Case and Research Letter
Azathioprine-Induced Hypersensitivity Reaction Presenting as Erythema Nodosum
Eritema nudoso como reacción de hipersensibilidad a la azatioprina
M. González-Olivares
, R. Khedaoui, C. Martínez-Morán, J. Borbujo
Corresponding author
Servicio de Dermatología y Anatomía Patológica, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, Spain
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González-Olivares, R. Khedaoui, C. Martínez-Morán, J. Borbujo" "autores" => array:4 [ 0 => array:4 [ "nombre" => "M." "apellidos" => "González-Olivares" "email" => array:1 [ 0 => "mgonzalezo@salud.madrid.org" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "R." "apellidos" => "Khedaoui" ] 2 => array:2 [ "nombre" => "C." "apellidos" => "Martínez-Morán" ] 3 => array:2 [ "nombre" => "J." "apellidos" => "Borbujo" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Dermatología y Anatomía Patológica, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Eritema nudoso como reacción de hipersensibilidad a la azatioprina" ] ] "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" => 1385 "Ancho" => 1300 "Tamanyo" => 196056 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Subcutaneous nodules with superficial erythema and erythematous-violaceous macules of residual appearance on the anterior and posterior aspects of both lower limbs.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Hypersensitivity reactions to drugs have a very varied clinical spectrum and can present different types of skin lesion, including erythema nodosum.</p><p id="par0010" class="elsevierStylePara elsevierViewall">A 44-year-old woman with no known drug allergies, diagnosed with Crohn disease 2 years earlier, had started treatment with azathioprine (AZT) 3 weeks prior to consultation because of laboratory and radiological signs of progression of her Crohn disease. She came to the emergency department with a 7-day history of painful erythematous lesions on both lower limbs, associated with general malaise, loss of appetite, and knee and ankle pain. She did not report fever.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Examination revealed multiple disperse, occasionally tender, erythematous subcutaneous nodules measuring between 10 and 20<span class="elsevierStyleHsp" style=""></span>mm on both lower limbs. There were also a number of violaceous macules of residual appearance measuring 15 to 20<span class="elsevierStyleHsp" style=""></span>mm in diameter (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Histopathology of a lesion showed thickening and fibrosis of septa in the subcutaneous cellular tissue, with a chronic inflammatory infiltrate formed of histiocytes and lymphocytes, and granulomas with multinucleated giant cells were also present (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>,<span class="elsevierStyleHsp" style=""></span>A and<span class="elsevierStyleHsp" style=""></span>B). No microorganisms were observed on staining with periodic acid-Schiff, Gram, and Ziehl-Neelsen stains. Laboratory findings were as follows: hemoglobin, 10.4<span class="elsevierStyleHsp" style=""></span>g/dL; mean corpuscular volume, 78.4<span class="elsevierStyleHsp" style=""></span>fL; mean corpuscular hemoglobin, 25.3<span class="elsevierStyleHsp" style=""></span>pg; elevation of the transaminases (alanine aminotransferase, 82<span class="elsevierStyleHsp" style=""></span>U/L); γ-glutamyl transferase, 126<span class="elsevierStyleHsp" style=""></span>U/L; C-reactive protein, 12.59<span class="elsevierStyleHsp" style=""></span>mg/dL (normal range, 0.1-0.5<span class="elsevierStyleHsp" style=""></span>mg/dL); and no abnormalities in the autoimmunity study. There was no induration on the tuberculin skin test and chest x-ray showed no changes (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">Given the possibility that the lesions could have been due to the AZT, it was decided to interrupt the treatment. This led to the resolution of systemic symptoms within 24<span class="elsevierStyleHsp" style=""></span>h and of the skin lesions within 3 days, with no other treatment. Based on these findings, we made a diagnosis of hypersensitivity reaction to AZT with cutaneous manifestations in the form of erythema nodosum.</p><p id="par0030" class="elsevierStylePara elsevierViewall">AZT is a precursor of 6-mercaptopurine and is used as an immunosuppressant drug for the treatment of chronic inflammatory diseases such as inflammatory bowel disease (IBD).</p><p id="par0035" class="elsevierStylePara elsevierViewall">Adverse effects associated with this drug are subdivided into early and late reactions.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Early reactions, including hypersensitivity reactions, are common.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">1</span></a> These are idiosyncratic reactions that occur in approximately 2% of patients in the first 4 weeks of treatment, though they are probably underdiagnosed.<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">1,2</span></a> Clinically they can present with fever, hypotension, general malaise, joint pain, gastrointestinal symptoms, hepatitis, pancreatitis, nephritis, pneumonia, pericarditis, and skin lesions.<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">1,3</span></a> After the interruption of treatment, the lesions resolve rapidly, within 2 to 3 days.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">2</span></a> Many cases are initially diagnosed as infectious diseases or exacerbations of the underlying disease, and the hypersensitivity reaction may not be detected until re-exposure to the drug.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">2,3</span></a> Symptom recurrence after rechallenge to the drug will confirm the cause-effect relationship, but as the reaction is more intense and develops more rapidly, occasionally within a few hours,<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">3</span></a> rechallenge is contraindicated.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">2</span></a> Patients with IBD have been considered to be at greater risk of hypersensitivity reactions to AZT; this may be due to a polymorphism in the gene that codes for inosine triphosphate pyrophosphatase.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">4</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">In 2011, Bidinger et al.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">2</span></a> reviewed all published cases of hypersensitivity to AZT, finding that approximately 50% presented cutaneous manifestations. The most common cutaneous presentation was Sweet syndrome, followed in order of frequency by nonspecific maculopapular, vesicular, pustular, or urticarial rashes, small-vessel vasculitis, erythema nodosum,<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">1,5</span></a> and acute generalized exanthematous pustulosis. A dozen more cases with skin involvement have been published since that time, the majority presenting as Sweet syndrome, though also including 2 cases of neutrophilic eccrine hidradenitis,<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">6,7</span></a> an association not previously described. The most common histopathology finding is a neutrophilic dermatosis.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">2</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Erythema nodosum associated with IBD is observed in up to 10% of patients with ulcerative colitis and 15% of those with Crohn disease. The course of the skin lesions usually parallels activity of the bowel disease and resolve with appropriate treatment of that disease.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">8</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Late reactions, such as myelosuppression, are dose dependent and can be avoided to a great extent by measuring activity of the enzyme thiopurine methyltransferase.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">1</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">In our patient, the lesions resolved within 3 days without treatment. After resolution of the alterations, treatment was started with infliximab, which had to be interrupted due to an infusion reaction and possible drug-induced dermatitis. A year after consultation, the patient has presented occasional outbreaks of her bowel disease, presenting as episodes of subacute intestinal occlusion, but no further episodes of erythema nodosum.</p><p id="par0065" class="elsevierStylePara elsevierViewall">The presence of erythema nodosum lesions in patients on treatment with AZT who do not present signs of an exacerbation of IBD or intercurrent infection must alert us to a possible hypersensitivity reaction to the drug.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of Interest</span><p id="par0070" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</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 "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: González-Olivares M. Eritema nudoso como reacción de hipersensibilidad a la azatioprina. Actas Dermosifiliogr. 2017;108:591–593.</p>" ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1385 "Ancho" => 1300 "Tamanyo" => 196056 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Subcutaneous nodules with superficial erythema and erythematous-violaceous macules of residual appearance on the anterior and posterior aspects of both lower limbs.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1134 "Ancho" => 1700 "Tamanyo" => 457370 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Histopathology. A, Septal thickening with fibrosis. Hematoxylin and eosin, original magnification ×4. B, Lymphohistiocytic infiltrate with granulomas in the septa. Hematoxylin and eosin, original magnification ×40.</p>" ] ] 2 => 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" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Abbreviations: F, female; IBD, inflammatory bowel disease; M, male.</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="" valign="top" scope="col" style="border-bottom: 2px solid black"> \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">Age, y, and Sex \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">Underlying Disease \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">Latency Period \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">Time to Resolution, 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">Recurrence After Rechallenge \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">de Fonclare et al.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">1</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">17, F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IBD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14 d \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16 d \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">49, F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IBD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8 d \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 d \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">75, M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IBD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14 d \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14 d \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Not performed \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Vargas-Hitos et al.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">5</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">65, F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bullous pemphigoid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7 d \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14 d \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Not performed \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1450888.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Review of Published Cases of Erythema Nodosum as a Hypersensitivity Reaction to Azathioprine.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:8 [ 0 => array:3 [ "identificador" => "bib0045" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Erythema nodosum-like eruption as a manifestation of azathioprine hypersensitivity in patients with inflammatory bowel disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "A.L. de Fonclare" 1 => "K. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 19 | 7 | 26 |
| 2024 October | 98 | 53 | 151 |
| 2024 September | 114 | 30 | 144 |
| 2024 August | 132 | 65 | 197 |
| 2024 July | 100 | 52 | 152 |
| 2024 June | 112 | 39 | 151 |
| 2024 May | 90 | 43 | 133 |
| 2024 April | 96 | 21 | 117 |
| 2024 March | 120 | 33 | 153 |
| 2024 February | 70 | 34 | 104 |
| 2024 January | 71 | 38 | 109 |
| 2023 December | 70 | 18 | 88 |
| 2023 November | 78 | 61 | 139 |
| 2023 October | 98 | 71 | 169 |
| 2023 September | 80 | 63 | 143 |
| 2023 August | 89 | 40 | 129 |
| 2023 July | 75 | 83 | 158 |
| 2023 June | 77 | 44 | 121 |
| 2023 May | 70 | 56 | 126 |
| 2023 April | 58 | 49 | 107 |
| 2023 March | 79 | 48 | 127 |
| 2023 February | 87 | 44 | 131 |
| 2023 January | 50 | 46 | 96 |
| 2022 December | 67 | 52 | 119 |
| 2022 November | 43 | 38 | 81 |
| 2022 October | 58 | 38 | 96 |
| 2022 September | 34 | 66 | 100 |
| 2022 August | 56 | 64 | 120 |
| 2022 July | 20 | 56 | 76 |
| 2022 June | 16 | 56 | 72 |
| 2022 May | 72 | 60 | 132 |
| 2022 April | 73 | 57 | 130 |
| 2022 March | 71 | 50 | 121 |
| 2022 February | 59 | 40 | 99 |
| 2022 January | 55 | 55 | 110 |
| 2021 December | 57 | 40 | 97 |
| 2021 November | 51 | 58 | 109 |
| 2021 October | 57 | 64 | 121 |
| 2021 September | 59 | 43 | 102 |
| 2021 August | 66 | 56 | 122 |
| 2021 July | 55 | 41 | 96 |
| 2021 June | 57 | 57 | 114 |
| 2021 May | 75 | 52 | 127 |
| 2021 April | 154 | 83 | 237 |
| 2021 March | 101 | 35 | 136 |
| 2021 February | 85 | 28 | 113 |
| 2021 January | 85 | 23 | 108 |
| 2020 December | 54 | 24 | 78 |
| 2020 November | 40 | 25 | 65 |
| 2020 October | 42 | 19 | 61 |
| 2020 September | 50 | 19 | 69 |
| 2020 August | 37 | 20 | 57 |
| 2020 July | 39 | 24 | 63 |
| 2020 June | 41 | 38 | 79 |
| 2020 May | 18 | 6 | 24 |
| 2020 April | 16 | 17 | 33 |
| 2020 March | 18 | 13 | 31 |
| 2020 February | 5 | 1 | 6 |
| 2019 December | 4 | 0 | 4 |
| 2019 September | 6 | 0 | 6 |
| 2019 May | 2 | 0 | 2 |
| 2019 February | 3 | 0 | 3 |
| 2019 January | 2 | 0 | 2 |
| 2018 December | 4 | 0 | 4 |
| 2018 November | 1 | 0 | 1 |
| 2018 October | 1 | 0 | 1 |
| 2018 September | 4 | 0 | 4 |
| 2018 February | 21 | 8 | 29 |
| 2018 January | 34 | 8 | 42 |
| 2017 December | 49 | 16 | 65 |
| 2017 November | 33 | 5 | 38 |
| 2017 October | 31 | 13 | 44 |
| 2017 September | 39 | 16 | 55 |
| 2017 August | 50 | 22 | 72 |
| 2017 July | 60 | 41 | 101 |
| 2017 June | 16 | 17 | 33 |
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