BACKGROUND Treatment of active rheumatoid arthritis may necessitate a methotrexate mono- or combination therapy. As in the present case, novel side effects may occur, when escalating therapy. CASE PRESENTATION A 63-year-old Caucasian female patient with rheumatoid arthritis on methotrexate for 8 years and on leflunomide for 6 years was admitted for weakness, edema, ascites, and petechiae of the lower legs. Comorbidities included a urinary tract infection, metabolic syndrome with obesity, type-2 diabetes without necessity for insulin or oral antidiabetics, and non-alcoholic fatty liver disease. Laboratory results showed acute liver failure, oliguric acute kidney injury, thrombocytopenia, and schistocyte-positive, Coombs-negative hemolytic anemia. On admission, her ADAMTS13 activity was decreased, and her leflunomide plasma level was elevated (120 μg/l). Due to severe hypoalbuminemia, an intravascular hypovolemia, and severe metabolic alcalosis with hypokalemia were found. For the newly diagnosed thrombotic microangiopathy, leflunomide and methotrexate were discontinued, and 4 units of fresh-frozen plasma were given. Steroid therapy was administered for 5 days, until thrombotic thrombocytopenic purpura was excluded. Intravenous human albumin, oral vitamin K, and cholestyramine were administered for liver failure and leflunomide overdosage, respectively. Liver biopsy revealed a non-alcoholic fatty liver disease transforming into liver cirrhosis. After 2 weeks, our patient was discharged. However, within 3 weeks after discharge, our patient was rehospitalized for a relapse of acute liver failure, urinary tract infection, and influenza. Leflunomide and methotrexate were not reintroduced before or thereafter. Over a period of 11 months after discharge, her thrombotic microangiopathy subsided, and her renal and liver function fully recovered. CONCLUSIONS Under a combination of leflunomide and methotrexate, liver toxicity and, for the first time, thrombotic microangiopathy occurred as side effects. Non-alcoholic fatty liver disease may have predisposed for the drug-induced liver toxicity.

中文翻译：

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来氟米特和甲氨蝶呤的联合治疗导致血栓性微血管病和肝毒性：一例报告。

背景技术活动性类风湿关节炎的治疗可能需要甲氨蝶呤单药或联合疗法。如当前情况，当逐步升级治疗时，可能会出现新的副作用。病例介绍一名63岁的白人女性类风湿性关节炎患者接受甲氨蝶呤治疗8年，来氟米特治疗6年，因小腿无力，浮肿，腹水和瘀点而入院。合并症包括尿路感染，肥胖的代谢综合征，不需要胰岛素或口服降糖药的2型糖尿病以及非酒精性脂肪肝。实验室结果显示急性肝功能衰竭，少尿性急性肾损伤，血小板减少和血吸虫细胞阳性，库姆斯阴性溶血性贫血。入院时，她的ADAMTS13活动减少，她的来氟米特血浆水平升高了（120μg/ l）。由于严重的低白蛋白血症，血管内血容量不足和严重的代谢性碱中毒伴低钾血症被发现。对于新诊断的血栓性微血管病，停用来氟米特和氨甲蝶呤，并给予4单位新鲜冷冻血浆。给予类固醇疗法5天，直到血栓性血小板减少性紫癜被排除在外。分别因肝功能衰竭和来氟米特过量服用静脉内人白蛋白，口服维生素K和消胆胺。肝活检显示非酒精性脂肪肝疾病转化为肝硬化。2周后，我们的病人出院了。但是，出院后3周内，我们的患者因急性肝衰竭，尿路感染和流感的复发而再次入院。来氟米特和氨甲蝶呤在治疗前后均未重新引入。出院后的11个月内，她的血栓性微血管病消退，肾脏和肝功能完全恢复。结论在来氟米特和甲氨蝶呤联合使用时，肝毒性和血栓性微血管病首次成为副作用。非酒精性脂肪肝可能是药物诱发的肝毒性的诱发因素。