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[ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figura 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 745 "Ancho" => 1827 "Tamanyo" => 109692 ] ] "descripcion" => array:1 [ "es" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Evolutivo de la creatinina y tratamientos administrados durante la hospitalización.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Carmen Sendra, María del Pilar Silva Ruiz, María Teresa Ferrer Rios, José Carlos Alarcón García, Juan Manuel Pascasio Acevedo" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Carmen" "apellidos" => "Sendra" ] 1 => array:2 [ "nombre" => "María del Pilar" "apellidos" => "Silva Ruiz" ] 2 => array:2 [ "nombre" => "María Teresa" "apellidos" => "Ferrer Rios" ] 3 => array:2 [ "nombre" => "José Carlos" "apellidos" => "Alarcón García" ] 4 => array:2 [ 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true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "442" "paginaFinal" => "443" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Carlos Bernardes, Diana Carvalho, Joana Saiote, Jaime Ramos" "autores" => array:4 [ 0 => array:4 [ "nombre" => "Carlos" "apellidos" => "Bernardes" "email" => array:1 [ 0 => "carlosfbernardes@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Diana" "apellidos" => "Carvalho" ] 2 => array:2 [ "nombre" => "Joana" "apellidos" => "Saiote" ] 3 => array:2 [ "nombre" => "Jaime" "apellidos" => "Ramos" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Gastroenterology Department, Centro Hospitalar de Lisboa Central, Lisbon, Portugal" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Vasculitis leucocitoclástica como complicación del adalimumab en el tratamiento de la enfermedad de Crohn: relato de tres casos" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 791 "Ancho" => 2333 "Tamanyo" => 150477 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Palpable purpuric lesions on both legs and feet in patients from cases 1 (A and B) and 3 (C).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Leukocytoclastic vasculitis (LV) is an uncommon small-vessel vasculitis which can be secondary to several drugs.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">1</span></a> Its association with adalimumab is extremely rare and has been described in only a few reports in the literature.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">2–4</span></a> We report the cases of three patients who developed histologically confirmed leukocytoclastic vasculitis following adalimumab therapy. Discontinuation of the drug led to complete resolution of the cutaneous manifestations in all cases.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Case 1: A 29-year-old female, diagnosed with colonic Crohn's disease six years earlier, developed palpable purpuric lesions in the lower limbs and trunk approximately sixteen months after adalimumab initiation as monotherapy (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A and B). Biopsies were compatible with leukocytoclastic vasculitis. All lesions disappeared in about four weeks following interruption of the anti-TNFalpha. Re-exposure to the drug, four months later, led to recurrence of the vasculitis and forced permanent discontinuation of the treatment.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">Case 2: A 60-year-old male, nineteen years after the diagnosis of ileocolonic and perianal Crohn's disease, was receiving azathioprine (2.5<span class="elsevierStyleHsp" style=""></span>mg/kg/day) for almost ten years when adalimumab was started. After fourteen months of combination therapy the patient presented with an one-month history of palpable purpura in the lower limbs which was histopathologically characterized as leukocytoclastic vasculitis (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>) and completely resolved with the withdrawal of the biological agent.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Case 3: A 44-year-old female, diagnosed with colonic and perianal Crohn's disease twentytwo years before, also treated with azathioprine (2<span class="elsevierStyleHsp" style=""></span>mg/kg/day), underwent biological treatment with adalimumab. Six years later, she was admitted due to palpable purpura in the lower limbs for the last three weeks, whose biopsies were compatible with leukocytoclastic vasculitis. Adalimumab was discontinued and complete resolution of the lesions was observed within two weeks. Three months later, given the unusually long latency period, raising doubts regarding the causality between the agent and the appearance of vasculitis, reintroduction of the drug was attempted. However, rapid and severe recurrence of the purpuric lesions occurred, leading to definitive withdrawal of the therapy (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>C).</p><p id="par0025" class="elsevierStylePara elsevierViewall">All patients were in clinical remission while receiving maintenance treatment with adalimumab (40<span class="elsevierStyleHsp" style=""></span>mg, every other week). Moreover, they were all previously exposed to infliximab, which was suspended due to primary non-response in the first female patient and due to a serious infusion reaction – without dermatological manifestations – in the remaining.</p><p id="par0030" class="elsevierStylePara elsevierViewall">The time between infliximab discontinuation to adalimumab initiation was 5 years (case 1), 9 years (case 2) and 10 months (case 3). With the exception of elevated C-reactive protein and erythrocyte sedimentation rate, laboratory evaluation – including human immunodeficiency virus and hepatitis C virus screening, autoimmune panel, search for cryoglobulins, serum protein electrophoresis and urinalysis – was unremarkable, allowing exclusion of alternative conditions and other organ involvement. In the three cases, skin biopsies showed perivascular damage and infiltration by polymorphonuclear cells, nuclear debris and fibrinoid necrosis, with also a few eosinophils (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). Interruption of the culprit drug was sufficient to allow total recovery of the vasculitis within two to four weeks, without the need for any additional pharmacological intervention in any case. No recurrences occurred after definitive suspension of the anti-TNFalpha agent.</p><p id="par0035" class="elsevierStylePara elsevierViewall">The development of skin complications is well-recognized in patients with inflammatory bowel disease, either in association with the disease itself or as a treatment-related adverse event.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">2–6</span></a> Ramos-Casals and colleagues identified 113 published cases of anti-TNFalpha associated vasculitis – including leukocytoclastic vasculitis – in a 13 year-period, with only 4% of them (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>5) arising in subjects receiving adalimumab.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">6</span></a> Although the pathophysiological mechanisms are not fully understood yet, it is postulated that those patients may undergo immunocomplex deposition and antiTNFalpha-induced apoptosis, followed by perivascular antigen accumulation and subsequent antibody formation, leading to progressive small-vessel damage.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">7,8</span></a> The fact that adalimumab is a fully humanized anti-TNFalpha antibody may justify the lower frequency of such complications when compared to infliximab. Interestingly, our three patients were treated with infliximab for a short period in the past, with two of them having developed severe infusion reactions. It is also worth noting that two of the patients were in combination therapy with azathioprine, which theoretically could further decrease the immunogenic potential of adalimumab and reduce the risk of those events. The time from drug introduction to onset of such hypersensitivity type III reactions is extremely variable, ranging from a few days to several years.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">7</span></a> Symptoms usually resolve in a few weeks with drug discontinuation; however, in refractory patients or in those with systemic involvement, treatment with colchicine, steroids or other immunosuppressants may be required.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">3,4</span></a> Despite some authors having reported the use of a different anti-TNFalpha blocker in patients who developed TNFalpha inhibitor-induced vasculitis, the risk of relapse is a major concern and may influence future treatment options.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">9</span></a> Thus, even in patients like ours, who attained complete remission without any specific therapy, the occurrence of these highly unusual but potentially serious conditions may represent a challenge for the management of the inflammatory bowel disease.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0040" class="elsevierStylePara elsevierViewall">Authors declare no conflicts of interest for this article.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflicts of interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 791 "Ancho" => 2333 "Tamanyo" => 150477 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Palpable purpuric lesions on both legs and feet in patients from cases 1 (A and B) and 3 (C).</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 855 "Ancho" => 2333 "Tamanyo" => 228554 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Skin biopsy findings compatible with leukocytoclastic vasculitis (case 2).</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:9 [ 0 => array:3 [ "identificador" => "bib0050" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "OD06–OD07" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nafcillin implicated in a case of cutaneous and gastrointestinal leukocytoclastic vasculitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "C. 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Scientific letter
Leukocytoclastic vasculitis complicating adalimumab therapy for Crohn's disease: Report of three cases
Vasculitis leucocitoclástica como complicación del adalimumab en el tratamiento de la enfermedad de Crohn: relato de tres casos
Carlos Bernardes
, Diana Carvalho, Joana Saiote, Jaime Ramos
Autor para correspondencia
Gastroenterology Department, Centro Hospitalar de Lisboa Central, Lisbon, Portugal