Review
Imiquimod in dermatology: an overview Edith Hanna, MD, Rami Abadi, MD, and Ossama Abbas, MD
American University of Beirut-Medical Center, Beirut, Lebanon Correspondence Ossama Abbas, MD Department of Dermatology American University of Beirut Medical Center Riad El Solh St., PO Box 11-0236 1107 2020, Beirut Lebanon E-mail:
[email protected]
Abstract Imiquimod is an immune response modifier commercially available as a 3.75 and 5% cream. Topical imiquimod stimulates the innate and adaptive immune responses and induces cytokine production. This allows its use for the treatment of a wide variety of benign and malignant skin conditions due to its potential antiviral, antitumor, and immunoregulatory effects. Currently, topical imiquimod is US Food and Drug Administration (FDA)-approved for the treatment of anogenital warts, actinic keratosis, and superficial basal cell carcinomas. However, it has also shown a beneficial effect in the treatment of many other skin disorders. In this review, we describe existing evidence on the mechanism of action of topical imiquimod, its FDA-approved indications, off-label uses, and side effects.
Conflicts of interest: None.
Introduction In 1995, a new class of immunomodulating agents represented by the molecule imiquimod appeared on the market. Imiquimod (Aldara; 3M Pharmaceuticals Saint Paul, Minnesota, United States) is an immune response modifier, also referred to as S-26308 or R-837, with synthetic formula equivalent to (1-(2-methylpropyl)-1H-imidazo [4,5-C]quinolin-4-amine) and molecular formula of C14H16N4 (Fig. 1). It was first US Food and Drug Administration (FDA) approved for the treatment of external genital and perianal warts in 1997 and then consecutively approved for actinic keratosis (AK) and superficial basal cell carcinoma (BCC).1,2 It is commercially available as a 5 and 3.75% cream, though the latter is not universally available. Topically applied imiquimod stimulates the innate and adaptive immune pathways and induces cytokine production. This makes it an attractive option for treating a wide variety of both benign and malignant dermatologic pathologies due to its potential antiviral, antitumor, and immunoregulatory effects. In this review, we describe the existing evidence on the mechanism of action of imiquimod and its FDA-approved indications, off-label uses, and side effects. Mechanism of action The exact mechanism of action of imiquimod is largely unknown. However, animal and human studies have suggested that imiquimod is an effective antiviral and antitumor agent that augments both major divisions of the
immune system: the innate and acquired immune responses. Imiquimod-induced cytokines can stimulate the innate immune system through the production of interferon (IFN)-a, tumor necrosis factor (TNF)-a, interleukin (IL)-6, and IL-8.3,4 Imiquimod was initially shown to be protective against herpes simplex virus (HSV), cytomegalovirus, and arbovirus infection in mice.5,6 This was mainly attributed to its induction of IFN-a in both animal models and humans.1,2 In addition, imiquimod was used as an antitumor agent in multiple mouse tumor models, with IFN-a being largely responsible for its effects.7 In fact, studies done in human peripheral blood mononuclear cell cultures showed that imiquimod induced the production of a vast pool of cytokines including IFN-a, TNF-a, IL-1, IL-1RA, IL-6, IL-8, IL-10, IL-12 p40, granulocyte colony stimulating factor, granulocyte/macrophage colony stimulating factor, macrophage inflammatory protein, and macrophage chemotactic protein-1.8,9 As a Toll-like receptor (TLR)-7 and TLR-8 agonist, imiquimod was shown to induce these proinflammatory cytokines through activation of the central transcription factor, nuclear factor kappa-B (NF-jB).10 At least partially, the effect of imiquimod has recently been shown to be also mediated by the skin recruitment and activation of plasmacytoid dendritic cells (PDCs), which are a unique subset of dendritic cells known to be the main source of locally produced type I IFNs, including IFN-a.11 Owing to its expression of TLR7 and -9 in their endosomal compartments, PDCs, after imiquimod treatment, become activated leading to the induction of 831
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International Journal of Dermatology 2016, 55, 831–844
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Review
Imiquimod in dermatology
Figure 1 Imiquimod’s molecular formula of C14H16N4
Hanna, Abadi and Abbas
TLR7/MyD88 signaling pathway, which leads to increased IFN-a production. Briefly, imiquimod binding to TLR7 on PDCs (and to a lesser extent on other dendritic cells or macrophages) leads to TLR7-cytoplasmic portion interaction with MyD88, which in turn facilitates association of MyD88 with IL-1 receptor-associated kinase leading to the activation of TNF receptor-activated 6 and eventually stimulation of NF-jB-mediated signaling (Fig. 2). Interestingly enough, its proinflammatory activity was also attributed to TLR independent pathways, mainly adenosine A (2A) receptor signaling pathways and receptor independent reduction of adenylyl cyclase activity.12 On a side note, imiquimod use was also suggested to enhance Langerhans cell migration from skin to draining lymph nodes.13
Figure 2 Mechanism of action of topical imiquimod: being a TLR-7 agonist, imiquimod activates NF-jB, which induces various proinflammatory cytokines, including IFN-a, TNF-a, IL-6, and IL-8. In addition, imiquimod can enhance acquired immunity by indirectly stimulating the production of TH1 cytokine, IFN-c. Furthermore, imiquimod, at higher concentrations, induces apoptosis of tumor cells through activation of Bcl-2 proteins and caspase family of proteases. GCSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte– macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; MCP, monocyte chemoattractant protein; NK-jB, nuclear factor kappa-B; TH1, T-helper type 1; TLR, Toll-like receptor; TNF, tumor necrosis factor International Journal of Dermatology 2016, 55, 831–844
ª 2016 The International Society of Dermatology
Hanna, Abadi and Abbas
Imiquimod in dermatology
In addition to inducing IFN and other cytokines, imiquimod can also enhance acquired immunity by indirectly stimulating the production of the T-helper (Th) type 1 cytokine, IFN-c. IFN-a release, in response to imiquimod use, induces the IL-12 receptor b2 subunit on Th1 cells. Th1 cells then consequently respond to IL-12 by producing IFN-c.14,15 However, cytotoxic T cells and natural killer cells have been implicated in IFN-c production. Furthermore, imiquimod, at higher concentrations, was shown to induce apoptosis of tumor cells through activation of Bcl-2 proteins and the caspase family of proteases.12 Finally, imiquimod has also shown anti-angiogenic properties, which are due to the production of anti-angiogenic cytokines such as IFNs, IL-10, and IL-12, upregulation of endogenous anti-angiogenic mediators such as tissue inhibitor of matrix metalloproteinase, and downregulation of pro-angiogenic molecules such as basic fibroblast growth factor and matrix metalloproteinase 9.16 FDA-approved indications for imiquimod use in cutaneous disorders Initially, the FDA approved imiquimod for the treatment of anogenital warts, and it has been approved for the treatment of AKs on the face/scalp and superficial BCCs (Table 1).
Review
Basal cell carcinoma
Even though surgery is considered first-line treatment for BCC, many other therapeutic modalities can be used, including imiquimod.19,20 Imiquimod is currently FDA-approved for the treatment of truncal/extremity small (
