black box warning for the potential for an increased risk of developing cancer with topical calcineurin inhibitors. “Given the long potential latency for cancer development, postmarketing studies with long follow-up are necessary to determine whether there is an association between TCIs and cancer,” the authors proposed.

The systematic review evaluated data from 408,366 patients from 11 studies published through 2020 that evaluated the use of TCIs and incidence of cancer or cancer mortality. The studies included 5 with a nonactive comparator or untreated control group, 2 that used a historical control group, and 4 that had an active comparator and included treatment with a topical corticosteroid. The meta-analysis included all studies that reported an effect estimate based on a placebo or active control. The TCIs were tacrolimus or pimecrolimus.

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In the 4 studies with a nonactive comparator, there was no increased risk of any cancer with TCI use (relative risk [RR], 1.03; 95% CI, 0.92-1.16; I2=10%). The results were similar in a sensitivity analysis for tacrolimus (RR, 0.93; 95% CI, 0.81-1.06), but there was a modestly elevated risk with pimecrolimus (RR, 1.16; 95% CI, 1.01-1.32). In 2 studies that included pediatric cohorts, there was no increased risk of any cancer (RR, 1.10; 95% CI, 0.59-2.06; I2=0%).

For specific cancer types, TCI use was not associated with an increased risk in developing skin cancers (RR, 0.72; 95% CI, 0.44-1.18; I2=57%), including melanoma or keratinocyte carcinoma. TCI use was associated with a decreased risk of melanoma (RR, 0.54; 95% CI, 0.33-0.86).

TCI use was associated with an increased risk of lymphoma. In the pooled analysis of 5 studies with nonactive comparators, the RR was 1.86 (95% CI, 1.39-2.49; I2=27%). The association remained when sensitivity analyses were performed.

TCI use also resulted in an increased risk of lymphoma in the 3 studies with topical corticosteroid comparators (RR, 1.35; 95% CI, 1.13-1.61; I2=0%). In 2 studies with pediatric groups, the association was not significant (RR, 1.78; 95% CI, 0.85-3.75; I2=35%).

The authors concluded that “The findings of this systematic review and meta-analysis suggest an association between TCI use and the risk of lymphoma, but not other cancers.” They added that “Combined with the low absolute risk of lymphoma, the potential increased risk attributable to TCI use for any individual patient is likely very small.”


Lam M, Zhu JW, Tadrous M, Drucker AM. Association between topical calcineurin inhibitor use and risk of cancer, including lymphoma, keratinocyte carcinoma, and melanoma: a systematic review and meta-analysis. JAMA Dermatol. Published online March 31, 2021. doi:10.1001/jamadermatol.2021.0345