RESEARCH - Methotrexate-induced pancytopenia more common than expected

[Guest guest]

Methotrexate-induced pancytopenia more common than expected

Rheumawire

Jul 29, 2005

Zosia Chustecka

Norwich, UK - The risk of pancytopenia with methotrexate may be higher than

has been assumed until now, a group of UK researchers write in the July

issue of Rheumatology [1]. " The importance of routine blood monitoring

cannot be emphasized enough, " they comment. " Methotrexate needs to be

monitored in the long term, even when the patient has been on a stable dose

for many months. "

Dr Anita Lim and colleagues at the Norfolk and Norwich University Hospital,

UK, report on their experience with 25 cases in 5 yearsthe largest reported

individual case series, they note. Pancytopenia affects all three blood cell

lines, and was defined in the study as a white blood cell count <3.5x109/L,

hemoglobin <11 g/dL, and platelet count <130x109/L. Lim, who is currently at

the Singapore National University Hospital, tells rheumawire that the main

message from their findings is: " Be vigilant for this late but potentially

fatal complication. "

" Blood monitoring should be continued indefinitely for the duration of

treatment, because hematological toxicity can occur even after many months

or years, as we discovered in our cohort, " Lim says. In their series, the

mean duration of treatment when pancytopenia was discovered was 36 months,

but three severe cases were identified after 84, 87, and 96 months of

treatment, and three less-severe cases were discovered after 78, 93, and 120

months of treatment. Of the 25 patients with this side effect, seven died

(28% mortality)five from sepsis and two from acute myeloid leukemia. " There

is no place for complacency, and one cannot say a patient has been on

methotrexate for many years and has never had any problems, therefore blood

monitoring can be discontinued, " Lim comments.

Six of the cases were identified in patients who had not been undergoing

regular blood monitoring; all six were in residential or nursing homes, the

authors note. Another nine cases were identified by routine blood

monitoring, as recommended by the British Rheumatology Society guidelines.

(These advocate fortnightly full blood count [FBC] and liver-function test

for the first six weeks and after each dose increment, and then suggest that

once the dose is stabilized, FBC be carried out monthly.)

On presentation, one patient had an acute coronary syndrome secondary to

anemia, seven had bleeding, nine had concomitant sepsis, and ten had oral

mucositis. Nearly half (12 patients) were taking folic- or folinic-acid

supplements. The authors comment that although folic-acid supplementation

has been shown to reduce liver toxicity, as well as mucosal and

gastrointestinal side effects, there have been no studies showing that it

has an unequivocal protective effect on hematological toxicity, and they

suggest that these specific tissues may have a distinctive susceptibility.

Nevertheless, they suggest that folic-acid supplementation, 5 mg weekly,

should be considered in all patients taking methotrexate.

Lim tells rheumawire that potential risk factors include renal impairment;

age over 75 years; low serum albumin (particularly <28 g/dL); pre-existing

folate deficiency and poor nutritional status; polypharmacy, with its risk

of drug interactions; and dosing errors, especially in view of its

once-weekly dosing. She adds: " Sepsis is a major cause of death,

particularly when pancytopenia is profound/severe; patients on methotrexate

who develop infections should stop the drug. "

The researchers were prompted to conduct their retrospective review after

they noticed increasing hospital admissions for methotrexate-related

pancytopenia at their hospital. They found records on 25 patients admitted

between 1999 and 2004. The catchment population served by the hospital is

550 000 people.

To estimate the prevalence of this side effect, Lim et al used data from the

Norfolk Arthritis Register, which puts the prevalence of rheumatoid

arthritis (RA) at 0.8%, and records that between 1999 and 2004, about 25% of

patients with RA received methotrexate. (They note, however, that

methotrexate is also used for other inflammatory conditions. In their series

of 25 patients, 19 had RA; the others were taking methotrexate for RA with

lupus [1 patient], Wegener's granulomatosis [3 patients], psoriatic

arthritis [1 patient], and giant cell arteritis [1 patient].)

From these figures, Lim et al estimate the prevalence of

methotrexate-induced pancytopenia in their cohort to be approximately 1.9%.

The authors note that a previous report [2] estimated the prevalence of all

hematological toxicities at 3% in methotrexate-treated RA patients. However,

in addition to pancytopenia, this study included leucopenia,

thrombocytopenia, and megaloblastic anemia. " This suggests that pancytopenia

caused by methotrexate is underestimated, as we more commonly see

leucopenia, thrombocytopenia, etc, on their own, " Lim explains.

" In our experience, methotrexate-induced pancytopenia is more common than

expected, and is probably underreported, " the researchers conclude.

Sources

1. Lim AY, Gaffney K, DG. Methotrexate-induced

pancytopenia: Serious and under-reported? Our experience of 25 cases in 5

years. Rheumatology 2005; 44:1051-1055.

2. Weinblatt ME. Toxicity of low dose methotrexate in

rheumatoid arthritis. J Rheumatol 1985; Suppl 12:35-39.

Not an MD

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org