Pancytopenia, including macrocytic anemia, associated with leflunomide in a rheumatoid arthritis patient

Toyokawa, Yasuhiko; Kingetsu, Isamu; Yasuda, Chiho; Yasuda, Jun; Yoshida, Ken; Kurosaka, Daitaro; Yamada, Akio

doi:10.3109/s10165-007-0613-8

Cited by 16 publications

(7 citation statements)

References 8 publications

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“…9 Direct pharmacologic inhibition of the electron transport chain results in decreased pyrimidine biosynthesis, 46 and a pharmacologic inhibitor of dihydroorotate dehydrogenase, leflunomide, has been reported to cause an anemia with megaloblastic features. 47 Furthermore, the demonstrated clinical efficacy of leflunomide as a potent lymphotoxin 48 suggests that an impairment of de novo pyrimidine biosynthesis may also underlie the impaired lymphopoiesis of both Polg A mice and patients with MDS.…”

Section: Discussionmentioning

confidence: 99%

Erythroid dysplasia, megaloblastic anemia, and impaired lymphopoiesis arising from mitochondrial dysfunction

Chen

Logan

Hochberg

et al. 2009

Blood

105

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Recent reports describe hematopoietic abnormalities in mice with targeted instability of the mitochondrial genome. However, these abnormalities have not been fully described. We demonstrate that mutant animals develop an age-dependent, macrocytic anemia with abnormal erythroid maturation and megaloblastic changes, as well as profound defects in lymphopoiesis. Mice die of severe fatal anemia at 15 months of age. Bonemarrow transplantation studies demonstrate that these abnormalities are intrinsic to the hematopoietic compartment and dependent upon the age of donor hematopoietic stem cells. These abnormalities are phenotypically similar to those found in patients with refractory anemia, suggesting that, in some cases, the myelodysplastic syndromes are caused by abnormalities of mitochondrial function. (Blood. 2009;114:4045-4053)

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Section: Discussionmentioning

confidence: 99%

Erythroid dysplasia, megaloblastic anemia, and impaired lymphopoiesis arising from mitochondrial dysfunction

Chen

Logan

Hochberg

et al. 2009

Blood

105

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“…Also of note, some of the drugs used to treat CVD may be implicated in megaloblastosis. [15][16][17][18][19] Likewise, ALIPs, while not specific, can also be seen in myelodysplastic syndrome, [20][21][22][23][24][25] during myeloid regeneration after myeloablative chemotherapy, and with granulocyte colony-stimulating factor therapy. 26 Lymphoid aggregates are a very nonspecific finding but have been associated with certain drug/therapy effects, other immune and inflammatory conditions, and viral infections.…”

Section: Quantitation Of Cell Lineages By Immunohistochemistrymentioning

confidence: 99%

Bone Marrow Examination for Unexplained Cytopenias Reveals Nonspecific Findings in Patients With Collagen Vascular Disease

Hunt

Salama

Sever

et al. 2013

Archives of Pathology &Amp; Laboratory Medicine

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Context.—Collagen vascular diseases are frequently included in the differential diagnosis for unexplained cytopenias and often prompt a bone marrow biopsy in this patient population to exclude malignancy. Few large-scale studies have characterized the bone marrow morphology in patients with collagen vascular disease, and most are limited to systemic lupus erythematosus or rheumatoid arthritis. Objective.—To identify morphologic and immunohistochemical abnormalities specific to each of a wide range of collagen vascular disease cases. Design.—We examined 102 cases of collagen vascular disease and 38 controls and evaluated the complete blood count, peripheral blood morphology, bone marrow morphology, as well as immunohistochemical staining, for numerous cell lineages. Results.—Bone marrow findings, including abnormalities such as lymphoid aggregates, lipogranulomas, or abnormal localization of immature precursors, were not significantly different as compared to the control group. Conclusions.—Bone marrow examination in patients with collagen vascular disease with cytopenias seldom provides new information. Caution should be exercised in interpreting morphologic findings suggestive of myelodysplasia since these are of a reactive nature in up to 27% of patients with collagen vascular disease. In a cost-effective diagnostic strategy, successful utilization may favor postponing a bone marrow biopsy while a more standardized autoimmune diagnostic panel is being performed.

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“…Leflunomide has been linked previously to pancytopenia with schistocyte-positive hemolytic anemia, although a concomitant TMA, e.g. due to cobalamine deficiency and/or leflunomide, was not considered there [5].…”

Section: Discussionmentioning

confidence: 99%

Thrombotic microangiopathy and liver toxicity due to a combination therapy of leflunomide and methotrexate: a case report

et al. 2020

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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.

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Pancytopenia, including macrocytic anemia, associated with leflunomide in a rheumatoid arthritis patient

Cited by 16 publications

References 8 publications

Erythroid dysplasia, megaloblastic anemia, and impaired lymphopoiesis arising from mitochondrial dysfunction

Erythroid dysplasia, megaloblastic anemia, and impaired lymphopoiesis arising from mitochondrial dysfunction

Bone Marrow Examination for Unexplained Cytopenias Reveals Nonspecific Findings in Patients With Collagen Vascular Disease

Thrombotic microangiopathy and liver toxicity due to a combination therapy of leflunomide and methotrexate: a case report

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