Reversible bone marrow toxicity in a RA patient switched from Arava to Remicade

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Rheumatology 2003; 42: 193-194

© 2003 British Society for Rheumatology

Letters to the Editor

Life-threatening reversible bone marrow toxicity in a rheumatoid

arthritis patient switched from leflunomide to infliximab

A. Marchesoni, M. Arreghini, B. Panni, N. Battafarano and L. Uziel1

Rheumatology, G. Pini Orthopaedic Institute and

1 S. Paolo Hospital, Internal Medicine I, Milan, Italy

SIR, As a result of the introduction of new disease-modifying

anti-rheumatic drugs (DMARDs) for the treatment of rheumatoid arthritis

(RA), patients with refractory RA tend to be treated with an increasing

number of different DMARDs, alone or in combination. This improves the

chances of achieving good disease control but also risks triggering

adverse reactions.

We report the case of a 66-yr-old man with RA in whom treatment with

some recently marketed DMARDs was responsible for life-threatening bone

marrow toxicity. The patient's clinical history included RA (since

1992), type II diabetes, essential arterial hypertension, chronic urate

nephropathy and mild renal failure. No history of abnormal blood cell

count was given. In September 1996, he started RA treatment with

methotrexate (MTX) 10 mg once a week, folic acid 5 mg twice a week and

nimesulide 100 mg/day. The results of blood investigations were normal,

with the exception of the erythrocyte sedimentation rate (ESR), which

was 32 mm in the first hour, and serum creatinine level (1.5 mg/dl

against a normal value of <1.3 mg/dl). At that time, he was also

receiving allopurinol 300 mg/day, and antidiabetic and antihypertensive

therapy. In February 1999, as he had a value of the Disease Activity

Score (DAS) modified for the 28-joint count [1] of 4.7,

hydroxychloroquine 250 mg/day was added to MTX. The arthritis improved

but in April 2000 MTX was discontinued as the patient had had a ureteral

stent positioned because of a stone obstructing the right ureter, and

hydroxychloroquine was continued alone. After a relapse of arthritis in

December 2000 (DAS=4.8), sulphasalazine was started with the aim of

gradually reaching a dose of 2 g/day within 4 weeks. The ureteral stent

had been removed but a small fibrotic kidney had developed, and his

serum creatinine level was 1.6 mg/dl. Sulphasalazine had to be

discontinued after a few weeks because of gastric intolerance and MTX

was again prescribed at a reduced dose of 5 mg/week because of mild

renal failure. In June 2001, the rheumatic condition was still very

active (DAS=5.1), and so MTX was discontinued and leflunomide was

started at 20 mg/day. At that time, the patient was also receiving

atenolol 100 mg/day, amlodipine 2.5 mg/day, furosemide 20 mg twice a

week, phenphormine 150 mg/day, glibenclamide 7.5 mg/day, allopurinol 300

mg/day, irbesartan 150 mg/day, hydrochlorothiazide 12.5 mg/day and

rabreprazole 20 mg/day. His serum creatinine level was 1.8 mg/dl and ESR

47 mm in the first hour; the results of all of the other blood tests

were normal. Given the absence of a treatment response after 3 months

(DAS=5.2), in September 2001 we decided to try anti-tumour necrosis

factor (TNF) therapy. Leflunomide was discontinued and, as required by

the planned infliximab therapy, MTX was resumed at a dose of 5 mg/week.

The first infliximab infusion, of 230 mg (3 mg/kg), was given 1 month

later in October 2001, when the patient was still receiving all of the

other medications described above. Blood tests revealed a serum

creatinine level of 2.3 mg/dl, an ESR of 86 mm in the first hour and a

reduced number of circulating platelets (125x109/l). Ten days later, the

patient came to our department complaining of fever (up to 40°C), severe

fatigue, severe ulcerative stomatitis and dysphagia. Urgent blood tests

showed serum creatinine 3.6 mg/dl and severe pancytopenia (white blood

cells 1.0x109/l, haemoglobin 7.5 g/dl and platelets 15x109/l). He was

hospitalized immediately and treated with transfusions (2 U red cells

and 1 U platelets), ceftriaxone, fluconazole, granulocyte colony

stimulating factor and cholestyramine. A few days later, his blood

cultures were positive for Staphylococcus epidermidis and so ceftriaxone

was replaced with imipenem. A bone marrow biopsy revealed changes

compatible with bone marrow hypoplasia. The patient recovered rapidly

and was discharged after 2 weeks with white blood cells 6.0x109/l,

haemoglobin 9.0 g/dl and platelets 450x109/l.

This case indicates what may happen with the aggressive use of the new

DMARDs. In brief, an RA patient who was no longer responsive to MTX was

first switched to leflunomide and then, because of a continuing lack of

response, to the combination of MTX and infliximab, and as result

developed a life-threatening bone marrow hypoplasia. We cannot be sure

which drug or combination of drugs or events was responsible for this

severe adverse reaction. Although at least one previous case has been

reported [2], leflunomide is not generally associated with severe bone

marrow toxicity and pancytopenia, and the incidence of pancytopenia was

very low (0.01-0.1%) in the clinical trials. However, given its

antiproliferative mechanism of action, it could theoretically induce

this adverse reaction. It is worth noting that the active metabolite of

leflunomide has a relatively long half-life (up to 4 weeks) and that

side-effects can develop several weeks after drug withdrawal. Infliximab

has not been associated with bone marrow toxicity either, but the

periodic safety update reports on TNF- inhibitors have mentioned very

rare cases of serious blood dyscrasia [3]. Finally, it is well-known

that even low doses of MTX may be responsible for leucopenia and

pancytopenia [4] and that allopurinol interacts with other drugs (e.g.

azathioprine) and increases their bone marrow toxicity [5]. Any of these

drugs alone could have caused the severe pancytopenia in this case, or

it could have been due to their interactions; furthermore, the mild

renal failure may also have played a role. The small number of

circulating platelets recorded just before infliximab treatment seems to

suggest that leflunomide (alone or perhaps by interacting with MTX)

could have been associated with this adverse event.

Although there is no way of knowing which specific drug was responsible

for the pancytopenia, we may speculate that switching rapidly from

leflunomide to MTX and infliximab (which may not be unusual in patients

with refractory RA) can lead to severe bone marrow toxicity, especially

in the presence of mild renal failure and allopurinol treatment. The

relatively long time elapsed between leflunomide discontinuation and the

development of the pancytopenia and the mild thrombocytopenia recorded

just before the therapy with infliximab seem to indicate that this agent

enhanced bone marrow toxicity that had been already triggered by

leflunomide. However, regardless of the possible pathogenetic

mechanisms, this case warns us that every possible precaution, including

suitable washout periods and cholestyramine administration after

leflunomide, should always be taken if an RA patient needs to be treated

first with leflunomide and then with infliximab and MTX in combination.

Notes

Correspondence to: A. Marchesoni. E-mail: marchesoni@...

References

1.. Gestel AM, Haagsma CJ, van Riel PLCM. Validation of rheumatoid

arthritis improvement criteria that include simplified joint counts.

Arthritis Rheum 1998;41:1845-50.[CrossRef][Medline]

2.. Auer J, Hinterreiter M, Allinger S, Kirchgatterer A, Knoflach P.

Severe pancytopenia after leflunomide in rheumatoid arthritis. Acta Med

Austriaca 2000;27:131-2.[CrossRef][Medline]

3.. Day R. Adverse reactions to TNF- inhibitors in rheumatoid

arthritis. Lancet 2002;359:540-1.[CrossRef][Medline]

4.. Ohosone Y, Okano Y, Kameda H et al. Clinical characteristics

related to methotrexate-induced pancytopenia. Clin Rheumatol

1997;16:321-3.[Medline]

5.. Kennedy DT, Hayney MS, Lake KD. Azathioprine and allopurinol: the

price of an avoidable drug interaction. Ann Pharmacother

1996;30:951-4.[Medline]

Accepted 21 June 2002

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