Low dose methotrexate and bone marrow suppression
BMJ 2003; 326 doi: https://doi.org/10.1136/bmj.326.7383.266 (Published 01 February 2003) Cite this as: BMJ 2003;326:266
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With regard to the potential MTX / omeprazole interaction mentioned
in Sosin's paper and subsequently by Anne Stillman in the Rapid Responses.
Stockleys Drug interactions (6ed, 2002) lists three cases where an
interaction between Methotrexate (MTX) and omeprazole was suspected,
although in the third case it was later disproven.
All of the patients involved were MTX for osteosarcoma. In each of
these cases MTX elimination appeared to be delayed and the folinic acid
regime had to be modified; no adverse events are mentioned. Stockleys
concludes that the interaction is not proven, as in the third case
discontinuing omeprazole made no difference to MTX excretion. The dose of
MTX employed ranged from 15 to 20 grams, i.e. fully 1000 times higher than
the doses used in Rheumatological practice (typically between 10 and 20
milligrams weekly).
Whether there would be any discernable interaction at a methotrexate
dose 1000 times lower still seems very dubious.
Competing interests:
None declared
Competing interests: No competing interests
EDITOR – We read with interest Sosin and Handa’s paper[1] on the
association between low dose methotrexate (MTX) and bone marrow
suppression. Whilst this paper highlights this association, it has also
provoked much unnecessary anxiety among GPs and patients. We seek to
address this. MTX is the single most commonly used disease modifying drug
in the treatment of rheumatoid arthritis (RA) in the Western world. The
incidence of bone marrow suppression with MTX is low (2-4%)[2] and is
reduced by co-administrating folic acid[3]. None of the patients in
Sosin’s paper were on folic acid. Furthermore, there was discrepancy in
the MTX dosing regimen in Sosin’s second case. In our experience, this
confusion is exacerbated by the two strengths of the MTX tablets (2.5 mg
and 10mg) having the same colour. This has now been rectified with 10mg
tablets being oval shaped and the 2.5mg tablets circular. A list of drugs
with potential adverse interactions with MTX was produced in Sosin’s
paper; of interest in RA are corticosteroids and NSAIDs.
Many RA patients
frequently require these drugs in conjunction with MTX. NSAID may
theoretically increase serum MTX levels by displacement of MTX from
protein binding sites or by reduction in renal excretion of MTX. However,
in the presence of normal renal function, this is of little clinical
relevance[4]. Corticosteroids have not been shown to influence the
pharmacokinetics of MTX and its main metabolite[4]. As for Sosin’s third
case, we wish to note that the risk of bone marrow suppression is higher
with administration of co-trimoxazole and MTX compared to trimethoprim and
MTX. In the event of MTX toxicity, the folinic acid rescue is often given.
The use of a novel MTX antidote, carboxypeptidase-G2 [5], which rapidly
metabolizes MTX in this context, awaits further evaluation.
MTX remains a safe and effective drug in RA. Removing the unintended
anxiety it generated, Sosin’s paper does remind us of the importance of
careful follow up of RA patients on MTX.
Antoni Chan
Specialist Registrar
antonichan@hotmail.com
Joel David
Consultant Rheumatologist
Department of Rheumatology,
Nuffield Orthopaedic Centre,
Windmill Road,
Headington
Oxford OX3 7LD
1. Sosin M, Handa S. Low dose methotrexate and bone marrow
suppression. BMJ 2003; 236:266-7.
2. Furst DE, Kremer JM. Methotrexate in rheumatoid arthritis. Arthritis
and Rheumatism 1988;31(3):305-14.
3. Griffith SM, Fisher J, Clarke S, Montgomery B, Jones PW, Saklatvala J
et al. Do patients with rheumatoid arthritis established on methotrexate
and folic acid 5 mg daily need to continue on folic acid supplements long
term? Rheumatology 2003;39:1102-9.
4. Bannwarth B, Pehourcq F, Schaeverbeke T, Dehais J. Clinical
pharmacokinetics of low dose pulse methotrexate in rheumatoid arthritis.
Clin Pharmacokinet 1996;30(3):194-210.
5. Krause AS, Weihrauch MR, Bode U, Fleishhack G, Elter T et al.
Carboxypeptidase- G2 rescue in cancer patients with delayed methotrexate
elimination after high dose methotrexate therapy. Leuk Lymphoma 2002;
43(11):2139-43.
Competing interests:
None declared
Competing interests: No competing interests
I am taking the liberty of responding as a RA patient, disease
duration 25 years and onset at age 13.
Confusion over dosage was very easy with the 2.5mg and 10mg
Methotrexate tablets looking nearly identical. Keen eyesight was required
to read the dosage on each tablet. I was once issued via the chemist 10mg
tablets labelled as 2.5mg so errors easily occurred. This should now be
avoided as the 10mg are now oval, easier for us to identify the
difference.
I take Meloxicam 15mg pday and Lansaprazole 30mg pday and your
article suggests this increases the risk of bone marrow suppression when
taken along-side Methotrexate. However I understand this is relatively the
norm for treating RA. I also take Co-proxamole and Folic Acid, the latter
helps reduce the nausea. I personally accept the risks involved as with
living day to day with RA any relief from its effects are welcomed. Good
information and knowledge helps me cope with RA and ensures I do my part
with regular bloodtests and recognition of warning signs.
Anne Stillman
Poole Dorset
Competing interests:
None declared
Competing interests: No competing interests
Sir-
I read with interest the Lesson of the week by Sosin and Handa on
Methotrexate (MTX) toxicity. Two points arise.
Firstly, bone marrow toxicity with MTX is not an early complication
of therapy. Only one of the cases (Case 2) mentioned by Sunil and Handa
had been on treatment for less than twelve months, and the authors suspect
he had been taking his therapy on a daily basis rather than weekly as
would have been recommended. This is consistent with what we showed in our
observational study (1), where the median delay to neutropenia with
methotrexate was 16.9 months, in contrast to other Disease-Modifying Anti-
Rheumatic Drugs (DMARDs) such as sulphasalazine (SAS) where the median
delay to neutropenia was 2.1 months. This has important implications for
monitoring protocols: however effective or ineffective monitoring is felt
to be, current guidelines specify more frequent monitoring early in
therapy. Whereas with some drugs, like SAS, toxicity may reflect
hypersensitivity, with MTX accumulation seems to fit the profile better.
This is consistent with what is known of its pharmacokinetics (2).
Secondly, there is a further potential source of serious drug errors
with MTX other than the weekly dosing regime. The drug comes in two tablet
sizes: 2.5mg and 10mg, which appear identical in colour, size and shape.
The 2.5mg tablet is used by preference in secondary care, as it allows
ready titration of the dose in small increments. However, patients may be
dispensed the 10mg tablet in the community if they are taking 10mg or 20mg
weekly. Unless the change in tablet dose is highlighted, they are at risk
of a fourfold overdose (e.g. a patient on 10mg weekly as 4 x2.5 mg
tablets, then dispensed a single 10mg tablet, may take 4 x10mg for 40mg
weekly). This is partially a patient education matter - we regularly
emphasise the importance of checking the tablet dose to our patients - and
partially a matter for the manufacturers and the NPSA. I understand from
the NPSA that the 10mg tablet is soon to change shape, but whilst stocks
of the old shape remain in circulation the potential for this error
remains.
Yours Sincerely
Matthew L. Grove.
(1) Grove ML, Hassell AB, Hay EM, Shadforth MF. Adverse reactions to
disease-modifying anti-rheumatic drugs in clinical practice. Q J Med 2001;
94: 309-319.
(2) Mofredj A, BMJ Rapid responses. Low dose methotrexate and bone
marrow suppression. http://bmj.com/cgi/eletters/326/7383/266
Competing interests:
None declared
Competing interests: No competing interests
In their "Lesson of the week" Sosin and Handa reported about bone
marrow suppression caused by treatment with methotrexate at low dosage in
rheumatoid arthritis. None of the reported patients took folate
supplementation (1).
Methotrexate is considered to have the best efficacy:toxicity ratio among
other, more expensive disease-modifying-antirheumatic-drugs, such as
azathioprine and cyclosporine or tumor necrosis factor alpha-antagonists
such as etanercept and infliximab. Recently it has been shown to enhance
the life expectancy of patients with rheumatoid arthritis (2). The
interindividual variability in the extent of oral absorption is marked,
ranging from 28-88%. Methotrexate is excreted mainly by the kidneys as
intact drug. Elimination may deteriorate as soon after six months of
treatment, methotrexate itself may affect the glomerular filtration rate
and tubular secretion (3). So especially in older patients, the dosage of
methotrexate should be stepped up carefully under frequent monitoring.
Sosin and Handa said that folate supplementation should be considered for
reducing the side effects of methotrexate without inhibiting efficacy.
What are the data supporting that advice? And which folate should be used:
folic acid or folinic acid ?
Under methotrexate medicaton red cell folate level decreases. Plasma
homocystein concentrations and side effects such as nausea, dyspepsia,
liver enzyme elevation, cytopenia, and drug withdrawal increase
concomitantly (4). Hyperhomocysteinemia has been implicated as an
independent risk factor for cardiovascular disease. The high mortality of
patients with rheumatoid arthritis is caused mainly by cardiovascular
events (2).
Open, prospective and randomised, controlled studies have consistently
shown that supplementation with folic or folinic acid can reduce side
effects such as liver enzyme elevations, gastrointestinal complaints and
withdrawal rate significantly (5,6). As others, van Ede et al showed in a
double blind, placebo controlled study that both folic and folinic acid
supplementation decreases plasma homocysteine concentrations in patients
taking low-dose methotrexate(4). In one recently published controlled
study the need for slightly higher methotrexate dosages for delivering the
same anti-inflammatory response was shown in patients taking folic acid
supplementation (6).
Folinic acid is more expensive than folic acid, it can bypass the effect
of methotrexate on dihydrofolate reductase and replete the intracellular
supply of reduced folate. As in Sosin and Handa’s patients it has been
used for "rescue medication" in methotrexate overdose or severe side
effects in rheumatology and oncology. The dosage in relation to the
methotrexate dosage regimens seem to be critical in terms of inhibiting
the efficacy of methotrexate (5).
A Cochrane review found a significant reduction of 79% and a non-
significant reduction of 42% of oral and gastrointestinal side effects for
supplementation with folic acid and folinic acid. Haematological side
effects could not analysed, owing to the scanty data (5). Folic acid
dosages of 5-27.5 mg per week seemed to be equipotent for this result,
without disturbing efficacy of methotrexate (5).
In conclusion, it seems to be strongly advisable to consider
supplementation with the inexpensive folic acid in every patient taking
low dose methotrexate. It prevents side effects of methotrexate
statistically and clinically significant. It reduces drug withdrawal and
methotrexate induced hyperhomocysteinemia. Subsequently it may reduce the
need for more expensive disease modifying antirheumatic drugs and may
protect against the high cardiovascular mortalitiy of patients with
rheumatoid arthritis.
1. Sosin M, Handa S. Lesson of the week. Low dose methotrexate and
bone marrow suppression. BMJ 2003;326:266-7.
2. Choi HK, Hernan MA, Seeger JD, Robins JM, Wolfe F. Methotrexate
and mortality in patients with rheumatoid arthritis: a prospective study.
Lancet 2002;359:1173-7.
3. Bannwarth B, Pehourcq F, Schaeverbeke T, Dehais J. Clinical
pharmacokinetics of low-dose pulse methotrexate in rheumatoid arthritis.
Clin Pharmacokinetics 1996;30:194-210.
4. Van Ede AE, Laan RF, Blom HJ, Boers GH, Haagsma CJ, Thomas CM et
al. Homocysteine and folate status in methotrexate-treated patients with
rheumatoid arthritis. Rheumatology (Oxford) 2002;41:658-65
5. Ortiz Z, Shea B, Suarez Almazor M, Moher D, Wells G, Tugwell P.
Folic acid and folinic acid for reducing side effects in patients
receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst
Rev 2000;2: CD000951.
6. Van Ede, AE, Laan RF, Rood MJ, Huizinga TWJ, van de Laar MA, van
Denderen CJ et al. Effect of folic or folinic acid supplementation on the
toxicity and efficacy of methotrexate in rheumatoid arthritis. Arthritis
Rheum 2001; 7:1515-24.
Competing interests:
None declared
Competing interests: No competing interests
Sir,
We have been interested in the paper by Sosin and Handa on bone marrow
suppression associated with low-dose methotrexate (MTX) therapy1. We would
like to comment on the circumstances under which this complication may
appear.
Due to its efficacy, low-dose MTX therapy has now gained wide acceptance
for its use early in the course of rheumathoïd arthritis2. However, up to
60 % of patients who receive MTX discontinue it because of adverse effects
most of which occur during the first year of therapy3. Gastrointestinal
complications are the most common adverse effects, but hepatotoxicity,
pulmonary toxicity, cutaneo-mucous toxicity, and haematologic toxicity
have been reported2, 3. Pancytopenia occurs in only 1.4% to 1.7% of
patients treated with MTX 2, 4. Although MTX toxicity may occur in the
absence of identifiable risk factors, several conditions favoring this
toxicity have been recognized2.
MTX is eliminated almost entirely by the kidneys. The risk of MTX toxicity
is therefore increased in patients with poor renal function, even
transient, due to a drug accumulation2, 3. Concomitant use of inhibitors
of renal tubular secretion may contribute to the accumulation of MTX, and
has been recognized as a risk factor for MTX toxicity3, 4. Other drugs
such as antibiotics, inhibitors of folate utilization and ranitidine have
also been reported as possible risk factors of MTX toxicity 2-4. Moreover,
concomitant medication with more than 5 drugs seems to be a major risk
factor for the appearance of pancytopenia during MTX therapy 5.
Hypoalbuminemia, folate deficiency and infections have also been reported
as possible risk factors of MTX therapy2.
Most of these conditions, especially impaired renal function due to the
age, hypoalbuminemia, folate deficiency, and medication with multiple
drugs are regularly encountered in older patients. In addition, the age
over 60 years has been specifically reported as a risk factor for the
development of pancytopenia during MTX therapy 2, 4. Interestingly, the 3
patients reported by Sosin and Handa are all over 65 years old1.
Additional information on the further case described in the table would be
more conclusive. Indeed, we could not eliminate a dosage error in this
patient. Aging may thus be the most important factor for the appearance
of pancytopenia in the first 3 patients1. Clinicians should be aware of
such a risk and thus prescribe with caution these medications in older
patients.
References
1- Sosin M, Handa S. Low dose methotrexate and bone marrow
suppression. Brit Med J 2003; 326: 266-7
2- Calvo-Romero JM. Severe pancytopenia associated with methotrexate
therapy for
Rheumatoid Arthritis. Ann Pharmacother 2001 ; 35 : 1575-7
3- Tett SE, Triggs EJ. Use of methotrexate in older patients. A risk
benefit assesment. Drugs Aging 1996; 9: 458-71
4- Laroche F, Perrot S, Menkes CJ. Pancytopenia in rheumatoid arthritis
treated with methotrexate. Presse Med 1996; 25: 1144-6
5- Gutierrez-Urena S, Molina JF, Garcia CO, Cuellar ML, Espinoza I.
Pancytopenia secondary to methotrexate therapy in rheumatoid arthritis.
Arthritis Rheum 1996; 39: 272-6
Competing interests:
None declared
Competing interests: No competing interests
The question of folic acid supplementation in patients receiving
methotrexate is complex. Rheumatological practice in Europe and USA seems
variable, with folic acid either not being used, or given at doses ranging
from 1 mg daily to 5 mg weekly or daily. Dermatologists are similarly
variable in their approach.1 The authors of the lesson of the week state
that folic acid supplementation has not been shown to reduce the efficacy
of methotrexate. Whilst this may be true, the studies investigating
this2,3 have been relatively small and of insufficient power.4 Of
interest is a study where patients with rheumatoid arthritis treated with
methotrexate were randomised to receive either placebo, folic acid (1
mg/day), or folinic acid (2.5 mg/week).5 The mean final dose of
methotrexate required for disease control was significantly higher in the
folic acid group (18.0 mg) and folinic acid group (16.4 mg), than in those
receiving placebo (14.5 mg). Thus whilst folic acid supplementation may
reduce some of the side effects of methotrexate (such as nausea, abnormal
liver enzymes), does it do this by reducing the biologically active dose?
Our policy for patients with psoriasis treated with methotrexate is
not to use routine folic acid supplementation. In patients who develop
macrocytosis we check red cell folate concentration and, if this is low,
add folic acid. I would be interested to know if the patient reported in
the lesson of the week as case 1, who had a normal full blood count one
month before admission with pancytopenia, did in fact have a macrocytosis,
and whether the red cell folate had been measured.
1. Kirby B, Lyon CC, Griffiths CE, Chalmers RJ.. The use of folic
acid supplementation in psoriasis patients receiving methotrexate: a
survey in the United Kingdom. Clin Exp Dermatol 2000;25:265-8
2.Morgan SL, Baggott JE, Vaughn WH et al. Supplementation with folic acid
during methotrexate therapy for rheumatoid arthritis. A double-blind,
placebo-controlled trial. Ann Intern Med 1994;121:833-41.
3. Griffith SM, Fisher J, Clarke S et al. Do patients with rheumatoid
arthritis established on methotrexate and folic acid 5 mg daily need to
continue folic acid suipplements long term? Rheumatology 2000; 39:1102-9
4. Cooper, B.A. Folic acid and methotrexate in rheumatoid arthritis. Ann
Intern Med 1994;124:73
5. van Ede AE, Laan RM, Rood MJ et al. Effect of folic or folinic acid
supplementation on the toxicity and efficacy of methotrexate in rheumatoid
arthritis. Arthritis Rheum 2000;44:1515-24.
Competing interests:
None declared
Competing interests: No competing interests
I would be interested to hear from any parties who have encountered
major sepsis in patients who have been on a combination of methotrexate
and leflunomide (unlicensed) for rheumatoid arthritis. In my opinion the
sepsis may have been partly attributable to the combination. The extremely
long half-life of the metabolite of lefunomide makes it a potential
problem. Thus an accurate medication history is essential if accelereated
elimination with cholestyramine is to be considered.
Competing interests:
None declared
Competing interests: No competing interests
Re: Marrow suppression by Methotrexate - trying to eliminate drug errors
Re: Methotrexate and bone marrow suppression
Trying to eliminate drug errors
Dear Sir,
Following on from the lesson of the week by Sosin and Handa (1) on
methotrexate toxicity, I agree with the comment made by Clarke (2) that
methotrexate has attracted an undeserved reputation as a dangerous drug.
This is unfortunate and the adverse publicity is mainly due to factors
other than the drug itself. Much is known about the toxicity of
methotrexate but perhaps we could do more to increase patients awareness
of the dosing schedules used when this drug is prescribed. However, as
Grove (3) points out and Stillman (4) so graphically illustrates, the
tablets themselves are a potential source of error for some patients. The
two strengths, 2.5mg and 10mg, are almost identical in colour, size and
shape. Despite the fact that there will be a change in the shape of the
10mg tablet, I am not convinced that this will help to avoid future
errors. On a personal level, I wonder whether we ‘need’ 10mg tablets at
all and question whether their availability and use makes dose
administration needlessly complicated for some patients.
After a near miss with oral methotrexate several years ago, we
decided to use only the 2.5mg tablets for easier dose titration but mainly
for reasons of safety and continuity. The change was driven by a
Consultant Dermatologist and we decided that all our Dermatology
outpatients on oral Methotrexate would always get their drug from the
hospital pharmacy. The Consultant argued very forcefully that with the
drive by the Government to encourage generic prescribing and dispensing,
changes in tablet presentation, colour, etc. happen so frequently that
patients often ‘miss‘ the obvious warning signs when something is changed
or dispensed wrongly. He reasoned that for a drug such as Methotrexate
where the margin for error is practically non-existent, we needed to
ensure that the patient was trained adequately and that the supply and the
identity of the drug could be guaranteed. Therefore, we purchased only
branded, identifiable 2.5mg Methotrexate tablets and his patients in the
clinic knew what to expect and what they were going to get. This
initiative soon spread to patients in other clinics and so far we have had
no problems.
Within the last few months, we have again endorsed this decision
through our Drugs and Therapeutics Panel to restrict supplies of oral
methotrexate within the Trust to the 2.5mg strength only. This has
effectively withdrawn the 10mg strength from circulation after other near
misses with the two strengths that we had become aware of in the Region.
When discussing our initiative with colleagues from other Trusts, I
was recently asked whether patients and staff could eventually become
‘desensitised’ to the risks of oral Methotrexate. Given the growth in the
use of oral Methotrexate in other patient groups, it is possible that
Methotrexate could become ‘just another drug’. Patients, for instance,
expect to take their tablets every day and ‘weekly dosing’ is a relatively
infrequent occurrence for prescribed medicines so complacency can creep
in.
The pharmaceutical industry could, with better packaging, do much
more to help eliminate the hazard. But given the range of doses that we
give to our patients (from 2.5mg up to 22.5mg once weekly), it could prove
difficult to get a ‘standard pack’. Therefore, perhaps the best safeguard
for patients is better education and information to manage the risks posed
by this drug.
Michael F Hannon, principal pharmacist
Newcastle NHS Hospitals Trust, Royal Victoria Infirmary, Newcastle upon
Tyne NE1 4LP. mike.hannon@nuth.northy.nhs.uk
References
1. Sosin M, Handa S. Low dose methotrexate and bone marrow suppression BMJ
2003 ; 326: 266-7 (1 February.)
2. Clarke A K. Methotrexate and bone marrow suppression BMJ 2003 ; 326 :
1145 (24 May.)
3. Grove M L. Methotrexate and bone marrow suppression BMJ 2003 ; 326 :
1145 (24 May.)
4. Stillman A. RA patients comment BMJ 2003 : 326 : 266 (21 April.)
Competing interests:
None declared
Competing interests: No competing interests