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

Abstract

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...

Successful Rituximab Monotherapy in Advanced-stage, Epstein-Barr Virus-positive Diffuse Large B-Cell Lymphoma in an Adolescent With Systemic Juvenile Idiopathic Arthritis

“…Of note, successful treatment of an iatrogenic LPD case was previously reported in an adolescent with polyarticular JIA who had complete regression of her stage 3A EBV+ DLBCL after cessation of her MTX and etanercept without additional therapy. 3 However, in contrast to our case, this DLBCL occurred 3 years from MTX initiation and 12 years from polyarticular JIA diagnosis and is more suggestive of an MTX-related LPD. Moreover, we assessed that the advanced stage and rapidly progressive nature of our patient's tumor did not warrant a trial of reduction of immunosuppression alone.…”

“…1 Iatrogenic LPDs are also reported among children with juvenile idiopathic arthritis (JIA) treated with long-term methotrexate (MTX) therapy. 2,3 Morphologically, iatrogenic LPDs are indistinguishable from de novo LPDs that occur in immunocompetent hosts. 4 The treatment of pediatric EBV+ DLBCL varies between de novo LPDs and PTLD.…”

“…8 Spontaneous regression of EBV+ DLBCL after the withdrawal of MTX has been reported in children and adults with inflammatory arthritis. 3,9,10 We describe an adolescent with stage III EBV+ DLBCL that occurred in the setting of systemic JIA (sJIA) treated with multiple immunosuppressive agents. This case presented a therapeutic challenge because of the multiple possible etiologies of the DLBCL and baseline organ dysfunction that increased risk for therapy-related toxicity.…”

“…Epstein-Barr virus-positive diffuse large B-cell lymphoma (EBV+ DLBCL) is a type of non-Hodgkin lymphoma that is commonly diagnosed as an iatrogenic immunodeficiency-associated lymphoproliferative disease (LPD) among recipients of solid organ or stem cell transplantation, namely post-transplant lymphoproliferative disease (PTLD) 1. Iatrogenic LPDs are also reported among children with juvenile idiopathic arthritis (JIA) treated with long-term methotrexate (MTX) therapy 2,3. Morphologically, iatrogenic LPDs are indistinguishable from de novo LPDs that occur in immunocompetent hosts 4…”

“…Multidrug, cytotoxic chemotherapy is recommended for de novo DLBCL,5–7 whereas reduction of immunosuppressive agents and/or rituximab is a typical first-line therapy in PTLD 8. Spontaneous regression of EBV+ DLBCL after the withdrawal of MTX has been reported in children and adults with inflammatory arthritis 3,9,10…”