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Topical immunomodulators are nonsteroidal agents that target the immune system for therapeutic effect in the skin. The macrolactams, pimecrolimus and tacrolimus, act as anti-inflammatory agents by binding immunophilin and inhibiting cytokine production. The imidazoquinoline amine, imiquimod, induces interferon (IFN) production and enhances immune responses, although several more potent analogs are under clinical investigation.

Topical Calcineurin Inhibitors

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Topical Calcineurin Inhibitors: Pimecrolimus and Tacrolimus at a Glance
  • Topical nonsteroidal anti-inflammatory agents.
  • US Food and Drug Administration approved for the short-term and intermittent long-term therapy of atopic dermatitis in patients older than 2 years.
  • Approved in Europe for twice weekly prophylactic therapy for atopic dermatitis in patients older than 2 years.
  • Extensively studied with an excellent record of short-term safety and efficacy when used appropriately.
  • Burning and stinging at the application site is the most common adverse event occurring in 10%–40%.
  • Theoretical risk of systemic immunosuppression and malignancy has resulted in the addition of a postmarketing, black-box warning label.
  • Widespread off-label use has been discouraged until long-term safety is more definitely established.

Intracellular signaling pathways are tightly controlled to maintain immune homeostasis. The nuclear factor of activated T cells (NFAT) family of transcription factors has emerged as a central regulator in immune signaling pathways that control lymphocyte activation and cytokine production.1 In the absence of receptor-mediated, calcium-dependent signaling, NFAT is sequestered in the cytoplasmic compartment in an inactive, phosphorylated state (Fig. 221-1). Signaling pathways emanating from antigen receptors induce calcium-dependent activation of calcineurin, which removes the phosphorylation from NFAT that leads to nuclear translocation and upregulation of proinflammatory gene expression. Tacrolimus and pimecrolimus turn off inflammation by interacting with FK-506 binding protein (FKBP). This drug-protein interaction prevents calcineurin from dephosphorylating NFAT, thereby inhibiting its nuclear translocation.2 The pleiotropic effects of calcineurin inhibitors include decreased T-cell proliferation and reduced inflammatory cytokine production of interleukin-2 (IL-2), IL-3, IL-4, IL-12, tumor necrosis factor, and IFN-γ.

Figure 221-1

Mechanism of action of calcineurin inhibitors. Ca = calcium; FKBP = FK-506 binding protein; NF-AT = nuclear factor of activated T cells.

Compared to cyclosporine, tacrolimus is 10–100 times more potent, has lower molecular weight, and penetrates the skin better. These enhanced pharmacological properties of tacrolimus provided a basis for experiments demonstrating topical inhibition of contact hypersensitivity and subsequent development as an ointment for treating atopic dermatitis.3,4 With topical tacrolimus therapy, more than 70% of patients have had moderate-to-excellent improvement in 3-week controlled trials, and 30%–40% have had greater than 90% improvement.5 In general, response to topical tacrolimus has been best observed in treating thinner skin areas such as the face and neck. During remissions, dosing may be reduced in frequency, but flares occur with discontinuance. Response is slow (over days to weeks), often incomplete on extremities (especially hands and feet), and in patients with lichenified ...

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