One study estimated that 20,000 hospitalisations and 2,600 deaths each year could be linked to a group of nonsteroidal anti-inflammatory drugs (NSAIDs) in rheumatoid patients. According to the FDA, "200,000 cases of gastrointestinal bleeding, with 10,000 to 20,000 deaths, occur each year due to the 68 million prescriptions of NSAIDs, used for arthritis.

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]

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.

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]

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]

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]

Jarolim DR, Katz AL.  Arthritis after chemotherapy.J Rheumatol. 1980 May-Jun;7(3):426-8. No abstract available.PMID: 7401080 [PubMed - indexed for MEDLINE]

PURPOSE: This report describes a previously unreported clinical phenomenon that occurs in some patients after completion of combination chemotherapy. METHODS AND RESULTS: Eight case reports are presented. Affected patients developed a syndrome of myalgias/arthralgias within several months of completing cyclophosphamide/fluorouracil (5FU)-containing adjuvant combination chemotherapy for breast cancer. These symptoms did not appear to be related to cancer recurrence or any common rheumatologic disorder. The syndrome generally resolved over several months. CONCLUSION: Postchemotherapy rheumatism is a syndrome of myalgias/arthralgias that usually develops 1 to 3 months after completion of adjuvant chemotherapy. Recognition of this syndrome can limit the need for extensive work-ups to exclude recurrent breast cancer or inflammatory rheumatologic diseases.

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]

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]

Loprinzi CL, Duffy J, Ingle JN. Postchemotherapy rheumatism.J Clin Oncol. 1993 Apr;11(4):768-70.PMID: 8478669 [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]

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.

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.

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]