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 (0.010.1%) 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{at}g\|[hyphen]\|pini.unimi.it
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