Imiquimod: A cytokine inducer

T he articles in this supplement address the use of topically applied imiquimod (Aldara, R-837, S-26308) for the treatment of various viral, malignant, and premalignant neoplasms and for the prevention of keloids. Costs to produce this supplement were underwritten by 3M Pharmaceuticals, the manufacturer of imiquimod. Many of the authors, including myself, have served as paid consultants for 3M Pharmaceuticals and many have received an honorarium and help in writing and submitting their articles for publication (from KPR, New York, NY). However, 3M Pharmaceuticals did not review the manuscripts or suggest changes to them, and all articles were peer reviewed. The studies presented here are preliminary. Much work must be done to establish the role and effectiveness of topical imiquimod cream in the treatment of these and other diseases. Studies need to define tumor types, duration of therapy, optimal frequency of application, cure rates, and side effects. Although these studies are case reports and summaries of small numbers of treated patients, most of the studies reported here involve two or more subjects. Anything can happen once, it seems, but when imiquimod successfully treats a number of patients with a specific condition, a coincidental association of applications with cure seems less likely than a cure resulting from true biologic actions. Imiquimod is an immune response modifier that helps eliminate external genital and perianal warts. Its mode of action is unique, because it does not directly kill the virus or blow up the virus-infected cell. Rather, imiquimod causes wart regression indirectly by inducing immune reactions and cytokine synthesis and secretion from epidermal keratinocytes, Langerhans’ cells, dermal lymphocytes, and especially macrophages and monocytes. Imiquimod’s immune-stimulating activities include cytokine and chemokine induction from monocytes and macrophages in vitro and in vivo, polyclonal B-lymphocyte activation in vitro and in vivo, and antiviral and antitumor activity in vivo.1-3 Imiquimod was marketed as a topical treatment for genital warts. In a randomized, double-blind study,4 209 patients applied either 5% imiquimod or vehicle placebo cream. At the 16-week end point, warts had disappeared in 54 of 90 patients in the treatment group (19 dropped out before 16 weeks). In contrast, complete resolution occurred in only 11 of 73 patients treated with vehicle control cream (27 dropped out). Furthermore, 39 of the treated patients remained wart-free for at least 12 weeks; the other 15 patients either were lost to follow-up or had recurrence. Adverse effects were minor and consisted mostly of erythema and erosions, although these were also seen with less frequency among control subjects. Only 4 of 327 subjects discontinued applications because of local skin or application site reactions. Other clinical trials have confirmed the efficacy of imiquimod in treating various types of warts.5,6 Some people believe that the drug acts as an irritant, inducing wart remission solely because of nonspecific inflammation under and around the warts. Although this is possible, the pharmacology of systemically administered imiquimod suggests a much more specific action. Imiquimod induces cytokines (Table I), including interferon alfa (IFN), interleukins 1, 5, 6, 8, 10, and 12, and tumor necrosis factor(TNF). This occurs not only in vitro after isolated peripheral blood mononuclear cells (lymphocytes and monocytes) are incubated with imiquimod but also in vivo when animals are fed imiquimod.7 This systemic effect suggests that induction of cytokine synthesis by imiquimod does not depend on irritation. Warts evade immune reactions that otherwise might lead to their elimination. The human papilloma virus (HPV) must infect basal keratinocytes to establish infection. HPV then lies relatively dormant in the basal layer of the epidermis. Only small From the Department of Dermatology, Mayo Medical School and Mayo Clinic Scottsdale. Funding sources: None. This article is part of a supplement sponsored by 3M Pharmaceuticals. Disclosure: Dr Dahl has worked for 3M as a paid consultant. Reprint requests: Mark V. Dahl, MD, Department of Dermatology, Mayo Clinic Scottsdale, 13400 East Shea Blvd, Scottsdale, AZ 85259. J Am Acad Dermatol 2002;47:S205-8. Copyright © 2002 by the American Academy of Dermatology, Inc. 0190-9622/2002/$35.00 0 16/0/126586 doi:10.1067/mjd.2002.126586