What is the risk of malignancy associated with topical calcineurin inhibitors (TCIs), such as pimecrolimus (Elidel) and tacrolimus (Protopic), in patients with atopic dermatitis?

From the Guidelines

The risk of malignancy associated with topical calcineurin inhibitors (TCIs) like pimecrolimus (Elidel) and tacrolimus (Protopic) in atopic dermatitis patients appears to be minimal based on current evidence. Despite initial concerns that led to black box warnings in 2006, long-term studies have not demonstrated a convincing causal relationship between TCI use and increased cancer risk 1. These medications work by inhibiting T-cell activation and inflammatory cytokine production, which theoretically could affect immune surveillance of malignant cells. However, the minimal systemic absorption of TCIs when applied topically significantly reduces this theoretical risk.

Key Considerations

• Patients should still follow recommended guidelines: apply TCIs only to affected areas, avoid use in immunocompromised individuals, minimize sun exposure on treated skin, and use them as second-line therapy after topical corticosteroids when possible.
• Children under 2 years should use these medications only under close medical supervision.
• Regular follow-up with a dermatologist is advisable for patients on long-term TCI therapy, but patients can be reassured that the actual cancer risk appears to be very low with appropriate use.
• The FDA's black box warning of an elevated risk of cancer with TCIs may worry some clinicians and patients, but several long-term safety studies suggest an increased relative risk of lymphoma with TCI use is not clinically meaningful 1.

Evidence Summary

• A 2023 study published in the Journal of the American Academy of Dermatology found that TCIs are a safe anti-inflammatory option for atopic dermatitis, particularly when there is concern for adverse events secondary to corticosteroid use 1.
• Another 2023 study published in the same journal found that the use of tacrolimus 0.1% and 0.03% ointments and pimecrolimus 1% cream is strongly recommended for adults with mild-to-moderate atopic dermatitis, with high certainty evidence 1.
• An older study from 2005 reported that the theoretical risk of malignancy with TCIs is based on animal data, but the doses at which cancers occur are substantially higher than the levels used in human subjects 1.

From the FDA Drug Label

WARNINGS WARNING Long-term Safety of Topical Calcineurin Inhibitors Has Not Been Established Although a causal relationship has not been established, rare cases of malignancy (e.g., skin and lymphoma) have been reported in patients treated with topical calcineurin inhibitors, including ELIDEL Cream. Prolonged systemic use of calcineurin inhibitors for sustained immunosuppression in animal studies and transplant patients following systemic administration has been associated with an increased risk of infections, lymphomas, and skin malignancies. While a causal relationship has not been established, rare cases of skin malignancy and lymphoma have been reported in patients treated with topical calcineurin inhibitors, including ELIDEL Cream

The risk of malignancy associated with topical calcineurin inhibitors (TCIs), such as pimecrolimus (Elidel) and tacrolimus (Protopic), in patients with atopic dermatitis is a concern due to the potential for immunosuppression. Although a causal relationship has not been established, rare cases of malignancy (e.g., skin and lymphoma) have been reported in patients treated with TCIs. Key points to consider:

• Continuous long-term use of TCIs should be avoided
• TCIs should not be used in immunocompromised adults and children
• The safety of TCIs has not been established beyond one year of non-continuous use 2

From the Research

Risk of Malignancy with Topical Calcineurin Inhibitors

The risk of malignancy associated with topical calcineurin inhibitors (TCIs), such as pimecrolimus and tacrolimus, in patients with atopic dermatitis has been a subject of concern and investigation.

• Studies have shown that the safety concerns regarding increased risk for lymphomas or skin cancer could not be confirmed, but will remain under careful observation 3.
• The FDA issued "black box" warnings for pimecrolimus cream and tacrolimus ointment in 2005 due to potential safety risks, including skin cancers and lymphomas, but current data do not support these concerns 4.
• A comprehensive body of evidence from clinical studies, post-marketing surveillance, and epidemiological investigations does not support potential safety concerns, including the risk of skin malignancy and lymphoma 5.

Long-Term Risk of Skin Cancer and Lymphoma

• A cohort study found little evidence associating use of topical calcineurin inhibitors with skin cancer and lymphoma, but confounding by indication, surveillance bias, and reverse causation may have influenced these results 6.
• The study found that incidence rate ratios for tacrolimus and pimecrolimus versus corticosteroid users in adults were generally less than 1 for most types of cancer, with some exceptions, such as cutaneous T-cell lymphoma and nonmelanoma skin cancer 6.
• The public health impact of these excess risks would be low and confined to the first years of exposure, even if causal 6.

Treatment Recommendations

• Topical calcineurin inhibitors are safe and efficacious in atopic dermatitis and can be used advantageously in problem zones, such as the face 4.
• TCIs should have defined roles in AD management, with TCIs favored for sensitive skin areas and instances where topical corticosteroids have proven ineffective, thereby minimizing the risk of adverse effects with both drug classes 7.
• The lymphoma incidence in the topical pimecrolimus-exposed population is up to approximately 54-fold less than that seen in the general US population, based on post-marketing surveillance of spontaneous, literature, and solicited reports 7.