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Reports of immunologic reactions to imiquimod: An assessment of actinic keratoses and treatment concerns in this era of litigation lotto

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Reports of immunologic reactions to imiquimod: An assessment of actinic keratoses and treatment concerns in this era of litigation lotto
Craig G Burkhart MPH MD
Dermatology Online Journal 11 (3): 40

Medical College of Ohio at Toledo, Sylvania, Ohio.

Two recent case reports have dropped a 'bomb of concern' on dermatologists who have (or intend to use) imiquimod (Aldara®) for actinic keratoses and basal cell carcinoma [1, 2]. To rehash the first case, an 18-year-old female with severe HLA-B27 spondyloarthropathy was treated with imiquimod for vulvar warts leading to a significant flair of her arthritis requiring 3 months to dissipate despite significant augmentation of her immunosuppression [1]. The second case apparently generated antibodies to desmoglien 1 with skin lesions of pemphigus foliaceus at the sites of application of imiquimod [2].

Relative to the first case report, the first query would be whether it even makes sense that a topical agent could cause a systemic reaction. I would say possibly so. First, the drug is absorbed in small quantities systemically with 0.9 percent of a radiolabeled dose being recovered in the urine and feces. Second, the drug normally causes systemic adverse reactions such as flu-like symptoms, fatigue, headache, diarrhea, and myalgias in 1-2 percent of patients.

The second question is whether Aldara® could produce a response that could evoke the worsening or development of immunologic disease. Again, I would say possibly so. Imiquimod is the first of a new class of drugs referred to as the immune response modifiers. These drugs have effect on the innate and the acquired arms of the immune system. Moreover, these drugs activate and enhance the migration of Langerhans cells, which are the vehicle by which the epidermis sends the antigens to the regional lymph nodes resulting in antigen presentation to T-lymphocyte memory cells. From animal studies, systemic augmentation of the immune response has been seen in both herpes simplex infections[3] and murine tumor growth [].4

There is a basic problem issue when reading articles related to actinic keratoses. Namely, is there any universal definition clinically, histologically, or molecularly as to what an actinic keratosis is? To this query, I find no specific criteria for the designation of this entity, and find the diagnosis relatively subjective by all parameters. On point, I offer two separate studies funded by 3M Pharmaceuticals. In one study, the authors reported clearance of 30 percent of patients with the vehicle alone![5] Another study found only 3.2 percent of clearance by means of vehicle alone![6] Similarly, the package insert on one of the competing therapies for actinic keratoses, namely Solaraze® gel by Bioglan, reports clearance by vehicle alone to be from 0 percent to as high as 33 percent depending on their various studies. What gives? I believe that the major problem relates to delineating the proper diagnosis clinically and histologically.

Continuing on this definition issue, actinic keratoses have been often described clinically as skin-colored to reddish brown or yellowish black, ill-defined, round or irregularly shaped, macule or papule, with possibly a dry firmly adherent scale. Other authors place less significance on appearance and suggest that the actinic keratosis is often better appreciated by palpation than visualization, because of its distinctive roughened quality. In terms of size, they are usually stated to be 1-3 mm, but can be up to several cm. If that isn't confusing enough, there are at least nine separate clinical types described, namely, erythematous (desquamative-keratotic), keratotic popular, verrucous or papillomatous, pigmented, cutaneous horn, spreading pigmented, lichen planus-like, proliferative, and actinic cheilitis.

Moreover, even the histopathology is not specific, and the criteria for diagnosis can be subtle. One review on the topic by a dermatopathologist begins by stating that literally actinic keratosis can be defined as hyperkeratosis caused by ultraviolet light [7]. Moreover, the entity can be defined either by architectural characteristics or on cytological grounds. One is struck by not only the variability in histological features, but also by the relatively nonspecific criteria utilized in documenting the entity pathologically. Molecular studies also lack explicit measurement, as differences are noted by the various subtypes or actinic keratoses [8].

Indeed, the exact location of the cellular defect with actinic keratoses is not defined either. For my opinion, I believe that the defect must lie in the basal layer of the epidermis. The cellular atypia must begin with genetic alterations in the cell's formation which becomes more demonstrative with differentiation and keratinization. This is the reason for the frequent reoccurrence (months later) of actinics after adequate initial resolution by means of any of the present treatment modalities. This also results in the need for return visits, as the defect in the basal cells are not corrected with merely superficial apoptosis. Scientific evidence for this concept is found in studies involving clonal chromosome abnormalities in this disease entity [9]. This concept allows for field cancerization in which a large field of epithelium has undergone preneoplastic alterations due to long-term exposure to cancer-producing agents. This would explain the uncovering of 'subclinical' actinic keratoses by the inflammatory response noted with the use various treatment modalities. Inasmuch as carcinogenesis can be viewed as a multistep process, multiple genetic changes are necessary within the defective basal cells for tumor progression from an actinic keratosis to a squamous cell carcinoma. To be sure, squamous cell cancers display more unbalanced aberrations cytologically than actinics [9]. Nevertheless, the development of a neoplasm is the product of various functional relationships between genetic and oncogenetic factors and the immune response.

Another question is whether there any medical concerns related to the use of the other immunologic new therapy, namely the biologics. Although these drugs do not cause the frequency of systemic sequelae associated with the typical immunosuppressive agents, blocking the inflammatory and other physiological functions of tumor necrosis factors does, at least, theoretically increase the possibility of serious infection and malignancies. Moreover, reports are surfacing with the use of tumor necrosis factor alpha antagonists with various disease conditions including demyelinating and neurologic events, granulomatous infections, lupus-like illnesses, and acute development of skin cancers. One author has suggested that this "signals the need for closer observation of patients (on biologics) using frequent full-skin and nodal examinations such as those necessary for organ transplant recipients taking immunosuppressants."

In truth, there probably is only a minimal medical potential of imiquimod (Aldara) causing a systemic immunostimulation with negative adverse effects. However, until more is known, due caution may be reasonable in the use of Aldara in patients who have systemic immunological disease or impairment, organ transplantation, or who take immunosuppressant therapy. In this era of litigation lottery, this may be the most 'reasonable' approach to avoid the 'unreasonable' tort.


1. Benson E. Imiquimod: potential risk of an immunostimulant. Austral J Dermatol 2004;45:123-4.

2. Lin R, Ladd DJ, Powell DJ, Way BV. Localized pemphigus foliaceus induced by topical imiquimod. Arch Dermatol 2004;140:889-90.

3. Harrison CJ, Miller RL, Bernstein DI. Post therapy suppression of genital herpes simplex virus recurrences and enhancement of HSV-specific T-cell memory by imiquimod in guinea pigs. Antimicrob Agents Chemother 1994;38:2059-64.

4. Sidky YA, Borden EC, Weeks CE, Reiter MJ, Hatcher JF, Bryan GT. Inhibition of murine tumor growth b an interferon-inducing imidazoquinolinamine. Cancer Res 1992;52:3528-33.

5. Chen K, Yap LM, Marks R, Shumack S. Short course therapy with imiquimod 5% cream for solar keratoses: a randomized controlled trial. Austral J Dermatol 2003:250-5.

6. Lebwohl M, Dinehart S, Whiting D, Lee P, Tawfik N, Jorizzo J, Lee JH, Fox TL. Imiquimod 5% cream for the treatment of actinic keratosis: results from two phase III, randomized, double-blind, parallel group, vehicle-controlled trials. J Am Acad Dermatol 2004;50:714-21.

7. Cockerell CJ. Pathology and pathobiology of the actinic (solar) keratosis. Br J Dermatol 2003:149 (Suppl.66):34-36.

8. Stanimirovic A, Cupic H, Tomas D, Balicevic D, Kruslin B, Belicza M. Expression of p53, bcl-2 and growth hormone receptor in atrophic type of actinic keratosis. J Dermatol Science 2004;34:49-53.

9. Jin Y, Jin C, Salemark L, Wennerberg J, Persson B, Jonsson N. Clonal chromosome abnormalities in premalignant lesions of the skin. Cancer Genetics Cytogenetics 2002;136:48-52

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