Review
Adverse Skin Effects of Imatinib, a Tyrosine Kinase Inhibitor
Efectos adversos cutáneos del imatinib (inhibidor de la tirosín cinasa)
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Pretel-Irazabal, A. Tuneu-Valls, N. Ormaechea-Pérez" "autores" => array:3 [ 0 => array:4 [ "nombre" => "M." "apellidos" => "Pretel-Irazabal" "email" => array:1 [ 0 => "mpretel@unav.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "A." "apellidos" => "Tuneu-Valls" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "N." "apellidos" => "Ormaechea-Pérez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Departamento de Dermatología, Clínica Universidad de Navarra, Pamplona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Departamento de Dermatología, Hospital de Donostia, San Sebastián, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Efectos adversos cutáneos del imatinib (inhibidor de la tirosín cinasa)" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 833 "Ancho" => 950 "Tamanyo" => 151018 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Fifty-one-year-old man diagnosed with chronic myeloid leukemia in treatment with imatinib for 1 month. Violaceous lichenoid lesions on the wrists and whitish plaques on the jugal mucosa, with histopathological diagnosis of mucosal lichen.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Imatinib mesylate (Glivec, Novartis; formerly known as STI 571) is an oral inhibitor of the tyrosine kinase BCR-Abl (a fusion protein from the Philadelphia chromosome, a cytogenetic abnormality of chronic myeloid leukemia [CML]), c-KIT, and platelet-derived growth factor receptor (PDGFR). The approval of this agent in 2001 by the US Food and Drug Administration revolutionized the treatment of patients with CML and significantly extended their overall survival.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Subsequently, the second generation of tyrosine kinase inhibitors nilotinib (Tasigna, Novartis) approved in 2007 and dasatinib (Sprycel; Bristol-Myers Squibb) approved in 2006, have extended the therapeutic options in patients intolerant of or resistant to imatinib.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Imatinib is also approved for treating other diseases such as unresectable <span class="elsevierStyleItalic">c-kit</span><span class="elsevierStyleMonospace"><span class="elsevierStyleSup">+</span></span> malignant gastrointestinal stromal tumors, acute Philadelphia chromosome<span class="elsevierStyleMonospace"><span class="elsevierStyleSup">+</span></span> lymphoblastic leukemia, myelodysplastic syndromes with PDGFR gene reordering, hypereosinophilic syndrome, and chronic eosinophilic leukemia. In dermatology, the agent has proved effective in certain diseases such as inoperable or metastatic dermatofibrosarcoma protuberans (DFSP),<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> sclerodermous graft-versus-host disease,<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> systemic sclerosis,<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> systemic mastocytosis,<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> and melanoma with <span class="elsevierStyleItalic">c-kit</span><span class="elsevierStyleSup">+</span> mutations.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the therapeutic targets in the different diseases in which imatinib has been used.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Doses of 400-600<span class="elsevierStyleHsp" style=""></span>mg/d are used in chronic CML and GIST. In accelerated CML and DFSP, a dose of up to 800<span class="elsevierStyleHsp" style=""></span>mg/d is indicated.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Adverse Effects of Imatinib</span><p id="par0025" class="elsevierStylePara elsevierViewall">Although the drug is generally well tolerated, up to 5.4% of patients have to discontinue treatment due to adverse effects.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Adverse effects are usually classified using the US National Cancer Institute scale, with 4 severity grades.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Most of the effects observed after administration of imatinib are mild or moderate in severity (grade 1 or 2).<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The grade 1 and 2 side effects most frequently observed after 5 years of follow-up in patients diagnosed for the first time with CML and treated with imatinib were edema, muscle cramps, diarrhea, nausea, musculoskeletal pain, skin rash and other skin conditions, abdominal pain, fatigue, joint pain, and headache.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Severe adverse effects, that is, grade 3 or 4 events, included neutropenia, thrombocytopenia, anemia, and liver enzyme elevation.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Imatinib appears to cause a higher rate of headache, diarrhea, vomiting, muscle spasm, and edema compared to other tyrosine kinase inhibitors.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> However, imatinib is associated with a lower rate of skin rash, headache, pruritus, elevated transaminases, and alopecia. Hematologic adverse effects such as neutropenia were observed in 20% of patients compared to 12% with nilotinib. The 2 drugs caused similar rates of grade 3 and 4 thrombocytopenia and anemia.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Dasatinib appears to cause lower rates of nausea, vomiting, muscle inflammation, rash, fluid retention, and headaches compared to imatinib.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Similar percentages of grade 3 and 4 neutropenia and a higher rate of thrombocytopenia were observed with dasatinib compared to imatinib.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> shows a comparison of the percentage of patients with drug-related adverse skin effects.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">In general, any grade 3 or 4 adverse effect is managed by suspending administration and resuming at a lower dose once the toxicity has resolved.</p><p id="par0050" class="elsevierStylePara elsevierViewall">In these patients, a careful assessment of the adverse effects is important because of the impact on treatment adherence and therefore efficacy. Adherence to treatment can essentially be improved by helping the patient to identify and manage side effects.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Adverse Cutaneous Effects of Imatinib</span><p id="par0055" class="elsevierStylePara elsevierViewall">Skin rash is one of the most common adverse effects of imatinib, and estimates of incidence range from 7% to 88.9%.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14,15</span></a> Most cases are mild and self-limiting, with onset shortly after starting administration of the drug.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a><a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> shows classification of the most common adverse cutaneous effects according to their severity.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> According to one study, 2.3% of patients treated at a dose of 400<span class="elsevierStyleHsp" style=""></span>mg/d and 5.3% of those treated at a dose of 800<span class="elsevierStyleHsp" style=""></span>mg/d<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> have severe adverse cutaneous effects.</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">The effects are thought to be independent of dose. A recent study reported such events in 7% of patients treated at a subtherapeutic dose of 25-140<span class="elsevierStyleHsp" style=""></span>mg/d and in 21% to 88% of patients treated with a dose of 400-800<span class="elsevierStyleHsp" style=""></span>mg/d.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> This fact, along with the relatively low molecular weight of the drug, suggests that the cutaneous toxicity of imatinib is mediated by a toxic pharmacologic effect rather than an immunogenic effect.</p><p id="par0065" class="elsevierStylePara elsevierViewall">Different types of skin reactions have been reported after using imatinib. These can be nonspecific, such as macular-papular rash, superficial edema, or pruritus, or less frequently, rash with clinically distinctive characteristics (lichenoid, psoriasiform, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome [SJS], etc).</p><p id="par0070" class="elsevierStylePara elsevierViewall">The most frequent adverse cutaneous effects associated with imatinib are described in the following sections.</p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Macular-Papular Rash</span><p id="par0075" class="elsevierStylePara elsevierViewall">Onset of rash caused by imatinib usually occurs a few days after starting treatment, although it can present after several months of treatment. According to some studies, rash is a frequent event and may present in up to 66.7% of patients within 2 months of starting the drug.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">The eruption is usually erythematous, macular-papular, sometimes desquamative, and pruritic (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). The lesions are located on the forearms, trunk, and legs, and less often on the face.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> They also present more frequently in patients who take high doses (><span class="elsevierStyleHsp" style=""></span>600<span class="elsevierStyleHsp" style=""></span>mg/d) of the drug, and so the rash is thought of as a pharmacological toxicity rather than a hypersensitivity reaction.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">Most cases of rash are self-limiting and readily treated with emollients, topical corticosteroids, and antihistamines. Dose reductions are therefore not needed. When the rash progresses to erythroderma, it is considered grade 4 toxicity, and suspension of the drug is indicated. In general, severe cases usually require treatment with oral corticosteroids and suspension of imatinib until the rash has improved to grade 1. Imatinib can then be reintroduced at a lower dose (50-100<span class="elsevierStyleHsp" style=""></span>mg/d) along with use of concomitant oral corticosteroids; the dose of imatinib can then be gradually increased.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">The initial recommended oral corticosteroid dose is usually 0.5-1<span class="elsevierStyleHsp" style=""></span>mg/kg of prednisone or equivalent. In certain patients, desensitization has been successful, suggesting that hypersensitivity mechanisms could also be present.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">In very severe cases, reintroduction of the drug is not recommended and replacement with nilotinib or dasatinib is recommended.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Superficial Edema</span><p id="par0100" class="elsevierStylePara elsevierViewall">One of the most frequent adverse cutaneous effects is superficial edema. According to several studies, between 48% and 65% of patients treated with this drug develop this complication within 6 weeks of starting treatment, often in association with weight gain.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Edema is normally mild to moderate in intensity, and presents on the face, and particularly the eyelids. It may be more severe in the mornings.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Edema of the limbs is much rarer. Central water retention (manifest as events such as pleural effusion and congestive heart failure) has also been reported in 1% to 3% of patients treated with imatinib.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Superficial edema is thought to be dose independent and arises as a result of increased pressure of interstitial dermal fluid caused by inhibition of PDGFR, which is responsible for interstitial fluid homeostasis.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">In most cases, management of superficial edema does not require the drug to be suspended or indeed any specific treatment. In some cases, a restriction of dietary salt and topical application of phenylephrine 0.25% may be beneficial.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> In patients with central edema, diuretics may be indicated.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Lichenoid Reactions</span><p id="par0115" class="elsevierStylePara elsevierViewall">Fifteen cases of lichenoid reactions have been reported in patients treated with imatinib.<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26–29</span></a> The lesions occurred on the skin and/or mucosa (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). These reactions appear to be dose dependent given that all reports were in patients who were receiving high doses of the drug (><span class="elsevierStyleHsp" style=""></span>400<span class="elsevierStyleHsp" style=""></span>mg/d). In most cases, onset occurred from 1 to 3 months after starting treatment, although some patients did not develop the lesions until 1 year after starting imatinib. Suspension of the drug was not necessary in most patients, and the reactions were managed satisfactorily with the use of oral corticosteroids or acitretin.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Pigmentary Disorders</span><p id="par0120" class="elsevierStylePara elsevierViewall">Several cases of pigmentary disorders due to the use of imatinib have been reported. Normally, hypopigmentation is manifest as hypochromic areas or diffuse or localized achromic areas, with remission after a dose reduction or discontinuation.<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">31,32</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Patients with dark phototypes are more likely to develop this adverse effect. Some studies have shown an incidence of hypopigmentation of 41% in patients treated for CML.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Likewise, cases of hair depigmentation have been reported (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0135" class="elsevierStylePara elsevierViewall">In addition, there have been case reports of patients treated with imatinib who develop skin, mucosal (hard palate), and nail hyperpigmentation.<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34–37</span></a> In a study of 118 patients with CML treated with imatinib, only 4% developed hyperpigmentation.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">These reactions are likely to occur because imatinib inhibits c-KIT in the melanocytes, thereby reducing the activity of these cells and leading to hypopigmentation.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> Moreover, imatinib can also cause hyperpigmentation by chelating one of its metabolites with iron and melanin in a mechanism similar to minocycline and antimalarial-associated hyperpigmentation.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Psoriasis and Psoriasiform Rash</span><p id="par0145" class="elsevierStylePara elsevierViewall">In a study of 54 patients treated with imatinib, 4 developed psoriasiform rash between 1 and 7 months after starting treatment.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Half of these patients had a history of psoriasis. There have also been reports of imatinib-related exacerbation of psoriasis.<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">39,40</span></a> Deguchi et al.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> reported psoriasiform palmoplantar hyperkeratosis and nail dystrophy after treatment with imatinib in 3 patients with no history of psoriasis. All patients improved after suspending or reducing the dose of the drug.</p><p id="par0150" class="elsevierStylePara elsevierViewall">However, a case was published in which psoriasis improved in a patient with a GIST who started treatment with 400<span class="elsevierStyleHsp" style=""></span>mg/d of imatinib.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">T lymphocytes are known to play an important pathogenic role in psoriasis and imatinib can modulate T lymphocyte signalling.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> The exact circumstances of the modulation are thought to influence whether a T-lymphocyte stimulatory or inhibitory effect occurs, leading to exacerbations or remissions, respectively, of the disease.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Pityriasis Rosea-Like Rash</span><p id="par0160" class="elsevierStylePara elsevierViewall">Several cases of rashes resembling pityriasis rosea have been reported in patients treated with imatinib. In most cases, rash onset was 1 to 2 months after starting treatment.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">In some cases, the relationship with imatinib seems fairly probable, as the skin lesions (clinically and pathologically consistent with pityriasis rosea) resolved after withdrawal of the drug and reappeared on rechallenge.<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">45,46</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">The pathogenesis of this adverse effect is unknown.</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Acute Generalized Exanthematous Pustulosis</span><p id="par0175" class="elsevierStylePara elsevierViewall">A case typical of acute generalized exanthematous pustulosis caused by imatinib has been reported.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">Subsequently, there were 3 reports of another 3 atypical cases in which an eruption with an atypical localization occurred between 1 and 4 years after starting the drug.<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">48–50</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Cases of acute generalized exanthematous pustulosis have not been reported in patients who received less than 600<span class="elsevierStyleHsp" style=""></span>mg/d of imatinib, and so this adverse effect is thought to be dose-dependent. The pathogenesis is not entirely understood.</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Stevens-Johnson Syndrome</span><p id="par0190" class="elsevierStylePara elsevierViewall">Several cases of SJS have been reported in patients treated with imatinib.<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">51–55</span></a> Hsiao et al.<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> described a patient with CML who developed signs and symptoms reminiscent of SJS one week after starting the drug. These resolved after withdrawal of the drug and reappeared on rechallenge, strongly suggesting that the drug played a role in the eruption.</p><p id="par0195" class="elsevierStylePara elsevierViewall">In other cases, however, the eruption did not appear after rechallenge at lower doses.<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">In another case report of SJS, a patient treated with 400<span class="elsevierStyleHsp" style=""></span>mg/d of imatinib underwent rechallenge at a dose of 200<span class="elsevierStyleHsp" style=""></span>mg/d and the lesions reappeared.<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a> At a second rechallenge at a dose of 100<span class="elsevierStyleHsp" style=""></span>mg/d and 1<span class="elsevierStyleHsp" style=""></span>mg/kg/d of prednisone, the lesions did not reappear. On suspending prednisone after 6 weeks, the imatinib dose was increased to 300<span class="elsevierStyleHsp" style=""></span>mg/d with no adverse effects.</p><p id="par0205" class="elsevierStylePara elsevierViewall">Some authors suggest that desensitization should be attempted to manage these severe mucocutaneous eruptions when the lesions reappear even with concomitant use of prednisone.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> Currently, with availability of alternatives such as dasatinib and nilotinib, we believe that switching to another drug is more appropriate in these cases.</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Neutrophilic Dermatoses</span><p id="par0210" class="elsevierStylePara elsevierViewall">Two cases of Sweet syndrome have been reported in patients treated with imatinib, and in one case the temporal association was clear.<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">56,57</span></a> There has also been a report of a case of a patient with imatinib-induced neutrophilic eccrine hidradenitis,<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> 2 cases of erythema nodosum,<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> 3 cases of recurrent neutrophilic paniculitis,<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">59–61</span></a> and a case of neutrophilic foliculitis.<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Toxic Epidermal Necrolysis</span><p id="par0215" class="elsevierStylePara elsevierViewall">A case report has been published of a patient with CML who developed a very severe blistering skin and mucosal eruption after allogeneic bone marrow transplantation (with fludarabine and busulphan conditioning) and treatment with imatinib.<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a> A causal relationship with imatinib is doubtful, as the patient was taking other drugs and the eruption appeared after 3 months of treatment with imatinib.</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Photosensitivity</span><p id="par0220" class="elsevierStylePara elsevierViewall">Two studies have been published of several cases of photosensitivity in patients in long-term treatment with imatinib,<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15,64</span></a> as well as a case of photo-induced dermatitis.<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Other Skin Reactions</span><p id="par0225" class="elsevierStylePara elsevierViewall">There have been case reports of fungoid-like mycosis,<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a> cutaneous porphyria cutanea tarda,<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a> pseudoporphyria,<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a> and skin fragility and blistering<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">69,70</span></a> in patients treated with imatinib.</p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conclusion</span><p id="par0230" class="elsevierStylePara elsevierViewall">Imatinib is a well-tolerated drug, although it is not devoid of adverse effects, some of which are serious. Cutaneous adverse reactions are among the most frequent side effects. In this article, we have exhaustively reviewed the side effects of this drug, paying particular attention to cutaneous effects, and we have provided guidance for their management. As this is a drug with many indications, including skin conditions, dermatologists are increasingly seeing patients in the clinic with adverse effects resulting from its use. Appropriate knowledge of these reactions and their management is of great importance, as adherence to treatment is essential to ensure efficacy in potentially fatal diseases such as CML.</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Ethical Responsibilities</span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Protection of human and animal subjects</span><p id="par0235" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this investigation.</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Confidentiality of data</span><p id="par0240" class="elsevierStylePara elsevierViewall">The authors declare that they have followed their hospital's protocol on the publication of data concerning patients and that all patients included in the study have received sufficient information and have given their written informed consent to participate in the study.</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Right to privacy and informed consent</span><p id="par0245" class="elsevierStylePara elsevierViewall">The authors declare that patient data do not appear in this article.</p></span></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conflicts of Interest</span><p id="par0250" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:2 [ "identificador" => "xres365526" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec345126" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres365525" "titulo" => "Resumen" ] 3 => array:2 [ "identificador" => "xpalclavsec345125" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Adverse Effects of Imatinib" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Adverse Cutaneous Effects of Imatinib" "secciones" => array:12 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Macular-Papular Rash" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Superficial Edema" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Lichenoid Reactions" ] 3 => array:2 [ "identificador" => "sec0035" "titulo" => "Pigmentary Disorders" ] 4 => array:2 [ "identificador" => "sec0040" "titulo" => "Psoriasis and Psoriasiform Rash" ] 5 => array:2 [ "identificador" => "sec0045" "titulo" => "Pityriasis Rosea-Like Rash" ] 6 => array:2 [ "identificador" => "sec0050" "titulo" => "Acute Generalized Exanthematous Pustulosis" ] 7 => array:2 [ "identificador" => "sec0055" "titulo" => "Stevens-Johnson Syndrome" ] 8 => array:2 [ "identificador" => "sec0060" "titulo" => "Neutrophilic Dermatoses" ] 9 => array:2 [ "identificador" => "sec0065" "titulo" => "Toxic Epidermal Necrolysis" ] 10 => array:2 [ "identificador" => "sec0070" "titulo" => "Photosensitivity" ] 11 => array:2 [ "identificador" => "sec0075" "titulo" => "Other Skin Reactions" ] ] ] 7 => array:2 [ "identificador" => "sec0080" "titulo" => "Conclusion" ] 8 => array:3 [ "identificador" => "sec0085" "titulo" => "Ethical Responsibilities" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0090" "titulo" => "Protection of human and animal subjects" ] 1 => array:2 [ "identificador" => "sec0095" "titulo" => "Confidentiality of data" ] 2 => array:2 [ "identificador" => "sec0100" "titulo" => "Right to privacy and informed consent" ] ] ] 9 => array:2 [ "identificador" => "sec0105" "titulo" => "Conflicts of Interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2012-10-05" "fechaAceptado" => "2013-01-13" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec345126" "palabras" => array:3 [ 0 => "Imatinib" 1 => "Adverse effect" 2 => "Skin" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec345125" "palabras" => array:3 [ 0 => "Imatinib" 1 => "Efecto adverso" 2 => "Piel" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Imatinib mesylate is a tyrosine kinase inhibitor that targets the BCR-ABL, c-kit, and PDGF (platelet-derived growth factor) receptors. Imatinib is mainly indicated for chronic myeloid leukemia and gastrointestinal stromal tumors but is also prescribed by dermatologists for dermatofibrosarcoma protuberans, systemic sclerosis, and systemic mastocytosis, among other conditions. Most adverse effects are mild or moderate and therapy is generally well tolerated. Adverse skin effects are very common and include nonspecific manifestations such as edema and maculopapular rashes or eruptions of diverse types (lichenoid or psoriasiform lesions, acute generalized exanthematic pustulosis, Stevens-Johnson syndrome, and more). Identifying and properly treating these reactions can help optimize adherence to treatment and improve the prognosis of the underlying disease.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">El imatinib mesilato es un inhibidor de la tirosín cinasa de administración oral que inhibe la BCR-abl, c-KIT y el <span class="elsevierStyleItalic">platelet-derived growth factor receptor</span> (PDGFR). Sus indicaciones fundamentales son la leucemia mieloide crónica y los tumores del estroma gastrointestinal. En Dermatología se emplea en enfermedades como el dermatofibrosarcoma protuberans, esclerosis sistémica y mastocitosis sistémica, entre otras. Es un fármaco en general bien tolerado, con la mayoría de efectos adversos leves o moderados. Los efectos secundarios dermatológicos son muy frecuentes e incluyen erupciones cutáneas inespecíficas como edema o erupciones maculopapulosas o con características clínicas distintivas (liquenoides, psoriasiformes, pustulosis exantemática aguda generalizada, síndrome de Stevens- Johnson…). Identificar y tratar correctamente estas reacciones puede ayudar a optimizar la adherencia del paciente al tratamiento y mejorar el pronóstico de su enfermedad de base.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Pretel-Irazabal M, Tuneu-Valls A, Ormaechea-Pérez N. Efectos adversos cutáneos del imatinib (inhibidor de la tirosín cinasa). Actas Dermosifiliogr. 2014;105:655–662.</p>" ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 633 "Ancho" => 950 "Tamanyo" => 141217 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Seventy-year-old man diagnosed with gastrointestinal stromal tumor in treatment with imatinib for 3 months. Desquamative, pruritic macular-papular rash on the trunk and limbs.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 833 "Ancho" => 950 "Tamanyo" => 151018 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Fifty-one-year-old man diagnosed with chronic myeloid leukemia in treatment with imatinib for 1 month. Violaceous lichenoid lesions on the wrists and whitish plaques on the jugal mucosa, with histopathological diagnosis of mucosal lichen.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 713 "Ancho" => 950 "Tamanyo" => 172378 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Thirty-six-year-old man with <span class="elsevierStyleItalic">c-kit<span class="elsevierStyleSup">+</span></span> metastatic melanoma in treatment with imatinib for 3 years. Depigmentation of the hair follicles of the scalp, eyebrows, and eyelashes.</p>" ] ] 3 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Chronic Lymphocytic Leukemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Bcr-abl \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gastrointestinal stromal tumor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">c-kit \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypereosinophilic syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">FIP1L1-PDGFRα \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Systemic mastocytosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">FIP1L1-PDGFRα \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Chronic myelomonocytic leukemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TEL-PDGFRβ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dermatofibrosarcoma protuberans \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">COL1A1-PDGFβ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Melanoma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">c-kit \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab549021.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Therapeutic Targets in the Different Diseases in Which Imatinib Is Used.</p>" ] ] 4 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Abbreviation: IC, isolated case. Source: Adapted from Amitay-Laish et al.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Drug \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Cutaneous Side Effects (% of Cases Treated) \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Imatinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Superficial edema (48-65)Macular-papular eruption (∼67)Pigmentary disordersHypopigmentation/depigmentation (41)Hyperpigmentation (∼4)Lichenoid reactions (IC)Psoriasis and psoriasiform eruption (IC)Pityriasis rosea-like eruption (IC)Acute generalized exanthematous pustulosis (IC)Stevens-Johnson syndrome (IC)Urticaria (IC)Neutrophilic dermatosis (IC)Photosensitivity (IC)Porphyria (IC)Pseudoporphyria (IC) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dasatinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rash (macular, papular, exfoliative) (11-27)Mucositis/stomatitis (16)Pruritus (11)Panniculitis (IC) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nilotinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rash (10-28)Pruritus (17-24)Cutaneous xerosis (13-17)Alopecia (6) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab549020.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Side Effects of the Different Tyrosine Kinase Inhibitors.</p>" ] ] 5 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="4" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Adverse Effect</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">Grade</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">Macular-Papular Rash</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">Periorbital Edema</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">Skin Hyperpigmentation</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">Skin Hypopigmentation</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Macules/papules covering <10% body surface area with or without symptoms (eg pruritus, burning, tightness) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Soft or non-pitting \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hyperpigmentation covering<<span class="elsevierStyleHsp" style=""></span>10% of body surface area; no psychosocial impact \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypopigmentation or depigmentation <<span class="elsevierStyleHsp" style=""></span>10% of body surface area; no psychosocial impact \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Macules/papules covering 10%-30% body surface area with or without symptoms (eg, pruritus, burning, tightness); limiting instrumental activities of daily living \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Indurated or pitting edema; topical intervention indicated \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hyperpigmentation ><span class="elsevierStyleHsp" style=""></span>10% of body surface area; psychosocial impact \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypopigmentation or depigmentation ><span class="elsevierStyleHsp" style=""></span>10% of body surface area; psychosocial impact \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Macules/papules covering >30% body surface area with or without associated symptoms; limiting self-care activities of daily living \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Edema associated with visual disturbance; increased intraocular pressure, glaucoma or retinal hemorrhage; optic neuritis; diuretics indicated; operative intervention indicated \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">--- \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">--- \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">--- \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">--- \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">--- \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">--- \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab549022.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Classification of Severity of Adverse Cutaneous Reactions Most Frequently Associated With Imatinib Use: United States National Cancer Institute Scale Version 4, Which Classifies Severity According to 4 Grades.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:70 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Molecularly targeted treatment for dermatofibrosarcoma protuberans" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "G. 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| año/Mes | Html | Total | |
|---|---|---|---|
| 2024 Noviembre | 11 | 3 | 14 |
| 2024 Octubre | 240 | 61 | 301 |
| 2024 Septiembre | 284 | 45 | 329 |
| 2024 Agosto | 368 | 61 | 429 |
| 2024 Julio | 374 | 62 | 436 |
| 2024 Junio | 266 | 59 | 325 |
| 2024 Mayo | 270 | 61 | 331 |
| 2024 Abril | 198 | 35 | 233 |
| 2024 Marzo | 269 | 46 | 315 |
| 2024 Febrero | 306 | 39 | 345 |
| 2024 Enero | 255 | 52 | 307 |
| 2023 Diciembre | 279 | 34 | 313 |
| 2023 Noviembre | 301 | 39 | 340 |
| 2023 Octubre | 287 | 46 | 333 |
| 2023 Septiembre | 299 | 48 | 347 |
| 2023 Agosto | 190 | 32 | 222 |
| 2023 Julio | 184 | 45 | 229 |
| 2023 Junio | 183 | 27 | 210 |
| 2023 Mayo | 201 | 35 | 236 |
| 2023 Abril | 111 | 28 | 139 |
| 2023 Marzo | 114 | 32 | 146 |
| 2023 Febrero | 88 | 19 | 107 |
| 2023 Enero | 89 | 32 | 121 |
| 2022 Diciembre | 117 | 40 | 157 |
| 2022 Noviembre | 70 | 31 | 101 |
| 2022 Octubre | 79 | 33 | 112 |
| 2022 Septiembre | 92 | 40 | 132 |
| 2022 Agosto | 71 | 47 | 118 |
| 2022 Julio | 66 | 45 | 111 |
| 2022 Junio | 68 | 42 | 110 |
| 2022 Mayo | 161 | 46 | 207 |
| 2022 Abril | 205 | 45 | 250 |
| 2022 Marzo | 213 | 70 | 283 |
| 2022 Febrero | 221 | 38 | 259 |
| 2022 Enero | 237 | 60 | 297 |
| 2021 Diciembre | 185 | 58 | 243 |
| 2021 Noviembre | 204 | 68 | 272 |
| 2021 Octubre | 249 | 69 | 318 |
| 2021 Septiembre | 171 | 72 | 243 |
| 2021 Agosto | 246 | 71 | 317 |
| 2021 Julio | 205 | 56 | 261 |
| 2021 Junio | 203 | 33 | 236 |
| 2021 Mayo | 191 | 30 | 221 |
| 2021 Abril | 543 | 51 | 594 |
| 2021 Marzo | 245 | 45 | 290 |
| 2021 Febrero | 226 | 42 | 268 |
| 2021 Enero | 151 | 42 | 193 |
| 2020 Diciembre | 156 | 39 | 195 |
| 2020 Noviembre | 88 | 28 | 116 |
| 2020 Octubre | 141 | 42 | 183 |
| 2020 Septiembre | 111 | 31 | 142 |
| 2020 Agosto | 82 | 37 | 119 |
| 2020 Julio | 101 | 27 | 128 |
| 2020 Junio | 76 | 39 | 115 |
| 2020 Mayo | 60 | 32 | 92 |
| 2020 Abril | 632 | 39 | 671 |
| 2020 Marzo | 53 | 36 | 89 |
| 2020 Febrero | 2 | 10 | 12 |
| 2020 Enero | 0 | 5 | 5 |
| 2019 Diciembre | 3 | 15 | 18 |
| 2019 Noviembre | 0 | 9 | 9 |
| 2019 Octubre | 1 | 6 | 7 |
| 2019 Septiembre | 5 | 14 | 19 |
| 2019 Agosto | 0 | 11 | 11 |
| 2019 Julio | 0 | 29 | 29 |
| 2019 Junio | 2 | 31 | 33 |
| 2019 Mayo | 0 | 39 | 39 |
| 2019 Abril | 1 | 64 | 65 |
| 2019 Marzo | 2 | 11 | 13 |
| 2019 Febrero | 1 | 11 | 12 |
| 2019 Enero | 0 | 10 | 10 |
| 2018 Diciembre | 4 | 0 | 4 |
| 2018 Noviembre | 2 | 0 | 2 |
| 2018 Octubre | 5 | 0 | 5 |
| 2018 Septiembre | 2 | 8 | 10 |
| 2018 Agosto | 0 | 25 | 25 |
| 2018 Julio | 0 | 29 | 29 |
| 2018 Junio | 0 | 17 | 17 |
| 2018 Mayo | 0 | 19 | 19 |
| 2018 Abril | 0 | 17 | 17 |
| 2018 Marzo | 6 | 16 | 22 |
| 2018 Febrero | 222 | 26 | 248 |
| 2018 Enero | 162 | 33 | 195 |
| 2017 Diciembre | 176 | 16 | 192 |
| 2017 Noviembre | 114 | 26 | 140 |
| 2017 Octubre | 121 | 23 | 144 |
| 2017 Septiembre | 95 | 24 | 119 |
| 2017 Agosto | 110 | 28 | 138 |
| 2017 Julio | 103 | 37 | 140 |
| 2017 Junio | 88 | 34 | 122 |
| 2017 Mayo | 77 | 27 | 104 |
| 2017 Abril | 75 | 10 | 85 |
| 2017 Marzo | 76 | 33 | 109 |
| 2017 Febrero | 54 | 35 | 89 |
| 2017 Enero | 57 | 26 | 83 |
| 2016 Diciembre | 64 | 18 | 82 |
| 2016 Noviembre | 123 | 32 | 155 |
| 2016 Octubre | 136 | 29 | 165 |
| 2016 Septiembre | 94 | 28 | 122 |
| 2016 Agosto | 3 | 9 | 12 |
| 2016 Julio | 9 | 8 | 17 |
| 2016 Junio | 14 | 3 | 17 |
| 2016 Mayo | 4 | 1 | 5 |
| 2016 Abril | 12 | 2 | 14 |
| 2016 Marzo | 12 | 3 | 15 |
| 2016 Febrero | 14 | 21 | 35 |
| 2016 Enero | 11 | 5 | 16 |
| 2015 Diciembre | 21 | 11 | 32 |
| 2015 Noviembre | 14 | 3 | 17 |
| 2015 Octubre | 18 | 2 | 20 |
| 2015 Septiembre | 17 | 5 | 22 |
| 2015 Agosto | 10 | 2 | 12 |
| 2015 Julio | 115 | 10 | 125 |
| 2015 Junio | 73 | 10 | 83 |
| 2015 Mayo | 74 | 7 | 81 |
| 2015 Abril | 54 | 16 | 70 |
| 2015 Marzo | 65 | 3 | 68 |
| 2015 Febrero | 95 | 7 | 102 |
| 2015 Enero | 39 | 8 | 47 |
| 2014 Diciembre | 34 | 9 | 43 |
| 2014 Noviembre | 40 | 5 | 45 |
| 2014 Octubre | 61 | 14 | 75 |
| 2014 Septiembre | 23 | 4 | 27 |
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