Letter to the Editor
Genetic Characteristics of Rheumatic Patients Developing Inflammatory Skin Lesions Induced by Biologic Therapy
Características genéticas de pacientes reumatológicos que desarrollan lesiones cutáneas inflamatorias inducidas por fármacos biológicos
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array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Elisa" "apellidos" => "Docampo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Xavier" "apellidos" => "Estivill" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "Joan" "apellidos" => "Maymó" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Reumatología, Hospital del Mar, Parc de Salut Mar, Universidad Autónoma de Barcelona, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Genomics and Disease Group, Centro de Regulación Genómica (CRG), Instituto Municipal de Investigación Médica (IMIM), Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Características genéticas de pacientes reumatológicos que desarrollan lesiones cutáneas inflamatorias inducidas por fármacos biológicos" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">The appearance of inflammatory skin lesions (ISL), induced by biological drugs, mainly cutaneous psoriasis, has been extensively described.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1–3</span></a> The hypothesis is that in patients with genetic susceptibility present an activation of alternative inflammatory pathways such as interferon-α 1.2, but this has not been demonstrated and no genetic studies in these patients exist.</p><p id="par0010" class="elsevierStylePara elsevierViewall">We conducted a prospective observational study analyzing genetic data from patients of the Rheumatology Department of the Hospital del Mar (Barcelona) who developed <span class="elsevierStyleItalic">de novo</span> ISL due to biological therapy between January 2008 and December 2012.</p><p id="par0015" class="elsevierStylePara elsevierViewall">The demographic and clinical variables evaluated were: age, sex, diagnosis of ISL, rheumatic disease and duration (in years), biologic drug employed and time from onset to the start of the drug (weeks). Genetic variables were the presence of HLA-B27, HLA-DR1, HLA-DR4 and HLA-DR7 alleles (detected by standard PCR), HLA-CW6 (Sanger sequencing using the indirect marker rs4406273) and the deletion of two genes <span class="elsevierStyleItalic">late cornified envelope</span> (LCE), LCE3C_LCE3B-del (with a <span class="elsevierStyleItalic">multiplex</span> PCR experiment<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a>). Fifteen patients who developed ISL (prevalence 2.5%) were included. They had a mean age of 43.9<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>12.4 years and 73.3% were female. The diagnoses of ISL were: seven skin psoriasis (five palmoplantar pustulosis, one with psoriasis <span class="elsevierStyleItalic">vulgaris</span> and <span class="elsevierStyleItalic">one with guttata</span>), three alopecia areata, two cutaneous lupus, one eczema, one suppurative hidradenitis and one with erythema multiforme. Rheumatological diagnoses were: three rheumatoid arthritis, ankylosing spondylitis 6, four non-radiological axial spondyloarthritis and two psoriatic arthritis, mean disease duration of 13.1<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.4 years. Biologic drugs were eight cases using adalimumab, etanercept in four, infliximab in two and abatacept in one, with a mean time of onset of 57.1<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>62.1 weeks.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Genetically, seven patients had HLA-B27, four were HLA-CW6 positive (26%), only one with psoriasis, one positive HLA-DR1, another HLA-DR4 and six HLA-DR7 positive patients (40%), three with psoriasis. In four patients (26.7%) two LCE3C-LCE3B deleted alleles were detected and 11 (73.3%) had one deleted allele (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). LCE3C_LCE3B allele frequency was 63.6%.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">The low proportion of patients with the presence of HLA-CW6 and HLA-DR7 alleles (especially in cases of psoriasis) stands out, lower than that found in populations of cutaneous psoriasis,<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">5–7</span></a> which could be due to the predominant type of psoriasis, palmoplantar pustulosis, since the average age of patients was older than 40 years (HLA-CW6 and HLA-DR7 alone have been associated with type <span class="elsevierStyleSmallCaps">I</span> psoriasis, with an onset before 40 years of age, and with the <span class="elsevierStyleItalic">vulgaris and guttate</span> subtypes<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a>).</p><p id="par0030" class="elsevierStylePara elsevierViewall">In our series, the presence of the deletion of the two LCE genes (allele frequency of 63.6%) was consistent with the frequently seen in population samples with inflammatory diseases (62%–70%) but higher than that reported in control populations (55%–60%).<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">4,8–10</span></a> But what stands out is that all patients with ISL had at least one copy of the LCE3C_LCE3B deleted alleles (absence of non-deleted homozygous individuals). In the general population, the frequency of non-deleted homozygotes is around 18%<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">4,9,10</span></a> and disruption of the skin barrier occurs in relation to the number of copies of LCE3C_LCE3B, being undetectable in carriers of the homozygous deletion<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> and reduced in heterozygotes.</p><p id="par0035" class="elsevierStylePara elsevierViewall">This observational study of a series of cases of ISL induced by biological drugs and is the first to include genetic data, although further studies are needed with larger numbers of patients and a control group to better study this process and help establish if there a pattern of genetic susceptibility as in the case of LCE3C_LCE3B deletions.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Financing</span><p id="par0040" class="elsevierStylePara elsevierViewall">The authors declare that there has been no financial support or commercial interest in carrying out this work.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflict of Interest</span><p id="par0045" class="elsevierStylePara elsevierViewall">The authors have no conflict of interest to state.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Financing" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Conflict of Interest" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Almirall M, Docampo E, Estivill X, Maymó J. Características genéticas de pacientes reumatológicos que desarrollan lesiones cutáneas inflamatorias inducidas por fármacos biológicos. Reumatol Clin. 2015;11:126–127.</p>" ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">LCE 3B-3C-LCE del, deletion of the late cornified envelope; ISL, induced skin lesions; N.p., number of patients; +, positive; D+, deleted; D−, non-deleted.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">ISL \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">N.p.Total \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">N.p.HLA-B27+ \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">N.p.HLA-CW6+ \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">N.p.HLA-DR1+ \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">N.p.HLA-DR4+ \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">N.p.HLA-DR7+ \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">LCE 3C-LCE 3B-delD+/D+ \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">LCE 3C-LCE 3B-delD+/D− \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Skin psoriasis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Alopecia areata \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Cutaneous lupus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Eczema \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Hydradenitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Erythema multiforme \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Total \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab681841.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Genetic Characteristics of Patients with Cutaneous Lesions Induced.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0055" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Anti-tumor necrosis factor therapies in immune-mediated rheumatic diseases. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 8 | 9 | 17 |
| 2024 October | 29 | 31 | 60 |
| 2024 September | 28 | 20 | 48 |
| 2024 August | 48 | 31 | 79 |
| 2024 July | 29 | 22 | 51 |
| 2024 June | 56 | 26 | 82 |
| 2024 May | 38 | 29 | 67 |
| 2024 April | 40 | 22 | 62 |
| 2024 March | 45 | 27 | 72 |
| 2024 February | 26 | 22 | 48 |
| 2024 January | 37 | 20 | 57 |
| 2023 December | 18 | 26 | 44 |
| 2023 November | 27 | 28 | 55 |
| 2023 October | 32 | 24 | 56 |
| 2023 September | 46 | 37 | 83 |
| 2023 August | 28 | 14 | 42 |
| 2023 July | 35 | 17 | 52 |
| 2023 June | 24 | 24 | 48 |
| 2023 May | 47 | 25 | 72 |
| 2023 April | 19 | 13 | 32 |
| 2023 March | 32 | 41 | 73 |
| 2023 February | 47 | 18 | 65 |
| 2023 January | 33 | 18 | 51 |
| 2022 December | 30 | 35 | 65 |
| 2022 November | 47 | 21 | 68 |
| 2022 October | 27 | 39 | 66 |
| 2022 September | 35 | 40 | 75 |
| 2022 August | 38 | 37 | 75 |
| 2022 July | 24 | 35 | 59 |
| 2022 June | 35 | 32 | 67 |
| 2022 May | 25 | 34 | 59 |
| 2022 April | 33 | 50 | 83 |
| 2022 March | 35 | 39 | 74 |
| 2022 February | 24 | 27 | 51 |
| 2022 January | 30 | 32 | 62 |
| 2021 December | 24 | 44 | 68 |
| 2021 November | 32 | 42 | 74 |
| 2021 October | 46 | 41 | 87 |
| 2021 September | 41 | 37 | 78 |
| 2021 August | 32 | 30 | 62 |
| 2021 July | 29 | 22 | 51 |
| 2021 June | 36 | 34 | 70 |
| 2021 May | 42 | 33 | 75 |
| 2021 April | 45 | 51 | 96 |
| 2021 March | 34 | 18 | 52 |
| 2021 February | 30 | 18 | 48 |
| 2021 January | 26 | 19 | 45 |
| 2020 December | 40 | 14 | 54 |
| 2020 November | 18 | 19 | 37 |
| 2020 October | 13 | 12 | 25 |
| 2020 September | 33 | 27 | 60 |
| 2020 August | 18 | 15 | 33 |
| 2020 July | 20 | 18 | 38 |
| 2020 June | 34 | 18 | 52 |
| 2020 May | 28 | 7 | 35 |
| 2020 April | 25 | 16 | 41 |
| 2020 March | 28 | 7 | 35 |
| 2018 May | 3 | 0 | 3 |
| 2018 April | 28 | 4 | 32 |
| 2018 March | 40 | 6 | 46 |
| 2018 February | 20 | 1 | 21 |
| 2018 January | 21 | 5 | 26 |
| 2017 December | 23 | 6 | 29 |
| 2017 November | 23 | 3 | 26 |
| 2017 October | 23 | 5 | 28 |
| 2017 September | 19 | 7 | 26 |
| 2017 August | 27 | 7 | 34 |
| 2017 July | 29 | 7 | 36 |
| 2017 June | 38 | 15 | 53 |
| 2017 May | 40 | 19 | 59 |
| 2017 April | 33 | 5 | 38 |
| 2017 March | 21 | 40 | 61 |
| 2017 February | 21 | 8 | 29 |
| 2017 January | 22 | 6 | 28 |
| 2016 December | 49 | 25 | 74 |
| 2016 November | 22 | 10 | 32 |
| 2016 October | 51 | 13 | 64 |
| 2016 September | 44 | 14 | 58 |
| 2016 August | 28 | 2 | 30 |
| 2016 July | 22 | 5 | 27 |
| 2015 December | 2 | 0 | 2 |
| 2015 November | 1 | 11 | 12 |
| 2015 October | 1 | 15 | 16 |
| 2015 September | 1 | 0 | 1 |
| 2015 August | 2 | 0 | 2 |
| 2015 July | 22 | 7 | 29 |
| 2015 June | 34 | 3 | 37 |
| 2015 May | 64 | 17 | 81 |
| 2015 April | 63 | 22 | 85 |
| 2015 March | 52 | 12 | 64 |
| 2015 February | 11 | 3 | 14 |
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