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an electroneurogram evidenced sensory-motor polyneuropathy&#59; and autoimmune tests revealed antinuclear antibodies &#40;titers of 1&#58;1280&#41;&#44; anti-Smith antibodies&#44; and anti-U1 ribonucleoprotein &#40;U1-RNP&#41; &#40;titers &#62; 1&#58;1&#46;600&#41;&#46; The results of other autoantibody tests were negative&#46; Histological study of biopsied samples of skin and muscle tissue from the arm revealed vacuolization of the basal layer and thickening of the basement membrane as well as a positive periodic acid-Schiff stain &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41; and signs of inflammatory myositis&#46; These findings led to a diagnosis of MCTD associated with Castleman disease and Hodgkin lymphoma&#46; In view of the reported association between Castleman disease and the human immunodeficiency virus and the human herpesvirus 8&#44; serology was performed to screen for these viruses&#44; with negative results in both cases&#46; The negative result for the human herpesvirus 8 was confirmed by a polymerase chain reaction assay in peripheral blood&#44; in which no viral load was detected&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">Initial treatment with corticosteroids and antimalarials had little effect on the symptoms of MCTD&#44; but subsequent treatment with rituximab achieved remission of both MCTD and Castleman disease&#46; The regimen used was 375<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> administered intravenously once a week for 4 weeks&#44; with a repeat cycle after 6 months&#44; in combination with methylprednisolone 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;d &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Discussion</span><p id="par0030" class="elsevierStylePara elsevierViewall">MCTD was first described in 1972 as a disorder characterized by a combination of the clinical features of systemic lupus erythematosus&#44; systemic scleroderma&#44; polymyositis&#47;dermatomyositis&#44; and rheumatoid arthritis in the presence of high titers of anti-U1-RNP&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">2</span></a> The most common clinical manifestations include Raynaud&#39;s phenomenon&#44; swollen hands&#44; fingers with a sausage appearance&#44; joint pain&#44; and muscle weakness&#46; The cutaneous manifestations include features consistent with a dermatomyositis-like or systemic lupus erythematosus-like photosensitivity&#44; ulcers&#44; Sjogren syndrome&#44; and urticarial vasculitis&#44; although no specific or pathognomonic clinical finding has been identified&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">3</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The diagnostic criteria proposed by Alarc&#243;n-Segovia et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">4</span></a> have a sensitivity of 100&#37;&#46; For a confirmed diagnosis&#44; the patient must fulfill the serologic criteria &#40;anti-U1-RNP autoantibodies with a titer in hemagglutination of &#62; 1&#58;1600&#41; and at least 3 of the clinical criteria&#44; which are swollen hands&#44; synovitis&#44; myositis&#44; Raynaud&#39;s phenomenon&#44; and acrosclerosis&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">There have been several reports of patients with Castleman disease presenting autoimmune manifestations&#44; with more cases of hemolytic anemia and fewer of connective tissue disease&#46; The onset of autoimmune manifestations has been reported as occurring both before and after the onset of Castleman disease&#46; To date&#44; only 3 cases of MCTD associated with Castleman disease have been reported in the literature&#46; Nanki et al<span class="elsevierStyleItalic">&#46;</span><a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">5</span></a> reported the case of a 60-year woman with multicentric Castleman disease and EMTC in which pharmacological remission was achieved following treatment with melphalan&#59; Chrispal et al<span class="elsevierStyleItalic">&#46;</span><a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">6</span></a> reported associated EMTC and Castleman disease in a 16-year-old girl&#59; and Hosaka et al&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">7</span></a> reported 3 cases of Castleman disease mimicking the features of collagen disease&#44; one of them with symptoms typical of MCTD&#46; No association with Hodgkin lymphoma was reported in any of these cases&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">In the case of our patient&#44; the treatment chosen was the anti-CD20 agent rituximab because an increased mean survival has been reported in patients with Castleman disease on rituximab-based therapies&#44; although there is less experience on the use of this therapy in EMTC&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">8</span></a> Remission of the clinical manifestations of subacute lupus has been reported in patients with MCTD as well as improvement in refractory thrombocytopenia and Raynaud&#39;s phenomenon&#59; the only adverse effect reported in these patients treated with rituximab was 1 case of severe ischemia&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">9&#8211;11</span></a> The therapeutic mechanism of rituximab involves depletion of CD20 positive cells&#44; which are its therapeutic target&#46; CD20 positive cells are directly or indirectly responsible for the dysregulated production of interleukin-6 and other cytokines&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">In this case it appears that 3 diseases may be related&#46; Overproduction of interleukin 6 by Reed-Sternberg cells and histiocytes in Hodgkin lymphoma has been demonstrated&#44; and this abnormal immune state is responsible for the association between Hodgkin lymphoma and Castleman disease&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">12</span></a> The resulting proinflammatory cytokine microenvironment may trigger an exaggerated immune response&#44; leading to a loss of tolerance and the development of an autoimmune disease&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">13</span></a></p></span></span>"
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Case and Research Letters
Mixed Connective Tissue Disease in a Patient With Castleman Disease and Hodgkin Lymphoma: Excellent Clinical Response to Rituximab
Enfermedad mixta del tejido conectivo en el contexto de enfermedad de Castleman y linfoma Hodgkin con excelente respuesta clínica a rituximab
T. Gracia-Cazañaa,
Corresponding author
tamara_gracia@hotmail.com

Corresponding author.
, C. Delgado-Beltránb, M.A. Concellónc, M.A. Fuertesd
a Servicio de Dermatología, Hospital de Barbastro, Huesca, Spain
b Servicio de Reumatología, Hospital Clínico Lozano Blesa, Zaragoza, Spain
c Servicio de Dermatología, Hospital Clínico Lozano Blesa, Zaragoza, Spain
d Servicio de Hematología, Hospital Clínico Lozano Blesa, Zaragoza, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Castleman disease &#40;CD&#41;&#44; or angiofollicular lymphoid hyperplasia&#44; is characterized by a process of reactive hyperplasia affecting the immune system&#46; The condition can&#44; therefore&#44; give rise to a clinical picture similar to that of either a connective tissue disease or an autoimmune disease&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">1</span></a> We report a case of Castleman disease and Hodgkin lymphoma in a patient who developed a mixed connective tissue disease &#40;MCTD&#41;&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Case Description</span><p id="par0010" class="elsevierStylePara elsevierViewall">The patient was a 49-year-old man&#44; who had recently been diagnosed with Hodgkin lymphoma and multicentric Castleman disease and was being treated with adriamycin&#44; bleomycin&#44; vinblastine&#44; and dacarbazine&#46; He was referred to our department when he developed skin lesions and photosensitivity in association with Raynaud&#39;s phenomenon and muscle weakness a month after completing chemotherapy&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Physical examination revealed the following&#58; erythematous-violaceous coloration on sun-exposed areas&#44; elbows&#44; and knees&#59; edema of the palms and soles&#59; and erythematous scaly papules on the dorsal surfaces of the interphalangeal and metacarpophalangeal joints of the hands consistent with Gottron papules &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Capillaroscopy demonstrated disorganization of the capillary bed&#44; loss of normal capillary distribution&#44; and a few thrombosed giant capillaries&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Two of the explorations performed yielded significant results&#58; an electroneurogram evidenced sensory-motor polyneuropathy&#59; and autoimmune tests revealed antinuclear antibodies &#40;titers of 1&#58;1280&#41;&#44; anti-Smith antibodies&#44; and anti-U1 ribonucleoprotein &#40;U1-RNP&#41; &#40;titers &#62; 1&#58;1&#46;600&#41;&#46; The results of other autoantibody tests were negative&#46; Histological study of biopsied samples of skin and muscle tissue from the arm revealed vacuolization of the basal layer and thickening of the basement membrane as well as a positive periodic acid-Schiff stain &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41; and signs of inflammatory myositis&#46; These findings led to a diagnosis of MCTD associated with Castleman disease and Hodgkin lymphoma&#46; In view of the reported association between Castleman disease and the human immunodeficiency virus and the human herpesvirus 8&#44; serology was performed to screen for these viruses&#44; with negative results in both cases&#46; The negative result for the human herpesvirus 8 was confirmed by a polymerase chain reaction assay in peripheral blood&#44; in which no viral load was detected&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">Initial treatment with corticosteroids and antimalarials had little effect on the symptoms of MCTD&#44; but subsequent treatment with rituximab achieved remission of both MCTD and Castleman disease&#46; The regimen used was 375<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> administered intravenously once a week for 4 weeks&#44; with a repeat cycle after 6 months&#44; in combination with methylprednisolone 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;d &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Discussion</span><p id="par0030" class="elsevierStylePara elsevierViewall">MCTD was first described in 1972 as a disorder characterized by a combination of the clinical features of systemic lupus erythematosus&#44; systemic scleroderma&#44; polymyositis&#47;dermatomyositis&#44; and rheumatoid arthritis in the presence of high titers of anti-U1-RNP&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">2</span></a> The most common clinical manifestations include Raynaud&#39;s phenomenon&#44; swollen hands&#44; fingers with a sausage appearance&#44; joint pain&#44; and muscle weakness&#46; The cutaneous manifestations include features consistent with a dermatomyositis-like or systemic lupus erythematosus-like photosensitivity&#44; ulcers&#44; Sjogren syndrome&#44; and urticarial vasculitis&#44; although no specific or pathognomonic clinical finding has been identified&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">3</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The diagnostic criteria proposed by Alarc&#243;n-Segovia et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">4</span></a> have a sensitivity of 100&#37;&#46; For a confirmed diagnosis&#44; the patient must fulfill the serologic criteria &#40;anti-U1-RNP autoantibodies with a titer in hemagglutination of &#62; 1&#58;1600&#41; and at least 3 of the clinical criteria&#44; which are swollen hands&#44; synovitis&#44; myositis&#44; Raynaud&#39;s phenomenon&#44; and acrosclerosis&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">There have been several reports of patients with Castleman disease presenting autoimmune manifestations&#44; with more cases of hemolytic anemia and fewer of connective tissue disease&#46; The onset of autoimmune manifestations has been reported as occurring both before and after the onset of Castleman disease&#46; To date&#44; only 3 cases of MCTD associated with Castleman disease have been reported in the literature&#46; Nanki et al<span class="elsevierStyleItalic">&#46;</span><a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">5</span></a> reported the case of a 60-year woman with multicentric Castleman disease and EMTC in which pharmacological remission was achieved following treatment with melphalan&#59; Chrispal et al<span class="elsevierStyleItalic">&#46;</span><a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">6</span></a> reported associated EMTC and Castleman disease in a 16-year-old girl&#59; and Hosaka et al&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">7</span></a> reported 3 cases of Castleman disease mimicking the features of collagen disease&#44; one of them with symptoms typical of MCTD&#46; No association with Hodgkin lymphoma was reported in any of these cases&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">In the case of our patient&#44; the treatment chosen was the anti-CD20 agent rituximab because an increased mean survival has been reported in patients with Castleman disease on rituximab-based therapies&#44; although there is less experience on the use of this therapy in EMTC&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">8</span></a> Remission of the clinical manifestations of subacute lupus has been reported in patients with MCTD as well as improvement in refractory thrombocytopenia and Raynaud&#39;s phenomenon&#59; the only adverse effect reported in these patients treated with rituximab was 1 case of severe ischemia&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">9&#8211;11</span></a> The therapeutic mechanism of rituximab involves depletion of CD20 positive cells&#44; which are its therapeutic target&#46; CD20 positive cells are directly or indirectly responsible for the dysregulated production of interleukin-6 and other cytokines&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">In this case it appears that 3 diseases may be related&#46; Overproduction of interleukin 6 by Reed-Sternberg cells and histiocytes in Hodgkin lymphoma has been demonstrated&#44; and this abnormal immune state is responsible for the association between Hodgkin lymphoma and Castleman disease&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">12</span></a> The resulting proinflammatory cytokine microenvironment may trigger an exaggerated immune response&#44; leading to a loss of tolerance and the development of an autoimmune disease&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">13</span></a></p></span></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Gracia-Caza&#241;a T&#44; Delgado-Beltr&#225;n C&#44; Concell&#243;n MA&#44; Fuertes MA&#46; Enfermedad mixta del tejido conectivo en el contexto de enfermedad de Castleman y linfoma Hodgkin con excelente respuesta cl&#237;nica a rituximab&#46; Actas Dermosifiliogr&#46; 2015&#59;106&#58;843&#8211;846&#46;</p>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">A&#44; Erythematous-violaceous rash on the face and neck&#44; which spares areas not exposed to sunlight&#44; such as the lower eyelids and the submental area&#59; alopecia due to chemotherapy also observed&#46; B&#44; Gottron papules on the metacarpophalangeal and interphalangeal joints&#46; C&#44; Edema in the soles of both feet&#46; D&#44; Swollen palms and sausage fingers&#46;</p>"
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Article information
ISSN: 15782190
Original language: English
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