Touching on contact pemphigus and pemphigus-like eruptions due to imiquimod
By Warren Heymann, MD
June 2, 2021
Vol. 3, No. 22
Most astute medical dermatologists are aware of drug-induced pemphigus, but many (including myself) may not be as familiar with topical medications being the responsible culprits. This commentary will focus on imiquimod-induced pemphigus and pemphigus-like eruptions (PLE).
My curiosity was piqued by the case of a 5-year-old girl treated for molluscum contagiosum on her legs with 5% imiquimod cream for 2 months prior to the appearance of a bullous eruption on her scalp, face, and upper trunk. Clinically, the lesions resembled bullous impetigo. Histologically, subcorneal acantholysis (a superficial pemphigus pattern), spongiosis, neutrophils and eosinophils were observed; direct and indirect immunofluorescence studies (DIF, IIF) were negative, as were serum antibodies for desmogleins 1 and 3. Prior to the biopsies, she was treated for presumed bullous impetigo with multiple antibiotics without observed improvement; following the biopsy, she responded rapidly to the discontinuation of imiquimod and the administration of prednisolone followed by dapsone. The authors concluded that their patient had a PLE induced by imiquimod by a mechanism distinct from the classical antibody-mediated pathway. (1)
(As an aside, Zhong et al  note that their case is an affirmation that imiquimod should not be prescribed for mollluscum contagiosum, as it is neither effective nor safe. ).
Campagne et al were the first to observe a localized PLE caused by imiquimod. It was prescribed for high-grade squamous cervical, vaginal, and vulvar intraepithelial neoplasia. Although it successfully resolved her HPV-induced lesions, she developed vulvar bullae demonstrating suprabasal acantholysis (pemphigus vulgaris histology) that responded to topical clobetasol. (3) It cannot be determined if this was pemphigus or a PLE only because immunofluorescence studies were not obtained. Bauza et al reported the case of a 60-year-old woman who, after application of imiquimod cream to 2 large superficial basal cell carcinomas, developed a PLE (with the histology of pemphigus vulgaris but negative DIF) both at and distant from the application site. (4)
Lo Schiavo et al reported a case of vulvar pemphigus vegetans (confirmed by histology, DIF, IIF and serology) in a 54-year-old woman with florid HPV papillomatosis, developing after 2 months of topical imiquimod. She responded to systemic steroids, topical clobetasol, with azathioprine for maintenance. The authors used the term “contact pemphigus,” (5) a term first coined by Brenner et al. (6)
Lin et al were the first to report pemphigus foliaceous (documented histologically including DIF) at the site of application of imiquimod in a 53-year-old woman with a history of multiple keratinocyte carcinomas. (7) The problem with this report is that the lesions in question were presumed keratinocyte carcinomas which were not biopsied — the possibility (albeit unlikely) that this was pemphigus foliaceus from the start cannot be ruled out. Sebaratnam et al reported a recurrence of documented pemphigus foliaceus following the use of imiquimod for a superficial basal cell carcinoma in a 52-year-old woman. Her history was remarkable for systemic lupus erythematosus and rheumatoid arthritis — her pemphigus foliaceus had been in remission for 3 years; within a week of imiquimod use, vesicles appeared on the face and forearms. (8) Most recently Shiraishi and Sayama reported a case of biopsy and immunologically-confirmed pemphigus foliaceus, with local and distant lesions, following the use of imiquimod for actinic keratoses in a 61-year-old man. His lesions rapidly responded to imiquimod discontinuation and the administration of systemic steroids. (9)
“Contact pemphigus” was conceptualized by Brenner et al in 1994, when the authors reviewed the literature on the topic, beginning with the first case attributed to tincture of benzoin, and other cases with pesticides, chromium sulfate, and feprazone suppositories. The authors noted that pemphigus may be induced by drugs, physical agents, infections, or neoplasms — contact with a responsible agent could alter epidermal structure forming a neoantigen or directly activate enzymes affecting keratinocyte adhesion. (6)
Far better recognized is drug-induced pemphigus caused by a combination of biochemical interactions and aberrant stimulation of host B cells producing intracellular IgG autoantibodies directed against the desmogleins or other pathomechanisms. The inciting medications can be classified based on their chemical structure, with the main groups being thiol drugs containing a sulfhydryl (-SH) group (notably penicillamine and captopril), phenol drugs, and non-thiol/phenol drugs. Thiol drugs are the most common cause of drug-induced pemphigus, inducing pemphigus by forming disulfide bonds that inhibit keratinocyte adhesion and/or affect plasminogen activator. (10)
Imiquimod is an imidazoquinolone amine, serving as a ligand for Toll-like 7 and 8 receptors, which stimulate innate and acquired immune responses. Imiquimod induces the local production of interferon (IFN)-alpha which is associated with the induction and maintenance of autoreactive B cells, which, in turn, have the potential to induce pemphigus antibodies in genetically predisposed patients, leading to classical pemphigus variants. Additionally, imiquimod also induces the production of other cytokines, such as TNF-alpha, interleukins-1, 6, 8, 10, and 12, and interleukin-1 receptor antagonist. Presumably these cytokines may provide additional pathways through which imiquimod induces pemphigus or PLE. (9)
In conclusion, imiquimod has the potential to induce pemphigus (vulgaris, vegetans, and foliaceus) and pemphigus-like eruptions, by classical immunological and/or alternative pathways. These adverse reactions may be local or extend beyond the site of imiquimod application. Cases characteristically respond to discontinuation of imiquimod combined with steroid therapy. Further study of these cases may yield insights to pemphigus pathogenesis, leading to novel therapeutic horizons.
Point to Remember: Think of “contact” pemphigus or pemphigus-like eruptions in patients treated with imiquimod who present with erosive lesions at, or distal to, the site of application of the drug. Discontinuation of imiquimod combined with steroid therapy is first-line management.
Our expert's viewpoint
Dedee F. Murrell
Professor and Chair, Department of Dermatology, St George Hospital, University of NSW, Sydney, Australia
Whenever I see a case of pemphigus, I think about what could have triggered this case in the particular patient. There are a number of environmental triggers in genetically susceptible patients which can do this, including, stress, medications, pesticides, and radiation; other exposures are less clear. (11, 12) Among these, contact pemphigus is relatively rare — the first case I diagnosed was the lady with pemphigus foliceus (PF) referred to above (8) who had been in complete remission for 1 year before her superficial basal cell carcinoma was treated with imiquimod. I was not aware until then that imiquimod could trigger pemphigus, nor that it could worsen other autoimmune diseases, including rheumatoid arthritis. As my PF patient developed the blistering in sites distal to the BCC it was obvious that her pemphigus was back. We postulated that the mechanism was by Toll-like receptor 7 activation and triggering of the innate immune system of macrophages, dendritic cells, and keratinocytes, producing cytokines such as interferon alpha, TNF alpha and IL-6. Finding that these cytokine pathways can trigger pemphigus flares suggests alternative avenues for the management of pemphigus. (13)
Ever since then I have not used imiquimod in patients with autoimmune conditions. When you see a patient with new onset blistering there are many disorders in the differential diagnosis, including viral and other infections, severe allergic contact dermatitis; autoimmune blistering disease is lower down the list of possibilities. If you are able to identify a trigger, such as contact pemphigus or drug-induced pemphigus, and withdraw it as soon as possible, there is a higher chance of the patient going into remission. Since dermatologists use imiquimod in everyday practice, it is important for us to be aware of these rare possibilities.
Zhong CS, Hasbun MT, Jones KM, Schmidt BAR, Hussain SH. Pemphigus-like eruption as a complication of molluscum contagiosum treatment with imiquimod in a 5-year-old girl. Pediatr Dermatol 2020; 37: 379-380.
Katz KA, Williams HC, van der Wouden JC. Imiquimod cream for molluscum contagiosum: Neither safe nor effective. Pediatr Dermatol 2018; 35: 282-283.
Campagne G, Roca M, Martinez A. Successful treatment of a high-grade intraepithelial neoplasia with imiquimod, with vulvar pemphigus as a side effect. Eur J Obstet Gynecol Reprod Biol 2003; 109: 224-227.
Bauza A, Del Pozo LJ, Saus C, Martin A. Pemphigus-like lesions induced by imiquimod. Clin Exp Dermatol 2009; 34: e60-62.
Lo Schiavo A, Sangiuliano S, Puca RV, Brunetti G, et al. Contact pemphigus: A side effect of imiquimod therapy. Int J Dermatol 20087; 47: 765-767.
Brenner S, Wolf R, Ruocco V. Contact pemphigus: a subgroup of induced pemphigus. Int J Dermatol1994;33: 843–845
Lin R, Ladd DJ Jr, Powell DJ, Way BV. Localized pemphigus foliaceus induced by topical imiquimod treatment. Arch Dermatol 2004; 140: 889-890.
Sebaratnam DF, Martin LK, Rubin AI, Tran K, et al. Reversible relapse of pemphigus foliaceus triggered by topical imiquimod suggests that Toll-like receptor inhibitors may be useful treatments for pemphigus. Clin Exp Dermatol 2011; 36: 91-93.
Shiraishi K, Sayama K. Pemphigus foliaceus induced by topical imiquimod treatment. Int J Dermatol 2018; 57: e155-e157.
Pile HD, Crane JS. Drug induced pemphigus. StatPeals [Internet]. Treasure Island (FL): StatPearls Publishing Jan 2020.
Schmidt E, Borradori L, Sprecher E, Marinovic B, Sinha A, Joly P: Genetic and Environmental Risk Factors of Autoimmune Bullous Diseases. In Blistering Diseases: Clinical features, pathogenesis, treatment. Springer 2015, Pages 131-141.
Vodo D, Sarig O, Sprecher E. The genetics of pemphigus. Series on Blistering Diseases. Front Med 14 August, 2018 , doi.org/10.3389/fmed.2018.00226
Temel, AB & Murrell DF (2019). Pharmacological advances in pemphigus. Current opinion in pharmacology. 46. 44-49. 10.1016/j.coph.2019.01.001.
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