Rheumatology Advance Access originally published online on December 13, 2005
Rheumatology 2006 45(3):363-364; doi:10.1093/rheumatology/kei202
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LETTER TO THE EDITOR |
Methotrexate-induced pancytopenia: serious and under reported? Our experience of 25 cases in 5 years: reply
Norfolk and Norwich University Hospital, Rheumatology Department, Norwich, UK
Correspondence to: A. Y. N. Lim. E-mail: anita_lim{at}nuh.com.sg
SIR, We are grateful to Dr Yazici, Dr Sathi et al. and Dr Marshall et al. for their comments regarding our experience of 25 cases of methotrexate (MTX)-induced pancytopenia in 5 years between 1999 and 2004 [1]. MTX is a relatively safe disease-modifying antirheumatic drug (DMARD); indeed it is the most widely prescribed DMARD in our centre, hence our concerns when we noted increasing hospital admissions due to MTX-induced pancytopenia.
We disagree with Dr Yazici that the adverse effect profile of MTX has changed despite great changes in its use and timing over the last 20 yr. More patients are being given folic acid, which undoubtedly has led to better tolerance in terms of reducing nausea, abdominal pain, mouth ulcers and deranged liver function tests. Buchbinder et al. [2] described a trend towards a learning curve, with reduced withdrawal of MTX with increasing experience in the use of MTX for each rheumatologist. Gutierrez-Urena et al. [3] report pancytopenia secondary to MTX in 70 patients, based on a literature search conducted to identify articles published during 1980–1995 presenting data on MTX-associated pancytopenia and two case reports from their experience. Of the five long-term prospective studies they analysed, 7 of 511 patients exposed to MTX developed pancytopenia (1.4%), suggesting that this is not an uncommon side-effect, with a frequency of 0.0007% (7/100 000) patients per year. In most cases, pancytopenia was transient, recovery occurring upon discontinuation of MTX and treatment of the disorder. In the study by Wluka et al. [4], 2.8% of patients (13/460) exposed to MTX discontinued MTX permanently because of pancytopenia and three of these patients died (23.1%). Five cases of pancytopenia occurred after 8 yr of MTX therapy despite folic acid supplementation in three patients. Wluka et al. also stress the need for monitoring for toxicity throughout the course of therapy as the risk of adverse effects persists even late in the course of treatment.
Dr Yazici suggests that the main reason for the cases of pancytopenia in our cohort may be the increased age and/or the multiple medications they were on concurrently. We have highlighted these and other risk factors, such as renal insufficiency, pre-existing folate deficiency, hypoalbuminaemia, pre-existing infection, possible drug interactions and dosing errors, which probably acted in concert, culminating in this potentially fatal complication. The concomitant administration of other drugs may influence the activity and toxicity of MTX. Interactions include those related to the pharmacokinetics of the drug(s) as well as those at the cellular level. Excretion of MTX is inhibited by weak organic acids, such as aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), piperacillin, penicillin G and probenicid [5]. Other drugs that have been implicated in the risk of MTX toxicity include acitretin, ciclosporin, chloramphenicol, ciprofloxacin, corticosteroids, doxycycline, nitrous oxide, omeprazole, phenytoin, pyrimethamine, co-trimoxazole, sulphonamides, tetracycline, trimethoprim, ranitidine and clozapine [6].
We described eight patients with renal impairment (Patients 1, 9, 11, 13, 18, 19, 20 and 23). Patient 8 was on long-term oxytetracycline and fucidic acid for an in situ infected hip prosthesis. Patient 13 was on Septrin as part of his treatment for Wegener's granulomatosis. Patient 23 had taken a 5-day course of cephradine for a presumed urinary tract infection and had been commenced on amoxicillin in the community on the day she was hospitalized. Blood cultures yielded Escherichia coli but the cause of death was a colonic haemorrhage. None of the other patients had been empirically treated with antibiotics prior to hospitalization. Patients who were hospitalized and who were clinically septic were commenced on intravenous antibiotics with intravenous folinic acid rescue. Antibiotic use varied depending on where the suspected source of infection was. Patient 15, who recovered, was the sole patient treated with intravenous benzylpenicillin and flucloxacillin for cellulitis. The other patients received an intravenous cephalosporin and gentamicin.
Although MTX-induced pancytopenia is uncommon, it is serious. Pancytopenia in the setting of concurrent sepsis has a high mortality; 5 of our 10 patients with sepsis died. We would caution that patients with an intercurrent infection should stop MTX.
We emphasize the need for continued blood monitoring even when a patient has been well on a stable drug dose for many months as bone marrow toxicity is a late complication of treatment. Two of our patients had previously developed pancytopenia with MTX, which recurred despite folic acid supplementation. We do not advocate restricting the use of MTX, which is well tolerated and more likely to be continued long-term than other DMARDs [7]. However, we recommend vigilance for potential risk factors when commencing and continuing a patient on MTX. Clinicians in real-life practice stop MTX depending on blood monitoring, and pancytopenia, which does not lead to a fatal outcome, is likely to be under-reported.
The authors have declared no conflicts of interest.
References
- Lim AYN, Gaffney K, Scott DGI. Methotrexate-induced pancytopenia: serious and under-reported? Our experience of 25 cases in 5 years. Rheumatology 2005;44:1051–5.
[Abstract/Free Full Text] - Buchbinder R, Hall S, Sambrook PN et al. Methotrexate therapy in rheumatoid arthritis: a life table review of 587 patients treated in community practice. J Rheumatol 1993;20:639–44.[Medline]
- Gutierrez-Urena S, Molina JF, Garcia CO et al. Pancytopenia secondary to methotrexate therapy in rheumatoid arthritis. Arthritis Rheum 1996;39:272–6.[Medline]
- Wluka A, Buchbinder R, Mylvaganam A et al. Longterm methotrexate use in rheumatoid arthritis: 12 year follow up of 460 patients treated in community practice. J Rheumatol 2000;27: 1864–71.[Medline]
- Chu E, Allegra C. Antifolates. In: Chabner BA, Longo DL, eds. Cancer chemotherapy and biotherapy. 2nd edn. Philadelphia: Lippincot-Raven, 1996:109–47.
- British National Formulary. Available at: www.bnf.org.
- Grove ML, Hassell AB et al. Adverse reactions to disease-modifying anti-rheumatic drugs in clinical practice. Q J Med 2001;94:309–19.
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