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and it has even triggered skin lesions in subacute lupus erythematosus<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">A 25-year-old woman had been followed by the rheumatology department for a 4-year history of SLE&#46; The diagnostic criteria did not include a history of photosensitivity&#46; Initial treatment was with rituximab &#40;500&#8239;mg every 15 days&#44; 2 sessions&#41;&#44; oral prednisone in tapering doses&#44; and subcutaneous methotrexate &#40;17&#46;5&#8239;mg weekly&#41;&#46; Owing to gastrointestinal adverse effects&#44; methotrexate was replaced by leflunomide &#40;3 daily doses of 100&#8239;mg followed by a maintenance dose of 20&#8239;mg&#47;d&#41; 3 months after initiation&#46; Two months after starting treatment with leflunomide and after intense exposure to sunlight at the beach&#44; the patient came to the clinic with a 24&#8239;-h history of very pruritic generalized maculopapular rash &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A-B&#41;&#44; which progressed to vesicular-bullous lesions in 48&#8239;hours&#46; These mainly affected the arms &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>C&#41; and were associated with pustules on the forehead &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A&#41;&#44; vesicles on the area of the lips &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B&#41;&#44; and ecchymotic macules and papules on both axillae &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>C&#41;&#46; Examination of the oral and genital mucosa was normal&#46; The laboratory workup revealed high titers for antinuclear antibodies &#40;1&#47;640 U&#47;mL&#41;&#44; anti-Ro&#47;SSA-60 &#40;157&#41;&#44; anti-Ro&#47;SSA-52 &#40;167&#41;&#44; and rheumatoid factor &#40;80 U&#47;mL&#41;&#46; Values for the remaining parameters&#44; including C3 and C4&#44; were normal&#46; Serology testing &#40;herpes simplex virus&#44; cytomegalovirus&#44; Epstein-Barr virus&#44; and human herpesvirus 6&#41; yielded negative results&#46; Histopathology of a punch biopsy specimen from a bullous lesion on the posterior trunk revealed an atrophied epidermis with foci of necrotic keratinocytes and spongiosis&#44; together with a subepidermal bullous formation and a moderate inflammatory perivascular mononuclear infiltrate of lymphocytes and eosinophils in the dermis that was compatible with phototoxic rash&#46; Direct immunofluorescence was negative&#46; Treatment with leflunomide was interrupted&#44; and systemic treatment with oral prednisone &#40;1&#8239;mg&#47;kg&#47;d&#41; was started&#46; The lesions had resolved completely after 10 days except for some residual hyperpigmentation&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">Patients with SLE are particularly sensitive to sunlight&#44; which is considered a trigger or aggravating factor of the disease&#46; It is rare for a diagnosis of SLE not to include photosensitivity as a criterion&#46; Of the various treatments used in SLE&#44; leflunomide is not a first choice&#59; therefore&#44; it is used in selected patients who experience adverse effects associated with other drugs&#44; such as methotrexate&#46; The literature contains many articles that consider leflunomide as the sole cause of subacute cutaneous lupus erythematosus &#40;SCLE&#41;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>&#44; as well as SCLE associated with erythema multiforme&#8211;type lesions and erythema multiforme major&#46; Some authors are in favor of diagnosing the co-occurrence of lupus erythematosus and erythema multiforme in the same patient as Rowell syndrome&#44; although this is considered controversial&#46; In fact&#44; in the year 2000&#44; Zeitouni et al&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> defined new criteria for the diagnosis of Rowell syndrome&#46; While the patient in the case we report fulfilled sufficient criteria to be diagnosed with this syndrome&#44; our main suspicion was leflunomide-induced phototoxic reaction&#46; Two months after the clinical picture had resolved&#44; the patient underwent patch testing with the European photopatch series &#40;Chemotechnique Diagnostics&#41; and leflunomide 1&#37;&#44; 5&#37;&#44; and 10&#37; in petrolatum&#44; with UV-A radiation at 10&#8239;J&#47;cm<span class="elsevierStyleSup">2</span>&#46; The reading was negative at 3&#8239;minutes and at 48 and 96&#8239;hours&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Photosensitive rash is common in patients with SLE and is included in the diagnostic criteria&#46; However&#44; in the present case&#44; we think that some of the drugs used in this disease could play a relevant role in triggering a phototoxic or photoallergic reaction&#46; Differentiating clinically between phototoxic rash and photosensitive rash in SLE can prove difficult&#46; Histopathology makes it possible to distinguish patients with true SLE&#44; in which immunofluorescence reveals deposits of immunoglobulin M and C3 at the dermal-epidermal junction&#44; findings that are absent in phototoxic rash&#46; Photopatch testing should be considered as an additional test&#44; with the objective of differentiating between phototoxic and photoallergic reactions&#46; As for laboratory findings&#44; a positive anti-Ro&#47;SSA titer should be considered a risk factor for drug-induced SLE<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>&#46; Furthermore&#44; antihistone antibodies are detected in more than 95&#37; of cases of drug-induced SLE&#44; although they are also observed in 50&#37;-70&#37; of cases of SLE that are not drug-induced&#46; In the case we report&#44; the histone antibody test was negative&#44; thus pointing us to a phototoxic reaction&#44; as initially suspected&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">In conclusion&#44; we think that when assessing a patient with characteristics similar to those described here&#44; the differential diagnosis should include drug-induced photosensitive rash&#44; especially after initiation of treatment such as leflunomide&#44; as in the present case&#46; Additional tests&#44; for example&#44; patch &#40;and photopatch&#41; testing&#44; are essential if we are to make an appropriate diagnosis&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0030" class="elsevierStylePara elsevierViewall">The authors declare that no funding was received for the present study&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflicts of Interest</span><p id="par0035" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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Case and Research Letters
Leflunomide-Induced Phototoxic Reaction in a Woman With Systemic Lupus Erythematosus
Erupción fototóxica inducida por leflunomida en una paciente con lupus eritematoso sistémico
F.J. Navarro-Triviñoa,
Corresponding author
fntmed@gmail.com

Corresponding author.
, N. Lucas-Colladob, J. Salvatierra-Ossoriob
a Servicio de Dermatología Médico-Quirúrgica y Venereología, Hospital Universitario San Cecilio, Granada, Spain
b Servicio de Reumatología, Hospital Universitario San Cecilio, Granada, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Leflunomide is an immunosuppressive agent that has been approved by the United States Food and Drug Administration for the treatment of rheumatoid arthritis and psoriatic arthritis&#46; It is also widely used off-label in other diseases&#44; such as ankylosing spondylitis and systemic lupus erythematosus &#40;SLE&#41;&#46; Leflunomide can produce adverse effects&#44; the most common of which are gastrointestinal symptoms&#44; hypertension&#44; and alopecia&#46; Although considered an efficacious and safe drug for the treatment of SLE&#44; leflunomide has been associated with cases of skin rash&#44; such as erythema multiforme<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>&#44; toxic epidermal necrolysis<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#44; and vasculitis<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#44; and it has even triggered skin lesions in subacute lupus erythematosus<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">A 25-year-old woman had been followed by the rheumatology department for a 4-year history of SLE&#46; The diagnostic criteria did not include a history of photosensitivity&#46; Initial treatment was with rituximab &#40;500&#8239;mg every 15 days&#44; 2 sessions&#41;&#44; oral prednisone in tapering doses&#44; and subcutaneous methotrexate &#40;17&#46;5&#8239;mg weekly&#41;&#46; Owing to gastrointestinal adverse effects&#44; methotrexate was replaced by leflunomide &#40;3 daily doses of 100&#8239;mg followed by a maintenance dose of 20&#8239;mg&#47;d&#41; 3 months after initiation&#46; Two months after starting treatment with leflunomide and after intense exposure to sunlight at the beach&#44; the patient came to the clinic with a 24&#8239;-h history of very pruritic generalized maculopapular rash &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A-B&#41;&#44; which progressed to vesicular-bullous lesions in 48&#8239;hours&#46; These mainly affected the arms &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>C&#41; and were associated with pustules on the forehead &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A&#41;&#44; vesicles on the area of the lips &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B&#41;&#44; and ecchymotic macules and papules on both axillae &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>C&#41;&#46; Examination of the oral and genital mucosa was normal&#46; The laboratory workup revealed high titers for antinuclear antibodies &#40;1&#47;640 U&#47;mL&#41;&#44; anti-Ro&#47;SSA-60 &#40;157&#41;&#44; anti-Ro&#47;SSA-52 &#40;167&#41;&#44; and rheumatoid factor &#40;80 U&#47;mL&#41;&#46; Values for the remaining parameters&#44; including C3 and C4&#44; were normal&#46; Serology testing &#40;herpes simplex virus&#44; cytomegalovirus&#44; Epstein-Barr virus&#44; and human herpesvirus 6&#41; yielded negative results&#46; Histopathology of a punch biopsy specimen from a bullous lesion on the posterior trunk revealed an atrophied epidermis with foci of necrotic keratinocytes and spongiosis&#44; together with a subepidermal bullous formation and a moderate inflammatory perivascular mononuclear infiltrate of lymphocytes and eosinophils in the dermis that was compatible with phototoxic rash&#46; Direct immunofluorescence was negative&#46; Treatment with leflunomide was interrupted&#44; and systemic treatment with oral prednisone &#40;1&#8239;mg&#47;kg&#47;d&#41; was started&#46; The lesions had resolved completely after 10 days except for some residual hyperpigmentation&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">Patients with SLE are particularly sensitive to sunlight&#44; which is considered a trigger or aggravating factor of the disease&#46; It is rare for a diagnosis of SLE not to include photosensitivity as a criterion&#46; Of the various treatments used in SLE&#44; leflunomide is not a first choice&#59; therefore&#44; it is used in selected patients who experience adverse effects associated with other drugs&#44; such as methotrexate&#46; The literature contains many articles that consider leflunomide as the sole cause of subacute cutaneous lupus erythematosus &#40;SCLE&#41;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>&#44; as well as SCLE associated with erythema multiforme&#8211;type lesions and erythema multiforme major&#46; Some authors are in favor of diagnosing the co-occurrence of lupus erythematosus and erythema multiforme in the same patient as Rowell syndrome&#44; although this is considered controversial&#46; In fact&#44; in the year 2000&#44; Zeitouni et al&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> defined new criteria for the diagnosis of Rowell syndrome&#46; While the patient in the case we report fulfilled sufficient criteria to be diagnosed with this syndrome&#44; our main suspicion was leflunomide-induced phototoxic reaction&#46; Two months after the clinical picture had resolved&#44; the patient underwent patch testing with the European photopatch series &#40;Chemotechnique Diagnostics&#41; and leflunomide 1&#37;&#44; 5&#37;&#44; and 10&#37; in petrolatum&#44; with UV-A radiation at 10&#8239;J&#47;cm<span class="elsevierStyleSup">2</span>&#46; The reading was negative at 3&#8239;minutes and at 48 and 96&#8239;hours&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Photosensitive rash is common in patients with SLE and is included in the diagnostic criteria&#46; However&#44; in the present case&#44; we think that some of the drugs used in this disease could play a relevant role in triggering a phototoxic or photoallergic reaction&#46; Differentiating clinically between phototoxic rash and photosensitive rash in SLE can prove difficult&#46; Histopathology makes it possible to distinguish patients with true SLE&#44; in which immunofluorescence reveals deposits of immunoglobulin M and C3 at the dermal-epidermal junction&#44; findings that are absent in phototoxic rash&#46; Photopatch testing should be considered as an additional test&#44; with the objective of differentiating between phototoxic and photoallergic reactions&#46; As for laboratory findings&#44; a positive anti-Ro&#47;SSA titer should be considered a risk factor for drug-induced SLE<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>&#46; Furthermore&#44; antihistone antibodies are detected in more than 95&#37; of cases of drug-induced SLE&#44; although they are also observed in 50&#37;-70&#37; of cases of SLE that are not drug-induced&#46; In the case we report&#44; the histone antibody test was negative&#44; thus pointing us to a phototoxic reaction&#44; as initially suspected&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">In conclusion&#44; we think that when assessing a patient with characteristics similar to those described here&#44; the differential diagnosis should include drug-induced photosensitive rash&#44; especially after initiation of treatment such as leflunomide&#44; as in the present case&#46; Additional tests&#44; for example&#44; patch &#40;and photopatch&#41; testing&#44; are essential if we are to make an appropriate diagnosis&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0030" class="elsevierStylePara elsevierViewall">The authors declare that no funding was received for the present study&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflicts of Interest</span><p id="par0035" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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Article information
ISSN: 15782190
Original language: English
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