Epstein-Barr Virus Associated Hodgkin Lymphoma in a 9-Year-Old Girl Receiving Long-Term Methotrexate Therapy for Juvenile Idiopathic Arthritis

Takeyama, Junji; Satō, Atsushi; Nakano, Kyoko; Abukawa, Daiki; Ichinohazama, Ryo; Imaizumi, Masue

doi:10.1097/01.mph.0000212960.66221.e7

Cited by 14 publications

(6 citation statements)

References 12 publications

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“…Further, some cases of lymphoma are reported in JIA patients treated with MTX and other immunosuppressants, some of them EBV-associated (8). Three cases have been reported where JIA patients developed lymphoma after combination therapy of MTX and etanercept and with other immunosuppressants in two of the cases (9).…”

Section: Discussionmentioning

confidence: 99%

Spontaneous regression of Epstein-Barr virusassociated lymphoproliferative disorder in a juvenile idiopathic arthritis patient after the discontinuation of methotrexate and etanercept

et al. 2017

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IntroductionLymphoproliferative disorders (LPDs) occur at an increased rate in immunosuppressed patients. Patients with juvenile idiopathic arthritis (JIA) also seem to be at an increased risk for malignancies, particularly lymphomas (1). It is still debated whether antirheumatic treatment enhances this risk. To our knowledge, this is the first case of a JIA patient suffering from EBV-associated LPD on combination with etanercept and methotrexate (MTX), showing spontaneous regression of the disorder after the discontinuation of immunosuppressive treatment. Case PresentationA 16-year-old female was diagnosed with rheumatoid factor-negative polyarticular JIA at the age of 4 years. The patient also had a complex congenital cardiac anomaly, a left multicystic kidney, tracheomalacia and obstruction of the trachea at the bifurcation of the pulmonary artery, anomalies of the ribs and vertebrae, mental retardation, sensorineural hearing loss, growth retardation, and delayed puberty. Diagnostic tests for thrombophilia revealed elevated lipoprotein a levels and elevated homocysteine levels due to a methylentetrahydrofolate reductase (MTHFR) mutation. Microdeletion 22q was ruled out, and a microarray assay in search of an underlying genetic disorder showed normal results.After the diagnosis of JIA, MTX treatment was started, but discontinued due to elevated liver enzyme levels 10 months later. Consecutive treatment consisted of repeated intra-articular steroid applications. At the age of 13 years, JIA relapsed with multiple joint involvement, and treatment with MTX in reduced dosage with folate acid and etanercept was initiated, leading to an acceptable clinical condition but with functional impairment due to restricted joint movements.At the age of 16 years, the patient reported multiple subcutaneous nodules on the legs. On palpation, the nodules were 0.5 to 2.0 cm in size; the largest of these nodules was slightly tender. A case of a 16-year-old female with polyarticular juvenile idiopathic arthritis (JIA) since the age of 4 years is reported here. This patient also suffered from multiple congenital anomalies. On long-term treatment with oral methotrexate (MTX) and etanercept, multiple subcutaneous nodules were detected, which were accompanied by increased lactate dehydrogenase and uric acid levels. A biopsy of the largest nodule revealed Epstein-Barr (EB) virus-positive diffuse large B-cell lymphoma (DLBCL). The patient was classified as clinical stage IIIA due to a mediastinal lesion. Immunosuppressive treatment was discontinued immediately, which led to regression of the remaining nodules and normalization of the lactate dehydrogenase levels. The patient was considered to have an iatrogenic lymphoproliferative disorder classified as "other iatrogenic immunodeficiency-associated lymphoproliferative disorders" by the World health organization (WHO). To our knowledge, this is the first case report of a JIA patient with EBV-positive DLBCL following the administration of etanercept and methotrexate and spontaneous...

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Section: Discussionmentioning

confidence: 99%

Spontaneous regression of Epstein-Barr virusassociated lymphoproliferative disorder in a juvenile idiopathic arthritis patient after the discontinuation of methotrexate and etanercept

et al. 2017

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“…Awareness of a past or current EBV infection has been shown to be beneficial in determining treatment options for patients with certain rheumatic diseases. As noted in this review, JIA patients treated with MTX may lead to mishandling of EBV by T cells [17,18]. Additionally, EBV-infected ITP patients demonstrated a slower remission rate following treatment with steroids [28].…”

Section: Resultsmentioning

confidence: 82%

“…Recently, it was reported that a 9-year-old girl with a 7-year history of IgM rheumatoid factor (RF)-positive polyarticular JIA had been treated with methotrexate (MTX) and later developed nodular sclerosing Hodgkin lymphoma [17]. She had IgG EBV antibodies, while IgM EBV antibodies were negative.…”

Section: Juvenile Idiopathic Arthritis (Jia)mentioning

confidence: 99%

Rheumatic manifestations of Epstein-Barr virus in children

Gilliam

Reed²,

Syed³

et al. 2015

J Pediatr Infect Dis

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Epstein-Barr virus (EBV) is known to cause infectious mononucleosis; in addition, it is strongly associated with malignancies. Studies have also demonstrated that EBV infection may trigger the development of systemic lupus erythematosus. EBV infection has been implicated in complicating treatment of juvenile idiopathic arthritis, in addition to triggering cytokine production. Awareness of a past or present EBV infection has been highlighted as an important factor in determining treatment options in several diseases. Repeated associations have been described between EBV infection and various rheumatic diseases and complications of rheumatic disease, including Kawasaki disease, immune thrombocytopenic purpura, and hemophagocytic lymphohistiocytosis. We present a review of recent literature demonstrating the significance of EBV infection in rheumatic diseases, and complications of rheumatic disease, in children.

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“…Although rare, MTX has been reported to induce hypersensitivity pneumonitis 88 and Hodgkin lymphoma associated with Epstein-Barr virus. 89 MTX is also known to cause dermatologic side effects such as oral ulcers, urticaria, alopecia, and cutaneous nodules.…”

Section: ' Treatmentmentioning

confidence: 99%