Characteristics, Management, and Prognostic Implications of Adverse Effects of Immune Checkpoint Inhibitors: A Systematic Review

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"apellidos" => "Juan-Carpena" "email" => array:1 [ 0 => "gloria5289@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "J.C." "apellidos" => "Palazón-Cabanes" ] 2 => array:2 [ "nombre" => "M." "apellidos" => "Blanes-Martínez" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Dermatología, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Revisión sistemática de los efectos adversos cutáneos causados por fármacos inhibidores de los puntos de control inmunitario: características, manejo y pronóstico" ] ] "resumenGrafico" => array:2 [ "original" => 1 "multimedia" => array:5 [ "identificador" => "fig0025" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "fx1.jpeg" "Alto" => 955 "Ancho" => 1333 "Tamanyo" => 125456 ] ] ] ] "textoCompleto" => "IntroductionImmune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer. Their demonstrated efficacy and association with longer survival times have been demonstrated in a broad spectrum of advanced tumors.<a class="elsevierStyleCrossRefs" href="#bib0480">1–4</a>ICIs stimulate the immune system, activating tumor-destroying T cells, but as a consequence of this stimulus, diverse autoimmune or autoinflammatory events can be triggered.<a class="elsevierStyleCrossRefs" href="#bib0495">4–7</a> Known as immune-related adverse events (irAEs), they can appear in any organ or tissue, but among the most frequently described are dermatologic toxicities, found in approximately a third of patients on these drugs.<a class="elsevierStyleCrossRefs" href="#bib0495">4,7</a>Information from clinical trials on the incidence and profiles of dermatologic irAEs is difficult to evaluate because cutaneous toxicity is usually recorded in generical terms in clinical trials.<a class="elsevierStyleCrossRefs" href="#bib0515">8,9</a> Our current understanding of these reactions therefore comes mainly from clinical practice as reflected in retrospective studies, case series, and individual case reports, with all the limitations those sources imply.<a class="elsevierStyleCrossRefs" href="#bib0495">4,5,9</a>Our aim was to review and synthesize the literature on irAEs in patients being treated with ICIs, describe the reactions, the drug regimens used, and the prognostic implications.MethodsWe used the terms immune checkpoint inhibitors and skin toxicity to search PubMed and the Web of Science for the period from January 2015 to May 2021. We also searched the Cochrane Library without specifying time limits. Two authors (G.J.C. and M.B.M.) independently reviewed titles and abstracts to select articles with information on the frequency and characteristics of cutaneous irAEs in patients with ICI-treated cancer, on the treatments that are used, or on prognosis. Other relevant articles were identified by searching the reference lists of the retrieved articles.Relevant articles could report any study design and be published in English or Spanish provided they included data on the number or percentages of patients on ICIs, measured associations or survival rates, or at least described in detail the observed skin eruptions (including type of rash, type of ICIs, and latency from the start of treatment). Any type of ICI in monotherapy or in combination was of interest for the review. Two authors (G.J.C. and M.B.M.) independently read the full texts of the selected articles. Articles without abstracts were also read in full. We included the most up-to-date articles, excluding older ones whose results were included in more recent publications or that had redundant information.ResultsThe literature search suggested a total of 394 articles. Ninety-five with up-to-date information were selected for the final review (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Among those chosen were 2 systematic reviews, 4 meta-analyses, and 1 clinical trial. The remaining references were retrospective studies, narrative reviews, and case reports or case series.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Pathogenesis and FrequencyTwo groups of ICIs are currently available: cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors and programmed cell death protein 1 (PD1) or ligand 1 (PDL1) inhibitors (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). The CTLA-4 receptor controls the immune response in stages prior to the PD1/PDL1 pathway, which regulates later stages of response, mainly involving peripheral tissues.<a class="elsevierStyleCrossRef" href="#bib0480">1</a> The pathogenesis of irAEs is not yet fully understood. However, although it is known that the activation of CD4+ and CD8+ T cells produced by blocking PD1 and PDL1 is beneficial from the perspective of cancer treatment due to the effect on tumor cells, their inhibition also plays a fundamental role in the development of irAEs in general and cell toxicity in particular.<a class="elsevierStyleCrossRef" href="#bib0480">1</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Even though all ICIs have similar safety profiles, there are differences in irAE type, frequency, latency, and seriousness associated with each ICI, given that molecular targets and pharmacokinetic characteristics differ from one to another.<a class="elsevierStyleCrossRefs" href="#bib0500">5,6</a>Ipilimumab induces dose-dependent skin irAEs more often than PD1/PDL1 blockers (in 50% vs 10%–30%) of cases.<a class="elsevierStyleCrossRefs" href="#bib0485">2,8–12</a> In addition, ipilimumab-associated events occur earlier after start of treatment and are more severe.<a class="elsevierStyleCrossRefs" href="#bib0480">1–3</a> Ipilimumab in combination with PD1/PDL1 blockers has been linked to the highest incidences of cutaneous toxicity of any degree of severity, especially if pembrolizumab is part of the regimen.<a class="elsevierStyleCrossRefs" href="#bib0505">6,9</a> PD1 inhibitors (mainly pembrolizumab) confer higher risk of dermatologic irAEs than PDL1 inhibitors do, whereas avelumab is associated with lower risk.<a class="elsevierStyleCrossRef" href="#bib0500">5</a>It is important to point out that various irAEs can coincide in the same patient and that multisystem irAEs develop in up to 9% of those treated. Common associations are dermatitis–pneumonitis and dermatitis–thyroiditis. Skin toxicities often appear first.<a class="elsevierStyleCrossRef" href="#bib0525">10</a>Associations between type of irAE and tumor type have recently been suggested, given that more cases of skin irAEs have been reported in patients with melanoma than other tumors.<a class="elsevierStyleCrossRef" href="#bib0495">4</a> However, we think caution is called for when interpreting this association, as it could be a product of reporting bias, arising from the fact that dermatologists are usually involved in the treatment and follow-up of melanoma.Types of Cutaneous Toxicity and CharacteristicsThe irAEs most often reported in clinical trials are exanthema (rash or dermatitis), pruritus, vitiligo, and hair loss.<a class="elsevierStyleCrossRefs" href="#bib0495">4,5,8,9</a> However, more diverse ICI-induced dermatologic toxicities are found in clinical practice. We base this review on the classification most commonly used at this time.<a class="elsevierStyleCrossRefs" href="#bib0540">13,14</a> It consists of the following 4 large groups: inflammatory conditions, immunobullous conditions, alterations of keratinocytes, and alterations of epidermal melanocytes. Some authors, however, consider these categories to be imprecise and have modified them. We will group melanocytic changes in a larger category of pigmentary alterations and also add 2 sections: hair and nail involvement and other rare dermatoses.<a class="elsevierStyleCrossRef" href="#bib0530">11</a>The severity of toxicities is usually evaluated with the Common Terminology Criteria for Adverse Events (CTCAE), which specifies 4 grades according to the affected body surface area (BSA) (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<a class="elsevierStyleCrossRefs" href="#bib0540">13,15,16</a> Some authors, however, recommend also taking the nature of a dermatosis into consideration in order to more precisely characterize the severity of the clinical picture.<a class="elsevierStyleCrossRefs" href="#bib0540">13,15,17,18</a><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Inflammatory EruptionsMaculopapular RashesAlong with pruritus, maculopapular rashes are the most common irAEs. They develop in approximately 25% of ipilimumab-treated patients, 15% of those on anti-PD1 antibody treatments, and 10% of those on anti-PDL1 drugs. Up to 45% of patients on combined anti-CTLA-4/PD1 therapy can be affected, however.<a class="elsevierStyleCrossRefs" href="#bib0520">9,13,18</a> The rashes tend to be mild: fewer than 3% of cases are rated grade 3 or higher in severity.<a class="elsevierStyleCrossRef" href="#bib0520">9</a>The eruption typically develops early, in the first 2 to 6 weeks of treatment, although it may also appear later. The fairly nonspecific clinical signs are confluent, pruritic maculopapular lesions on the trunk and sometimes on the extremities. Peripheral blood eosinophilia may be detected.<a class="elsevierStyleCrossRefs" href="#bib0565">18,19</a>The most common histologic pattern is that of a spongiotic dermatitis with a superficial perivascular lymphocytic infiltrate with eosinophils, although a lichenoid pattern has also been reported on occasion.<a class="elsevierStyleCrossRefs" href="#bib0565">18,20,21</a>Because this irAE is mild, it can usually be managed with symptomatic therapy (oral antihistamines and topical corticosteroids), even when 30% of the BSA is covered; if the rash is refractory to topical applications, systemic corticosteroids are needed.<a class="elsevierStyleCrossRefs" href="#bib0540">13,15,16,18,22</a>A maculopapular rash may precede other skin conditions. Follow-up is therefore necessary, and clinically atypical, severe, persistent, or recurrent lesions should be biopsied.<a class="elsevierStyleCrossRefs" href="#bib0530">11,17,18,22–25</a>PruritusPruritus is one of the most prevalent irAEs, presenting in up to 32% of patients on ICIs.<a class="elsevierStyleCrossRef" href="#bib0605">26</a> Itching may be associated with other dermatoses, be the first sign of more severe irAEs such as bullous pemphigoid, or be an isolated event indicating increased activation of the skin's immune system.If xerosis is present, the pruritus must be treated. When itching is mild or intermittent (grades 1–2), topical corticosteroids, oral antihistamines, and emollient creams are recommended. In cases in which symptoms are difficult to control and greatly impair the patient's quality of life (grade 3), treatments that have been used include γ-aminobutyric acid A receptor antagonists, aprepitant, phototherapy, naloxone, naltrexone, omalizumab, and dupilumab. The reported results vary. Treatment with the culprit drug must be suspended on rare occasions.<a class="elsevierStyleCrossRefs" href="#bib0540">13,22,26–29</a>Lichenoid EruptionsLichenoid reactions have been reported mainly in association with anti-PD1/PDL1 drugs, and according to some authors these rashes have the histopathologic pattern most often seen in ICI-associated irAEs.<a class="elsevierStyleCrossRefs" href="#bib0570">19,21,23,30,31</a>Lichenoid eruptions develop later than maculopapular rashes, appearing at 3 months from the start of treatment on average (range, 1 day to 14 months).<a class="elsevierStyleCrossRefs" href="#bib0590">23,31,32</a> Clinical signs vary from forms resembling lichen planus to more atypical presentations with hypertrophic or erosive lesions. They may also resemble lichen planus pemphigoides or lichen sclerosus. Nail alterations are sometimes observed.<a class="elsevierStyleCrossRefs" href="#bib0580">21,23,31,33,34</a> Pruritus is a common symptom and may be difficult to treat.<a class="elsevierStyleCrossRef" href="#bib0650">35</a> Mucosal involvement is not unusual and may be the only presentation, in the form of whitish striae or erosive or atrophic lesions (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>, A and B). Characteristics may sometimes overlap with those of eczematous dermatitis or resemble a maculopapular rash. In such cases a definitive histopathologic diagnosis is required,<a class="elsevierStyleCrossRefs" href="#bib0565">18,21,23,31,33,34</a> meaning that the incidence of lichenoid dermatitis may be underestimated.<a class="elsevierStyleCrossRefs" href="#bib0560">17,20,35</a><elsevierMultimedia ident="fig0010"></elsevierMultimedia>Biopsy can demonstrate the classic changes of lichen planus: a band-like lymphocytic infiltrate, hypergranulosis, and irregular acanthosis. However, spongiosis, parakeratosis, eosinophils, or a slight degree of interface dermatitis may be evident, consistent with a diagnosis of lichenoid dermatitis.<a class="elsevierStyleCrossRefs" href="#bib0575">20,21,23,33</a>Corticosteroids are the first line of treatment. Even rashes covering a large area respond well. If the eruption is refractory, systemic corticosteroids, phototherapy, oral acitretin, or even methotrexate or apremilast may be prescribed. Treatment with the culprit drug generally need not be suspended; in some cases therapy has been restarted without recurrence of the reaction.<a class="elsevierStyleCrossRefs" href="#bib0560">17,23,33,35</a>Lichenoid eruptions have been associated with a good response to oncologic therapy.<a class="elsevierStyleCrossRef" href="#bib0635">32</a>Eczematous EruptionsEczemas occur mainly in patients on anti-PD1/PDL1 inhibitors.<a class="elsevierStyleCrossRefs" href="#bib0545">14,19,30</a>They typically present later than maculopapular rashes, usually after 3 months of treatment.<a class="elsevierStyleCrossRefs" href="#bib0570">19,32</a> However, they may appear up to 2 years after therapy.<a class="elsevierStyleCrossRef" href="#bib0625">30</a> Lesions may be generalized or local and are usually accompanied by pruritus.<a class="elsevierStyleCrossRefs" href="#bib0570">19,30</a> On biopsy, spongiosis can be seen in the epidermis and a perivascular inflammatory infiltrate in the dermis.<a class="elsevierStyleCrossRef" href="#bib0575">20</a>Depending on severity, topical or systemic corticosteroids, topical tacrolimus, oral antihistamines, or UV-B phototherapy may be prescribed.<a class="elsevierStyleCrossRef" href="#bib0625">30</a>PsoriasisReports of both de novo and exacerbated psoriasis associated with anti-PD1 inhibitors, and less often with anti-PDL1 blockers and ipilimumab, have been published.<a class="elsevierStyleCrossRef" href="#bib0655">36</a> Mean latency after start of therapy ranges from 1 to 8 months. Exacerbations present earlier than de novo cases.<a class="elsevierStyleCrossRefs" href="#bib0655">36–38</a>The most common form of presentation is plaque psoriasis, followed by palmoplantar psoriasis. Pustular forms (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>C) have been documented as have guttate, inverse, erythrodermic, and nail psoriasis, as well as sebopsoriasis, combinations of subtypes, and associations with psoriatic arthritis.<a class="elsevierStyleCrossRefs" href="#bib0660">37–40</a>Histologic findings tend to be those typical of eczema, although a degree of spongiosis has also been reported, especially in inverse psoriasis lesions.<a class="elsevierStyleCrossRefs" href="#bib0570">19,20</a>The pathogenic mechanisms are unclear, but it appears that PD1 inhibition activates Th1 and Th17 pathways with consequent overexpression of interferon-γ, IL-2, tumor necrosis factor, IL-6, and IL-17.<a class="elsevierStyleCrossRefs" href="#bib0545">14,20,36</a>Symptoms are usually mild (BSA≤10%) in most patients and respond well to high-potency topical corticosteroids combined with calcipotriol.<a class="elsevierStyleCrossRefs" href="#bib0655">36,38</a> Adding phototherapy (narrowband UV-B) or acitretin is recommended if there is no response. Refractory cases can be treated with methotrexate, apremilast, or biologics (preferably anti-tumor necrosis factor agents) as a last resort; results vary.<a class="elsevierStyleCrossRefs" href="#bib0560">17,38,39</a> Systemic corticosteroids have been used, but they are best reserved for achieving a rapid response or after other measures have failed.<a class="elsevierStyleCrossRefs" href="#bib0665">38,39</a> The culprit drug must be suspended temporarily or definitively in fewer than half the cases.<a class="elsevierStyleCrossRefs" href="#bib0655">36,38</a>Sarcoidosis-Like Granulomatous EruptionsGranulomatous dermatitis resembling sarcoidosis appears in a variable percentage of patients on ICIs—ranging from 0.65% to 22% in different series.<a class="elsevierStyleCrossRefs" href="#bib0680">41–43</a> These reactions have been reported with the use of anti-PD1/PDL1 antibodies and ipilimumab.<a class="elsevierStyleCrossRefs" href="#bib0565">18,41,43</a>Latency ranges from 1.5 to 7 months after start of therapy, although reactions can develop several months after treatment stopped. The organs most commonly affected are the mediastinal and hilar lymph nodes, the lungs, and the skin. Skin signs consist of erythematous papules or nodules coalescing into plaques; the lesions are pruritic, sometimes painful, and located on the face or extremities.<a class="elsevierStyleCrossRefs" href="#bib0680">41–43</a> Histology demonstrates nonnecrotizing granulomas.<a class="elsevierStyleCrossRefs" href="#bib0575">20,41</a>A proliferation of Th1 and Th17 cells induced by anti-CTLA-4 antibodies has been reported. The adverse reaction could be paradoxical, however, given that patients with sarcoidosis have higher expression of PD1 in T cells. Thus, blocking the PD1 receptor could be considered a therapeutic strategy in this disease.<a class="elsevierStyleCrossRefs" href="#bib0575">20,41,43</a>Skin lesions are treated with high-potency topical corticosteroids. If the response is unsatisfactory, systemic corticosteroids are prescribed. Oral hydroxychloroquine has occasionally been used.<a class="elsevierStyleCrossRef" href="#bib0680">41</a> Lymph node and lung involvement must be ruled out. When skin lesions are persistent or extensive, radiologic signs progress, lung function deteriorates, or other organs are affected, systemic corticosteroids should be started and the culprit ICI suspended. Once the corticosteroid dose has been reduced to 10mg/kg/d or less and the patient is asymptomatic, restarting ICI therapy can be considered.<a class="elsevierStyleCrossRefs" href="#bib0680">41–43</a>Neutrophilic DermatosesSeveral types of neutrophilic dermatoses, mainly Sweet syndrome, have been linked to ICIs. The characteristics of these irAEs are given in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>.<a class="elsevierStyleCrossRefs" href="#bib0695">44,45</a><elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Serious Adverse Skin ReactionsThe frequency of serious skin reactions to ICIs is low, affecting fewer than 3% of patients on these drugs,<a class="elsevierStyleCrossRefs" href="#bib0500">5,9,14,24</a> but cases of Stevens–Johnson syndrome, toxic epidermal necrolysis (TEC), DRESS (drug reaction with eosinophilia and systemic symptoms), and acute generalized exanthematous pustulosis have been reported.<a class="elsevierStyleCrossRefs" href="#bib0545">14,24,44,46–48</a>ICI-induced cases of TEC can have atypical, late presentations that develop up to 12 weeks after therapy started. These irAEs begin as maculopapular eruptions and persist for weeks until blistering and epidermal detachment appear.<a class="elsevierStyleCrossRefs" href="#bib0565">18,24,48,49</a>Biopsy for direct immunofluorescence is indicated in such cases to rule out an immunobullous reaction.<a class="elsevierStyleCrossRef" href="#bib0715">48</a> The culprit agent must be suspended, the patient hospitalized, and life support measures initiated. Systemic corticosteroids are recommended to treat ICI-induced TEC, unlike TEC induced by other drugs. Treatment continues until symptoms improve to grade 1, at which point the dose is gradually reduced.<a class="elsevierStyleCrossRefs" href="#bib0540">13,15,16,24,48</a> Intravenous infliximab, ciclosporin, and immunoglobulins have been used.<a class="elsevierStyleCrossRefs" href="#bib0560">17,24,49</a> Mortality can be as high as 50%–60%.<a class="elsevierStyleCrossRefs" href="#bib0715">48,49</a>Eruptions Resembling Connective Tissue DiseasesConnective tissue diseases associated with ICIs are emerging toxicities.<a class="elsevierStyleCrossRefs" href="#bib0725">50–55</a> De novo diseases account for 0.025% of the observations in patients on ICI therapy, and the incidence is similar in men and women. They develop mainly in the context of treatment with anti-PD1/PDL1<a class="elsevierStyleCrossRefs" href="#bib0725">50,52</a> antibodies. Cases of subacute lupus erythematosus have been described and are the most common irAE in this category. Reports of scleroderma, dermatomyositis, and eosinophilic fasciitis have also been published.<a class="elsevierStyleCrossRef" href="#bib0725">50</a> The average latency is 8 months (range, 0.5–26 months). Clinical features are the typical ones,<a class="elsevierStyleCrossRef" href="#bib0725">50</a> save for the fact that scleroderma due to pembrolizumab is more diffuse and of rapid onset, while nivolumab induces a more localized reaction.<a class="elsevierStyleCrossRef" href="#bib0735">52</a>Immunobullous EruptionsBullous pemphigoid is the main type of immunobullous eruption, although individual cases of herpetiform and linear IgA dermatoses have also been reported.<a class="elsevierStyleCrossRefs" href="#bib0530">11,14,56</a>Bullous pemphigoid, which has an incidence of 1% to 8%, has usually been linked to combined anti-PD1/PDL1 treatment, but has occasionally been associated with ipilimumab.<a class="elsevierStyleCrossRefs" href="#bib0545">14,19,25,56–58</a>Developing 6 months after start of treatment (range, 2 weeks to 25 months),<a class="elsevierStyleCrossRefs" href="#bib0570">19,25,56,57,59–61</a> these reactions have a typical clinical picture of intense pruritus, erythema, edema, and tense blisters filled with clear fluid. They may be scattered over any part of the body (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>, A–C), localized, affect mucosal surfaces, or progress without blistering.<a class="elsevierStyleCrossRefs" href="#bib0755">56,60,62</a> There is usually a prebullous phase of a few weeks (in 34.5%) or a period with pruritus but no lesions.<a class="elsevierStyleCrossRefs" href="#bib0600">25,57,60,61</a> Subepidermal blisters rich in eosinophils are a typical finding in biopsied tissue, and direct immunofluorescence shows linear IgG and C3 deposition.<a class="elsevierStyleCrossRefs" href="#bib0575">20,56,60,61,63</a><elsevierMultimedia ident="fig0015"></elsevierMultimedia>One pathogenic mechanism proposed is cross reactivity between cutaneous and tumor antigens (as melanomas and microcytic carcinomas seem to express BP180). Another is a worsening of preexisting, subclinical pemphigoid disease due to immune system stimulus. It is unclear whether B-cell activation (caused by anti-BP180 antibodies) occurs directly on contact with ICIs or is mediated by T cells.<a class="elsevierStyleCrossRefs" href="#bib0575">20,62–64</a>For a minority of patients, symptoms can be controlled with topical corticosteroids, but more severe symptoms (grade 2 or higher) require systemic treatment. Many also require additional drugs, such as doxycycline, nicotinamide, dapsone, methotrexate, intravenous immunoglobulins, omalizumab, or rituximab. In half or more cases, ICI therapy must be suspended and systemic corticosteroids maintained, given that the clinical picture may be persistent—lasting months after the ICI is withdrawn—or recurrent.<a class="elsevierStyleCrossRefs" href="#bib0530">11,26,27,56,57,60,61</a>Some authors have reported an association between this toxicity or elevated anti-BP180 IgG titers on the one hand and a favorable response to oncologic therapy on the other.<a class="elsevierStyleCrossRefs" href="#bib0795">64,65</a>Alterations in KeratinocytesGrover disease has been reported in association with both anti-CTLA-4 and anti-PD1/PDL1 drugs.<a class="elsevierStyleCrossRefs" href="#bib0565">18,19</a> Authors recommend biopsying lesions to confirm the diagnosis, as samples show the typical signs of Grover disease.<a class="elsevierStyleCrossRefs" href="#bib0530">11,17,18,20</a>Actinic keratosis, basal cell carcinoma, seborrheic warts, epidermoid carcinoma, and eruptive keratoacanthomas have been reported in patients on anti-PD1/PDL1 blockers.<a class="elsevierStyleCrossRefs" href="#bib0545">14,30</a> The pathogenic mechanism in relation to ICIs is unknown.Pigmentary ChangesVitiligoVitiligo is a common adverse effect linked to both anti-CTLA-4 and anti-PD1/PDL1 therapy. It develops mainly in patients with melanoma, the incidence ranging from 2.8% to 48% in case series.<a class="elsevierStyleCrossRefs" href="#bib0545">14,30,66,67</a> This irAE has also been reported in ICI-treated patients with lung cancer, however.<a class="elsevierStyleCrossRefs" href="#bib0815">68,69</a>Latency after start of treatment ranges from 30 to 758 days.<a class="elsevierStyleCrossRefs" href="#bib0805">66,67,70,71</a> Reactive vitiligo differs from the common form in that it usually presents with mottled lesions that merge into larger macules distributed across sun-exposed parts of the body (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>, A and B) and is not associated with the Koebner phenomenon.<a class="elsevierStyleCrossRefs" href="#bib0805">66,70,72</a> In addition, according to Larsabal et al.,<a class="elsevierStyleCrossRef" href="#bib0825">70</a> patients with this irAE have no family or personal histories of vitiligo, thyroiditis, or autoimmune disease but do have elevated expression of CXCR3 on CD8+ T cells in blood and perilesional tissues.<a class="elsevierStyleCrossRef" href="#bib0825">70</a><elsevierMultimedia ident="fig0020"></elsevierMultimedia>The pathogenic mechanism that has been suggested is cross reactivity between tumor cells and melanocytic antigens (glycoprotein 100, MelanA/MART-1, tyrosinase, etc.).<a class="elsevierStyleCrossRefs" href="#bib0565">18,20,66,67</a>Lesions persist after ICI therapy is interrupted. Specific treatment other than protection from sun exposure is unnecessary, although topical corticosteroids, topical tacrolimus, phototherapy, and laser therapy have all been tried, with limited results.<a class="elsevierStyleCrossRefs" href="#bib0560">17,18,59,67,69,73</a>Both the appearance of vitiligo and its spread and progression have been related to a favorable response to oncologic treatment.<a class="elsevierStyleCrossRefs" href="#bib0635">32,66,72,74–76</a>Other Pigmentary AlterationsRepigmentation of gray hair and regression of preexisting melanocytic nevi or the appearance of poliosis (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>B), associated or not with vitiligo have been described in patients with ICI-treated melanoma.<a class="elsevierStyleCrossRefs" href="#bib0545">14,18,67,73</a>Hair and Nail AbnormalitiesThe various types of hair and nail alterations that have been reported are listed in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>. Hair loss—mainly alopecia areata—is the most common event, with an incidence ranging from 1% to 27% according to sources consulted.<a class="elsevierStyleCrossRefs" href="#bib0520">9,18</a><elsevierMultimedia ident="tbl0020"></elsevierMultimedia>Other Dermatoses<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a> lists other dermatoses that have been reported sporadically in single case reports. Most are inflammatory in nature. Their pathogenesis and the prognostic implications are unknown.<elsevierMultimedia ident="tbl0025"></elsevierMultimedia>Managing Skin ToxicitiesGiven the frequency of and morbidity associated with cutaneous irAEs, dermatology plays an important role in the multidisciplinary care of patients on ICIs. Dermatologists intervene by providing a precise diagnosis, optimal management of treatment, and a proper perspective on the prognostic relevance of skin reactions.<a class="elsevierStyleCrossRef" href="#bib0840">73</a>Dermatologists should be involved early in the care of these patients to assess skin condition at baseline, before ICIs are introduced, or patients should at least be referred to us soon after a cutaneous toxicity appears.<a class="elsevierStyleCrossRefs" href="#bib0585">22,67,73</a> When a skin reaction presents, a detailed clinical history and an exhaustive physical examination of the skin and mucosal surfaces are necessary, and infections must be ruled out along with possible adverse effects due to other drug treatments or systemic diseases.<a class="elsevierStyleCrossRef" href="#bib0585">22</a>The treatment of cutaneous irAEs will be based on severity, as mentioned earlier. CTCAE categories in function of BSA are currently used to classify severity.<a class="elsevierStyleCrossRefs" href="#bib0540">13,15,16,18</a> However, some authors find this grading system to be inadequate and call for evaluations based on the nature of the particular skin eruption, its location, and its effect on quality of life.<a class="elsevierStyleCrossRefs" href="#bib0560">17,77</a>Throughout the sections of this review we have pointed out that systemic corticosteroids are the cornerstone in the management of serious cutaneous toxicities (grade 2 or higher). Nonetheless, their impact on survival is a point of contention. Some studies suggest that high doses of prednisone (>10mg/d) could reduce the efficacy of ICIs and lead to a poor oncologic outcome.<a class="elsevierStyleCrossRefs" href="#bib0495">4,78,79</a> Others report that such doses do not have a negative effect on tumor response, provided the corticosteroid had not been administered before the ICI was started.<a class="elsevierStyleCrossRefs" href="#bib0560">17,80,81</a> Nonetheless, whenever possible, dermatologists should attempt to use other treatment modalities that can target the particular toxicity.<a class="elsevierStyleCrossRef" href="#bib0560">17</a>Prognostic Significance of irAEsMore and more studies are reporting associations between cutaneous irAEs in general and certain reactions in particular on the one hand and tumor response rates on the other—as well as their association with longer progression-free and overall survival rates.<a class="elsevierStyleCrossRefs" href="#bib0495">4,10,32,38,64–66,71,72,74–76,82,83</a> However, like other authors, we believe these observations must be interpreted cautiously given the limitations of the retrospective and small-scale studies on which the conclusions are based. Moreover, the clinical significance of severe irAEs is still unclear and bias in the analysis of survival is difficult to control for: it is possible that patients who live longer also develop more irAEs simply because they have been in treatment longer.<a class="elsevierStyleCrossRefs" href="#bib0600">25,38,78,79,84</a>ConclusionsICIs are the future of oncologic therapy, and the incidence of cutaneous toxicities derived from them will rise. Although our understanding of irAEs is improving, many issues remain to be clarified regarding their characterization and classification, pathogenesis, management, and relation to prognosis. Dermatologists play an essential role in diagnosing and treating toxicities, many of which have considerable impact on cancer patients’ quality of life.Conflict of InterestsThe authors declare that they have no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:15 [ 0 => array:3 [ "identificador" => "xres1718478" "titulo" => "Graphical abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:3 [ "identificador" => "xres1718480" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 2 => array:2 [ "identificador" => "xpalclavsec1518648" "titulo" => "Keywords" ] 3 => array:3 [ "identificador" => "xres1718479" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0015" ] ] ] 4 => array:2 [ "identificador" => "xpalclavsec1518647" "titulo" => "Palabras clave" ] 5 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 6 => array:2 [ "identificador" => "sec0010" "titulo" => "Methods" ] 7 => array:2 [ "identificador" => "sec0015" "titulo" => "Results" ] 8 => array:2 [ "identificador" => "sec0020" "titulo" => "Pathogenesis and Frequency" ] 9 => array:3 [ "identificador" => "sec0025" "titulo" => "Types of Cutaneous Toxicity and Characteristics" "secciones" => array:6 [ 0 => array:3 [ "identificador" => "sec0030" "titulo" => "Inflammatory Eruptions" "secciones" => array:9 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Maculopapular Rashes" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Pruritus" ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "Lichenoid Eruptions" ] 3 => array:2 [ "identificador" => "sec0050" "titulo" => "Eczematous Eruptions" ] 4 => array:2 [ "identificador" => "sec0055" "titulo" => "Psoriasis" ] 5 => array:2 [ "identificador" => "sec0060" "titulo" => "Sarcoidosis-Like Granulomatous Eruptions" ] 6 => array:2 [ "identificador" => "sec0065" "titulo" => "Neutrophilic Dermatoses" ] 7 => array:2 [ "identificador" => "sec0070" "titulo" => "Serious Adverse Skin Reactions" ] 8 => array:2 [ "identificador" => "sec0075" "titulo" => "Eruptions Resembling Connective Tissue Diseases" ] ] ] 1 => array:2 [ "identificador" => "sec0080" "titulo" => "Immunobullous Eruptions" ] 2 => array:2 [ "identificador" => "sec0085" "titulo" => "Alterations in Keratinocytes" ] 3 => array:3 [ "identificador" => "sec0090" "titulo" => "Pigmentary Changes" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0095" "titulo" => "Vitiligo" ] 1 => array:2 [ "identificador" => "sec0100" "titulo" => "Other Pigmentary Alterations" ] ] ] 4 => array:2 [ "identificador" => "sec0105" "titulo" => "Hair and Nail Abnormalities" ] 5 => array:2 [ "identificador" => "sec0110" "titulo" => "Other Dermatoses" ] ] ] 10 => array:2 [ "identificador" => "sec0115" "titulo" => "Managing Skin Toxicities" ] 11 => array:2 [ "identificador" => "sec0120" "titulo" => "Prognostic Significance of irAEs" ] 12 => array:2 [ "identificador" => "sec0125" "titulo" => "Conclusions" ] 13 => array:2 [ "identificador" => "sec0130" "titulo" => "Conflict of Interests" ] 14 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2021-06-30" "fechaAceptado" => "2021-09-26" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1518648" "palabras" => array:5 [ 0 => "Immune checkpoint inhibitors" 1 => "Cutaneous immune-related adverse events" 2 => "Skin toxicity" 3 => "Immunotherapy" 4 => "Programmed cell death protein 1 inhibitors" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1518647" "palabras" => array:5 [ 0 => "Puntos de control inmunitario" 1 => "Efectos adversos inmunorrelacionados" 2 => "Toxicidad cutánea" 3 => "Inmunoterapia" 4 => "Inhibidores de PD-1" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Immune checkpoint inhibitors (ICIs) have significantly advanced the treatment of cancer. They are not, however, free of adverse effects. These effects are called immune-related adverse events (irAEs) and often involve the skin. Most of the information on cutaneous irAEs comes from clinical practice. We therefore conducted a thorough review of the characteristics of cutaneous irAEs, recommendations for treatment, and their association with prognosis. The most common events are exanthema, pruritus, vitiligo, and hair loss, although ICIs can cause a wide range of cutaneous dermatoses. The reported association observed between certain reactions and a favorable response to cancer treatment should be interpreted with caution. Dermatologists should be involved in the multidisciplinary care of patients being treated with ICIs as they have an essential role in the diagnosis and treatment of cutaneous irAEs." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Los fármacos inhibidores de los puntos de control inmunitario han supuesto un importante avance en el tratamiento oncológico. Sin embargo, su uso no está exento de reacciones no deseadas, denominadas efectos adversos inmunorrelacionados, siendo los cutáneos particularmente frecuentes. El conocimiento que tenemos sobre los efectos adversos inmunorrelacionados cutáneos procede fundamentalmente de la práctica clínica. Por lo tanto, en este trabajo se revisan en detalle sus características, así como las recomendaciones sobre su tratamiento y sus implicaciones pronósticas. Los más frecuentes son el exantema, el prurito, el vitíligo y la alopecia; sin embargo, estos fármacos pueden producir una amplia variedad de dermatosis. La asociación observada entre ciertos tipos de reacciones cutáneas con una respuesta oncológica favorable al tratamiento debe interpretarse con cautela. El dermatólogo ha de participar en el cuidado multidisciplinar de estos pacientes, pues desempeña un papel fundamental en el diagnóstico y el tratamiento de estas reacciones cutáneas adversas." ] ] "multimedia" => array:10 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2056 "Ancho" => 2500 "Tamanyo" => 259940 ] ] "descripcion" => array:1 [ "en" => "Flow diagram of article retrieval, processing, and reading, where irAE refers to cutaneous immune-related adverse event." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1262 "Ancho" => 1500 "Tamanyo" => 244107 ] ] "descripcion" => array:1 [ "en" => "Inflammatory dermatoses. A and B, Erosive oral lesions in a 60-year-old man with stage IV adenocarcinoma of the bronchi and lungs in treatment with durvalumab. Histology demonstrated lichenoid dermatitis. C, Plantar pustulosis in a 68-year-old woman with stage IV adenocarcinoma of the bronchi and lungs in treatment with pembrolizumab." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1076 "Ancho" => 1500 "Tamanyo" => 263456 ] ] "descripcion" => array:1 [ "en" => "A–C, Very extensive bullous pemphigoid eruption in a 69-year-old man on combined durvalumab and tremelimumab treatment for stage IV nonsmall cell lung cancer. Lesions persisted even after treatment was interrupted." ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1359 "Ancho" => 900 "Tamanyo" => 158221 ] ] "descripcion" => array:1 [ "en" => "Extensive vitiligo in a 69-year-old man treated with nivolumab for stage IV squamous cell carcinoma. The patient had no personal or family history of vitiligo. A, Confluence of mottled hypopigmented macules on the back. B, Vitiligo of the scalp associated with the whitened hair of poliosis." ] ] 4 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; EMA, European Medicines Agency; ICI, immune checkpoint inhibitor; PD1, programmed cell death protein 1; PDL1, ligand of PD1." "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"><th 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" scope="col" style="border-bottom: 2px solid black">ICI type \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">EMA approval date \t\t\t\t\t\t\n \t\t\t\t\t\t</th></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 " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-CTLA-4</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ipilimumab \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">July 2011 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tremelimumab \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">July 2019 \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 " colspan="2" align="left" valign="\n \t\t\t\t\ttop\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 " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-PD1</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nivolumab \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">June 2015 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pembrolizumab \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">July 2015 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cemiplimab \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">June 2019 \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 " colspan="2" align="left" valign="\n \t\t\t\t\ttop\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 " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-PDL1</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Atezolizumab \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">September 2017 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Avelumab \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">September 2017 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Durvalumab \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">September 2018 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2917546.png" ] ] ] ] "descripcion" => array:1 [ "en" => "ICI Types and Dates of Approval by the EMA." ] ] 5 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Source: Haanen et al.<a class="elsevierStyleCrossRef" href="#bib0540">13</a>Abbreviations: ADL, activities of daily living; BSA, body surface area; CTCAE, Common Terminology Criteria for Adverse Events; ICU, intensive care unit; TEC, toxic epidermal necrolysis; SJS, Stevens–Johnson syndrome." "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"><th 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" scope="col" style="border-bottom: 2px solid black">Grade \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Characteristics \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " 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">Covering<10% BSA, with or without symptoms (pruritus, burning, tightness) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " 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">Covering 10%–30% BSA, with or without symptoms; ADL interference \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " 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">Covering>30% BSA, with or without symptoms; ADL interference \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " 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">SJS, TEC, bullous dermatitis covering>30% BSA requiring hospitalization and ICU admission \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2917545.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Severity of Skin irAEs Graded According to the CTCAE and Exemplified by Maculopapular Rashes." ] ] 6 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviation: ICI, immune checkpoint inhibitor." "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"><th 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" scope="col" style="border-bottom: 2px solid black">Type \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Characteristics \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Treatment \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sweet Syndrome<a class="elsevierStyleCrossRefs" href="#bib0695">44,45</a> (the most often reported) \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">Clinical features exclusively described with ipilimumab. Mean latency, 9 wks \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">Topical±systemic corticosteroidsOther options: dapsone, ciclosporinConsider suspending culprit drug. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pyoderma gangrenosum<a class="elsevierStyleCrossRef" href="#bib0695">44</a> \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">Typical ulcer. Rare. Exclusively described with ipilimumab. Mean latency, 16 wks \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">Topical+systemic corticosteroids; infliximabTreat the ulcer, manage pain, apply topical antibiotics.Suspend the culprit drug. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Acute, localized exanthematous pustulosis<a class="elsevierStyleCrossRef" href="#bib0695">44</a> \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">Rare. Subcorneal vesicles with neutrophils, localized \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">Topical corticosteroids. Culprit drug need not be suspended. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2917543.png" ] ] ] ] "descripcion" => array:1 [ "en" => "ICI-Associated Neutrophilic Dermatoses." ] ] 7 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Sources: Apalla et al.,<a class="elsevierStyleCrossRef" href="#bib0530">11</a>Sibaud,<a class="elsevierStyleCrossRef" href="#bib0565">18</a> Ocampo et al.,<a class="elsevierStyleCrossRef" href="#bib0900">85</a> Dasanu et al.<a class="elsevierStyleCrossRef" href="#bib0905">86</a>Abbreviation: ICI, immune checkpoint inhibitor." "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"><th 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" scope="col" style="border-bottom: 2px solid black">Type \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Characteristics \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Alopecia areata \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">Most frequent and severe with ipilimumabPartial or universalisTypical histology: nonscarring with a perifollicular lymphocytic infiltrate \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Changes in hair texture \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">ThickeningChange from straight to curly \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nail changes \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">Dystrophy, sometimes associated with onychomadesis or onychoschiziaColor changesDiffuse onycholysis and paronychia affecting all digitsProbable psoriatic or lichenoid etiology \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2917547.png" ] ] ] ] "descripcion" => array:1 [ "en" => "ICI-Associated Hair and Nail Alterations." ] ] 8 => array:8 [ "identificador" => "tbl0025" "etiqueta" => "Table 5" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at5" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviation: ICI, immune checkpoint inhibitor." "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=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pityriasis rubra pilaris<a class="elsevierStyleCrossRefs" href="#bib0545">14,19</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Eruptions resembling pityriasis rosea<a class="elsevierStyleCrossRefs" href="#bib0545">14,19</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hidradenitis suppurativa<a class="elsevierStyleCrossRef" href="#bib0910">87</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sjögren syndrome<a class="elsevierStyleCrossRef" href="#bib0565">18</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Acneiform eruption and papulopustular rosacea<a class="elsevierStyleCrossRefs" href="#bib0545">14,18</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vasculitis<a class="elsevierStyleCrossRef" href="#bib0565">18</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; 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=> array:2 [ …2] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0485" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Immune checkpoint inhibitors to treat cutaneous malignancies" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaad.2020.03.131" "Revista" => array:6 [ "tituloSerie" => "J Am Acad Dermatol" "fecha" => "2020" "volumen" => "83" "paginaInicial" => "1239" "paginaFinal" => "1253" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0490" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Systemic treatments for metastatic cutaneous melanoma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/14651858.CD011123.pub2" "Revista" => array:4 [ "tituloSerie" => "Cochrane Database Syst Rev" "fecha" => "2018" "volumen" => "2" "paginaInicial" => "CD011123" ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0495" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Incidence of skin and respiratory immune-related adverse events correlates with specific tumor types in patients treated with checkpoint inhibitors" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3389/fonc.2020.570752" "Revista" => array:6 [ "tituloSerie" => "Front Oncol" "fecha" => "2021" "volumen" => "10" "paginaInicial" => "1" "paginaFinal" => "9" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0500" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Immune-related adverse events with PD-1 versus PD-L1 inhibitors: a meta-analysis of 8730 patients from clinical trials" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2217/fon-2020-1222" "Revista" => array:5 [ "tituloSerie" => "Fut Oncol" "fecha" => "2021" "volumen" => "17" "paginaInicial" => "2545" "paginaFinal" => "2558" ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0505" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Immune-related adverse events associated with immune checkpoint inhibitors: an updated comprehensive disproportionality analysis of the FDA adverse event reporting system" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.intimp.2021.107498" "Revista" => array:5 [ "tituloSerie" => "Int Immunopharmacol" "fecha" => "2021" "volumen" => "95" "paginaInicial" => "107498" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0510" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Immune checkpoint inhibitor toxicity in 2018" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/jama.2018.13995" "Revista" => array:6 [ "tituloSerie" => "JAMA" "fecha" => "2018" "volumen" => "320" "paginaInicial" => "1702" "paginaFinal" => "1703" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0515" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Characterization and management of dermatologic adverse events to agents targeting the PD-1 receptor" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/CCM.0b013e31823a96d.Hydrogen" "Revista" => array:6 [ "tituloSerie" => "Eur J Cancer" "fecha" => "2016" "volumen" => "60" "paginaInicial" => "12" "paginaFinal" => "25" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0520" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Patients with lung cancer undergoing immune checkpoint inhibitors: a meta-analysis of dermatological toxicities" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.critrevonc.2020.102983" "Revista" => array:4 [ "tituloSerie" => "Crit Rev Oncol Hematol" "fecha" => "2020" "volumen" => "152" "paginaInicial" => "102983" ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0525" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Multisystem immune-related adverse events associated with immune checkpoint inhibitors for treatment of non-small cell lung cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => true …1 ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/jamaoncol.2020.5012" "Revista" => array:5 [ "tituloSerie" => "JAMA Oncol" "fecha" => "2020" "volumen" => "6" "paginaInicial" => "1952" "paginaFinal" => "1956" ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0530" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cutaneous adverse events of immune checkpoint inhibitors: a literature review" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.5826/dpc.1101a155" "Revista" => array:4 [ "tituloSerie" => "Dermatol Pr Concept" "fecha" => "2021" "volumen" => "11" "paginaInicial" => "e2021155" ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0535" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Association of anti-programmed cell death 1 antibody treatment with risk of recurrence of toxic effects after immune-related adverse events of ipilimumab in patients with metastatic melanoma" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/jamadermatol.2020.2149" "Revista" => array:6 [ "tituloSerie" => "JAMA Dermatol" "fecha" => "2020" "volumen" => "156" "paginaInicial" => "982" "paginaFinal" => "986" "link" => array:1 [ …1] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0540" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/annonc/mdx225" "Revista" => array:4 [ "tituloSerie" => "Ann Oncol" "fecha" => "2017" "volumen" => "28" "link" => array:1 [ …1] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0545" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diverse types of dermatologic toxicities from immune checkpoint blockade therapy" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/cup.12858" "Revista" => array:6 [ "tituloSerie" => "J Cutan Pathol" "fecha" => "2017" "volumen" => "44" "paginaInicial" => "158" "paginaFinal" => "176" "link" => array:1 [ …1] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0550" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American society of clinical oncology clinical practice guideline" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2017776385" "Revista" => array:6 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2018" "volumen" => "36" "paginaInicial" => "1714" "paginaFinal" => "1768" "link" => array:1 [ …1] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0555" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "New NCCN guidelines: recognition and management of immunotherapy-related toxicity" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.6004/jnccn.2018.0047" "Revista" => array:6 [ "tituloSerie" => "J Natl Compr Canc Netw" "fecha" => "2018" "volumen" => "16" "paginaInicial" => "594" "paginaFinal" => "596" "link" => array:1 [ …1] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0560" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cutaneous Immune-Related Adverse Events (irAEs) to immune checkpoint inhibitors: a dermatology perspective on management" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1177/1203475420943260" "Revista" => array:6 [ "tituloSerie" => "J Cutan Med Surg" "fecha" => "2021" "volumen" => "25" "paginaInicial" => "59" "paginaFinal" => "76" "link" => array:1 [ …1] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0565" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Dermatologic reactions to immune checkpoint inhibitors: skin toxicities and immunotherapy" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s40257-017-0336-3" "Revista" => array:6 [ "tituloSerie" => "Am J Clin Dermatol" "fecha" => "2018" "volumen" => "19" "paginaInicial" => "345" "paginaFinal" => "361" "link" => array:1 [ …1] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0570" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Inflammatory eruptions associated with immune checkpoint inhibitor therapy: a single-institution retrospective analysis with stratification of reactions by toxicity and implications for management" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaad.2018.10.062" "Revista" => array:6 [ "tituloSerie" => "J Am Acad Dermatol" "fecha" => "2019" "volumen" => "80" "paginaInicial" => "990" "paginaFinal" => "997" "link" => array:1 [ …1] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0575" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Dermatologic toxicities to immune checkpoint inhibitor therapy: a review of histopathologic features" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaad.2020.04.105" "Revista" => array:6 [ "tituloSerie" => "J Am Acad Dermatol" "fecha" => "2020" "volumen" => "83" "paginaInicial" => "1130" "paginaFinal" => "1143" "link" => array:1 [ …1] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0580" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical and histologic features of lichenoid mucocutaneous eruptions due to anti-programmed cell death 1 and anti-programmed cell death ligand 1 immunotherapy" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/jamadermatol.2016.2226" "Revista" => array:6 [ "tituloSerie" => "JAMA Dermatol" "fecha" => "2016" "volumen" => "152" "paginaInicial" => "1128" "paginaFinal" => "1136" "link" => array:1 [ …1] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0585" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Management of immune checkpoint inhibitor-related dermatologic adverse events" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/1759-7714.13275" "Revista" => array:6 [ "tituloSerie" => "Thorac Cancer" "fecha" => "2020" "volumen" => "11" "paginaInicial" => "488" "paginaFinal" => "492" "link" => array:1 [ …1] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0590" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Lichenoid dermatologic toxicity from immune checkpoint blockade therapy: a detailed examination of the clinicopathologic features" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/DAD.0000000000000688" "Revista" => array:6 [ "tituloSerie" => "Am J Dermatopathol" "fecha" => "2017" "volumen" => "39" "paginaInicial" => "121" "paginaFinal" => "129" "link" => array:1 [ …1] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0595" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Toxic epidermal necrolysis occurring with immune checkpoint inhibitors" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.5070/d3268049884" "Revista" => array:3 [ "tituloSerie" => "Dermatol Online J" "fecha" => "2020" "volumen" => "26" ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0600" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Bullous pemphigoid associated with anti-programmed cell death protein 1 and anti-programmed cell death ligand 1 therapy: a review of the literature" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2340/00015555-3740" "Revista" => array:3 [ "tituloSerie" => "Acta Derm Venereol" "fecha" => "2021" "volumen" => "101" ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0605" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Treatment outcomes of immune-related cutaneous adverse events" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.18.02141" "Revista" => array:6 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2019" "volumen" => "37" "paginaInicial" => "2746" "paginaFinal" => "2758" "link" => array:1 [ …1] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0610" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "IgE blockade with omalizumab reduces pruritus related to immune checkpoint inhibitors and anti-HER2 therapies" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.annonc.2021.02.016" "Revista" => array:6 [ "tituloSerie" => "Ann Oncol" "fecha" => "2021" "volumen" => "32" "paginaInicial" => "736" "paginaFinal" => "745" "link" => array:1 [ …1] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0615" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "PD-1 blockade-induced Pruritus treated with a mu-opioid receptor antagonist" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMc1805637" "Revista" => array:5 [ "tituloSerie" => "N Engl J Med" "fecha" => "2018" "volumen" => "379" "paginaInicial" => "1578" "paginaFinal" => "1579" ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0620" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Aprepitant for refractory nivolumab-induced pruritus" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.lungcan.2017.04.020" "Revista" => array:6 [ "tituloSerie" => "Lung Cancer" "fecha" => "2017" "volumen" => "109" "paginaInicial" => "58" "paginaFinal" => "61" "link" => array:1 [ …1] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0625" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: a single-institution cohort" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaad.2015.10.029" "Revista" => array:5 [ "tituloSerie" => "J Am Acad Dermatol" "fecha" => "2016" "volumen" => "74" "paginaInicial" => "455" "paginaFinal" => "461" ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0630" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Bullous lichen planus and anti-programmed cell death-1 therapy: case report and literature review" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.annder.2019.07.008" "Revista" => array:5 [ "tituloSerie" => "Ann Dermatol Venereol" "fecha" => "2020" "volumen" => "147" "paginaInicial" => "221" "paginaFinal" => "227" ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0635" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Survival and prognosis of individuals receiving programmed cell death 1 inhibitor with and without immunologic cutaneous adverse events" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaad.2019.06.035" "Revista" => array:6 [ "tituloSerie" => "J Am Acad Dermatol" "fecha" => "2020" "volumen" => "82" "paginaInicial" => "311" "paginaFinal" => "316" "link" => array:1 [ …1] ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0640" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Oral lichenoid reactions associated with anti-PD-1/PD-L1 therapies: clinicopathological findings" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/jdv.14284" "Revista" => array:5 [ "tituloSerie" => "J Eur Acad Dermatol Venereol" "fecha" => "2017" "volumen" => "31" "paginaInicial" => "e464" "paginaFinal" => "e469" ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0645" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pembrolizumab-induced lichen planus pemphigoides in a patient with metastatic Merkel cell carcinoma" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jdcr.2020.03.007" "Revista" => array:6 [ "tituloSerie" => "JAAD Case Rep" "fecha" => "2020" "volumen" => "6" "paginaInicial" => "1045" "paginaFinal" => "1047" "link" => array:1 [ …1] ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib0650" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cutaneous immune-related adverse events to checkpoint inhibitors" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.clindermatol.2020.06.011" "Revista" => array:6 [ "tituloSerie" => "Clin Dermatol" "fecha" => "2020" "volumen" => "38" "paginaInicial" => "660" "paginaFinal" => "678" "link" => array:1 [ …1] ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0655" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Psoriasis and psoriasiform reactions secondary to immune checkpoint inhibitors" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/dth.14830" "Revista" => array:5 [ "tituloSerie" => "Dermatol Ther" "fecha" => "2021" "volumen" => "34" "paginaInicial" => "1" "paginaFinal" => "6" ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0660" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Anti-PD1-induced psoriasis: a study of 21 patients" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/jdv.14011" "Revista" => array:6 [ "tituloSerie" => "J Eur Acad Dermatol Venereol" "fecha" => "2017" "volumen" => "31" "paginaInicial" => "e254" "paginaFinal" => "e257" "link" => array:1 [ …1] ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib0665" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Immune checkpoint-mediated psoriasis: a multicenter European study of 115 patients from the European Network for Cutaneous Adverse Event to Oncologic Drugs (ENCADO) group" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaad.2020.08.137" "Revista" => array:5 [ "tituloSerie" => "J Am Acad Dermatol" "fecha" => "2021" "volumen" => "84" "paginaInicial" => "1310" "paginaFinal" => "1320" ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib0670" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pembrolizumab-induced psoriasis in metastatic melanoma: activity and safety of apremilast, a case report" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3389/fonc.2020.579445" "Revista" => array:5 [ "tituloSerie" => "Front Oncol" "fecha" => "2020" "volumen" => "10" "paginaInicial" => "579445" "link" => array:1 [ …1] ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib0675" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Development of de novo psoriasis during nivolumab therapy in a patient with small cell lung cancer" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1177/1078155219877234" "Revista" => array:6 [ "tituloSerie" => "J Oncol Pharm Pract" "fecha" => "2020" "volumen" => "26" "paginaInicial" => "256" "paginaFinal" => "258" "link" => array:1 [ …1] ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib0680" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Case report and review of 7 similar cases in the literature: cutaneous sarcoidosis as side effect of pembrolizumab plus chemotherapy in stage iv squamous cell carcinoma of lung" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/CJI.0000000000000351" "Revista" => array:6 [ "tituloSerie" => "J Immunother" "fecha" => "2021" "volumen" => "44" "paginaInicial" => "90" "paginaFinal" => "94" "link" => array:1 [ …1] ] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib0685" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Sarcoidosis-like reactions in cancer patients treated with immune checkpoint inhibitors: experience in a Spanish hospital" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s12094-020-02546-w" "Revista" => array:6 [ "tituloSerie" => "Clin Transl Oncol" "fecha" => "2021" "volumen" => "23" "paginaInicial" => "1474" "paginaFinal" => "1480" "link" => array:1 [ …1] ] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib0690" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Drug-induced sarcoidosis-like reaction in adjuvant immunotherapy: increased rate and mimicker of metastasis" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ejca.2020.02.024" "Revista" => array:6 [ "tituloSerie" => "Eur J Cancer" "fecha" => "2020" "volumen" => "131" "paginaInicial" => "18" "paginaFinal" => "26" "link" => array:1 [ …1] ] ] ] ] ] ] 43 => array:3 [ "identificador" => "bib0695" "etiqueta" => "44" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Neutrophilic dermatoses as adverse effects of checkpoint inhibitors: a review" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/dth.13074" "Revista" => array:4 [ "tituloSerie" => "Dermatol Ther" "fecha" => "2019" "volumen" => "32" "paginaInicial" => "e13074" ] ] ] ] ] ] 44 => array:3 [ "identificador" => "bib0700" "etiqueta" => "45" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Sweet's syndrome under ipilimumab therapy and a brief comparison of the cases in literature" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1177/1078155220906885" "Revista" => array:6 [ "tituloSerie" => "J Oncol Pharm Pract" "fecha" => "2020" "volumen" => "26" "paginaInicial" => "1762" "paginaFinal" => "1764" "link" => array:1 [ …1] ] ] ] ] ] ] 45 => array:3 [ "identificador" => "bib0705" "etiqueta" => "46" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Serious cutaneous toxicities with immune checkpoint inhibitors in the U.S. Food and Drug Administration adverse event reporting system" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1634/theoncologist.2019-0250" "Revista" => array:6 [ "tituloSerie" => "Oncologist" "fecha" => "2019" "volumen" => "24" "paginaInicial" => "e1228" "paginaFinal" => "e1231" "link" => array:1 [ …1] ] ] ] ] ] ] 46 => array:3 [ "identificador" => "bib0710" "etiqueta" => "47" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pembrolizumab-induced Stevens–Johnson Syndrome with severe ocular complications" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1080/09273948.2021.1896006" "Revista" => array:5 [ "tituloSerie" => "Ocul Immunol Inflamm" "fecha" => "2021" "volumen" => "7" "paginaInicial" => "1" "paginaFinal" => "3" ] ] ] ] ] ] 47 => array:3 [ "identificador" => "bib0715" "etiqueta" => "48" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Combination therapy of ipilimumab and nivolumab-associated toxic epidermal necrolysis (TEN) in a patient with metastatic melanoma: a case report and literature review" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/CJI.0000000000000302" "Revista" => array:6 [ "tituloSerie" => "J Immunother" "fecha" => "2019" "volumen" => "43" "paginaInicial" => "89" "paginaFinal" => "92" "link" => array:1 [ …1] ] ] ] ] ] ] 48 => array:3 [ "identificador" => "bib0720" "etiqueta" => "49" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Stevens–Johnson syndrome and toxic epidermal necrolysis-like reactions to checkpoint inhibitors: a systematic review" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/ijd.14811" "Revista" => array:5 [ "tituloSerie" => "Int J Clin Oncol" "fecha" => "2020" "volumen" => "59" "paginaInicial" => "e183" "paginaFinal" => "e188" ] ] ] ] ] ] 49 => array:3 [ "identificador" => "bib0725" "etiqueta" => "50" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "De novo cutaneous connective tissue disease temporally associated with immune checkpoint inhibitor therapy: a retrospective analysis" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaad.2020.10.054" "Revista" => array:6 [ "tituloSerie" => "J Am Acad Dermatol" "fecha" => "2021" "volumen" => "84" "paginaInicial" => "864" "paginaFinal" => "869" "link" => array:1 [ …1] ] ] ] ] ] ] 50 => array:3 [ "identificador" => "bib0730" "etiqueta" => "51" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "De novo subacute cutaneous lupus erythematosus-like eruptions in the setting of programmed death-1 or programmed death ligand-1 inhibitor therapy: clinicopathological correlation" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/ced.14449" "Revista" => array:6 [ "tituloSerie" => "Clin Exp Dermatol" "fecha" => "2021" "volumen" => "46" "paginaInicial" => "328" "paginaFinal" => "337" "link" => array:1 [ …1] ] ] ] ] ] ] 51 => array:3 [ "identificador" => "bib0735" "etiqueta" => "52" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Risk of scleroderma according to the type of immune checkpoint inhibitors" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.autrev.2020.102596" "Revista" => array:5 [ "tituloSerie" => "Autoimmun Rev" "fecha" => "2020" "volumen" => "19" "paginaInicial" => "102596" "link" => array:1 [ …1] ] ] ] ] ] ] 52 => array:3 [ "identificador" => "bib0740" "etiqueta" => "53" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Immune checkpoint inhibitor-associated scleroderma-like syndrome: a report of a Pembrolizumab-induced “eosinophilic fasciitis-like” case and a review of the literature" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s40744-020-00246-z" "Revista" => array:5 [ "tituloSerie" => "Rheumatol Ther" "fecha" => "2020" "volumen" => "7" "paginaInicial" => "1045" "paginaFinal" => "1052" ] ] ] ] ] ] 53 => array:3 [ "identificador" => "bib0745" "etiqueta" => "54" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Subacute cutaneous lupus erythematosus with melanocyte elimination induced by pembrolizumab" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/1346-8138.15316" "Revista" => array:6 [ "tituloSerie" => "J Dermatol" "fecha" => "2020" "volumen" => "47" "paginaInicial" => "e217" "paginaFinal" => "e219" "link" => array:1 [ …1] ] ] ] ] ] ] 54 => array:3 [ "identificador" => "bib0750" "etiqueta" => "55" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Anti-transcriptional intermediary factor 1-γ antibody-positive dermatomyositis induced by nivolumab for lung adenocarcinoma: A case report" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s10637-020-00974-7" "Revista" => array:6 [ "tituloSerie" => "Invest New Drugs" "fecha" => "2021" "volumen" => "39" "paginaInicial" => "251" "paginaFinal" => "255" "link" => array:1 [ …1] ] ] ] ] ] ] 55 => array:3 [ "identificador" => "bib0755" "etiqueta" => "56" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Bullous disorders associated with anti-PD-1 and anti-PD-L1 therapy: a retrospective analysis evaluating the clinical and histopathologic features, frequency, and impact on cancer therapy" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaad.2018.07.008" "Revista" => array:6 [ "tituloSerie" => "J Am Acad Dermatol" "fecha" => "2018" "volumen" => "79" "paginaInicial" => "1081" "paginaFinal" => "1088" "link" => array:1 [ …1] ] ] ] ] ] ] 56 => array:3 [ "identificador" => "bib0760" "etiqueta" => "57" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A review of bullous pemphigoid associated with PD-1 and PD-L1 inhibitors" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/ijd.13984" "Revista" => array:6 [ "tituloSerie" => "Int J Dermatol" "fecha" => "2018" "volumen" => "57" "paginaInicial" => "664" "paginaFinal" => "669" "link" => array:1 [ …1] ] ] ] ] ] ] 57 => array:3 [ "identificador" => "bib0765" "etiqueta" => "58" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Bullous disorders associated with PD-1 and PD-L1 inhibitors: pharmacovigilance analysis of the United States Food and Drug Administration Adverse Event Reporting System from the Research on Adverse Drug Events And Reports Program" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaad.2020.01.059" "Revista" => array:6 [ "tituloSerie" => "J Am Acad Dermatol" "fecha" => "2020" "volumen" => "83" "paginaInicial" => "955" "paginaFinal" => "957" "link" => array:1 [ …1] ] ] ] ] ] ] 58 => array:3 [ "identificador" => "bib0770" "etiqueta" => "59" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Immune checkpoint inhibitor-related dermatologic adverse events" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaad.2020.03.132" "Revista" => array:6 [ "tituloSerie" => "J Am Acad Dermatol" "fecha" => "2020" "volumen" => "83" "paginaInicial" => "1255" "paginaFinal" => "1268" "link" => array:1 [ …1] ] ] ] ] ] ] 59 => array:3 [ "identificador" => "bib0775" "etiqueta" => "60" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Retrospective analysis of checkpoint inhibitor therapy-associated cases of bullous pemphigoid from six German dermatology centers" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3389/fimmu.2020.588582" "Revista" => array:5 [ "tituloSerie" => "Front Immunol" "fecha" => "2021" "volumen" => "11" "paginaInicial" => "588582" "link" => array:1 [ …1] ] ] ] ] ] ] 60 => array:3 [ "identificador" => "bib0780" "etiqueta" => "61" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Management of immune checkpoint inhibitor-induced bullous pemphigoid" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaad.2020.05.045" "Revista" => array:6 [ "tituloSerie" => "J Am Acad Dermatol" "fecha" => "2021" "volumen" => "84" "paginaInicial" => "540" "paginaFinal" => "543" "link" => array:1 [ …1] ] ] ] ] ] ] 61 => array:3 [ "identificador" => "bib0785" "etiqueta" => "62" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Bullous pemphigoid in elderly woman affected by non-small cell lung cancer treated with pembrolizumab: a case report and review of literature" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1177/1078155220946370" "Revista" => array:6 [ "tituloSerie" => "J Oncol Pharm Pract" "fecha" => "2021" "volumen" => "27" "paginaInicial" => "727" "paginaFinal" => "733" "link" => array:1 [ …1] ] ] ] ] ] ] 62 => array:3 [ "identificador" => "bib0790" "etiqueta" => "63" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pruritic bullous skin eruption in a male patient receiving immunotherapy for oropharyngeal cancer" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/ijd.14742" "Revista" => array:6 [ "tituloSerie" => "Int J Dermatol" "fecha" => "2020" "volumen" => "59" "paginaInicial" => "685" "paginaFinal" => "686" "link" => array:1 [ …1] ] ] ] ] ] ] 63 => array:3 [ "identificador" => "bib0795" "etiqueta" => "64" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "BP180-specific IgG is associated with skin adverse events, therapy response, and overall survival in non-small cell lung cancer patients treated with checkpoint inhibitors" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaad.2019.08.045" "Revista" => array:5 [ "tituloSerie" => "J Am Acad Dermatol" "fecha" => "2020" "volumen" => "82" "paginaInicial" => "854" "paginaFinal" => "861" ] ] ] ] ] ] 64 => array:3 [ "identificador" => "bib0800" "etiqueta" => "65" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Bullous pemphigoid after anti-PD-1 therapy: a retrospective case-control study evaluating impact on tumor response and survival outcomes" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaad.2019.12.068" "Revista" => array:5 [ "tituloSerie" => "J Am Acad Dermatol" "fecha" => "2020" "volumen" => "10" "paginaInicial" => "30048" "paginaFinal" => "30057" ] ] ] ] ] ] 65 => array:3 [ "identificador" => "bib0805" "etiqueta" => "66" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/jamadermatol.2015.2707" "Revista" => array:6 [ "tituloSerie" => "JAMA Dermatol" "fecha" => "2016" "volumen" => "152" "paginaInicial" => "45" "paginaFinal" => "51" "link" => array:1 [ …1] ] ] ] ] ] ] 66 => array:3 [ "identificador" => "bib0810" "etiqueta" => "67" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cutaneous adverse reactions to anti-PD-1 treatment—a systematic review" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaad.2020.04.058" "Revista" => array:6 [ "tituloSerie" => "J Am Acad Dermatol" "fecha" => "2020" "volumen" => "83" "paginaInicial" => "1415" "paginaFinal" => "1424" "link" => array:1 [ …1] ] ] ] ] ] ] 67 => array:3 [ "identificador" => "bib0815" "etiqueta" => "68" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Aggravation of depigmentation for a non-small-cell lung cancer patient with pre-existing vitiligo using anti-programmed cell death-1 therapy: case report" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2217/imt-2019-0090" "Revista" => array:6 [ "tituloSerie" => "Immunotherapy" "fecha" => "2020" "volumen" => "12" "paginaInicial" => "175" "paginaFinal" => "181" "link" => array:1 [ …1] ] ] ] ] ] ] 68 => array:3 [ "identificador" => "bib0820" "etiqueta" => "69" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Vitiligo-like depigmentation after pembrolizumab treatment in patients with non-small cell lung cancer: a case report" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.21037/tlcr-20-386" "Revista" => array:5 [ "tituloSerie" => "Trans Lung Cancer Res" "fecha" => "2020" "volumen" => "9" "paginaInicial" => "1585" "paginaFinal" => "1590" ] ] ] ] ] ] 69 => array:3 [ "identificador" => "bib0825" "etiqueta" => "70" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Vitiligo-like lesions occurring in patients receiving anti-programmed cell death-1 therapies are clinically and biologically distinct from vitiligo" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaad.2016.10.044" "Revista" => array:6 [ "tituloSerie" => "J Am Acad Dermatol" "fecha" => "2017" "volumen" => "76" "paginaInicial" => "863" "paginaFinal" => "870" "link" => array:1 [ …1] ] ] ] ] ] ] 70 => array:3 [ "identificador" => "bib0830" "etiqueta" => "71" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Vitiligo under anti-programmed cell death-1 therapy is associated with increased survival in melanoma patients" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaad.2019.11.017" "Revista" => array:6 [ "tituloSerie" => "J Am Acad Dermatol" "fecha" => "2020" "volumen" => "82" "paginaInicial" => "770" "paginaFinal" => "772" "link" => array:1 [ …1] ] ] ] ] ] ] 71 => array:3 [ "identificador" => "bib0835" "etiqueta" => "72" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Immune checkpoint inhibitor associated vitiligo and its impact on survival in patients with metastatic melanoma: an Italian Melanoma Intergroup study" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.esmoop.2021.100064" "Revista" => array:4 [ "tituloSerie" => "ESMO Open" "fecha" => "2021" "volumen" => "6" "paginaInicial" => "100064" ] ] ] ] ] ] 72 => array:3 [ "identificador" => "bib0840" "etiqueta" => "73" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cutaneous toxicities of immune checkpoint inhibitors: the role of the dermatologist" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Yale J Biol Med" "fecha" => "2020" "volumen" => "93" "paginaInicial" => "123" "paginaFinal" => "132" "link" => array:1 [ …1] ] ] ] ] ] ] 73 => array:3 [ "identificador" => "bib0845" "etiqueta" => "74" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Association between immune-related adverse events and recurrence-free survival among patients with stage iii melanoma randomized to receive pembrolizumab or placebo: a secondary analysis of a randomized clinical trial" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/jamaoncol.2019.5570" "Revista" => array:6 [ "tituloSerie" => "JAMA Oncol" "fecha" => "2020" "volumen" => "6" "paginaInicial" => "519" "paginaFinal" => "527" "link" => array:1 [ …1] ] ] ] ] ] ] 74 => array:3 [ "identificador" => "bib0850" "etiqueta" => "75" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Vitiligo expansion and extent correlate with durable response in anti-programmed death 1 antibody treatment for advanced melanoma: a multi-institutional retrospective study" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/1346-8138.15345" "Revista" => array:6 [ "tituloSerie" => "J Dermatol" "fecha" => "2020" "volumen" => "47" "paginaInicial" => "629" "paginaFinal" => "635" "link" => array:1 [ …1] ] ] ] ] ] ] 75 => array:3 [ "identificador" => "bib0855" "etiqueta" => "76" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Correlation between cutaneous adverse events and prognosis in patients with melanoma treated with nivolumab: a single institutional retrospective study" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/1346-8138.15309" "Revista" => array:6 [ "tituloSerie" => "J Dermatol" "fecha" => "2020" "volumen" => "47" "paginaInicial" => "622" "paginaFinal" => "628" "link" => array:1 [ …1] ] ] ] ] ] ] 76 => array:3 [ "identificador" => "bib0860" "etiqueta" => "77" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Immunotherapy-mediated dermatological adverse events: the urgent need for a common, clinically meaningful, management strategy" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00520-020-05701-9" "Revista" => array:5 [ "tituloSerie" => "Support Care Cancer" "fecha" => "2020" "volumen" => "28" "paginaInicial" => "5597" "paginaFinal" => "5599" ] ] ] ] ] ] 77 => array:3 [ "identificador" => "bib0865" "etiqueta" => "78" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Immune-related adverse events and efficacy—the more it hurts, the better it works?" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.19.02446" "Revista" => array:5 [ "tituloSerie" => "JAMA Oncol" "fecha" => "2020" "volumen" => "7" "paginaInicial" => "945" "link" => array:1 [ …1] ] ] ] ] ] ] 78 => array:3 [ "identificador" => "bib0870" "etiqueta" => "79" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Revisiting the association between skin toxicity and better response in advanced cancer patients treated with immune checkpoint inhibitors" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/s12967-020-02612-5" "Revista" => array:6 [ "tituloSerie" => "J Transl Med" "fecha" => "2020" "volumen" => "18" "paginaInicial" => "1" "paginaFinal" => "6" "link" => array:1 [ …1] ] ] ] ] ] ] 79 => array:3 [ "identificador" => "bib0875" "etiqueta" => "80" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Immune-related adverse events and efficacy—the more it hurts, the better it works? Reply" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3389/fonc.2020.574752" "Revista" => array:4 [ "tituloSerie" => "JAMA Oncol" "fecha" => "2021" "volumen" => "10" "paginaInicial" => "E1" ] ] ] ] ] ] 80 => array:3 [ "identificador" => "bib0880" "etiqueta" => "81" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2015661389" "Revista" => array:5 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2017" "volumen" => "35" "paginaInicial" => "785" "paginaFinal" => "792" ] ] ] ] ] ] 81 => array:3 [ "identificador" => "bib0885" "etiqueta" => "82" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Correlation between immune-related adverse events and prognosis in patients with various cancers treated with anti PD-1 antibody" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/s12885-020-07142-3" "Revista" => array:6 [ "tituloSerie" => "BMC Cancer" "fecha" => "2020" "volumen" => "20" "paginaInicial" => "1" "paginaFinal" => "8" "link" => array:1 [ …1] ] ] ] ] ] ] 82 => array:3 [ "identificador" => "bib0890" "etiqueta" => "83" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Characterization of dermatitis after PD-1/PD-L1 inhibitor therapy and association with multiple oncologic outcomes: a retrospective case–control study" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaad.2018.05.035" "Revista" => array:6 [ "tituloSerie" => "J Am Acad Dermatol" "fecha" => "2018" "volumen" => "79" "paginaInicial" => "1047" "paginaFinal" => "1052" "link" => array:1 [ …1] ] ] ] ] ] ] 83 => array:3 [ "identificador" => "bib0895" "etiqueta" => "84" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Management of immune-related adverse events affecting outcome in patients treated with checkpoint inhibitors" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ejca.2016.11.021" "Revista" => array:5 [ "tituloSerie" => "JAMA Oncol" "fecha" => "2017" "volumen" => "72" "paginaInicial" => "156" "paginaFinal" => "165" ] ] ] ] ] ] 84 => array:3 [ "identificador" => "bib0900" "etiqueta" => "85" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Bluish-gray fingernail discoloration due to the use of nivolumab" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1177/1078155220929974" "Revista" => array:5 [ "tituloSerie" => "J Oncol Pharm Pract Pract" "fecha" => "2021" "volumen" => "27" "paginaInicial" => "457" "paginaFinal" => "459" ] ] ] ] ] ] 85 => array:3 [ "identificador" => "bib0905" "etiqueta" => "86" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Persistently curly hair phenotype with the use of nivolumab for squamous cell lung cancer" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1177/1078155216674355" "Revista" => array:6 [ "tituloSerie" => "J Oncol Pharm Pract" "fecha" => "2017" "volumen" => "23" "paginaInicial" => "638" "paginaFinal" => "640" "link" => array:1 [ …1] ] ] ] ] ] ] 86 => array:3 [ "identificador" => "bib0910" "etiqueta" => "87" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Anti-PD-1-induced hidradenitis suppurativa" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Dermatopathol" "fecha" => "2021" "volumen" => "8" "paginaInicial" => "37" "paginaFinal" => "39" ] ] ] ] ] ] 87 => array:3 [ "identificador" => "bib0915" "etiqueta" => "88" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Acrocyanosis after neoadjuvant Ipilimumab plus nivolumab: a case report" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2265.1992.tb02256.x" "Revista" => array:5 [ "tituloSerie" => "Clin Exp Reum" "fecha" => "2020" "volumen" => "38" "paginaInicial" => "1031" "paginaFinal" => "1032" ] ] ] ] ] ] 88 => array:3 [ "identificador" => "bib0920" "etiqueta" => "89" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Angioedema late in the course of adjuvant nivolumab therapy for melanoma" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1177/1078155219881181" "Revista" => array:6 [ "tituloSerie" => "J Oncol Pharm Pract" "fecha" => "2020" "volumen" => "26" "paginaInicial" => "1019" "paginaFinal" => "1021" "link" => array:1 [ …1] ] ] ] ] ] ] 89 => array:3 [ "identificador" => "bib0925" "etiqueta" => "90" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hypohidrosis as an immune-related adverse event of checkpoint inhibitor therapy" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2217/imt-2020-0002" "Revista" => array:5 [ "tituloSerie" => "Immunotherapy" "fecha" => "2020" "volumen" => "12" "paginaInicial" => "951" "paginaFinal" => "956" ] ] ] ] ] ] 90 => array:3 [ "identificador" => "bib0930" "etiqueta" => "91" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Ipilimumab/nivolumab-induced pseudolymphoma in a patient with malignant melanoma" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/cup.13604" "Revista" => array:6 [ "tituloSerie" => "J 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Characteristics, Management, and Prognostic Implications of Adverse Effects of Immune Checkpoint Inhibitors: A Systematic Review

Revisión sistemática de los efectos adversos cutáneos causados por fármacos inhibidores de los puntos de control inmunitario: características, manejo y pronóstico

G. Juan-Carpena

Corresponding author

gloria5289@gmail.com

Corresponding author.

, J.C. Palazón-Cabanes, M. Blanes-Martínez

Servicio de Dermatología, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Immune checkpoint inhibitors &#40;ICIs&#41; have revolutionized the treatment of cancer&#46; Their demonstrated efficacy and association with longer survival times have been demonstrated in a broad spectrum of advanced tumors&#46;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">1&#8211;4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">ICIs stimulate the immune system&#44; activating tumor-destroying T cells&#44; but as a consequence of this stimulus&#44; diverse autoimmune or autoinflammatory events can be triggered&#46;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">4&#8211;7</span></a> Known as immune-related adverse events &#40;irAEs&#41;&#44; they can appear in any organ or tissue&#44; but among the most frequently described are dermatologic toxicities&#44; found in approximately a third of patients on these drugs&#46;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">4&#44;7</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Information from clinical trials on the incidence and profiles of dermatologic irAEs is difficult to evaluate because cutaneous toxicity is usually recorded in generical terms in clinical trials&#46;<a class="elsevierStyleCrossRefs" href="#bib0515"><span class="elsevierStyleSup">8&#44;9</span></a> Our current understanding of these reactions therefore comes mainly from clinical practice as reflected in retrospective studies&#44; case series&#44; and individual case reports&#44; with all the limitations those sources imply&#46;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">4&#44;5&#44;9</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Our aim was to review and synthesize the literature on irAEs in patients being treated with ICIs&#44; describe the reactions&#44; the drug regimens used&#44; and the prognostic implications&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Methods</span><p id="par0025" class="elsevierStylePara elsevierViewall">We used the terms <span class="elsevierStyleItalic">immune checkpoint inhibitors</span> and <span class="elsevierStyleItalic">skin toxicity</span> to search PubMed and the Web of Science for the period from January 2015 to May 2021&#46; We also searched the Cochrane Library without specifying time limits&#46; Two authors &#40;G&#46;J&#46;C&#46; and M&#46;B&#46;M&#46;&#41; independently reviewed titles and abstracts to select articles with information on the frequency and characteristics of cutaneous irAEs in patients with ICI-treated cancer&#44; on the treatments that are used&#44; or on prognosis&#46; Other relevant articles were identified by searching the reference lists of the retrieved articles&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Relevant articles could report any study design and be published in English or Spanish provided they included data on the number or percentages of patients on ICIs&#44; measured associations or survival rates&#44; or at least described in detail the observed skin eruptions &#40;including type of rash&#44; type of ICIs&#44; and latency from the start of treatment&#41;&#46; Any type of ICI in monotherapy or in combination was of interest for the review&#46; Two authors &#40;G&#46;J&#46;C&#46; and M&#46;B&#46;M&#46;&#41; independently read the full texts of the selected articles&#46; Articles without abstracts were also read in full&#46; We included the most up-to-date articles&#44; excluding older ones whose results were included in more recent publications or that had redundant information&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Results</span><p id="par0035" class="elsevierStylePara elsevierViewall">The literature search suggested a total of 394 articles&#46; Ninety-five with up-to-date information were selected for the final review &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Among those chosen were 2 systematic reviews&#44; 4 meta-analyses&#44; and 1 clinical trial&#46; The remaining references were retrospective studies&#44; narrative reviews&#44; and case reports or case series&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Pathogenesis and Frequency</span><p id="par0040" class="elsevierStylePara elsevierViewall">Two groups of ICIs are currently available&#58; cytotoxic T-lymphocyte-associated antigen 4 &#40;CTLA-4&#41; inhibitors and programmed cell death protein 1 &#40;PD1&#41; or ligand 1 &#40;PDL1&#41; inhibitors &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; The CTLA-4 receptor controls the immune response in stages prior to the PD1&#47;PDL1 pathway&#44; which regulates later stages of response&#44; mainly involving peripheral tissues&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">1</span></a> The pathogenesis of irAEs is not yet fully understood&#46; However&#44; although it is known that the activation of CD4<span class="elsevierStyleSup">&#43;</span> and CD8<span class="elsevierStyleSup">&#43;</span> T cells produced by blocking PD1 and PDL1 is beneficial from the perspective of cancer treatment due to the effect on tumor cells&#44; their inhibition also plays a fundamental role in the development of irAEs in general and cell toxicity in particular&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">1</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">Even though all ICIs have similar safety profiles&#44; there are differences in irAE type&#44; frequency&#44; latency&#44; and seriousness associated with each ICI&#44; given that molecular targets and pharmacokinetic characteristics differ from one to another&#46;<a class="elsevierStyleCrossRefs" href="#bib0500"><span class="elsevierStyleSup">5&#44;6</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Ipilimumab induces dose-dependent skin irAEs more often than PD1&#47;PDL1 blockers &#40;in 50&#37; vs 10&#37;&#8211;30&#37;&#41; of cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0485"><span class="elsevierStyleSup">2&#44;8&#8211;12</span></a> In addition&#44; ipilimumab-associated events occur earlier after start of treatment and are more severe&#46;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">1&#8211;3</span></a> Ipilimumab in combination with PD1&#47;PDL1 blockers has been linked to the highest incidences of cutaneous toxicity of any degree of severity&#44; especially if pembrolizumab is part of the regimen&#46;<a class="elsevierStyleCrossRefs" href="#bib0505"><span class="elsevierStyleSup">6&#44;9</span></a> PD1 inhibitors &#40;mainly pembrolizumab&#41; confer higher risk of dermatologic irAEs than PDL1 inhibitors do&#44; whereas avelumab is associated with lower risk&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">5</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">It is important to point out that various irAEs can coincide in the same patient and that multisystem irAEs develop in up to 9&#37; of those treated&#46; Common associations are dermatitis&#8211;pneumonitis and dermatitis&#8211;thyroiditis&#46; Skin toxicities often appear first&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">10</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Associations between type of irAE and tumor type have recently been suggested&#44; given that more cases of skin irAEs have been reported in patients with melanoma than other tumors&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">4</span></a> However&#44; we think caution is called for when interpreting this association&#44; as it could be a product of reporting bias&#44; arising from the fact that dermatologists are usually involved in the treatment and follow-up of melanoma&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Types of Cutaneous Toxicity and Characteristics</span><p id="par0065" class="elsevierStylePara elsevierViewall">The irAEs most often reported in clinical trials are exanthema &#40;rash or dermatitis&#41;&#44; pruritus&#44; vitiligo&#44; and hair loss&#46;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">4&#44;5&#44;8&#44;9</span></a> However&#44; more diverse ICI-induced dermatologic toxicities are found in clinical practice&#46; We base this review on the classification most commonly used at this time&#46;<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">13&#44;14</span></a> It consists of the following 4 large groups&#58; inflammatory conditions&#44; immunobullous conditions&#44; alterations of keratinocytes&#44; and alterations of epidermal melanocytes&#46; Some authors&#44; however&#44; consider these categories to be imprecise and have modified them&#46; We will group melanocytic changes in a larger category of pigmentary alterations and also add 2 sections&#58; hair and nail involvement and other rare dermatoses&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">11</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">The severity of toxicities is usually evaluated with the Common Terminology Criteria for Adverse Events &#40;CTCAE&#41;&#44; which specifies 4 grades according to the affected body surface area &#40;BSA&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">13&#44;15&#44;16</span></a> Some authors&#44; however&#44; recommend also taking the nature of a dermatosis into consideration in order to more precisely characterize the severity of the clinical picture&#46;<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">13&#44;15&#44;17&#44;18</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Inflammatory Eruptions</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Maculopapular Rashes</span><p id="par0075" class="elsevierStylePara elsevierViewall">Along with pruritus&#44; maculopapular rashes are the most common irAEs&#46; They develop in approximately 25&#37; of ipilimumab-treated patients&#44; 15&#37; of those on anti-PD1 antibody treatments&#44; and 10&#37; of those on anti-PDL1 drugs&#46; Up to 45&#37; of patients on combined anti-CTLA-4&#47;PD1 therapy can be affected&#44; however&#46;<a class="elsevierStyleCrossRefs" href="#bib0520"><span class="elsevierStyleSup">9&#44;13&#44;18</span></a> The rashes tend to be mild&#58; fewer than 3&#37; of cases are rated grade 3 or higher in severity&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">9</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">The eruption typically develops early&#44; in the first 2 to 6 weeks of treatment&#44; although it may also appear later&#46; The fairly nonspecific clinical signs are confluent&#44; pruritic maculopapular lesions on the trunk and sometimes on the extremities&#46; Peripheral blood eosinophilia may be detected&#46;<a class="elsevierStyleCrossRefs" href="#bib0565"><span class="elsevierStyleSup">18&#44;19</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">The most common histologic pattern is that of a spongiotic dermatitis with a superficial perivascular lymphocytic infiltrate with eosinophils&#44; although a lichenoid pattern has also been reported on occasion&#46;<a class="elsevierStyleCrossRefs" href="#bib0565"><span class="elsevierStyleSup">18&#44;20&#44;21</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Because this irAE is mild&#44; it can usually be managed with symptomatic therapy &#40;oral antihistamines and topical corticosteroids&#41;&#44; even when 30&#37; of the BSA is covered&#59; if the rash is refractory to topical applications&#44; systemic corticosteroids are needed&#46;<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">13&#44;15&#44;16&#44;18&#44;22</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">A maculopapular rash may precede other skin conditions&#46; Follow-up is therefore necessary&#44; and clinically atypical&#44; severe&#44; persistent&#44; or recurrent lesions should be biopsied&#46;<a class="elsevierStyleCrossRefs" href="#bib0530"><span class="elsevierStyleSup">11&#44;17&#44;18&#44;22&#8211;25</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Pruritus</span><p id="par0100" class="elsevierStylePara elsevierViewall">Pruritus is one of the most prevalent irAEs&#44; presenting in up to 32&#37; of patients on ICIs&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">26</span></a> Itching may be associated with other dermatoses&#44; be the first sign of more severe irAEs such as bullous pemphigoid&#44; or be an isolated event indicating increased activation of the skin&#39;s immune system&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">If xerosis is present&#44; the pruritus must be treated&#46; When itching is mild or intermittent &#40;grades 1&#8211;2&#41;&#44; topical corticosteroids&#44; oral antihistamines&#44; and emollient creams are recommended&#46; In cases in which symptoms are difficult to control and greatly impair the patient&#39;s quality of life &#40;grade 3&#41;&#44; treatments that have been used include &#947;-aminobutyric acid A receptor antagonists&#44; aprepitant&#44; phototherapy&#44; naloxone&#44; naltrexone&#44; omalizumab&#44; and dupilumab&#46; The reported results vary&#46; Treatment with the culprit drug must be suspended on rare occasions&#46;<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">13&#44;22&#44;26&#8211;29</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Lichenoid Eruptions</span><p id="par0110" class="elsevierStylePara elsevierViewall">Lichenoid reactions have been reported mainly in association with anti-PD1&#47;PDL1 drugs&#44; and according to some authors these rashes have the histopathologic pattern most often seen in ICI-associated irAEs&#46;<a class="elsevierStyleCrossRefs" href="#bib0570"><span class="elsevierStyleSup">19&#44;21&#44;23&#44;30&#44;31</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Lichenoid eruptions develop later than maculopapular rashes&#44; appearing at 3 months from the start of treatment on average &#40;range&#44; 1 day to 14 months&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0590"><span class="elsevierStyleSup">23&#44;31&#44;32</span></a> Clinical signs vary from forms resembling lichen planus to more atypical presentations with hypertrophic or erosive lesions&#46; They may also resemble lichen planus pemphigoides or lichen sclerosus&#46; Nail alterations are sometimes observed&#46;<a class="elsevierStyleCrossRefs" href="#bib0580"><span class="elsevierStyleSup">21&#44;23&#44;31&#44;33&#44;34</span></a> Pruritus is a common symptom and may be difficult to treat&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">35</span></a> Mucosal involvement is not unusual and may be the only presentation&#44; in the form of whitish striae or erosive or atrophic lesions &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#44; A and B&#41;&#46; Characteristics may sometimes overlap with those of eczematous dermatitis or resemble a maculopapular rash&#46; In such cases a definitive histopathologic diagnosis is required&#44;<a class="elsevierStyleCrossRefs" href="#bib0565"><span class="elsevierStyleSup">18&#44;21&#44;23&#44;31&#44;33&#44;34</span></a> meaning that the incidence of lichenoid dermatitis may be underestimated&#46;<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">17&#44;20&#44;35</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">Biopsy can demonstrate the classic changes of lichen planus&#58; a band-like lymphocytic infiltrate&#44; hypergranulosis&#44; and irregular acanthosis&#46; However&#44; spongiosis&#44; parakeratosis&#44; eosinophils&#44; or a slight degree of interface dermatitis may be evident&#44; consistent with a diagnosis of lichenoid dermatitis&#46;<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">20&#44;21&#44;23&#44;33</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Corticosteroids are the first line of treatment&#46; Even rashes covering a large area respond well&#46; If the eruption is refractory&#44; systemic corticosteroids&#44; phototherapy&#44; oral acitretin&#44; or even methotrexate or apremilast may be prescribed&#46; Treatment with the culprit drug generally need not be suspended&#59; in some cases therapy has been restarted without recurrence of the reaction&#46;<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">17&#44;23&#44;33&#44;35</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Lichenoid eruptions have been associated with a good response to oncologic therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">32</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Eczematous Eruptions</span><p id="par0135" class="elsevierStylePara elsevierViewall">Eczemas occur mainly in patients on anti-PD1&#47;PDL1 inhibitors&#46;<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">14&#44;19&#44;30</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">They typically present later than maculopapular rashes&#44; usually after 3 months of treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0570"><span class="elsevierStyleSup">19&#44;32</span></a> However&#44; they may appear up to 2 years after therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">30</span></a> Lesions may be generalized or local and are usually accompanied by pruritus&#46;<a class="elsevierStyleCrossRefs" href="#bib0570"><span class="elsevierStyleSup">19&#44;30</span></a> On biopsy&#44; spongiosis can be seen in the epidermis and a perivascular inflammatory infiltrate in the dermis&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">20</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Depending on severity&#44; topical or systemic corticosteroids&#44; topical tacrolimus&#44; oral antihistamines&#44; or UV-B phototherapy may be prescribed&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">30</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Psoriasis</span><p id="par0150" class="elsevierStylePara elsevierViewall">Reports of both de novo and exacerbated psoriasis associated with anti-PD1 inhibitors&#44; and less often with anti-PDL1 blockers and ipilimumab&#44; have been published&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">36</span></a> Mean latency after start of therapy ranges from 1 to 8 months&#46; Exacerbations present earlier than de novo cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0655"><span class="elsevierStyleSup">36&#8211;38</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">The most common form of presentation is plaque psoriasis&#44; followed by palmoplantar psoriasis&#46; Pustular forms &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>C&#41; have been documented as have guttate&#44; inverse&#44; erythrodermic&#44; and nail psoriasis&#44; as well as sebopsoriasis&#44; combinations of subtypes&#44; and associations with psoriatic arthritis&#46;<a class="elsevierStyleCrossRefs" href="#bib0660"><span class="elsevierStyleSup">37&#8211;40</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Histologic findings tend to be those typical of eczema&#44; although a degree of spongiosis has also been reported&#44; especially in inverse psoriasis lesions&#46;<a class="elsevierStyleCrossRefs" href="#bib0570"><span class="elsevierStyleSup">19&#44;20</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">The pathogenic mechanisms are unclear&#44; but it appears that PD1 inhibition activates T<span class="elsevierStyleSmallCaps">h</span>1 and T<span class="elsevierStyleSmallCaps">h</span>17 pathways with consequent overexpression of interferon-&#947;&#44; IL-2&#44; tumor necrosis factor&#44; IL-6&#44; and IL-17&#46;<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">14&#44;20&#44;36</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">Symptoms are usually mild &#40;BSA<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>10&#37;&#41; in most patients and respond well to high-potency topical corticosteroids combined with calcipotriol&#46;<a class="elsevierStyleCrossRefs" href="#bib0655"><span class="elsevierStyleSup">36&#44;38</span></a> Adding phototherapy &#40;narrowband UV-B&#41; or acitretin is recommended if there is no response&#46; Refractory cases can be treated with methotrexate&#44; apremilast&#44; or biologics &#40;preferably anti-tumor necrosis factor agents&#41; as a last resort&#59; results vary&#46;<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">17&#44;38&#44;39</span></a> Systemic corticosteroids have been used&#44; but they are best reserved for achieving a rapid response or after other measures have failed&#46;<a class="elsevierStyleCrossRefs" href="#bib0665"><span class="elsevierStyleSup">38&#44;39</span></a> The culprit drug must be suspended temporarily or definitively in fewer than half the cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0655"><span class="elsevierStyleSup">36&#44;38</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Sarcoidosis-Like Granulomatous Eruptions</span><p id="par0175" class="elsevierStylePara elsevierViewall">Granulomatous dermatitis resembling sarcoidosis appears in a variable percentage of patients on ICIs&#8212;ranging from 0&#46;65&#37; to 22&#37; in different series&#46;<a class="elsevierStyleCrossRefs" href="#bib0680"><span class="elsevierStyleSup">41&#8211;43</span></a> These reactions have been reported with the use of anti-PD1&#47;PDL1 antibodies and ipilimumab&#46;<a class="elsevierStyleCrossRefs" href="#bib0565"><span class="elsevierStyleSup">18&#44;41&#44;43</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">Latency ranges from 1&#46;5 to 7 months after start of therapy&#44; although reactions can develop several months after treatment stopped&#46; The organs most commonly affected are the mediastinal and hilar lymph nodes&#44; the lungs&#44; and the skin&#46; Skin signs consist of erythematous papules or nodules coalescing into plaques&#59; the lesions are pruritic&#44; sometimes painful&#44; and located on the face or extremities&#46;<a class="elsevierStyleCrossRefs" href="#bib0680"><span class="elsevierStyleSup">41&#8211;43</span></a> Histology demonstrates nonnecrotizing granulomas&#46;<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">20&#44;41</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">A proliferation of T<span class="elsevierStyleSmallCaps">h</span>1 and T<span class="elsevierStyleSmallCaps">h</span>17 cells induced by anti-CTLA-4 antibodies has been reported&#46; The adverse reaction could be paradoxical&#44; however&#44; given that patients with sarcoidosis have higher expression of PD1 in T cells&#46; Thus&#44; blocking the PD1 receptor could be considered a therapeutic strategy in this disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">20&#44;41&#44;43</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">Skin lesions are treated with high-potency topical corticosteroids&#46; If the response is unsatisfactory&#44; systemic corticosteroids are prescribed&#46; Oral hydroxychloroquine has occasionally been used&#46;<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">41</span></a> Lymph node and lung involvement must be ruled out&#46; When skin lesions are persistent or extensive&#44; radiologic signs progress&#44; lung function deteriorates&#44; or other organs are affected&#44; systemic corticosteroids should be started and the culprit ICI suspended&#46; Once the corticosteroid dose has been reduced to 10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d or less and the patient is asymptomatic&#44; restarting ICI therapy can be considered&#46;<a class="elsevierStyleCrossRefs" href="#bib0680"><span class="elsevierStyleSup">41&#8211;43</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Neutrophilic Dermatoses</span><p id="par0195" class="elsevierStylePara elsevierViewall">Several types of neutrophilic dermatoses&#44; mainly Sweet syndrome&#44; have been linked to ICIs&#46; The characteristics of these irAEs are given in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#46;<a class="elsevierStyleCrossRefs" href="#bib0695"><span class="elsevierStyleSup">44&#44;45</span></a></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Serious Adverse Skin Reactions</span><p id="par0200" class="elsevierStylePara elsevierViewall">The frequency of serious skin reactions to ICIs is low&#44; affecting fewer than 3&#37; of patients on these drugs&#44;<a class="elsevierStyleCrossRefs" href="#bib0500"><span class="elsevierStyleSup">5&#44;9&#44;14&#44;24</span></a> but cases of Stevens&#8211;Johnson syndrome&#44; toxic epidermal necrolysis &#40;TEC&#41;&#44; DRESS &#40;drug reaction with eosinophilia and systemic symptoms&#41;&#44; and acute generalized exanthematous pustulosis have been reported&#46;<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">14&#44;24&#44;44&#44;46&#8211;48</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">ICI-induced cases of TEC can have atypical&#44; late presentations that develop up to 12 weeks after therapy started&#46; These irAEs begin as maculopapular eruptions and persist for weeks until blistering and epidermal detachment appear&#46;<a class="elsevierStyleCrossRefs" href="#bib0565"><span class="elsevierStyleSup">18&#44;24&#44;48&#44;49</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">Biopsy for direct immunofluorescence is indicated in such cases to rule out an immunobullous reaction&#46;<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">48</span></a> The culprit agent must be suspended&#44; the patient hospitalized&#44; and life support measures initiated&#46; Systemic corticosteroids are recommended to treat ICI-induced TEC&#44; unlike TEC induced by other drugs&#46; Treatment continues until symptoms improve to grade 1&#44; at which point the dose is gradually reduced&#46;<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">13&#44;15&#44;16&#44;24&#44;48</span></a> Intravenous infliximab&#44; ciclosporin&#44; and immunoglobulins have been used&#46;<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">17&#44;24&#44;49</span></a> Mortality can be as high as 50&#37;&#8211;60&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0715"><span class="elsevierStyleSup">48&#44;49</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Eruptions Resembling Connective Tissue Diseases</span><p id="par0215" class="elsevierStylePara elsevierViewall">Connective tissue diseases associated with ICIs are emerging toxicities&#46;<a class="elsevierStyleCrossRefs" href="#bib0725"><span class="elsevierStyleSup">50&#8211;55</span></a> De novo diseases account for 0&#46;025&#37; of the observations in patients on ICI therapy&#44; and the incidence is similar in men and women&#46; They develop mainly in the context of treatment with anti-PD1&#47;PDL1<a class="elsevierStyleCrossRefs" href="#bib0725"><span class="elsevierStyleSup">50&#44;52</span></a> antibodies&#46; Cases of subacute lupus erythematosus have been described and are the most common irAE in this category&#46; Reports of scleroderma&#44; dermatomyositis&#44; and eosinophilic fasciitis have also been published&#46;<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">50</span></a> The average latency is 8 months &#40;range&#44; 0&#46;5&#8211;26 months&#41;&#46; Clinical features are the typical ones&#44;<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">50</span></a> save for the fact that scleroderma due to pembrolizumab is more diffuse and of rapid onset&#44; while nivolumab induces a more localized reaction&#46;<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">52</span></a></p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Immunobullous Eruptions</span><p id="par0220" class="elsevierStylePara elsevierViewall">Bullous pemphigoid is the main type of immunobullous eruption&#44; although individual cases of herpetiform and linear IgA dermatoses have also been reported&#46;<a class="elsevierStyleCrossRefs" href="#bib0530"><span class="elsevierStyleSup">11&#44;14&#44;56</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">Bullous pemphigoid&#44; which has an incidence of 1&#37; to 8&#37;&#44; has usually been linked to combined anti-PD1&#47;PDL1 treatment&#44; but has occasionally been associated with ipilimumab&#46;<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">14&#44;19&#44;25&#44;56&#8211;58</span></a></p><p id="par0230" class="elsevierStylePara elsevierViewall">Developing 6 months after start of treatment &#40;range&#44; 2 weeks to 25 months&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0570"><span class="elsevierStyleSup">19&#44;25&#44;56&#44;57&#44;59&#8211;61</span></a> these reactions have a typical clinical picture of intense pruritus&#44; erythema&#44; edema&#44; and tense blisters filled with clear fluid&#46; They may be scattered over any part of the body &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#44; A&#8211;C&#41;&#44; localized&#44; affect mucosal surfaces&#44; or progress without blistering&#46;<a class="elsevierStyleCrossRefs" href="#bib0755"><span class="elsevierStyleSup">56&#44;60&#44;62</span></a> There is usually a prebullous phase of a few weeks &#40;in 34&#46;5&#37;&#41; or a period with pruritus but no lesions&#46;<a class="elsevierStyleCrossRefs" href="#bib0600"><span class="elsevierStyleSup">25&#44;57&#44;60&#44;61</span></a> Subepidermal blisters rich in eosinophils are a typical finding in biopsied tissue&#44; and direct immunofluorescence shows linear IgG and C3 deposition&#46;<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">20&#44;56&#44;60&#44;61&#44;63</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0235" class="elsevierStylePara elsevierViewall">One pathogenic mechanism proposed is cross reactivity between cutaneous and tumor antigens &#40;as melanomas and microcytic carcinomas seem to express BP180&#41;&#46; Another is a worsening of preexisting&#44; subclinical pemphigoid disease due to immune system stimulus&#46; It is unclear whether B-cell activation &#40;caused by anti-BP180 antibodies&#41; occurs directly on contact with ICIs or is mediated by T cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">20&#44;62&#8211;64</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">For a minority of patients&#44; symptoms can be controlled with topical corticosteroids&#44; but more severe symptoms &#40;grade 2 or higher&#41; require systemic treatment&#46; Many also require additional drugs&#44; such as doxycycline&#44; nicotinamide&#44; dapsone&#44; methotrexate&#44; intravenous immunoglobulins&#44; omalizumab&#44; or rituximab&#46; In half or more cases&#44; ICI therapy must be suspended and systemic corticosteroids maintained&#44; given that the clinical picture may be persistent&#8212;lasting months after the ICI is withdrawn&#8212;or recurrent&#46;<a class="elsevierStyleCrossRefs" href="#bib0530"><span class="elsevierStyleSup">11&#44;26&#44;27&#44;56&#44;57&#44;60&#44;61</span></a></p><p id="par0245" class="elsevierStylePara elsevierViewall">Some authors have reported an association between this toxicity or elevated anti-BP180 IgG titers on the one hand and a favorable response to oncologic therapy on the other&#46;<a class="elsevierStyleCrossRefs" href="#bib0795"><span class="elsevierStyleSup">64&#44;65</span></a></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Alterations in Keratinocytes</span><p id="par0250" class="elsevierStylePara elsevierViewall">Grover disease has been reported in association with both anti-CTLA-4 and anti-PD1&#47;PDL1 drugs&#46;<a class="elsevierStyleCrossRefs" href="#bib0565"><span class="elsevierStyleSup">18&#44;19</span></a> Authors recommend biopsying lesions to confirm the diagnosis&#44; as samples show the typical signs of Grover disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0530"><span class="elsevierStyleSup">11&#44;17&#44;18&#44;20</span></a></p><p id="par0255" class="elsevierStylePara elsevierViewall">Actinic keratosis&#44; basal cell carcinoma&#44; seborrheic warts&#44; epidermoid carcinoma&#44; and eruptive keratoacanthomas have been reported in patients on anti-PD1&#47;PDL1 blockers&#46;<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">14&#44;30</span></a> The pathogenic mechanism in relation to ICIs is unknown&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Pigmentary Changes</span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Vitiligo</span><p id="par0260" class="elsevierStylePara elsevierViewall">Vitiligo is a common adverse effect linked to both anti-CTLA-4 and anti-PD1&#47;PDL1 therapy&#46; It develops mainly in patients with melanoma&#44; the incidence ranging from 2&#46;8&#37; to 48&#37; in case series&#46;<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">14&#44;30&#44;66&#44;67</span></a> This irAE has also been reported in ICI-treated patients with lung cancer&#44; however&#46;<a class="elsevierStyleCrossRefs" href="#bib0815"><span class="elsevierStyleSup">68&#44;69</span></a></p><p id="par0265" class="elsevierStylePara elsevierViewall">Latency after start of treatment ranges from 30 to 758 days&#46;<a class="elsevierStyleCrossRefs" href="#bib0805"><span class="elsevierStyleSup">66&#44;67&#44;70&#44;71</span></a> Reactive vitiligo differs from the common form in that it usually presents with mottled lesions that merge into larger macules distributed across sun-exposed parts of the body &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#44; A and B&#41; and is not associated with the Koebner phenomenon&#46;<a class="elsevierStyleCrossRefs" href="#bib0805"><span class="elsevierStyleSup">66&#44;70&#44;72</span></a> In addition&#44; according to Larsabal et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0825"><span class="elsevierStyleSup">70</span></a> patients with this irAE have no family or personal histories of vitiligo&#44; thyroiditis&#44; or autoimmune disease but do have elevated expression of CXCR3 on CD8<span class="elsevierStyleSup">&#43;</span> T cells in blood and perilesional tissues&#46;<a class="elsevierStyleCrossRef" href="#bib0825"><span class="elsevierStyleSup">70</span></a></p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0270" class="elsevierStylePara elsevierViewall">The pathogenic mechanism that has been suggested is cross reactivity between tumor cells and melanocytic antigens &#40;glycoprotein 100&#44; MelanA&#47;MART-1&#44; tyrosinase&#44; etc&#46;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0565"><span class="elsevierStyleSup">18&#44;20&#44;66&#44;67</span></a></p><p id="par0275" class="elsevierStylePara elsevierViewall">Lesions persist after ICI therapy is interrupted&#46; Specific treatment other than protection from sun exposure is unnecessary&#44; although topical corticosteroids&#44; topical tacrolimus&#44; phototherapy&#44; and laser therapy have all been tried&#44; with limited results&#46;<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">17&#44;18&#44;59&#44;67&#44;69&#44;73</span></a></p><p id="par0280" class="elsevierStylePara elsevierViewall">Both the appearance of vitiligo and its spread and progression have been related to a favorable response to oncologic treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0635"><span class="elsevierStyleSup">32&#44;66&#44;72&#44;74&#8211;76</span></a></p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Other Pigmentary Alterations</span><p id="par0285" class="elsevierStylePara elsevierViewall">Repigmentation of gray hair and regression of preexisting melanocytic nevi or the appearance of poliosis &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>B&#41;&#44; associated or not with vitiligo have been described in patients with ICI-treated melanoma&#46;<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">14&#44;18&#44;67&#44;73</span></a></p></span></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Hair and Nail Abnormalities</span><p id="par0290" class="elsevierStylePara elsevierViewall">The various types of hair and nail alterations that have been reported are listed in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#46; Hair loss&#8212;mainly alopecia areata&#8212;is the most common event&#44; with an incidence ranging from 1&#37; to 27&#37; according to sources consulted&#46;<a class="elsevierStyleCrossRefs" href="#bib0520"><span class="elsevierStyleSup">9&#44;18</span></a></p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Other Dermatoses</span><p id="par0295" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a> lists other dermatoses that have been reported sporadically in single case reports&#46; Most are inflammatory in nature&#46; Their pathogenesis and the prognostic implications are unknown&#46;</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia></span></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Managing Skin Toxicities</span><p id="par0300" class="elsevierStylePara elsevierViewall">Given the frequency of and morbidity associated with cutaneous irAEs&#44; dermatology plays an important role in the multidisciplinary care of patients on ICIs&#46; Dermatologists intervene by providing a precise diagnosis&#44; optimal management of treatment&#44; and a proper perspective on the prognostic relevance of skin reactions&#46;<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">73</span></a></p><p id="par0305" class="elsevierStylePara elsevierViewall">Dermatologists should be involved early in the care of these patients to assess skin condition at baseline&#44; before ICIs are introduced&#44; or patients should at least be referred to us soon after a cutaneous toxicity appears&#46;<a class="elsevierStyleCrossRefs" href="#bib0585"><span class="elsevierStyleSup">22&#44;67&#44;73</span></a> When a skin reaction presents&#44; a detailed clinical history and an exhaustive physical examination of the skin and mucosal surfaces are necessary&#44; and infections must be ruled out along with possible adverse effects due to other drug treatments or systemic diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">22</span></a></p><p id="par0310" class="elsevierStylePara elsevierViewall">The treatment of cutaneous irAEs will be based on severity&#44; as mentioned earlier&#46; CTCAE categories in function of BSA are currently used to classify severity&#46;<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">13&#44;15&#44;16&#44;18</span></a> However&#44; some authors find this grading system to be inadequate and call for evaluations based on the nature of the particular skin eruption&#44; its location&#44; and its effect on quality of life&#46;<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">17&#44;77</span></a></p><p id="par0315" class="elsevierStylePara elsevierViewall">Throughout the sections of this review we have pointed out that systemic corticosteroids are the cornerstone in the management of serious cutaneous toxicities &#40;grade 2 or higher&#41;&#46; Nonetheless&#44; their impact on survival is a point of contention&#46; Some studies suggest that high doses of prednisone &#40;&#62;10<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41; could reduce the efficacy of ICIs and lead to a poor oncologic outcome&#46;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">4&#44;78&#44;79</span></a> Others report that such doses do not have a negative effect on tumor response&#44; provided the corticosteroid had not been administered before the ICI was started&#46;<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">17&#44;80&#44;81</span></a> Nonetheless&#44; whenever possible&#44; dermatologists should attempt to use other treatment modalities that can target the particular toxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">17</span></a></p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Prognostic Significance of irAEs</span><p id="par0320" class="elsevierStylePara elsevierViewall">More and more studies are reporting associations between cutaneous irAEs in general and certain reactions in particular on the one hand and tumor response rates on the other&#8212;as well as their association with longer progression-free and overall survival rates&#46;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">4&#44;10&#44;32&#44;38&#44;64&#8211;66&#44;71&#44;72&#44;74&#8211;76&#44;82&#44;83</span></a> However&#44; like other authors&#44; we believe these observations must be interpreted cautiously given the limitations of the retrospective and small-scale studies on which the conclusions are based&#46; Moreover&#44; the clinical significance of severe irAEs is still unclear and bias in the analysis of survival is difficult to control for&#58; it is possible that patients who live longer also develop more irAEs simply because they have been in treatment longer&#46;<a class="elsevierStyleCrossRefs" href="#bib0600"><span class="elsevierStyleSup">25&#44;38&#44;78&#44;79&#44;84</span></a></p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Conclusions</span><p id="par0325" class="elsevierStylePara elsevierViewall">ICIs are the future of oncologic therapy&#44; and the incidence of cutaneous toxicities derived from them will rise&#46; Although our understanding of irAEs is improving&#44; many issues remain to be clarified regarding their characterization and classification&#44; pathogenesis&#44; management&#44; and relation to prognosis&#46; Dermatologists play an essential role in diagnosing and treating toxicities&#44; many of which have considerable impact on cancer patients&#8217; quality of life&#46;</p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Conflict of Interests</span><p id="par0330" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflict of interest&#46;</p></span></span>"
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          "identificador" => "xres1718478"
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        5 => array:2 [
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          "titulo" => "Introduction"
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          "titulo" => "Methods"
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          "identificador" => "sec0015"
          "titulo" => "Results"
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        8 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Pathogenesis and Frequency"
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        9 => array:3 [
          "identificador" => "sec0025"
          "titulo" => "Types of Cutaneous Toxicity and Characteristics"
          "secciones" => array:6 [
            0 => array:3 [
              "identificador" => "sec0030"
              "titulo" => "Inflammatory Eruptions"
              "secciones" => array:9 [
                0 => array:2 [
                  "identificador" => "sec0035"
                  "titulo" => "Maculopapular Rashes"
                ]
                1 => array:2 [
                  "identificador" => "sec0040"
                  "titulo" => "Pruritus"
                ]
                2 => array:2 [
                  "identificador" => "sec0045"
                  "titulo" => "Lichenoid Eruptions"
                ]
                3 => array:2 [
                  "identificador" => "sec0050"
                  "titulo" => "Eczematous Eruptions"
                ]
                4 => array:2 [
                  "identificador" => "sec0055"
                  "titulo" => "Psoriasis"
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                5 => array:2 [
                  "identificador" => "sec0060"
                  "titulo" => "Sarcoidosis-Like Granulomatous Eruptions"
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                6 => array:2 [
                  "identificador" => "sec0065"
                  "titulo" => "Neutrophilic Dermatoses"
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                7 => array:2 [
                  "identificador" => "sec0070"
                  "titulo" => "Serious Adverse Skin Reactions"
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                8 => array:2 [
                  "identificador" => "sec0075"
                  "titulo" => "Eruptions Resembling Connective Tissue Diseases"
                ]
              ]
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            1 => array:2 [
              "identificador" => "sec0080"
              "titulo" => "Immunobullous Eruptions"
            ]
            2 => array:2 [
              "identificador" => "sec0085"
              "titulo" => "Alterations in Keratinocytes"
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              "titulo" => "Pigmentary Changes"
              "secciones" => array:2 [
                0 => array:2 [
                  "identificador" => "sec0095"
                  "titulo" => "Vitiligo"
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                1 => array:2 [
                  "identificador" => "sec0100"
                  "titulo" => "Other Pigmentary Alterations"
                ]
              ]
            ]
            4 => array:2 [
              "identificador" => "sec0105"
              "titulo" => "Hair and Nail Abnormalities"
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            5 => array:2 [
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              "titulo" => "Other Dermatoses"
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          ]
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        10 => array:2 [
          "identificador" => "sec0115"
          "titulo" => "Managing Skin Toxicities"
        ]
        11 => array:2 [
          "identificador" => "sec0120"
          "titulo" => "Prognostic Significance of irAEs"
        ]
        12 => array:2 [
          "identificador" => "sec0125"
          "titulo" => "Conclusions"
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        13 => array:2 [
          "identificador" => "sec0130"
          "titulo" => "Conflict of Interests"
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          "titulo" => "References"
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    "fechaRecibido" => "2021-06-30"
    "fechaAceptado" => "2021-09-26"
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          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1518648"
          "palabras" => array:5 [
            0 => "Immune checkpoint inhibitors"
            1 => "Cutaneous immune-related adverse events"
            2 => "Skin toxicity"
            3 => "Immunotherapy"
            4 => "Programmed cell death protein 1 inhibitors"
          ]
        ]
      ]
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          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1518647"
          "palabras" => array:5 [
            0 => "Puntos de control inmunitario"
            1 => "Efectos adversos inmunorrelacionados"
            2 => "Toxicidad cut&#225;nea"
            3 => "Inmunoterapia"
            4 => "Inhibidores de PD-1"
          ]
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    "resumen" => array:2 [
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Immune checkpoint inhibitors &#40;ICIs&#41; have significantly advanced the treatment of cancer&#46; They are not&#44; however&#44; free of adverse effects&#46; These effects are called immune-related adverse events &#40;irAEs&#41; and often involve the skin&#46; Most of the information on cutaneous irAEs comes from clinical practice&#46; We therefore conducted a thorough review of the characteristics of cutaneous irAEs&#44; recommendations for treatment&#44; and their association with prognosis&#46; The most common events are exanthema&#44; pruritus&#44; vitiligo&#44; and hair loss&#44; although ICIs can cause a wide range of cutaneous dermatoses&#46; The reported association observed between certain reactions and a favorable response to cancer treatment should be interpreted with caution&#46; Dermatologists should be involved in the multidisciplinary care of patients being treated with ICIs as they have an essential role in the diagnosis and treatment of cutaneous irAEs&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0015" class="elsevierStyleSection elsevierViewall"><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Los f&#225;rmacos inhibidores de los puntos de control inmunitario han supuesto un importante avance en el tratamiento oncol&#243;gico&#46; Sin embargo&#44; su uso no est&#225; exento de reacciones no deseadas&#44; denominadas efectos adversos inmunorrelacionados&#44; siendo los cut&#225;neos particularmente frecuentes&#46; El conocimiento que tenemos sobre los efectos adversos inmunorrelacionados cut&#225;neos procede fundamentalmente de la pr&#225;ctica cl&#237;nica&#46; Por lo tanto&#44; en este trabajo se revisan en detalle sus caracter&#237;sticas&#44; as&#237; como las recomendaciones sobre su tratamiento y sus implicaciones pron&#243;sticas&#46; Los m&#225;s frecuentes son el exantema&#44; el prurito&#44; el vit&#237;ligo y la alopecia&#59; sin embargo&#44; estos f&#225;rmacos pueden producir una amplia variedad de dermatosis&#46; La asociaci&#243;n observada entre ciertos tipos de reacciones cut&#225;neas con una respuesta oncol&#243;gica favorable al tratamiento debe interpretarse con cautela&#46; El dermat&#243;logo ha de participar en el cuidado multidisciplinar de estos pacientes&#44; pues desempe&#241;a un papel fundamental en el diagn&#243;stico y el tratamiento de estas reacciones cut&#225;neas adversas&#46;</p></span>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Flow diagram of article retrieval&#44; processing&#44; and reading&#44; where irAE refers to cutaneous immune-related adverse event&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Inflammatory dermatoses&#46; A and B&#44; Erosive oral lesions in a 60-year-old man with stage IV adenocarcinoma of the bronchi and lungs in treatment with durvalumab&#46; Histology demonstrated lichenoid dermatitis&#46; C&#44; Plantar pustulosis in a 68-year-old woman with stage IV adenocarcinoma of the bronchi and lungs in treatment with pembrolizumab&#46;</p>"
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          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; CTLA-4&#44; cytotoxic T-lymphocyte-associated antigen 4&#59; EMA&#44; European Medicines Agency&#59; ICI&#44; immune checkpoint inhibitor&#59; PD1&#44; programmed cell death protein 1&#59; PDL1&#44; ligand of PD1&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th 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" scope="col" style="border-bottom: 2px solid black">ICI type&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">EMA approval date&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Anti-CTLA-4</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Ipilimumab&nbsp;\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">July 2011&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Tremelimumab&nbsp;\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">July 2019&nbsp;\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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Anti-PD1</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Nivolumab&nbsp;\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">June 2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Pembrolizumab&nbsp;\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">July 2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Cemiplimab&nbsp;\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">June 2019&nbsp;\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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Anti-PDL1</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Atezolizumab&nbsp;\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">September 2017&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Avelumab&nbsp;\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">September 2017&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Durvalumab&nbsp;\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">September 2018&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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        "descripcion" => array:1 [
          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">ICI Types and Dates of Approval by the EMA&#46;</p>"
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      5 => array:8 [
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        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
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            "identificador" => "at2"
            "detalle" => "Table "
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Source</span>&#58; Haanen et al&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">13</span></a></p><p id="spar0090" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; ADL&#44; activities of daily living&#59; BSA&#44; body surface area&#59; CTCAE&#44; Common Terminology Criteria for Adverse Events&#59; ICU&#44; intensive care unit&#59; TEC&#44; toxic epidermal necrolysis&#59; SJS&#44; Stevens&#8211;Johnson syndrome&#46;</p>"
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              "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"><th 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" scope="col" style="border-bottom: 2px solid black">Grade&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Characteristics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\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">Covering<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>10&#37; BSA&#44; with or without symptoms &#40;pruritus&#44; burning&#44; tightness&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\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">Covering 10&#37;&#8211;30&#37; BSA&#44; with or without symptoms&#59; ADL interference&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\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">Covering<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>30&#37; BSA&#44; with or without symptoms&#59; ADL interference&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\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">SJS&#44; TEC&#44; bullous dermatitis covering<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>30&#37; BSA requiring hospitalization and ICU admission&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Severity of Skin irAEs Graded According to the CTCAE and Exemplified by Maculopapular Rashes&#46;</p>"
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          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviation</span>&#58; ICI&#44; immune checkpoint inhibitor&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Type&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Characteristics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sweet Syndrome<a class="elsevierStyleCrossRefs" href="#bib0695"><span class="elsevierStyleSup">44&#44;45</span></a> &#40;the most often reported&#41;&nbsp;\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">Clinical features exclusively described with ipilimumab&#46; Mean latency&#44; 9 wks&nbsp;\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">Topical<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>systemic corticosteroidsOther options&#58; dapsone&#44; ciclosporinConsider suspending culprit drug&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pyoderma gangrenosum<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">44</span></a>&nbsp;\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">Typical ulcer&#46; Rare&#46; Exclusively described with ipilimumab&#46; Mean latency&#44; 16 wks&nbsp;\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">Topical<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>systemic corticosteroids&#59; infliximabTreat the ulcer&#44; manage pain&#44; apply topical antibiotics&#46;Suspend the culprit drug&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Acute&#44; localized exanthematous pustulosis<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">44</span></a>&nbsp;\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
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                  \t\t\t\t">Rare&#46; Subcorneal vesicles with neutrophils&#44; localized&nbsp;\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">Topical corticosteroids&#46; Culprit drug need not be suspended&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">ICI-Associated Neutrophilic Dermatoses&#46;</p>"
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          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Sources</span>&#58; Apalla et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">11</span></a>Sibaud&#44;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">18</span></a> Ocampo et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0900"><span class="elsevierStyleSup">85</span></a> Dasanu et al&#46;<a class="elsevierStyleCrossRef" href="#bib0905"><span class="elsevierStyleSup">86</span></a></p><p id="spar0095" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviation</span>&#58; ICI&#44; immune checkpoint inhibitor&#46;</p>"
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              "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"><th 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" scope="col" style="border-bottom: 2px solid black">Type&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Characteristics&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alopecia areata&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Most frequent and severe with ipilimumabPartial or universalisTypical histology&#58; nonscarring with a perifollicular lymphocytic infiltrate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Changes in hair texture&nbsp;\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">ThickeningChange from straight to curly&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nail changes&nbsp;\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">Dystrophy&#44; sometimes associated with onychomadesis or onychoschiziaColor changesDiffuse onycholysis and paronychia affecting all digitsProbable psoriatic or lichenoid etiology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">ICI-Associated Hair and Nail Alterations&#46;</p>"
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          "leyenda" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviation</span>&#58; ICI&#44; immune checkpoint inhibitor&#46;</p>"
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                0 => """
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t">Pityriasis rubra pilaris<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">14&#44;19</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Eruptions resembling pityriasis rosea<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">14&#44;19</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hidradenitis suppurativa<a class="elsevierStyleCrossRef" href="#bib0910"><span class="elsevierStyleSup">87</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Sj&#246;gren syndrome<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">18</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">Acneiform eruption and papulopustular rosacea<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">14&#44;18</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vasculitis<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">18</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">Erythema nodosum-type panniculitis<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">18</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Angioedema<a class="elsevierStyleCrossRef" href="#bib0920"><span class="elsevierStyleSup">89</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hypohidrosis<a class="elsevierStyleCrossRef" href="#bib0925"><span class="elsevierStyleSup">90</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pseudolymphoma<a class="elsevierStyleCrossRef" href="#bib0930"><span class="elsevierStyleSup">91</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">Granuloma annulare<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">18</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Granulomatous herpes zoster<a class="elsevierStyleCrossRef" href="#bib0935"><span class="elsevierStyleSup">92</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Pruritus simplex&#44; nodular pruritus<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">14</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Photosensitivity<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">18</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">Progressive mucocutaneous eruption associated with immunotherapy<a class="elsevierStyleCrossRef" href="#bib0950"><span class="elsevierStyleSup">95</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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                      "titulo" => "Immune-related adverse events associated with immune checkpoint blockade"
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                          "autores" => array:3 [ …3]
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                        "fecha" => "2018"
                        "volumen" => "378"
                        "paginaInicial" => "158"
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                      "titulo" => "Immune checkpoint inhibitors to treat cutaneous malignancies"
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                          "etal" => true
                          "autores" => array:6 [ …6]
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                    0 => array:2 [
                      "doi" => "10.1016/j.jaad.2020.03.131"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Acad Dermatol"
                        "fecha" => "2020"
                        "volumen" => "83"
                        "paginaInicial" => "1239"
                        "paginaFinal" => "1253"
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                      "titulo" => "Systemic treatments for metastatic cutaneous melanoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
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                      "doi" => "10.1016/j.intimp.2021.107498"
                      "Revista" => array:5 [
                        "tituloSerie" => "Int Immunopharmacol"
                        "fecha" => "2021"
                        "volumen" => "95"
                        "paginaInicial" => "107498"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0510"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Immune checkpoint inhibitor toxicity in 2018"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1001/jama.2018.13995"
                      "Revista" => array:6 [
                        "tituloSerie" => "JAMA"
                        "fecha" => "2018"
                        "volumen" => "320"
                        "paginaInicial" => "1702"
                        "paginaFinal" => "1703"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0515"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Characterization and management of dermatologic adverse events to agents targeting the PD-1 receptor"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/CCM.0b013e31823a96d.Hydrogen"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Cancer"
                        "fecha" => "2016"
                        "volumen" => "60"
                        "paginaInicial" => "12"
                        "paginaFinal" => "25"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0520"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Patients with lung cancer undergoing immune checkpoint inhibitors&#58; a meta-analysis of dermatological toxicities"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.critrevonc.2020.102983"
                      "Revista" => array:4 [
                        "tituloSerie" => "Crit Rev Oncol Hematol"
                        "fecha" => "2020"
                        "volumen" => "152"
                        "paginaInicial" => "102983"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0525"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Multisystem immune-related adverse events associated with immune checkpoint inhibitors for treatment of non-small cell lung cancer"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                           …1
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1001/jamaoncol.2020.5012"
                      "Revista" => array:5 [
                        "tituloSerie" => "JAMA Oncol"
                        "fecha" => "2020"
                        "volumen" => "6"
                        "paginaInicial" => "1952"
                        "paginaFinal" => "1956"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0530"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cutaneous adverse events of immune checkpoint inhibitors&#58; a literature review"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.5826/dpc.1101a155"
                      "Revista" => array:4 [
                        "tituloSerie" => "Dermatol Pr Concept"
                        "fecha" => "2021"
                        "volumen" => "11"
                        "paginaInicial" => "e2021155"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0535"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association of anti-programmed cell death 1 antibody treatment with risk of recurrence of toxic effects after immune-related adverse events of ipilimumab in patients with metastatic melanoma"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1001/jamadermatol.2020.2149"
                      "Revista" => array:6 [
                        "tituloSerie" => "JAMA Dermatol"
                        "fecha" => "2020"
                        "volumen" => "156"
                        "paginaInicial" => "982"
                        "paginaFinal" => "986"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0540"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Management of toxicities from immunotherapy&#58; ESMO Clinical Practice Guidelines for diagnosis&#44; treatment and follow-up"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/annonc/mdx225"
                      "Revista" => array:4 [
                        "tituloSerie" => "Ann Oncol"
                        "fecha" => "2017"
                        "volumen" => "28"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0545"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diverse types of dermatologic toxicities from immune checkpoint blockade therapy"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/cup.12858"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Cutan Pathol"
                        "fecha" => "2017"
                        "volumen" => "44"
                        "paginaInicial" => "158"
                        "paginaFinal" => "176"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0550"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy&#58; American society of clinical oncology clinical practice guideline"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/JCO.2017776385"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "2018"
                        "volumen" => "36"
                        "paginaInicial" => "1714"
                        "paginaFinal" => "1768"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0555"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "New NCCN guidelines&#58; recognition and management of immunotherapy-related toxicity"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.6004/jnccn.2018.0047"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Natl Compr Canc Netw"
                        "fecha" => "2018"
                        "volumen" => "16"
                        "paginaInicial" => "594"
                        "paginaFinal" => "596"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0560"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cutaneous Immune-Related Adverse Events &#40;irAEs&#41; to immune checkpoint inhibitors&#58; a dermatology perspective on management"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1177/1203475420943260"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Cutan Med Surg"
                        "fecha" => "2021"
                        "volumen" => "25"
                        "paginaInicial" => "59"
                        "paginaFinal" => "76"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0565"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Dermatologic reactions to immune checkpoint inhibitors&#58; skin toxicities and immunotherapy"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s40257-017-0336-3"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Clin Dermatol"
                        "fecha" => "2018"
                        "volumen" => "19"
                        "paginaInicial" => "345"
                        "paginaFinal" => "361"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0570"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Inflammatory eruptions associated with immune checkpoint inhibitor therapy&#58; a single-institution retrospective analysis with stratification of reactions by toxicity and implications for management"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaad.2018.10.062"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Acad Dermatol"
                        "fecha" => "2019"
                        "volumen" => "80"
                        "paginaInicial" => "990"
                        "paginaFinal" => "997"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0575"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Dermatologic toxicities to immune checkpoint inhibitor therapy&#58; a review of histopathologic features"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaad.2020.04.105"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Acad Dermatol"
                        "fecha" => "2020"
                        "volumen" => "83"
                        "paginaInicial" => "1130"
                        "paginaFinal" => "1143"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0580"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical and histologic features of lichenoid mucocutaneous eruptions due to anti-programmed cell death 1 and anti-programmed cell death ligand 1 immunotherapy"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1001/jamadermatol.2016.2226"
                      "Revista" => array:6 [
                        "tituloSerie" => "JAMA Dermatol"
                        "fecha" => "2016"
                        "volumen" => "152"
                        "paginaInicial" => "1128"
                        "paginaFinal" => "1136"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0585"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Management of immune checkpoint inhibitor-related dermatologic adverse events"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/1759-7714.13275"
                      "Revista" => array:6 [
                        "tituloSerie" => "Thorac Cancer"
                        "fecha" => "2020"
                        "volumen" => "11"
                        "paginaInicial" => "488"
                        "paginaFinal" => "492"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0590"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Lichenoid dermatologic toxicity from immune checkpoint blockade therapy&#58; a detailed examination of the clinicopathologic features"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/DAD.0000000000000688"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Dermatopathol"
                        "fecha" => "2017"
                        "volumen" => "39"
                        "paginaInicial" => "121"
                        "paginaFinal" => "129"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0595"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Toxic epidermal necrolysis occurring with immune checkpoint inhibitors"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.5070/d3268049884"
                      "Revista" => array:3 [
                        "tituloSerie" => "Dermatol Online J"
                        "fecha" => "2020"
                        "volumen" => "26"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0600"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Bullous pemphigoid associated with anti-programmed cell death protein 1 and anti-programmed cell death ligand 1 therapy&#58; a review of the literature"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2340/00015555-3740"
                      "Revista" => array:3 [
                        "tituloSerie" => "Acta Derm Venereol"
                        "fecha" => "2021"
                        "volumen" => "101"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0605"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Treatment outcomes of immune-related cutaneous adverse events"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/JCO.18.02141"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "2019"
                        "volumen" => "37"
                        "paginaInicial" => "2746"
                        "paginaFinal" => "2758"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0610"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "IgE blockade with omalizumab reduces pruritus related to immune checkpoint inhibitors and anti-HER2 therapies"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.annonc.2021.02.016"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Oncol"
                        "fecha" => "2021"
                        "volumen" => "32"
                        "paginaInicial" => "736"
                        "paginaFinal" => "745"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib0615"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "PD-1 blockade-induced Pruritus treated with a mu-opioid receptor antagonist"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMc1805637"
                      "Revista" => array:5 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2018"
                        "volumen" => "379"
                        "paginaInicial" => "1578"
                        "paginaFinal" => "1579"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0620"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Aprepitant for refractory nivolumab-induced pruritus"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.lungcan.2017.04.020"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lung Cancer"
                        "fecha" => "2017"
                        "volumen" => "109"
                        "paginaInicial" => "58"
                        "paginaFinal" => "61"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0625"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cutaneous adverse events &#40;AEs&#41; of anti-programmed cell death &#40;PD&#41;-1 therapy in patients with metastatic melanoma&#58; a single-institution cohort"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaad.2015.10.029"
                      "Revista" => array:5 [
                        "tituloSerie" => "J Am Acad Dermatol"
                        "fecha" => "2016"
                        "volumen" => "74"
                        "paginaInicial" => "455"
                        "paginaFinal" => "461"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib0630"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Bullous lichen planus and anti-programmed cell death-1 therapy&#58; case report and literature review"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.annder.2019.07.008"
                      "Revista" => array:5 [
                        "tituloSerie" => "Ann Dermatol Venereol"
                        "fecha" => "2020"
                        "volumen" => "147"
                        "paginaInicial" => "221"
                        "paginaFinal" => "227"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib0635"
              "etiqueta" => "32"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Survival and prognosis of individuals receiving programmed cell death 1 inhibitor with and without immunologic cutaneous adverse events"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaad.2019.06.035"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Acad Dermatol"
                        "fecha" => "2020"
                        "volumen" => "82"
                        "paginaInicial" => "311"
                        "paginaFinal" => "316"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib0640"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Oral lichenoid reactions associated with anti-PD-1&#47;PD-L1 therapies&#58; clinicopathological findings"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/jdv.14284"
                      "Revista" => array:5 [
                        "tituloSerie" => "J Eur Acad Dermatol Venereol"
                        "fecha" => "2017"
                        "volumen" => "31"
                        "paginaInicial" => "e464"
                        "paginaFinal" => "e469"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib0645"
              "etiqueta" => "34"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pembrolizumab-induced lichen planus pemphigoides in a patient with metastatic Merkel cell carcinoma"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jdcr.2020.03.007"
                      "Revista" => array:6 [
                        "tituloSerie" => "JAAD Case Rep"
                        "fecha" => "2020"
                        "volumen" => "6"
                        "paginaInicial" => "1045"
                        "paginaFinal" => "1047"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib0650"
              "etiqueta" => "35"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cutaneous immune-related adverse events to checkpoint inhibitors"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.clindermatol.2020.06.011"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Dermatol"
                        "fecha" => "2020"
                        "volumen" => "38"
                        "paginaInicial" => "660"
                        "paginaFinal" => "678"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib0655"
              "etiqueta" => "36"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Psoriasis and psoriasiform reactions secondary to immune checkpoint inhibitors"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/dth.14830"
                      "Revista" => array:5 [
                        "tituloSerie" => "Dermatol Ther"
                        "fecha" => "2021"
                        "volumen" => "34"
                        "paginaInicial" => "1"
                        "paginaFinal" => "6"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib0660"
              "etiqueta" => "37"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Anti-PD1-induced psoriasis&#58; a study of 21 patients"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/jdv.14011"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Eur Acad Dermatol Venereol"
                        "fecha" => "2017"
                        "volumen" => "31"
                        "paginaInicial" => "e254"
                        "paginaFinal" => "e257"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib0665"
              "etiqueta" => "38"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Immune checkpoint-mediated psoriasis&#58; a multicenter European study of 115 patients from the European Network for Cutaneous Adverse Event to Oncologic Drugs &#40;ENCADO&#41; group"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaad.2020.08.137"
                      "Revista" => array:5 [
                        "tituloSerie" => "J Am Acad Dermatol"
                        "fecha" => "2021"
                        "volumen" => "84"
                        "paginaInicial" => "1310"
                        "paginaFinal" => "1320"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib0670"
              "etiqueta" => "39"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pembrolizumab-induced psoriasis in metastatic melanoma&#58; activity and safety of apremilast&#44; a case report"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3389/fonc.2020.579445"
                      "Revista" => array:5 [
                        "tituloSerie" => "Front Oncol"
                        "fecha" => "2020"
                        "volumen" => "10"
                        "paginaInicial" => "579445"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            39 => array:3 [
              "identificador" => "bib0675"
              "etiqueta" => "40"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Development of de novo psoriasis during nivolumab therapy in a patient with small cell lung cancer"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1177/1078155219877234"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Oncol Pharm Pract"
                        "fecha" => "2020"
                        "volumen" => "26"
                        "paginaInicial" => "256"
                        "paginaFinal" => "258"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            40 => array:3 [
              "identificador" => "bib0680"
              "etiqueta" => "41"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Case report and review of 7 similar cases in the literature&#58; cutaneous sarcoidosis as side effect of pembrolizumab plus chemotherapy in stage iv squamous cell carcinoma of lung"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/CJI.0000000000000351"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Immunother"
                        "fecha" => "2021"
                        "volumen" => "44"
                        "paginaInicial" => "90"
                        "paginaFinal" => "94"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            41 => array:3 [
              "identificador" => "bib0685"
              "etiqueta" => "42"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Sarcoidosis-like reactions in cancer patients treated with immune checkpoint inhibitors&#58; experience in a Spanish hospital"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s12094-020-02546-w"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Transl Oncol"
                        "fecha" => "2021"
                        "volumen" => "23"
                        "paginaInicial" => "1474"
                        "paginaFinal" => "1480"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            42 => array:3 [
              "identificador" => "bib0690"
              "etiqueta" => "43"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Drug-induced sarcoidosis-like reaction in adjuvant immunotherapy&#58; increased rate and mimicker of metastasis"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ejca.2020.02.024"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Cancer"
                        "fecha" => "2020"
                        "volumen" => "131"
                        "paginaInicial" => "18"
                        "paginaFinal" => "26"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            43 => array:3 [
              "identificador" => "bib0695"
              "etiqueta" => "44"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Neutrophilic dermatoses as adverse effects of checkpoint inhibitors&#58; a review"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/dth.13074"
                      "Revista" => array:4 [
                        "tituloSerie" => "Dermatol Ther"
                        "fecha" => "2019"
                        "volumen" => "32"
                        "paginaInicial" => "e13074"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            44 => array:3 [
              "identificador" => "bib0700"
              "etiqueta" => "45"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Sweet&#39;s syndrome under ipilimumab therapy and a brief comparison of the cases in literature"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1177/1078155220906885"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Oncol Pharm Pract"
                        "fecha" => "2020"
                        "volumen" => "26"
                        "paginaInicial" => "1762"
                        "paginaFinal" => "1764"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            45 => array:3 [
              "identificador" => "bib0705"
              "etiqueta" => "46"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Serious cutaneous toxicities with immune checkpoint inhibitors in the U&#46;S&#46; Food and Drug Administration adverse event reporting system"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1634/theoncologist.2019-0250"
                      "Revista" => array:6 [
                        "tituloSerie" => "Oncologist"
                        "fecha" => "2019"
                        "volumen" => "24"
                        "paginaInicial" => "e1228"
                        "paginaFinal" => "e1231"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            46 => array:3 [
              "identificador" => "bib0710"
              "etiqueta" => "47"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pembrolizumab-induced Stevens&#8211;Johnson Syndrome with severe ocular complications"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1080/09273948.2021.1896006"
                      "Revista" => array:5 [
                        "tituloSerie" => "Ocul Immunol Inflamm"
                        "fecha" => "2021"
                        "volumen" => "7"
                        "paginaInicial" => "1"
                        "paginaFinal" => "3"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            47 => array:3 [
              "identificador" => "bib0715"
              "etiqueta" => "48"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Combination therapy of ipilimumab and nivolumab-associated toxic epidermal necrolysis &#40;TEN&#41; in a patient with metastatic melanoma&#58; a case report and literature review"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/CJI.0000000000000302"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Immunother"
                        "fecha" => "2019"
                        "volumen" => "43"
                        "paginaInicial" => "89"
                        "paginaFinal" => "92"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            48 => array:3 [
              "identificador" => "bib0720"
              "etiqueta" => "49"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Stevens&#8211;Johnson syndrome and toxic epidermal necrolysis-like reactions to checkpoint inhibitors&#58; a systematic review"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/ijd.14811"
                      "Revista" => array:5 [
                        "tituloSerie" => "Int J Clin Oncol"
                        "fecha" => "2020"
                        "volumen" => "59"
                        "paginaInicial" => "e183"
                        "paginaFinal" => "e188"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            49 => array:3 [
              "identificador" => "bib0725"
              "etiqueta" => "50"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "De novo cutaneous connective tissue disease temporally associated with immune checkpoint inhibitor therapy&#58; a retrospective analysis"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaad.2020.10.054"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Acad Dermatol"
                        "fecha" => "2021"
                        "volumen" => "84"
                        "paginaInicial" => "864"
                        "paginaFinal" => "869"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            50 => array:3 [
              "identificador" => "bib0730"
              "etiqueta" => "51"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "De novo subacute cutaneous lupus erythematosus-like eruptions in the setting of programmed death-1 or programmed death ligand-1 inhibitor therapy&#58; clinicopathological correlation"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/ced.14449"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Exp Dermatol"
                        "fecha" => "2021"
                        "volumen" => "46"
                        "paginaInicial" => "328"
                        "paginaFinal" => "337"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            51 => array:3 [
              "identificador" => "bib0735"
              "etiqueta" => "52"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Risk of scleroderma according to the type of immune checkpoint inhibitors"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.autrev.2020.102596"
                      "Revista" => array:5 [
                        "tituloSerie" => "Autoimmun Rev"
                        "fecha" => "2020"
                        "volumen" => "19"
                        "paginaInicial" => "102596"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            52 => array:3 [
              "identificador" => "bib0740"
              "etiqueta" => "53"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Immune checkpoint inhibitor-associated scleroderma-like syndrome&#58; a report of a Pembrolizumab-induced &#8220;eosinophilic fasciitis-like&#8221; case and a review of the literature"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s40744-020-00246-z"
                      "Revista" => array:5 [
                        "tituloSerie" => "Rheumatol Ther"
                        "fecha" => "2020"
                        "volumen" => "7"
                        "paginaInicial" => "1045"
                        "paginaFinal" => "1052"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            53 => array:3 [
              "identificador" => "bib0745"
              "etiqueta" => "54"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Subacute cutaneous lupus erythematosus with melanocyte elimination induced by pembrolizumab"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/1346-8138.15316"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Dermatol"
                        "fecha" => "2020"
                        "volumen" => "47"
                        "paginaInicial" => "e217"
                        "paginaFinal" => "e219"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            54 => array:3 [
              "identificador" => "bib0750"
              "etiqueta" => "55"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Anti-transcriptional intermediary factor 1-&#947; antibody-positive dermatomyositis induced by nivolumab for lung adenocarcinoma&#58; A case report"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s10637-020-00974-7"
                      "Revista" => array:6 [
                        "tituloSerie" => "Invest New Drugs"
                        "fecha" => "2021"
                        "volumen" => "39"
                        "paginaInicial" => "251"
                        "paginaFinal" => "255"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            55 => array:3 [
              "identificador" => "bib0755"
              "etiqueta" => "56"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Bullous disorders associated with anti-PD-1 and anti-PD-L1 therapy&#58; a retrospective analysis evaluating the clinical and histopathologic features&#44; frequency&#44; and impact on cancer therapy"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaad.2018.07.008"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Acad Dermatol"
                        "fecha" => "2018"
                        "volumen" => "79"
                        "paginaInicial" => "1081"
                        "paginaFinal" => "1088"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            56 => array:3 [
              "identificador" => "bib0760"
              "etiqueta" => "57"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A review of bullous pemphigoid associated with PD-1 and PD-L1 inhibitors"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/ijd.13984"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Dermatol"
                        "fecha" => "2018"
                        "volumen" => "57"
                        "paginaInicial" => "664"
                        "paginaFinal" => "669"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            57 => array:3 [
              "identificador" => "bib0765"
              "etiqueta" => "58"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Bullous disorders associated with PD-1 and PD-L1 inhibitors&#58; pharmacovigilance analysis of the United States Food and Drug Administration Adverse Event Reporting System from the Research on Adverse Drug Events And Reports Program"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaad.2020.01.059"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Acad Dermatol"
                        "fecha" => "2020"
                        "volumen" => "83"
                        "paginaInicial" => "955"
                        "paginaFinal" => "957"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            58 => array:3 [
              "identificador" => "bib0770"
              "etiqueta" => "59"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Immune checkpoint inhibitor-related dermatologic adverse events"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaad.2020.03.132"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Acad Dermatol"
                        "fecha" => "2020"
                        "volumen" => "83"
                        "paginaInicial" => "1255"
                        "paginaFinal" => "1268"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
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            59 => array:3 [
              "identificador" => "bib0775"
              "etiqueta" => "60"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Retrospective analysis of checkpoint inhibitor therapy-associated cases of bullous pemphigoid from six German dermatology centers"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3389/fimmu.2020.588582"
                      "Revista" => array:5 [
                        "tituloSerie" => "Front Immunol"
                        "fecha" => "2021"
                        "volumen" => "11"
                        "paginaInicial" => "588582"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            60 => array:3 [
              "identificador" => "bib0780"
              "etiqueta" => "61"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Management of immune checkpoint inhibitor-induced bullous pemphigoid"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaad.2020.05.045"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Acad Dermatol"
                        "fecha" => "2021"
                        "volumen" => "84"
                        "paginaInicial" => "540"
                        "paginaFinal" => "543"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            61 => array:3 [
              "identificador" => "bib0785"
              "etiqueta" => "62"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Bullous pemphigoid in elderly woman affected by non-small cell lung cancer treated with pembrolizumab&#58; a case report and review of literature"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1177/1078155220946370"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Oncol Pharm Pract"
                        "fecha" => "2021"
                        "volumen" => "27"
                        "paginaInicial" => "727"
                        "paginaFinal" => "733"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            62 => array:3 [
              "identificador" => "bib0790"
              "etiqueta" => "63"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pruritic bullous skin eruption in a male patient receiving immunotherapy for oropharyngeal cancer"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/ijd.14742"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Dermatol"
                        "fecha" => "2020"
                        "volumen" => "59"
                        "paginaInicial" => "685"
                        "paginaFinal" => "686"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            63 => array:3 [
              "identificador" => "bib0795"
              "etiqueta" => "64"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "BP180-specific IgG is associated with skin adverse events&#44; therapy response&#44; and overall survival in non-small cell lung cancer patients treated with checkpoint inhibitors"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaad.2019.08.045"
                      "Revista" => array:5 [
                        "tituloSerie" => "J Am Acad Dermatol"
                        "fecha" => "2020"
                        "volumen" => "82"
                        "paginaInicial" => "854"
                        "paginaFinal" => "861"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            64 => array:3 [
              "identificador" => "bib0800"
              "etiqueta" => "65"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Bullous pemphigoid after anti-PD-1 therapy&#58; a retrospective case-control study evaluating impact on tumor response and survival outcomes"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaad.2019.12.068"
                      "Revista" => array:5 [
                        "tituloSerie" => "J Am Acad Dermatol"
                        "fecha" => "2020"
                        "volumen" => "10"
                        "paginaInicial" => "30048"
                        "paginaFinal" => "30057"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            65 => array:3 [
              "identificador" => "bib0805"
              "etiqueta" => "66"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1001/jamadermatol.2015.2707"
                      "Revista" => array:6 [
                        "tituloSerie" => "JAMA Dermatol"
                        "fecha" => "2016"
                        "volumen" => "152"
                        "paginaInicial" => "45"
                        "paginaFinal" => "51"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            66 => array:3 [
              "identificador" => "bib0810"
              "etiqueta" => "67"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cutaneous adverse reactions to anti-PD-1 treatment&#8212;a systematic review"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaad.2020.04.058"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Acad Dermatol"
                        "fecha" => "2020"
                        "volumen" => "83"
                        "paginaInicial" => "1415"
                        "paginaFinal" => "1424"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            67 => array:3 [
              "identificador" => "bib0815"
              "etiqueta" => "68"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Aggravation of depigmentation for a non-small-cell lung cancer patient with pre-existing vitiligo using anti-programmed cell death-1 therapy&#58; case report"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2217/imt-2019-0090"
                      "Revista" => array:6 [
                        "tituloSerie" => "Immunotherapy"
                        "fecha" => "2020"
                        "volumen" => "12"
                        "paginaInicial" => "175"
                        "paginaFinal" => "181"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            68 => array:3 [
              "identificador" => "bib0820"
              "etiqueta" => "69"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Vitiligo-like depigmentation after pembrolizumab treatment in patients with non-small cell lung cancer&#58; a case report"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.21037/tlcr-20-386"
                      "Revista" => array:5 [
                        "tituloSerie" => "Trans Lung Cancer Res"
                        "fecha" => "2020"
                        "volumen" => "9"
                        "paginaInicial" => "1585"
                        "paginaFinal" => "1590"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            69 => array:3 [
              "identificador" => "bib0825"
              "etiqueta" => "70"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Vitiligo-like lesions occurring in patients receiving anti-programmed cell death-1 therapies are clinically and biologically distinct from vitiligo"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaad.2016.10.044"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Acad Dermatol"
                        "fecha" => "2017"
                        "volumen" => "76"
                        "paginaInicial" => "863"
                        "paginaFinal" => "870"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            70 => array:3 [
              "identificador" => "bib0830"
              "etiqueta" => "71"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Vitiligo under anti-programmed cell death-1 therapy is associated with increased survival in melanoma patients"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaad.2019.11.017"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Acad Dermatol"
                        "fecha" => "2020"
                        "volumen" => "82"
                        "paginaInicial" => "770"
                        "paginaFinal" => "772"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            71 => array:3 [
              "identificador" => "bib0835"
              "etiqueta" => "72"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Immune checkpoint inhibitor associated vitiligo and its impact on survival in patients with metastatic melanoma&#58; an Italian Melanoma Intergroup study"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.esmoop.2021.100064"
                      "Revista" => array:4 [
                        "tituloSerie" => "ESMO Open"
                        "fecha" => "2021"
                        "volumen" => "6"
                        "paginaInicial" => "100064"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            72 => array:3 [
              "identificador" => "bib0840"
              "etiqueta" => "73"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cutaneous toxicities of immune checkpoint inhibitors&#58; the role of the dermatologist"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Yale J Biol Med"
                        "fecha" => "2020"
                        "volumen" => "93"
                        "paginaInicial" => "123"
                        "paginaFinal" => "132"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            73 => array:3 [
              "identificador" => "bib0845"
              "etiqueta" => "74"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association between immune-related adverse events and recurrence-free survival among patients with stage <span class="elsevierStyleSmallCaps">iii</span> melanoma randomized to receive pembrolizumab or placebo&#58; a secondary analysis of a randomized clinical trial"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1001/jamaoncol.2019.5570"
                      "Revista" => array:6 [
                        "tituloSerie" => "JAMA Oncol"
                        "fecha" => "2020"
                        "volumen" => "6"
                        "paginaInicial" => "519"
                        "paginaFinal" => "527"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            74 => array:3 [
              "identificador" => "bib0850"
              "etiqueta" => "75"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Vitiligo expansion and extent correlate with durable response in anti-programmed death 1 antibody treatment for advanced melanoma&#58; a multi-institutional retrospective study"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/1346-8138.15345"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Dermatol"
                        "fecha" => "2020"
                        "volumen" => "47"
                        "paginaInicial" => "629"
                        "paginaFinal" => "635"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            75 => array:3 [
              "identificador" => "bib0855"
              "etiqueta" => "76"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Correlation between cutaneous adverse events and prognosis in patients with melanoma treated with nivolumab&#58; a single institutional retrospective study"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/1346-8138.15309"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Dermatol"
                        "fecha" => "2020"
                        "volumen" => "47"
                        "paginaInicial" => "622"
                        "paginaFinal" => "628"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            76 => array:3 [
              "identificador" => "bib0860"
              "etiqueta" => "77"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Immunotherapy-mediated dermatological adverse events&#58; the urgent need for a common&#44; clinically meaningful&#44; management strategy"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00520-020-05701-9"
                      "Revista" => array:5 [
                        "tituloSerie" => "Support Care Cancer"
                        "fecha" => "2020"
                        "volumen" => "28"
                        "paginaInicial" => "5597"
                        "paginaFinal" => "5599"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            77 => array:3 [
              "identificador" => "bib0865"
              "etiqueta" => "78"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Immune-related adverse events and efficacy&#8212;the more it hurts&#44; the better it works&#63;"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/JCO.19.02446"
                      "Revista" => array:5 [
                        "tituloSerie" => "JAMA Oncol"
                        "fecha" => "2020"
                        "volumen" => "7"
                        "paginaInicial" => "945"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            78 => array:3 [
              "identificador" => "bib0870"
              "etiqueta" => "79"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Revisiting the association between skin toxicity and better response in advanced cancer patients treated with immune checkpoint inhibitors"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/s12967-020-02612-5"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Transl Med"
                        "fecha" => "2020"
                        "volumen" => "18"
                        "paginaInicial" => "1"
                        "paginaFinal" => "6"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            79 => array:3 [
              "identificador" => "bib0875"
              "etiqueta" => "80"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Immune-related adverse events and efficacy&#8212;the more it hurts&#44; the better it works&#63; Reply"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3389/fonc.2020.574752"
                      "Revista" => array:4 [
                        "tituloSerie" => "JAMA Oncol"
                        "fecha" => "2021"
                        "volumen" => "10"
                        "paginaInicial" => "E1"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            80 => array:3 [
              "identificador" => "bib0880"
              "etiqueta" => "81"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Safety profile of nivolumab monotherapy&#58; a pooled analysis of patients with advanced melanoma"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/JCO.2015661389"
                      "Revista" => array:5 [
                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "2017"
                        "volumen" => "35"
                        "paginaInicial" => "785"
                        "paginaFinal" => "792"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            81 => array:3 [
              "identificador" => "bib0885"
              "etiqueta" => "82"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Correlation between immune-related adverse events and prognosis in patients with various cancers treated with anti PD-1 antibody"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/s12885-020-07142-3"
                      "Revista" => array:6 [
                        "tituloSerie" => "BMC Cancer"
                        "fecha" => "2020"
                        "volumen" => "20"
                        "paginaInicial" => "1"
                        "paginaFinal" => "8"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            82 => array:3 [
              "identificador" => "bib0890"
              "etiqueta" => "83"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Characterization of dermatitis after PD-1&#47;PD-L1 inhibitor therapy and association with multiple oncologic outcomes&#58; a retrospective case&#8211;control study"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaad.2018.05.035"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Acad Dermatol"
                        "fecha" => "2018"
                        "volumen" => "79"
                        "paginaInicial" => "1047"
                        "paginaFinal" => "1052"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            83 => array:3 [
              "identificador" => "bib0895"
              "etiqueta" => "84"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Management of immune-related adverse events affecting outcome in patients treated with checkpoint inhibitors"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ejca.2016.11.021"
                      "Revista" => array:5 [
                        "tituloSerie" => "JAMA Oncol"
                        "fecha" => "2017"
                        "volumen" => "72"
                        "paginaInicial" => "156"
                        "paginaFinal" => "165"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            84 => array:3 [
              "identificador" => "bib0900"
              "etiqueta" => "85"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Bluish-gray fingernail discoloration due to the use of nivolumab"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1177/1078155220929974"
                      "Revista" => array:5 [
                        "tituloSerie" => "J Oncol Pharm Pract Pract"
                        "fecha" => "2021"
                        "volumen" => "27"
                        "paginaInicial" => "457"
                        "paginaFinal" => "459"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            85 => array:3 [
              "identificador" => "bib0905"
              "etiqueta" => "86"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Persistently curly hair phenotype with the use of nivolumab for squamous cell lung cancer"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1177/1078155216674355"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Oncol Pharm Pract"
                        "fecha" => "2017"
                        "volumen" => "23"
                        "paginaInicial" => "638"
                        "paginaFinal" => "640"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            86 => array:3 [
              "identificador" => "bib0910"
              "etiqueta" => "87"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Anti-PD-1-induced hidradenitis suppurativa"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Dermatopathol"
                        "fecha" => "2021"
                        "volumen" => "8"
                        "paginaInicial" => "37"
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                        0 => array:2 [ …2]
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                        "tituloSerie" => "Clin Exp Reum"
                        "fecha" => "2020"
                        "volumen" => "38"
                        "paginaInicial" => "1031"
                        "paginaFinal" => "1032"
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                    0 => array:2 [
                      "titulo" => "Angioedema late in the course of adjuvant nivolumab therapy for melanoma"
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                        0 => array:2 [ …2]
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                        "tituloSerie" => "J Oncol Pharm Pract"
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                        "volumen" => "26"
                        "paginaInicial" => "1019"
                        "paginaFinal" => "1021"
                        "link" => array:1 [ …1]
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                    0 => array:2 [
                      "titulo" => "Hypohidrosis as an immune-related adverse event of checkpoint inhibitor therapy"
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                        0 => array:2 [ …2]
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                        "paginaInicial" => "951"
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                      "titulo" => "Ipilimumab&#47;nivolumab-induced pseudolymphoma in a patient with malignant melanoma"
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                        0 => array:2 [ …2]
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                    0 => array:2 [
                      "doi" => "10.1111/cup.13604"
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                        "tituloSerie" => "J Cutan Pathol"
                        "fecha" => "2020"
                        "volumen" => "47"
                        "paginaInicial" => "390"
                        "paginaFinal" => "393"
                        "link" => array:1 [ …1]
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                    0 => array:2 [
                      "titulo" => "Herpes zoster granulomatous dermatitis in metastatic lung cancer treated with nivolumab&#58; a case report"
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                        0 => array:2 [ …2]
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                        "tituloSerie" => "Thorac Cancer"
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                        "volumen" => "11"
                        "paginaInicial" => "1330"
                        "paginaFinal" => "1333"
                        "link" => array:1 [ …1]
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                      "titulo" => "Radiation recall dermatitis after treatment of stage <span class="elsevierStyleSmallCaps">iv</span> breast cancer with nivolumab&#58; a case report"
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                        0 => array:2 [ …2]
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                        "tituloSerie" => "Immunotherapy"
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                        "volumen" => "12"
                        "paginaInicial" => "123"
                        "paginaFinal" => "130"
                        "link" => array:1 [ …1]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nivolumab-induced contact dermatitis in a patient with advanced lung cancer"
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                        0 => array:2 [ …2]
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                    0 => array:2 [
                      "doi" => "10.1016/j.rmcr.2020.101134"
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                        "tituloSerie" => "Respir Med Case Rep"
                        "fecha" => "2020"
                        "volumen" => "30"
                        "paginaInicial" => "101134"
                        "link" => array:1 [ …1]
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                        "paginaFinal" => "1477"
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Article information

ISSN: 00017310
Original language: English

DOI:10.1016/j.ad.2021.09.009

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