Wyeth Lederle
Drug adverse reactions citations

Blackburn WD Jr, Alarcon GS. Impotence in three rheumatoid arthritis patients treated with methotrexate.Arthritis Rheum. 1989 Oct;32(10):1341-2. No abstract available.PMID: 2803334 [PubMed - indexed for MEDLINE]

Bargallo N, Burrel M, Berenguer J, Cofan F, Bunesch L, Mercader JM.   Cortical laminar necrosis caused by immunosuppressive therapy and chemotherapy.AJNR Am J Neuroradiol. 2000 Mar;21(3):479-84.PMID: 10730638 [PubMed - indexed for MEDLINE]

We report three patients in whom neurologic symptoms and cortical laminar necrosis developed after immunosuppressive treatment (cyclosporin A and FK 506) and polychemotherapy (vincristine and methotrexate). Initial neuroradiologic studies showed cortical and white matter involvement. Follow-up studies showed cortical hyper-intense lesions on T1-weighted MR images, consistent with cortical laminar necrosis. The clinical and radiologic data indicate that a transient hypoxic-ischemic process could have been responsible for the encephalic lesions in these three patients.

Combe B, Sany J.  Extraarticular manifestations during methotrexate therapy for rheumatoid arthritis.J Rheumatol. 1995 Apr;22(4):790. No abstract available.PMID: 7791187 [PubMed - indexed for MEDLINE]

Dubin Kerr L, Troy K, Isola L.Temporal association between the use of methotrexate and development of leukemia in 2 patients with rheumatoid arthritis.J Rheumatol. 1995 Dec;22(12):2356-8.PMID: 8835576 [PubMed - indexed for MEDLINE]

To date only a single case of leukemia coincident with the use of methotrexate (MTX) in rheumatoid arthritis (RA) has been reported. We report 2 additional patients with RA, each of whom developed leukemia after receiving short term low dose MTX. Whether these cases represent an adverse effect of MTX treatment has yet to be determined.

Ebner F, Ranner G, Slavc I, Urban C, Kleinert R, Radner H, Einspieler R, Justich E.   MR findings in methotrexate-induced CNS abnormalities. AJR Am J Roentgenol. 1989 Dec;153(6):1283-8.PMID: 2816647 [PubMed - indexed for MEDLINE]
MR of the brain was performed in eight patients (mean age, 14.9 years) with osteogenic sarcoma during or after IV treatment with high-dose methotrexate. MR detected brain abnormalities in four patients, three of whom had concomitant neurologic dysfunction. Pathologic findings demonstrated on MR were (1) chronic brain edema, demonstrable over a period of 3-14 months (proved by autopsy in one patient); (2) multifocal white matter necrosis; and (3) deep brain atrophy. MR appears to be valuable in the detection of abnormalities induced by treatment with high-dose methotrexate.

Ellman MH, Hurwitz H, Thomas C, Kozloff M.  Lymphoma developing in a patient with rheumatoid arthritis taking low dose weekly methotrexate.J Rheumatol. 1991 Nov;18(11):1741-3.PMID: 1787499 [PubMed - indexed for MEDLINE]

envresse I, Dietzmann A, Massenkeil G, Spath-Schwalbe E, Possinger K.   Subacute encephalopathy after combination chemotherapy including moderate-dose methotrexate in a patient with gastric cancer.Anticancer Drugs. 1999 Mar;10(3):293-4.PMID: 10327035 [PubMed - indexed for MEDLINE]
An episode of subacute encephalopathy after the infusion of a moderate dose of methotrexate (1500 mg/m2) (MTX) is reported in a young adult with metastastic gastric cancer. Weakness of the right arm, focal seizures, lethargy and confusion appeared on day 10. High signal intensity in periventricular white matter was observed on T2-weighted magnetic resonance imaging. Symptoms resolved spontaneously and completely after 48 h. We believe that this represents an unusual case of moderate-dose MTX-induced neurotoxicity in a patient with gastric cancer, which has not previously been reported.

Finger DR, Klipple GL.  Gynecomastia following low dose methotrexate therapy for rheumatoid arthritis.J Rheumatol. 1995 Apr;22(4):796-7. No abstract available.PMID: 7791195 [PubMed - indexed for MEDLINE]

Grisold W, Lutz D, Wolf D. Necrotizing myelopathy associated with acute lymphoblastic leukemia. Case report and review of literature. Acta Neuropathol (Berl). 1980;49(3):231-5. PMID: 6929156 [PubMed - indexed for MEDLINE]
The clinico-pathological findings are reported of a 16-year-old boy with acute lymphoblastic leukemia who during chemotherapy which included intrathecal Methotrexate developed a transverse cord lesion 5 months before death. Autopsy revealed necrotizing myelopathy of the T8--T10 segments and moderate lymphoblastic infiltration of the cerebrospinal meninges and spinal nerve roots. Neither parenchymal infiltration nor vascular lesions were found. The pathogenesis of this rare lesion associated with acute lymphoblastic leukemia remains obscure.

Grardel B, Fauquert P, Hardouin P. Malignancy in patients with rheumatoid arthritis treated with methotrexate.J Rheumatol. 1997 Apr;24(4):805-6; discussion 806-7. No abstract available.PMID: 9101525 [PubMed - indexed for MEDLINE]

Iqbal MP, Ali AA, Alvi AA [corrected to Ali AA].  Severe bone marrow suppression in a patient with rheumatoid arthritis on methotrexate.J Pak Med Assoc. 1993 Dec;43(12):262-3. No abstract available.PMID: 8133640 [PubMed - indexed for MEDLINE]

Ilhan I, Cila A, Buyukpamukcu M, Akyuz C, Kutluk T, Berberoglu S. Methotrexate-induced leukoencephalopathy. A case report. Turk J Pediatr. 1995 Jul-Sep;37(3):275-8.PMID: 7502368 [PubMed - indexed for MEDLINE]
A six-year-old girl with non-Hodgkin's lymphoma who was treated with both intravenous (IV) and intrathecal (IT) methotrexate and developed brain damage secondary to the cytostatic drug is described. This patient displayed hypertension, hypothermia/hyperthermia, lethargy, deterioration and coma as clinical findings, and bilateral, focal white matter hyperintensities in the occipital lobes were seen in her magnetic resonance imaging (MRI). Treatment-related leukoencephalopathy is one such adverse effect of IT methotrexate administration on the central nervous system and usually appears in a generalized form.

Kolte B, Baer AN, Sait SN, O'Loughlin KL, Stewart CC, Barcos M, Wetzler M, Baer MR.   Acute myeloid leukemia in the setting of low dose weekly methotrexate therapy for rheumatoid arthritis.Leuk Lymphoma. 2001 Jul;42(3):371-8.PMID: 11699401 [PubMed - indexed for MEDLINE]

Methotrexate is in widespread use as second-line therapy for rheumatoid arthritis. Treatment with methotrexate in this and other settings has not been associated with the development of therapy-related leukemias. Four patients with rheumatoid arthritis are reported who developed acute myeloid leukemia (AML) while receiving low dose weekly methotrexate therapy in the absence of previous or concomitant treatment with known leukemogenic agents. AML in these four patients was of different morphologic subtypes and was associated with heterogeneous cytogenetic abnormalities, cell surface marker expression and multidrug resistance protein expression. None of the recognized features of therapy-related leukemia were present in these four nor in five previously-reported patients. It is likely that the occurrence of AML in patients with rheumatoid arthritis in the setting of methotrexate therapy represents the coincidence of these two diseases, and does not reflect a causal relationship.

Kevat SG, Hill WR, McCarthy PJ, Ahern MJ.  Pancytopenia induced by low-dose methotrexate for rheumatoid arthritis.Aust N Z J Med. 1988 Aug;18(5):697-700.PMID: 3245825 [PubMed - indexed for MEDLINE]

Lovblad K, Kelkar P, Ozdoba C, Ramelli G, Remonda L, Schroth G. Pure methotrexate encephalopathy presenting with seizures: CT and MRI features.Pediatr Radiol. 1998 Feb;28(2):86-91.PMID: 9472050 [PubMed - indexed for MEDLINE]

With the advent of chemotherapy, mortality rates in acute lymphoblastic leukaemia (ALL) have decreased, but complications in the central nervous system have appeared. These include direct involvement of the brain itself and the development of chemotherapy-related encephalopathy as a delayed reaction. In most reported cases, this encephalopathy is believed to be due to necrotising angiitis arising from the combination of chemotherapy with adjuvant radiotherapy. We report the cases of four children with ALL who had been treated with high-dose intravenous and intrathecal chemotherapy but no radiation therapy, and who were admitted to hospital because of seizures. CT of the brain revealed the presence of diffuse periventricular white matter hypodensities in all cases and subcortical hyperdense foci in three cases. MRI showed diffuse hyperintense white matter lesions on T2-weighted images in all four patients; hypointense changes were observed on susceptibility-sensitive FLASH sequences in the hyperdense foci seen on CT as well as changes that were hyperintense on T1-weighted images. It was, therefore, concluded that the lesions corresponded to a leukoencephalopathy with calcific deposits. These findings are of a pure form of methotrexate encephalopathy causing seizures.

Laroche F, Perrot S, Menkes CJ.Pancytopenia in rheumatoid arthritis patients receiving methotrexate.Rev Rhum Engl Ed. 1996 May;63(5):381-2. No abstract available.PMID: 8789889 [PubMed - indexed for MEDLINE]

Marce S, Bannwarth B, Schaeverbeke T, Dehais J.[Neutropenia after the first administration of methotrexate in rheumatoid arthritis]Rev Rhum Ed Fr. 1993 Nov 30;60(11):843-4. French. No abstract available.PMID: 8054935 [PubMed - indexed for MEDLINE]

Mueller S, Bell W, Seibert J.Cerebral calcifications associated with intrathecal methotrexate therapy in acute lymphocytic leukemia.J Pediatr. 1976 Apr;88(4 Pt. 1):650-3. No abstract available.PMID: 1062546 [PubMed - indexed for MEDLINE]

Omdal R, Goransson L, Bergrem H.Fatal outcome of low-dose methotrexate therapy in rheumatoid arthritis.Clin Rheumatol. 1993 Jun;12(2):283-4. No abstract available.PMID: 8358998 [PubMed - indexed for MEDLINE]

Pointud P, Prudat M, Peron JM.Acute leukemia after low dose methotrexate therapy in a patient with rheumatoid arthritis.J Rheumatol. 1993 Jul;20(7):1215-6.PMID: 8371222 [PubMed - indexed for MEDLINE]

An 83-year-old woman with seropositive rheumatoid arthritis (RA) developed acute myeloid leukemia after receiving weekly methotrexate (MTX) for 33 months (total dose 690 mg). Although cytogenetic abnormalities typical of damage by cytotoxic agents were not documented, our case may be the first report of acute myeloid leukemia in RA with MTX. We estimate that 6 similar cases should have been observed in France by chance alone. The absence of other reports suggests either that MTX possesses a paradoxical protective effect or that it is not considered a risk factor for malignancy by rheumatologists. Since the number of patients with RA taking MTX can be estimated with reasonable accuracy, the reporting of all suspected cases could help to assess the safety of the drug in rheumatology.

Reznik M. Acute ascending poliomyelomalacia after treatment of acute lymphocytic leukemia.Acta Neuropathol (Berl). 1979 Feb 15;45(2):153-7.PMID: 283679 [PubMed - indexed for MEDLINE]

This paper reports the case of a 16-year-old girl with acute lymphoblastic leukemia who received chemotherapy including intrathecal injections of methotrexate and preventive irradiation of the brain, but not of the spinal cord. Several months later, she died from an acute ascending poliomyelitic syndrome evolving during 10 days. Clinical, bacteriological, and viral investigations failed to demonstrate any pathological agent. Autopsy revealed an acute ischemic lesion involving both anterior horns of the whole spinal cord and extending from the lower segment up to the mesencephalic region, without significant alteration of the white matter. Neither tumoral invasion, nor vascular obstruction was found. The pathogenesis of this yet undescribed lesion remained unclear but a metabolic disorder seemed the most plausible pathological factor.

Stewart M, Malkovska V, Krishnan J, Lessin L, Barth W.  Lymphoma in a patient with rheumatoid arthritis receiving methotrexate treatment: successful treatment with rituximab.Ann Rheum Dis. 2001 Sep;60(9):892-3.

Stone JA, Castillo M, Mukherji SK. Leukoencephalopathy complicating an Ommaya reservoir and chemotherapy.Neuroradiology. 1999 Feb;41(2):134-6. PMID: 10090607 [PubMed - indexed for MEDLINE]
We describe the imaging findings in an unusual case of biopsy-proven, methotrexate-induced leukoencephalopathy complicating a malfunctioning Ommaya reservoir in a patient with lymphoma.

Sukenik S, Ariad S, Flusser D.  Malignancy in patients with rheumatoid arthritis treated with methotrexate.J Rheumatol. 1997 Apr;24(4):806; discussion 806-7. No abstract available.PMID: 9101526 [PubMed - indexed for MEDLINE]

Thomas E, Leroux JL, Blotman F.Gynecomastia in patients with rheumatoid arthritis treated with methotrexate.J Rheumatol. 1994 Sep;21(9):1777-8. No abstract available.PMID: 7799373 [PubMed - indexed for MEDLINE]