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We welcome the article by Lin et al,1 “Localized Pemphigus Foliaceus Induced by Topical Imiquimod Treatment,” the first case report of imiquimod-induced localized pemphigus foliaceus. Only 2 months after this first case report, a second one was published.2 We would like to address several aspects of the possible mechanisms involved in the induction of pemphigus foliaceus by topical imiquimod treatment. Pemphigus is generally considered to stem from a genetic predisposition to the disease triggered and/or exacerbated by one or more exogenous factors,3 including topical contact, in which case it is called contact pitalicigus.4 This subgroup of induced pemphigus can be elicited by a systemic effect via absorption or by direct alteration of skin structure that causes the formation of neoantigens and later pemphigus antibodies. Other possible mechanisms are activation of enzymes that cause keratinocyte disaggregation, inhibition of enzymes that cause keratinocyte aggregation, or generalized allergic reaction such as contact dermatitis or contact urticaria that leads to pemphigus.3 In their article, Lin et al1 refer to the production of interferon induced by the use of imiquimod. Topical imiquimod is known to induce the production of interferon alfa, tumor necrosis factor (TNF) α, interleukin (IL) 1, IL-1 receptor antagonist, IL-6, IL-8, IL-10, IL-12, and additional cytokines.5 Most of these cytokines can either induce pemphigus or are found in high levels in the serum of patients with pemphigus. Pemphigus vulgaris and pemphigus foliaceus have been reported to be induced by interferon alfa,6,7 and high interferon alfa levels have been reported in these diseases.8 Increased serum levels of TNF-α have been reported in pemphigus vulgaris and have been correlated with disease activity.9 Involvement of TNF-α has also been reported in pemphigus vulgaris acantholysis via urokinase plasminogen activator.10 Anti–TNF-α was recently reported to be effective in the treatment of pemphigus vulgaris.11 Pemphigus foliaceus has been shown to be associated with TNF-α gene polymorphism in position-308.12 High levels of IL-1 have been measured in patients with endemic pemphigus foliaceus.13 Interleukin 1 also plays a part in pemphigus vulgaris acantholysis via urokinase plasminogen activator.10 Increased serum levels of IL-6 have been reported in pemphigus vulgaris and have been correlated with disease activity.9 In contrast, IL-8 immunoreactivity was not altered in autoimmune bullous diseases, including pemphigus.14 Some studies have reported low or undetectable levels of IL-10 in serum samples of patients with pemphigus,15,16 whereas others report high IL-10 levels.17 Serum IL-12 levels in patients with endemic pemphigus foliaceus (fogo selvagem) were found to be increased.18 We conclude that topical imiquimod can induce contact pemphigus via the induction of production of several cytokines, among them interferon. Correspondence: Dr Brenner, Department of Dermatology, Tel Aviv Sourasky Medical Center, 6 Weizman St, Tel Aviv 64239, Israel (firstname.lastname@example.org). Financial Disclosure: None. References 1. Lin RLadd DJ JrPowell DJWay BV Localized pemphigus foliaceus induced by topical imiquimod treatment Arch Dermatol 2004;140889- 890PubMedGoogle ScholarCrossref 2. Campagne GRoca MMartinez 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;109224- 227PubMedGoogle ScholarCrossref 3. Brenner SMashiah JTamir EGoldberg IWohl Y PEMPHIGUS: an acronym for a disease with multiple etiologies Skinmed 2003;2163- 167PubMedGoogle ScholarCrossref 4. Brenner SWolf RRuocco V Contact pemphigus: a subgroup of induced pemphigus Int J Dermatol 1994;33843- 845PubMedGoogle ScholarCrossref 5. Sauder DN Immunomodulatory and pharmacologic properties of imiquimod J Am Acad Dermatol 2000;43S6- S11PubMedGoogle ScholarCrossref 6. Raanani PBen-Bassat I Immune-mediated complications during interferon therapy in hematological patients Acta Haematol 2002;107133- 144PubMedGoogle ScholarCrossref 7. Marinho RTJohnson NWFatela NM et al. Oropharyngeal pemphigus in a patient with chronic hepatitis C during interferon alpha-2a therapy Eur J Gastroenterol Hepatol 2001;13869- 872PubMedGoogle ScholarCrossref 8. Prummer OZillikens DPorzsolt F High-titer interferon-alpha antibodies in a patient with pemphigus foliaceus Exp Dermatol 1996;5213- 217PubMedGoogle ScholarCrossref 9. D'Auria LBonifati CMussi A et al. Cytokines in the sera of patients with pemphigus vulgaris Eur Cytokine Netw 1997;8383- 387PubMedGoogle Scholar 10. Feliciani CToto PWang BSauder DNAmerio PTulli A Urokinase plasminogen activator mRNA is induced by IL-1alpha and TNF-alpha in in vitro acantholysis Exp Dermatol 2003;12466- 471PubMedGoogle ScholarCrossref 11. Berookhim BFischer HDWeinberg JM Treatment of recalcitrant pemphigus vulgaris with the tumor necrosis factor alpha antagonist etanercept Cutis 2004;74245- 247PubMedGoogle Scholar 12. Torzecka JDNarbutt JSysa-Jedrzejowska A et al. Tumour necrosis factor-alpha polymorphism as one of the complex inherited factors in pemphigus Mediators Inflamm 2003;12303- 307PubMedGoogle ScholarCrossref 13. Rocha-Rodrigues DBPaschoini GPereira SAdos Reis MATeixeira Vde PRodrigues Junior V High levels of interleukin-1 in patients with endemic pemphigus foliaceus Clin Diagn Lab Immunol 2003;10741- 743PubMedGoogle Scholar 14. Bornscheuer EZillikens DSchroder JMSticherling M Lack of expression of interleukin 8 and RANTES in autoimmune bullous skin diseases Dermatology 1999;198118- 121PubMedGoogle ScholarCrossref 15. Baroni APerfetto BRuocco EGreco RCriscuolo DRuocco V Cytokine pattern in blister fluid and sera of patients with pemphigus Dermatology 2002;205116- 121PubMedGoogle ScholarCrossref 16. Veldman CHohne ADieckmann DSchuler GHertl M Type I regulatory T cells specific for desmoglein 3 are more frequently detected in healthy individuals than in patients with pemphigus vulgaris J Immunol 2004;1726468- 6475PubMedGoogle ScholarCrossref 17. Bhol KCRojas AIKhan IUAhmed AR Presence of interleukin 10 in the serum and blister fluid of patients with pemphigus vulgaris and pemphigoid Cytokine 2000;121076- 1083PubMedGoogle ScholarCrossref 18. Zeoti DMFigueiredo JFChiossi MPRoselino AM Serum cytokines in patients with Brazilian pemphigus foliaceus (fogo selvagem) Braz J Med Biol Res 2000;331065- 1068PubMedGoogle ScholarCrossref
Archives of Dermatology – American Medical Association
Published: Jul 1, 2005
Keywords: pemphigus foliaceus,imiquimod
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