Are Topical Calcineurin Inhibitors Really Such Demons?

Helper or Enemy?

Do you still remember what you were doing in the year 2000? If dermatology is your field, you might have been eagerly anticipating the market arrival of topical tacrolimus and pimecrolimus. These calcineurin inhibitors quickly became essential helpers in the fight against atopic dermatitis and other dermatoses. Despite the proven benefits for both adults and children with atopic dermatitis and positive experiences regarding their safety and tolerability, a few years after their market introduction, there was loud talk about their side effects. In the USA, they were even classified among drugs with a black box warning — a black-bordered warning about dangerous side effects that patients can find in the drug's leaflet. The content was downright scary — it warned about the risk of skin cancer and lymphomas. The use of these topical forms of medication subsequently plummeted dramatically.

The Drug Helps, the Box Stays

But let's continue reminiscing. In 2005, none of us knew that one day the iPhone would exist. In 2020, we spend a lot of time glued to our smartphones, and although our lives have transformed in this way, the black-bordered warning hasn’t changed at all.

Almost every dermatologist has personal experiences with these medications and probably knows of numerous clinical units where a therapeutic effect has been proven — for example, vitiligo, facial psoriasis, genital psoriasis, inverse psoriasis, seborrheic dermatitis, contact dermatitis, lichen planus and sclerosus, morphea, and cutaneous lupus. These drugs are commonly used for other dermatoses, even though their effect is not formally as well-proven — such as in cases of refractory granuloma faciale or leg ulcers.

Broad Anti-Inflammatory Effect

The mechanism of action of topical calcineurin inhibitors involves suppressing the production of pro-inflammatory cytokines. First, they bind to macrophilin 12 (also known as FKBP 12) in the cytoplasm of target cells, then inhibit the activation of mast cells and neutrophils. Pimecrolimus exerts its effect through T lymphocytes and mast cells, while tacrolimus also reduces the function of basophils and eosinophils, and induces apoptosis of Langerhans cells. This explains their broad anti-inflammatory effect. Rabbit model studies indicate that they might also help prevent the development of hypertrophic scars.

Safety, Tolerability, and Management of Adverse Reactions

Tolerance to these drugs is generally very good; only immediately after application do some patients feel burning, itching, or observe erythema at the application site — mainly adults, to a lesser extent children. Alleviating these symptoms can be achieved through the application of preparations that improve skin barrier function and cooling the topical calcineurin inhibitor before use.

Serious adverse events such as severe allergic reactions or acute renal failure are rare. More commonly, impetigo or herpetic eczema or trichomegaly may occur. Long-term, the risk of developing lymphoma is no higher than in the general population, and no causal relationship has been established between the risk of lymphoma and the application of topical calcineurin inhibitors.

Time Will Tell

What will it be like when dermatologists in 2040 look back at the year 2020? Will it be with smiles and a sense of satisfaction that topical calcineurin inhibitors have rid themselves of that sinister warning and perhaps even expanded their list of indications?

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Source: Heymann W. R. Topical tacrolimus topics. Dermatology World Insights and Inquiries 2020 Aug 26; 2 (34). Available at: www.aad.org/dw/dw-insights-and-inquiries/2020-archive/august/topical-tacrolimus