Hepatic Methotrexate-Associated Lymphoproliferative Disorder Complicated by Hemophagocytic Lymphohistiocytosis in a Patient with Inflammatory Myositis: A Case Report
Introduction/Background/Significance: Methotrexate (MTX), an immunosuppressant used for rheumatoid arthritis (RA) and inflammatory myopathies, predisposes patients to lymphoproliferative disorders (LPDs).1-3 Hepatic MTX-associated LPDs (MTX-LPDs) are rare, with only eleven reported cases.4 Most occur in RA patients, with only 6% of cases seen in patients with psoriasis or dermatomyositis.5 We present a rare case of hepatic MTX-LPD complicated by secondary hemophagocytic lymphohistiocytosis (HLH) in a patient with inflammatory myositis.
Materials and Methods/Case Presentation/Objective: A 55-year-old Caucasian female with inflammatory myositis treated with MTX for 20 years presented with confusion, weakness, liver lesions, and several months of cyclic fevers. Liver nodules were detected on MRI seven months prior to presentation, with initial biopsies revealing necrotic tissue. Six months prior, her fevers developed and was clinically diagnosed with lymphoma. Despite discontinuing MTX and starting IVIG at that time, her symptoms progressed. Two weeks prior to presentation, she developed severe hyponatremia and neurological decline, leading to her transfer to a tertiary center.
On presentation, she was somnolent but arousable (Glasgow Coma Score 13), with a BMI of 17.1 kg/m2. She was tachycardic (138/min) and hypotensive (105/66 mmHg), with notable cachexia, increased speech latency, non-voluntary saccades, 4/5 strength in the bilateral extremities, difficulty following commands, bilateral pleural effusions, and ascites. Laboratory findings revealed hyponatremia (110 mmol/L) and elevated CRP, sIL-2R, EBV markers, hepatobiliary enzymes and SAAG. Imaging revealed multiple liver lesions and moderate pleural effusions. Fine needle aspiration of a liver tumor identified atypical lymphohistiocytic populations. Histology confirmed EBV-positive large B-cell lymphoma (LBCL) with angioinvasion and kappa light chain restriction. Molecular pathology revealed clonal B-cell gene rearrangement. She was diagnosed with MTX-LPD complicated by HLH and admitted for treatment.
Results/Description/Main Outcome Measures: The patient began treatment with etoposide and dexamethasone for HLH. Despite an initial decrease in ferritin, her condition worsened, requiring ICU transfer for respiratory failure and hemodynamic instability. Dexamethasone was also discontinued due to steroid-induced psychosis. Following a liver biopsy confirming LBCL, R-EPOCH chemotherapy was initiated. However, the patient developed Takotsubo cardiomyopathy and doxorubicin was withheld. Additional complications included ileus, Clostridium difficile infection, and bilateral lower extremity deep vein thrombosis.
After brief improvement, HLH recurred. A second R-EPOCH cycle, with 50% dose reduction, was administered but multifocal pleural consolidations led to reintubation and another ICU transfer. Although her labs normalized and oxygen needs decreased, recurrent aspiration pneumonia and persistent hypoxia necessitated further ICU transfers and a third R-EPOCH cycle. The patient continued to deteriorate and her R-EPOCH regimen was transitioned to anakinra and ruxolitinib. Although ferritin and sIL-2R improved, she developed DIC and sepsis, contributing to multiorgan failure. The patient passed away peacefully after transitioning to comfort care.
Conclusions: This case highlights the rare occurrence of hepatic MTX-LPD complicated by HLH in a patient with inflammatory myositis. MTX-associated LPDs are rare but carry significant mortality, particularly when complicated by HLH, a hyperinflammatory condition with a high ICU mortality rate.6-9 Early recognition and aggressive management of lymphoma and HLH are crucial.10 Regular monitoring and a high index of suspicion are essential in patients on long-term immunosuppressive therapy, with multidisciplinary approaches recommended to optimize outcomes.
