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confirmed by biopsy&#46; Imiquimod 5&#37; cream was prescribed for topical treatment&#44; five times per week&#46; After two weeks&#44; fever&#44; diarrhea&#44; myalgia&#44; and fatigue associated with exulceration of the initial lesion and onset of erythematous papulosquamous lesions on the scalp&#44; face&#44; and trunk began &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Treatment was discontinued&#46; Laboratory tests did not show any changes&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Despite the introduction of topical corticoids and oral antihistamines&#44; there was worsening of the eruption with craniocaudal sense and confluence of the lesions &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Biopsy of the lesions was performed and prednisone was started&#44; at 40<span class="elsevierStyleHsp" style=""></span>mg per day&#46; In the histology&#44; psoriasiform hyperplasia of the epidermis&#44; hyperparakeratosis alternated with orthokeratosis&#44; areas of hypogranulosis&#44; moderate superficial perivascular lymphohistiocytic infiltrate&#44; and foci of acantholytic dyskeratosis were observed &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">Four weeks after the onset of the eruption&#44; the patient was erythrodermic&#44; with areas of healthy skin associated with ectropion and orange palmoplantar keratoderma&#46; The clinical&#8211;histopathological diagnosis of PRP was defined&#46; Methotrexate was introduced orally at a dose of 15<span class="elsevierStyleHsp" style=""></span>mg per week and the oral corticosteroid was withdrawn gradually&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Serologic tests &#40;HIV&#44; hepatitis B and C&#41; were negative and abdominal ultrasound and chest X-ray were normal&#46; There was a progressive improvement in the erythrodermic condition after three months&#44; when methotrexate reduction was started&#46; The cutaneous surface was normalized nine months after the onset of the disease &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Discussion</span><p id="par0035" class="elsevierStylePara elsevierViewall">PRP is a rare disorder of keratinization&#46; The classic form &#40;Type I&#41; occurs in adults of both sexes&#44; with eruption of follicular papules that converge in scaly erythematous-orange plaques&#44; with craniocaudal spreading&#44; usually evolving to erythroderma with healthy skin islets and palmoplantar keratoderma&#46; Also described are atypical forms&#44; the involvement of children&#44; and a form associated with HIV infection&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Histopathology shows psoriasiform hyperplasia&#44; follicular hyperkeratosis&#44; hyperparakeratosis alternated with orthokeratosis&#44; and superficial perivascular lymphocytic infiltrate&#46; The occurrence of acantholytic dyskeratosis&#44; as in the present case&#44; is common and may induce diagnostic errors due to histological similarity with Grover&#39;s&#44; Darier&#39;s&#44; or pemphigus&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> In 1997&#44; Magro and Crowson suggested that the presence of acantholytic dyskeratosis is frequent and may serve as a predictive factor of PRP in the histopathological differentiation with psoriasis&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Despite the unclear etiology&#44; one of the main hypotheses for PRP is an exacerbated immune response to antigenic triggers&#46; Viral&#44; bacterial&#44; neoplastic&#44; and autoimmune diseases &#8211; as well as immune-modifying drugs &#8211; are believed to play a role in its pathogenesis&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1&#8211;3</span></a> The T-helper 1 &#40;Th1&#41; immune response pathway is activated&#44; with increased proinflammatory cytokines such as tumor necrosis factor-&#945;&#44; interferon-&#945;&#44; interleukin-1&#44; interleukin-6&#44; interleukin-17&#44; and interleukin-23&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Activation of the Th1 response would also be responsible for the poor vitamin A action found on the skin affected by PRP&#46; Inflammatory cytokines alter the signaling of retinoid keratinocyte receptors&#44; leading to abnormal keratinization and epidermal hyperplasia&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> Among the therapeutic options for PRP are oral retinoids&#44; methotrexate&#44; phototherapy&#44; and biological agents with anti-tumor necrosis factor-&#945;&#44; anti-interleukin-17&#44; and anti-interleukin-23 activity&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1&#44;2</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Imiquimod is an immune response stimulating agent&#44; indicated for topical treatment of actinic keratosis&#44; superficial basal cell carcinoma&#44; and condyloma acuminatum&#46; In recent years&#44; its use has expanded to treat other off-label dermatological conditions&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">As a toll-like receptor-7 &#40;TLR-7&#41; agonist observed in the cells of the innate immune system &#40;dendritic cells and macrophages&#41; and keratinocytes&#44; imiquimod performs antitumor and antiviral actions&#46; Its binding to TLR-7 promotes increased production of Th1 proinflammatory cytokines such as tumor necrosis factor-&#945;&#44; IFN-&#945;&#44; interleukin-1&#44; interleukin-6&#44; and interleukin-8&#44; among others&#44; as well as inhibiting the anti-inflammatory pathway Th2&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Its topical use is safe and well tolerated&#44; with local and reversible transient reactions&#44; but systemic adverse effects may occur&#46; Flu-like symptoms&#44; myalgia&#44; fever&#44; headache&#44; and fatigue have been reported&#44; reversible with medication suspension&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a> More than the systemic absorption of imiquimod&#44; the systemic circulation of inflammatory cytokines is credited with the etiology of these adverse effects&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Imiquimod has been associated with the onset and exacerbation of inflammatory skin eruptions such as psoriasis&#44; exfoliative dermatitis&#44; erythema multiforme&#44; pemphigus&#44; and subacute lupus&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> Psoriasis has been induced by topical imiquimod in rats&#44; with increased interferon-&#945; and interleukin-1&#44; interleukin-6&#44; interleukin-17&#44; and interleukin-23&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">In 2008&#44; Yang et al&#46; reported exacerbation of PRP in a 67-year-old patient under treatment with topical imiquimod 5&#37; for actinic keratosis on the face and scalp&#46; Two weeks after starting imiquimod&#44; as in the present report&#44; the patient developed an influenza-like illness associated with spreading of the follicular erythematous-desquamative lesions&#46; There was improvement after 26 months of treatment with acitretin&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">In 2010&#44; G&#243;mez-Moyano et al&#46; described erythrodermic PRP in a 56-year-old patient during treatment with imiquimod for superficial basal cell carcinoma on the back&#46; As in the present case&#44; the histopathology had foci of acantholytic dyskeratosis&#46; There was improvement of PRP after two months with acitretin&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Atanaskova Mesinkovska et al&#46;&#44; in 2011&#44; published a case of acantholytic PRP in a 65-year-old patient with topical use of imiquimod 3&#46;75&#37; for treatment of actinic keratosis&#46; She presented improvement after narrowband ultraviolet B radiation phototherapy&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">The causal relationship between imiquimod and PRP remains unknown&#46; Imiquimod may have been a trigger for PRP&#44; as it promotes activation of the Th1 inflammatory pathway and the systemic cytokine circulation of tumor necrosis factor-&#945;&#44; interferon-&#945;&#44; corroborating the main theory for PRP pathogenesis&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1&#44;4&#44;5</span></a> Flu-like systemic symptoms occurred after the use of imiquimod&#44; without any evidence of an infectious process&#44; which is an adverse effect that is already well documented&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">5&#44;6</span></a> In addition&#44; the use of methotrexate&#44; with antagonistic action upon tumor necrosis factor-&#945;&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> resulted in regression of the lesions&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">The use of immunologically active drugs in dermatology has been growing consistently&#46; The dermatologist should be able to recognize possible systemic side effects and the exacerbation or outbreak of inflammatory skin diseases&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Financial support</span><p id="par0100" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Authors&#8217; contribution</span><p id="par0105" class="elsevierStylePara elsevierViewall">Oriete Gerin Leite&#58; Approval of the final version of the manuscript&#59; conception and planning of the study&#59; elaboration and writing of the manuscript&#59; effective participation in research orientation&#59; critical review of the literature&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Sandra Tagliolatto&#58; Approval of the final version of the manuscript&#59; conception and planning of the study&#59; elaboration and writing of the manuscript&#59; effective participation in research orientation&#59; intellectual participation in propaedeutic and&#47;or therapeutic conduct of the cases studied&#59; critical review of the manuscript&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Elemir Macedo de Souza&#58; Approval of the final version of the manuscript&#59; intellectual participation in propaedeutic and&#47;or therapeutic conduct of the cases studied&#59; critical review of the literature&#59; critical review of the manuscript&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Maria Let&#237;cia Cintra&#58; Approval of the final version of the manuscript&#59; elaboration and writing of the manuscript&#59; intellectual participation in propaedeutic and&#47;or therapeutic conduct of the cases studied&#59; critical review of the literature&#59; critical review of the manuscript&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Conflicts of interest</span><p id="par0125" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Topical use of immune response modifiers&#44; such as imiquimod&#44; has increased in dermatology&#46; Although its topical use is well tolerated&#44; it may be associated with exacerbations of generalized cutaneous inflammatory diseases&#44; possibly through the systemic circulation of pro-inflammatory cytokines&#46; This report describes a case of development of pityriasis rubra pilaris&#44; a rare erythematous-papulosquamous dermatosis&#44; in a woman aged 60 years during treatment with imiquimod 5&#37; cream for actinic keratosis&#46; It evolved with erythrodermic conditions and palmoplantar keratoderma&#44; presenting progressive clinical resolution after the introduction of methotrexate&#46; The authors emphasize the importance of recognizing possible systemic reactions associated with the topical use of imiquimod&#46;</p></span>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Confluence of the lesions and evolution to erythroderma&#44; with areas of healthy skin&#46; Note the palmar involvement with orange keratoderma&#46;</p>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Skin&#44; abdominal region&#44; panoramic view&#58; &#40;A&#41; hyperkeratosis&#44; psoriasiform acanthosis&#44; and moderate superficial perivascular lymphoid infiltrate&#59; &#40;B&#41; detail of the previous image &#8211; there is altered hyperparakeratosis&#59; &#40;C&#41; area of acantholytic dyskeratosis and supra-basal intraepidermal cleft&#59; &#40;D&#41; marked congestion &#40;arrow&#41; with transepidermal elimination of red blood cells&#46; Hematoxylin &#38; eosin&#44; original magnification of 100&#215; &#40;A&#41; and 400&#215; &#40;B&#8211;D&#41;&#46;</p>"
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Case Report
Acantholytic pityriasis rubra pilaris associated with topical use of imiquimod 5%: case report and literature review
Oriete Gerin Leitea,
Autor para correspondência
oriete.leite@gmail.com

Corresponding author.
, Sandra Tagliolattoa,b, Elemir Macedo de Souzac, Maria Letícia Cintrad
a Dermoclínica, Campinas, SP, Brazil
b Department of Dermatology, Universidade Federal de São Paulo, São Paulo, SP, Brazil
c Discipline of Dermatology, Department of Clinical Medicine, Universidade Estadual de Campinas, Campinas, SP, Brazil
d Department of Anatomical Pathology, Universidade Estadual de Campinas, Campinas, SP, Brazil
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Disease resolution after nine months&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Pityriasis rubra pilaris &#40;PRP&#41; is a rare erythematous papulosquamous dermatosis&#44; clinically and pathologically similar to psoriasis&#46; It has undetermined etiology&#44; and although described as self-limiting&#44; it can profoundly affect the patient&#39;s quality of life&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The association of PRP with the use of imiquimod in the treatment of actinic keratosis and superficial basal cell carcinoma has been reported in three articles&#46; This report describes a case of PRP during the use of imiquimod for actinic keratosis&#44; with a good response to treatment with methotrexate&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Case report</span><p id="par0015" class="elsevierStylePara elsevierViewall">A 60-year-old Caucasian female patient had actinic keratosis for three months in the right chest&#44; confirmed by biopsy&#46; Imiquimod 5&#37; cream was prescribed for topical treatment&#44; five times per week&#46; After two weeks&#44; fever&#44; diarrhea&#44; myalgia&#44; and fatigue associated with exulceration of the initial lesion and onset of erythematous papulosquamous lesions on the scalp&#44; face&#44; and trunk began &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Treatment was discontinued&#46; Laboratory tests did not show any changes&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Despite the introduction of topical corticoids and oral antihistamines&#44; there was worsening of the eruption with craniocaudal sense and confluence of the lesions &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Biopsy of the lesions was performed and prednisone was started&#44; at 40<span class="elsevierStyleHsp" style=""></span>mg per day&#46; In the histology&#44; psoriasiform hyperplasia of the epidermis&#44; hyperparakeratosis alternated with orthokeratosis&#44; areas of hypogranulosis&#44; moderate superficial perivascular lymphohistiocytic infiltrate&#44; and foci of acantholytic dyskeratosis were observed &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">Four weeks after the onset of the eruption&#44; the patient was erythrodermic&#44; with areas of healthy skin associated with ectropion and orange palmoplantar keratoderma&#46; The clinical&#8211;histopathological diagnosis of PRP was defined&#46; Methotrexate was introduced orally at a dose of 15<span class="elsevierStyleHsp" style=""></span>mg per week and the oral corticosteroid was withdrawn gradually&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Serologic tests &#40;HIV&#44; hepatitis B and C&#41; were negative and abdominal ultrasound and chest X-ray were normal&#46; There was a progressive improvement in the erythrodermic condition after three months&#44; when methotrexate reduction was started&#46; The cutaneous surface was normalized nine months after the onset of the disease &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Discussion</span><p id="par0035" class="elsevierStylePara elsevierViewall">PRP is a rare disorder of keratinization&#46; The classic form &#40;Type I&#41; occurs in adults of both sexes&#44; with eruption of follicular papules that converge in scaly erythematous-orange plaques&#44; with craniocaudal spreading&#44; usually evolving to erythroderma with healthy skin islets and palmoplantar keratoderma&#46; Also described are atypical forms&#44; the involvement of children&#44; and a form associated with HIV infection&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Histopathology shows psoriasiform hyperplasia&#44; follicular hyperkeratosis&#44; hyperparakeratosis alternated with orthokeratosis&#44; and superficial perivascular lymphocytic infiltrate&#46; The occurrence of acantholytic dyskeratosis&#44; as in the present case&#44; is common and may induce diagnostic errors due to histological similarity with Grover&#39;s&#44; Darier&#39;s&#44; or pemphigus&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> In 1997&#44; Magro and Crowson suggested that the presence of acantholytic dyskeratosis is frequent and may serve as a predictive factor of PRP in the histopathological differentiation with psoriasis&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Despite the unclear etiology&#44; one of the main hypotheses for PRP is an exacerbated immune response to antigenic triggers&#46; Viral&#44; bacterial&#44; neoplastic&#44; and autoimmune diseases &#8211; as well as immune-modifying drugs &#8211; are believed to play a role in its pathogenesis&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1&#8211;3</span></a> The T-helper 1 &#40;Th1&#41; immune response pathway is activated&#44; with increased proinflammatory cytokines such as tumor necrosis factor-&#945;&#44; interferon-&#945;&#44; interleukin-1&#44; interleukin-6&#44; interleukin-17&#44; and interleukin-23&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Activation of the Th1 response would also be responsible for the poor vitamin A action found on the skin affected by PRP&#46; Inflammatory cytokines alter the signaling of retinoid keratinocyte receptors&#44; leading to abnormal keratinization and epidermal hyperplasia&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> Among the therapeutic options for PRP are oral retinoids&#44; methotrexate&#44; phototherapy&#44; and biological agents with anti-tumor necrosis factor-&#945;&#44; anti-interleukin-17&#44; and anti-interleukin-23 activity&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1&#44;2</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Imiquimod is an immune response stimulating agent&#44; indicated for topical treatment of actinic keratosis&#44; superficial basal cell carcinoma&#44; and condyloma acuminatum&#46; In recent years&#44; its use has expanded to treat other off-label dermatological conditions&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">As a toll-like receptor-7 &#40;TLR-7&#41; agonist observed in the cells of the innate immune system &#40;dendritic cells and macrophages&#41; and keratinocytes&#44; imiquimod performs antitumor and antiviral actions&#46; Its binding to TLR-7 promotes increased production of Th1 proinflammatory cytokines such as tumor necrosis factor-&#945;&#44; IFN-&#945;&#44; interleukin-1&#44; interleukin-6&#44; and interleukin-8&#44; among others&#44; as well as inhibiting the anti-inflammatory pathway Th2&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Its topical use is safe and well tolerated&#44; with local and reversible transient reactions&#44; but systemic adverse effects may occur&#46; Flu-like symptoms&#44; myalgia&#44; fever&#44; headache&#44; and fatigue have been reported&#44; reversible with medication suspension&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a> More than the systemic absorption of imiquimod&#44; the systemic circulation of inflammatory cytokines is credited with the etiology of these adverse effects&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Imiquimod has been associated with the onset and exacerbation of inflammatory skin eruptions such as psoriasis&#44; exfoliative dermatitis&#44; erythema multiforme&#44; pemphigus&#44; and subacute lupus&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> Psoriasis has been induced by topical imiquimod in rats&#44; with increased interferon-&#945; and interleukin-1&#44; interleukin-6&#44; interleukin-17&#44; and interleukin-23&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">In 2008&#44; Yang et al&#46; reported exacerbation of PRP in a 67-year-old patient under treatment with topical imiquimod 5&#37; for actinic keratosis on the face and scalp&#46; Two weeks after starting imiquimod&#44; as in the present report&#44; the patient developed an influenza-like illness associated with spreading of the follicular erythematous-desquamative lesions&#46; There was improvement after 26 months of treatment with acitretin&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">In 2010&#44; G&#243;mez-Moyano et al&#46; described erythrodermic PRP in a 56-year-old patient during treatment with imiquimod for superficial basal cell carcinoma on the back&#46; As in the present case&#44; the histopathology had foci of acantholytic dyskeratosis&#46; There was improvement of PRP after two months with acitretin&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Atanaskova Mesinkovska et al&#46;&#44; in 2011&#44; published a case of acantholytic PRP in a 65-year-old patient with topical use of imiquimod 3&#46;75&#37; for treatment of actinic keratosis&#46; She presented improvement after narrowband ultraviolet B radiation phototherapy&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">The causal relationship between imiquimod and PRP remains unknown&#46; Imiquimod may have been a trigger for PRP&#44; as it promotes activation of the Th1 inflammatory pathway and the systemic cytokine circulation of tumor necrosis factor-&#945;&#44; interferon-&#945;&#44; corroborating the main theory for PRP pathogenesis&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1&#44;4&#44;5</span></a> Flu-like systemic symptoms occurred after the use of imiquimod&#44; without any evidence of an infectious process&#44; which is an adverse effect that is already well documented&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">5&#44;6</span></a> In addition&#44; the use of methotrexate&#44; with antagonistic action upon tumor necrosis factor-&#945;&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> resulted in regression of the lesions&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">The use of immunologically active drugs in dermatology has been growing consistently&#46; The dermatologist should be able to recognize possible systemic side effects and the exacerbation or outbreak of inflammatory skin diseases&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Financial support</span><p id="par0100" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Authors&#8217; contribution</span><p id="par0105" class="elsevierStylePara elsevierViewall">Oriete Gerin Leite&#58; Approval of the final version of the manuscript&#59; conception and planning of the study&#59; elaboration and writing of the manuscript&#59; effective participation in research orientation&#59; critical review of the literature&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Sandra Tagliolatto&#58; Approval of the final version of the manuscript&#59; conception and planning of the study&#59; elaboration and writing of the manuscript&#59; effective participation in research orientation&#59; intellectual participation in propaedeutic and&#47;or therapeutic conduct of the cases studied&#59; critical review of the manuscript&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Elemir Macedo de Souza&#58; Approval of the final version of the manuscript&#59; intellectual participation in propaedeutic and&#47;or therapeutic conduct of the cases studied&#59; critical review of the literature&#59; critical review of the manuscript&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Maria Let&#237;cia Cintra&#58; Approval of the final version of the manuscript&#59; elaboration and writing of the manuscript&#59; intellectual participation in propaedeutic and&#47;or therapeutic conduct of the cases studied&#59; critical review of the literature&#59; critical review of the manuscript&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Conflicts of interest</span><p id="par0125" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Topical use of immune response modifiers&#44; such as imiquimod&#44; has increased in dermatology&#46; Although its topical use is well tolerated&#44; it may be associated with exacerbations of generalized cutaneous inflammatory diseases&#44; possibly through the systemic circulation of pro-inflammatory cytokines&#46; This report describes a case of development of pityriasis rubra pilaris&#44; a rare erythematous-papulosquamous dermatosis&#44; in a woman aged 60 years during treatment with imiquimod 5&#37; cream for actinic keratosis&#46; It evolved with erythrodermic conditions and palmoplantar keratoderma&#44; presenting progressive clinical resolution after the introduction of methotrexate&#46; The authors emphasize the importance of recognizing possible systemic reactions associated with the topical use of imiquimod&#46;</p></span>"
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