Case report
Deep Vein Thrombosis in A Patient with Lepromatous Leprosy Receiving Thalidomide to Treat Leprosy Reaction
Trombosis venosa profunda en paciente con lepra lepromatosa tratado con talidomida por leprorreacción
G. Hebe Petiti-Martin
, M. Villar-Buill, I. de la Hera, L. Fuertes, M. Burgués-Calderón, R. Rivera-Díaz, F. Vanaclocha
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Servicio de Dermatología, Hospital 12 de Octubre, Madrid Spain
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Hebe Petiti-Martin, M. Villar-Buill, I. de la Hera, L. Fuertes, M. Burgués-Calderón, R. Rivera-Díaz, F. Vanaclocha" "autores" => array:7 [ 0 => array:4 [ "nombre" => "G." "apellidos" => "Hebe Petiti-Martin" "email" => array:1 [ 0 => "gisepetiti@hotmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "M." "apellidos" => "Villar-Buill" ] 2 => array:2 [ "nombre" => "I." "apellidos" => "de la Hera" ] 3 => array:2 [ "nombre" => "L." "apellidos" => "Fuertes" ] 4 => array:2 [ "nombre" => "M." "apellidos" => "Burgués-Calderón" ] 5 => array:2 [ "nombre" => "R." "apellidos" => "Rivera-Díaz" ] 6 => array:2 [ "nombre" => "F." "apellidos" => "Vanaclocha" ] ] "afiliaciones" => array:1 [ 0 => array:1 [ "entidad" => "Servicio de Dermatología, Hospital 12 de Octubre, Madrid Spain" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Trombosis venosa profunda en paciente con lepra lepromatosa tratado con talidomida por leprorreacción" ] ] "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" => 972 "Ancho" => 1335 "Tamanyo" => 121782 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Painful infiltrated erythematous plaques with a loss of touch sensation.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Leprosy, or Hansen disease, is a chronic granulomatous infection caused by <span class="elsevierStyleItalic">Myobacterium leprae</span>. It mainly affects cool parts of the body, such as the skin, the upper airways, the anterior segment of the eye, the superficial segments of the peripheral nerves, and the testicles. <span class="elsevierStyleItalic">Mycobacterium lepromatosis</span> sp. nov is a new, recently identified, mycobacterium<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> that causes diffuse lepromatous leprosy (or diffuse leprosy of Lucio and Latapo<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>). This form of leprosy is endemic in Mexico and the Caribbean.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Leprosy can be classified as paucibacillary (when no acid-fact bacilli are found in tissues or smears) or multibacillary (when 1 or more acid-alcohol-fast bacilli are found in tissues or smears). According to the guidelines of the World Health Organization, paucibacillary leprosy should be treated with a combined regimen of sulfone and rifampicin for 6 months, whereas multibacillary leprosy should be treated with sulfone, rifampicin, and clofazimine for a year. Other bactericidal antibiotics for infections caused by <span class="elsevierStyleItalic">M leprae</span> are available for patients with refractory or recurrent disease or for patients who do not respond to conventional treatment or who have sulfone intolerance. Examples are fluoroquinolones, minocycline, and clarithromycin.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Patients with leprosy can develop acute, immune-mediated reactions, known as type 1 (reversal) reactions or type 2 reactions (erythema nodosum leprosum).</p><p id="par0020" class="elsevierStylePara elsevierViewall">Thalidomide is the treatment of choice for severe or recurrent erythema nodosum leprosum. Its use, however, has been linked to serious complications such as deep vein thrombosis,<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> teratogenicity, neuropathy, and hyperkalemia.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Case Description</span><p id="par0025" class="elsevierStylePara elsevierViewall">We report the case of a 43-year-old Brazilian man who consulted in 2008 for skin lesions of 3 years’ duration. The lesions were painful, well-demarcated, slightly infiltrated erythematous plaques with a loss of touch sensation (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>); they were located on the limbs, the arms, the buttocks, and the trunk. Skin biopsy showed interstitial granulomatous dermatitis with a moderate superficial perivascular lymphocytic infiltrate and aggregates of histiocytes at the interface between the reticular and the papillary dermis. Ziehl-Neelsen staining showed small numbers of acid-alcohol-fast bacilli, arranged singly and in clumps (globi). The mucus and lymph study was positive (bacteriological index 2+ and morphological index of 40%), and electromyography showed a mild to moderate sensory-predominant axonal polyneuropathy. The initial diagnosis was borderline lepromatous leprosy (although this was later revised to lepromatous leprosy) and treatment was initiated with rifampicin 600<span class="elsevierStyleHsp" style=""></span>mg/d, clofazimine 50<span class="elsevierStyleHsp" style=""></span>mg/d (plus 300<span class="elsevierStyleHsp" style=""></span>mg on the first day of the month), and sulfone 100<span class="elsevierStyleHsp" style=""></span>mg/d. Six months after starting treatment, the patient presented with new lesions, worsening of existing lesions, and fever of 38<span class="elsevierStyleHsp" style=""></span>°C. A second skin biopsy showed a predominantly perivascular and periadnexal granulomatous reaction with foamy histiocytes that spared the epidermis. Ziehl-Neelsen staining showed abundant bacilli. Although the significance of these findings was initially unclear, the case was diagnosed as a type 1 leprosy reaction and treatment with prednisone 30<span class="elsevierStyleHsp" style=""></span>mg/d was initiated. The lesions, however, continued to worsen (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>) and new lesions suggestive of erythema nodosum leprosum appeared. In view of this new situation, the patient was started on thalidomide (up to 150<span class="elsevierStyleHsp" style=""></span>mg/d) with gradual tapering of the corticosteroid dose. Two months after starting treatment with thalidomide, the patient presented with swelling and pain in the right leg and Doppler ultrasound revealed an infrapopliteal deep vein thrombosis. The laboratory tests showed normal complete blood count and biochemistry and coagulation profiles but slightly elevated antiphospholipid antibody levels: immunoglobulin (Ig) A anti-β<span class="elsevierStyleInf">2</span>-glycoprotein I antibodies (anti-β<span class="elsevierStyleInf">2</span>GPI), 34.0 U (normal value, <<span class="elsevierStyleHsp" style=""></span>20 U); IgG antiphosphatidylserine antibodies, 33.6 U (normal value, <<span class="elsevierStyleHsp" style=""></span>16.0 U); IgG anticardiolipin antibodies (aCL), 27.70 IgG phospholipid units (GPL)/mL (normal value, <<span class="elsevierStyleHsp" style=""></span>25.00 GPL/mL), and normal IgM aCL levels. Thalidomide was withdrawn and anticoagulation treatment was initiated with enoxaparin followed by acenocoumarol. The tests were repeated after 8 weeks, with negative or normal results in all cases.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0030" class="elsevierStylePara elsevierViewall">The presence of antiphospholipid antibodies has been linked to numerous infectious diseases, both viral (human immunodeficiency virus infection, hepatitis C virus infection, and parvovirus B19 infection) and bacterial (syphilis, malaria, and leprosy); the antibodies are generally transient and can disappear with treatment.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The presence of aCL and anti-β<span class="elsevierStyleInf">2</span>GPI antibodies has been reported in 42.7% (range, 21%-67%) and 44.8% (range, 2.9%-89%), respectively, of patients with lepromatous leprosy or borderline lepromatous leprosy.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> One study observed that aCL antibody positivity was more common in patients with multibacillary leprosy (80.7%) than in those with paucibacillary leprosy (8.3%) and that titers were not affected by treatment.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The presence of aCL, lupus anticoagulant, or anti-β<span class="elsevierStyleInf">2</span>GPI is considered to be independent of the risk of thrombosis, and antiphospholipid syndrome (APS) is only considered to exist in a patient with vascular thrombotic events or complications of pregnancy if a positive test result is obtained for 1 of these antibodies on 2 or more occasions at least 12 weeks apart.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Our patient had IgA anti-β<span class="elsevierStyleInf">2</span>GPI, which are not included in the classification criteria for APS. Even if they were, however, the criteria would not apply as these antibodies were detected on only 1 occasion.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Most studies indicate that antiphospholipid antibodies in infections are mainly of the IgM isotype,<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> but Loizou et al.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> found that IgA aCL were more common in patients with leprosy. The matter is somewhat controversial as many authors have reported that infection-related antiphospholipid antibodies are not associated with procoagulant states.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> In autoimmune disorders, such as systemic lupus erythematous and primary APS, the binding of antiphospholipid antibodies to phospholipids is enhanced by the cofactor β<span class="elsevierStyleInf">2</span>GPI. Nonthrombogenic antiphospholipid antibodies, however, do not require β<span class="elsevierStyleInf">2</span>GPI to enhance their binding to phospholipids. Two types of antiphospholipid antibodies are distinguished based on this difference: autoimmune (or β<span class="elsevierStyleInf">2</span>GPI-dependent) antibodies and infection-associated (or β<span class="elsevierStyleInf">2</span>GPI-independent) antibodies. The line between the 2, however, is somewhat blurred.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Akerkar et al.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> described a patient with borderline tuberculoid leprosy, gangrene, and elevated IgM aCL titers, while Wallin et al.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> described the case of a patient with lepromatous leprosy who developed bilateral fibular artery obstruction due to the presence of aCL and lupus anticoagulant, confirming that these antibodies can provoke thrombotic events.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Thalidomide used alone in patients with blood dyscrasias has not been associated with a higher rate of thrombotic events (deep vein thrombosis incidence of 1%). When the drug is used in association with other agents, however, such as dexamethasone or chemotherapy agents, the risk increases (up to 10%), particularly in patients with neoplastic disease (metastatic renal cell carcinoma, myelodysplastic syndrome, and multiple myeloma).<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> All the studies published to date have shown that the risk of thrombotic events in patients receiving thalidomide is highest in the first 2 months of treatment, an observation that is consistent with our case. In a study of 25 patients with skin diseases treated with thalidomide (100-300<span class="elsevierStyleHsp" style=""></span>mg/d) alone, 5 patients (20%) developed deep vein thrombosis and 4 of these had erythema nodosum leprosum.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">In our review of the literature, we found 4 patients with erythema nodosum leprosum treated with thalidomide and corticosteroids who developed deep vein thrombosis.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13–16</span></a> One of the patients was also receiving cyclophosphamide<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> and another developed pulmonary thromboembolism in addition to deep vein thrombosis.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">In our patient, who had transient antiphospholipid antibodies, probably in relation to his leprosy, the combined use of thalidomide and prednisone may have acted as a trigger of the thrombotic event.</p><p id="par0070" class="elsevierStylePara elsevierViewall">To conclude, we stress the importance of considering the risk of thromboembolic events in patients being treated with thalidomide for skin disorders, particularly when this drug is used in association with corticosteroids or chemotherapy agents or when other thrombophilic factors are present. More studies are needed to establish guidelines to prevent these serious complications in such patients.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflicts of Interest</span><p id="par0075" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:2 [ "identificador" => "xres97774" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec84928" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres97775" "titulo" => "Resumen" ] 3 => array:2 [ "identificador" => "xpalclavsec84929" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Case Description" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Discussion" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Conflicts of Interest" ] 8 => array:2 [ "identificador" => "xack35283" "titulo" => "Acknowledgments" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2011-06-13" "fechaAceptado" => "2011-12-18" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec84928" "palabras" => array:5 [ 0 => "Hansen disease" 1 => "Leprosy" 2 => "Leprosy reaction" 3 => "Thalidomide" 4 => "Deep vein thrombosis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec84929" "palabras" => array:5 [ 0 => "Enfermedad de Hansen" 1 => "Lepra" 2 => "Leprorreacción" 3 => "Talidomida" 4 => "Trombosis venosa profunda" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Thalidomide is the treatment of choice for severe or recurrent erythema nodosum leprosum. Its use has been associated with deep vein thrombosis in patients with blood disorders, however, particularly when used in combination with corticosteroids or chemotherapy. We describe a case of deep vein thrombosis in a 43-year-old man with lepromatous leprosy who was being treated with thalidomide and prednisone for a type 2 leprosy reaction (erythema nodosum leprosum); the patient also had transiently positive antiphospholipid antibody results. We stress the importance of considering deep vein thrombosis, a potentially fatal complication, in dermatology patients treated with thalidomide.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La talidomida es el fármaco de elección en el tratamiento del eritema nodoso leproso severo/recurrente. Su uso ha sido relacionado con trombosis venosas profundas (TVP) en pacientes con enfermedades hematológicas (especialmente cuando se le asocia con corticoides y quimioterapia).</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Presentamos un caso de TVP en un hombre de 43 años, con lepra lepromatosa en tratamiento con talidomida y prednisona por una leprorreación tipo 2 (eritema nodoso leproso), con anticuerpos antifosfolípidos positivos transitorios.</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Resaltamos la importancia de tener en cuenta esta posible complicación, potencialmente fatal, en pacientes tratados con talidomida por enfermedades dermatológicas.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara">Please cite this article as: Hebe Petiti-Martin G, et al. Trombosis venosa profunda en paciente con lepra lepromatosa tratado con talidomida por leprorreacción. Actas Dermosifiliogr.2013;104:67-70.</p>" ] ] "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" => 972 "Ancho" => 1335 "Tamanyo" => 121782 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Painful infiltrated erythematous plaques with a loss of touch sensation.</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" => 1852 "Ancho" => 1335 "Tamanyo" => 170371 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Worsening of previous lesions and appearance of multiple erythematous violaceous nodules (type 2 leprosy reaction/erythema nodosum leprosum).</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:16 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparative sequence analysis of Mycobacterium leprae and the new leprosy-causing Mycobacterium lepromatosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "X.Y. 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| 2019 Enero | 2 | 0 | 2 |
| 2018 Diciembre | 5 | 8 | 13 |
| 2018 Noviembre | 1 | 0 | 1 |
| 2018 Octubre | 6 | 1 | 7 |
| 2018 Septiembre | 5 | 0 | 5 |
| 2018 Mayo | 0 | 4 | 4 |
| 2018 Marzo | 1 | 2 | 3 |
| 2018 Febrero | 31 | 4 | 35 |
| 2018 Enero | 45 | 10 | 55 |
| 2017 Diciembre | 45 | 7 | 52 |
| 2017 Noviembre | 24 | 5 | 29 |
| 2017 Octubre | 34 | 2 | 36 |
| 2017 Septiembre | 39 | 6 | 45 |
| 2017 Agosto | 55 | 11 | 66 |
| 2017 Julio | 52 | 6 | 58 |
| 2017 Junio | 71 | 18 | 89 |
| 2017 Mayo | 54 | 7 | 61 |
| 2017 Abril | 50 | 10 | 60 |
| 2017 Marzo | 48 | 14 | 62 |
| 2017 Febrero | 42 | 9 | 51 |
| 2017 Enero | 47 | 13 | 60 |
| 2016 Diciembre | 47 | 13 | 60 |
| 2016 Noviembre | 75 | 13 | 88 |
| 2016 Octubre | 95 | 7 | 102 |
| 2016 Septiembre | 152 | 16 | 168 |
| 2016 Agosto | 56 | 11 | 67 |
| 2016 Julio | 58 | 19 | 77 |
| 2016 Junio | 11 | 14 | 25 |
| 2016 Mayo | 6 | 19 | 25 |
| 2016 Abril | 13 | 1 | 14 |
| 2016 Marzo | 6 | 2 | 8 |
| 2016 Febrero | 10 | 10 | 20 |
| 2016 Enero | 8 | 8 | 16 |
| 2015 Diciembre | 8 | 10 | 18 |
| 2015 Noviembre | 19 | 1 | 20 |
| 2015 Octubre | 11 | 4 | 15 |
| 2015 Septiembre | 11 | 3 | 14 |
| 2015 Agosto | 20 | 1 | 21 |
| 2015 Julio | 59 | 11 | 70 |
| 2015 Junio | 49 | 10 | 59 |
| 2015 Mayo | 100 | 25 | 125 |
| 2015 Abril | 84 | 11 | 95 |
| 2015 Marzo | 58 | 19 | 77 |
| 2015 Febrero | 58 | 16 | 74 |
| 2015 Enero | 58 | 10 | 68 |
| 2014 Diciembre | 27 | 3 | 30 |
| 2014 Noviembre | 20 | 6 | 26 |
| 2014 Octubre | 32 | 6 | 38 |
| 2014 Septiembre | 23 | 4 | 27 |
| 2014 Agosto | 21 | 8 | 29 |
| 2014 Julio | 19 | 8 | 27 |
| 2014 Junio | 30 | 6 | 36 |
| 2014 Mayo | 28 | 6 | 34 |
| 2014 Abril | 27 | 4 | 31 |
| 2014 Marzo | 23 | 7 | 30 |
| 2014 Febrero | 19 | 9 | 28 |
| 2014 Enero | 17 | 12 | 29 |
| 2013 Diciembre | 31 | 9 | 40 |
| 2013 Noviembre | 19 | 8 | 27 |
| 2013 Octubre | 19 | 7 | 26 |
| 2013 Septiembre | 18 | 7 | 25 |
| 2013 Agosto | 11 | 18 | 29 |
| 2013 Julio | 8 | 30 | 38 |
| 2013 Junio | 10 | 21 | 31 |
| 2013 Mayo | 9 | 25 | 34 |
| 2013 Abril | 10 | 13 | 23 |
| 2013 Marzo | 12 | 17 | 29 |
| 2013 Febrero | 6 | 5 | 11 |
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