Denosumab/methotrexate

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Denosumab/methotrexate Epstein-Barr virus infection, lymphoproliferative disorders and osteonecrosis of the jaw: case report

A 75-year-old woman developed Epstein-Barr virus (EBV) infection and lymphoproliferative disorders (LPD) during treatment with methotrexate for rheumatoid arthritis (RA). Additionally, she developed osteonecrosis of the jaw during treatment with denosumab for osteoporosis. The woman presented with bone exposure and persistent pain in the right maxillary mucosa. Her medical history was significant for schizophrenia, RA, osteoporosis and renal cancer. She had been receiving oral methotrexate 8mg every week since 1998. She also received SC denosumab 60mg every 6 months from 2013 to January 2018 for osteoporosis (the total dose administered was 600mg). At her first visit to a dentist due to pain in the right maxillary mucosa in early February 2018, her dentist suspected antiresorptive agent-related osteonecrosis of the jaw (ARONJ) owing to maxillary posterior bone exposure, pain and infection. She visited the department (current presentation) for further examination and treatment of the right maxillary lesion, which was causing her pain in mid-February 2018. Oral intake of food was impaired due to severe intraoral pain. Jaw bone exposure, infection from the right maxillary incisors to the molars and mucosal necrosis were observed. The lesion caused severe pain. The right maxillary canine and lateral incisor were loose, indicating moderate to severe periodontitis. CT scan and MRI showed osteosclerosis in the right maxillary jaw bone, and the upper right maxillary sinus mucosa was hypertrophic, indicating acute osteomyelitis. Blood test results suggested renal function impairment and slight inflammation. Cytodiagnosis and biopsy at the right maxillary mucosa was performed on the first medical examination day. She tested negative for intraepithelial lesion and malignancy on cytodiagnosis with granulation tissue on histopathology. A clinical diagnosis of ARONJ was considered, and the woman was treated with amoxicillin, clarithromycin and gargles for infection control. On day 18 of hospitalisation, the inflammatory findings remitted. However, on day 65 of admission, the mucosal necrosis and maxillary jaw bone exposure were found to have spread. Therefore, methotrexate-associated LPD was suspected due to the long-term administration history and rise in blood concentration of methotrexate owing to renal function impairment after nephrectomy. Therefore, re-biopsy was performed at the right maxillary mucosa. On day 72 of admission, she was diagnosed with methotrexate-associated LPD following several immune-histological examinations. Histopathological examination with haematoxylin and eosin staining showed severe inflammatory cell infiltration in the submucosal area. Granulation tissue in the deep subepithelial region revealed Hodgkin cell-like cells and Reed-Sternberg-like cells. Immunohistochemical staining showed several large CD20- and CD30-positive cells, which were positive for EBER-ISH. Since

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