Rheumatology Advance Access originally published online on December 6, 2005
Rheumatology 2006 45(3):362-363; doi:10.1093/rheumatology/kei201
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LETTER TO THE EDITOR |
Disease-modifying anti-rheumatic drugs are only one of a number of potential causes of myelosuppression: a careful drug history is necessary to elucidate the cause of an adverse event
Rheumatology, Queen Alexandra Hospital, Portsmouth and 1 Drug Safety Research Unit, Southampton, UK
Correspondence to: R. W. Marshall. E-mail: R.W.Marshall{at}doctors.org.uk
SIR, We read with interest the article by Lim et al. [1] concerning methotrexate (MTX)-induced pancytopenia, and present here three cases of drug-induced myelosuppression that illustrate that disease-modifying antirheumatic drugs (DMARDs) are not always to blame.
Case 1 was a 76-yr-old lady who was treated with MTX for her rheumatoid arthritis (RA). A routine blood test on 1 July 2004 showed that her haemoglobin (Hb) had fallen over 1 month from 11.1 g/dl to 8.4 g/dl, the white blood count (WBC) from 5.9 x 109/l (neutrophils 3.1 x 109/l) to 2.1 x 109/l (neutrophils 0.5 x 109/l) and platelets from 581 x 109/l to 310 x 109/l. The MTX was thought to be responsible. She was admitted to hospital, her medications were stopped and she was given folinic acid rescue. Her blood parameters improved.
At clinic review a drug history revealed that she had been taking MTX, folic acid and azapropazone without problem for over 10 yr, and ferrous sulphate for the past 6 months. Two months previously she had received intravenous flucloxacillin and benzylpenicillin, and had started lansoprazole. Haematological abnormalities are well recognized in these three drugs [2], and on balance it was felt that the lansoprazole was responsible. With much reservation the patient agreed to restart MTX, and regular haematological monitoring has been unremarkable since.
The second case was a 65-yr-old lady with longstanding RA, who had previously reacted to MTX (nausea and headaches), sulphasalazine (diarrhoea and vomiting), gold injections (rash) and penicillamine (flu-like illness). In March 2003 she commenced etanercept with an excellent response. Later that year she was prescribed meloxicam.
On 19 April 2004 a routine blood test showed Hb 12.9 g/dl, WBC 3.0 x 109/l (neutrophils 0.9 x 109/l) and platelets 218 x 109/l, having previously been normal. Etanercept and meloxicam were stopped, but repeat blood counts over the next 10 days showed no improvement. At clinic review on 4 May, a careful history revealed that she had commenced aspirin 75 mg daily on 19 February following a transient ischaemic attack.
Aspirin was stopped and she was monitored closely. She developed oesophageal candidiasis, which was successfully treated with fluconazole. A bone marrow and trephine biopsy showed maturation arrest of neutrophil production, with no evidence of dysplasia. By August 2004 her blood count had returned to normal (WBC 4.4 x 109/l, neutrophils 2.4 x 109/l). Her RA flared so she was commenced on prednisolone 10 mg daily, prior to the commencement of adalimumab.
Haematological abnormalities are well recognized with aspirin [2], but are rare with etanercept: neutropenia is listed as occurring in between 1/1000 and 1/10 000 patients. To July 2004, the Committee on Safety of Medicines (CSM) had received 16 case reports of neutropenia with etanercept. Aspirin was the likely cause in this patient as the neutropenia occurred within a few weeks of commencing therapy.
Case 3 was a 65-yr-old lady with longstanding RA who had been taking azathioprine 150 mg daily for 3 yr, along with coproxamol. A routine blood test in May 1997 showed Hb 11.1 g/dl, WBC 1.6 x 109/l (neutrophils 1.2 x 109/l) and platelets 30 x 109/l. She had been feeling unwell with anorexia, dry mouth, sore throat, weight loss and dysphagia, and was pyrexial. She was admitted to hospital, where repeat blood tests showed Hb 9.0 g/dl, WBC 0.4 x 109/l (neutrophils 0.2 x 109/l), platelets 9 x 109/l, international normalized ratio 1.8, Activated Partial Thromboplastin ratio (APTR) 2.7, bilirubin 56 µmol/l (normal range 3–20), albumin 23 g/l (37–50), aspartate transaminase 117 IU/l (12–40) and alkaline phosphatase 195 IU/l (30–95).
Examination showed established rheumatoid arthritis, but no synovitis; temperature 38°C and a purpuric rash on the legs but no other localizing signs. Azathioprine was stopped and she was given supportive treatment and repeated transfusions. Blood cultures were consistently sterile, although she developed oropharyngeal candidiasis and a coliform urinary infection. Ultrasound of the abdomen confirmed hepatosplenomegaly.
She improved over 1 month and was discharged. A drug history revealed that prior to admission she had received a week's triple therapy with clarithromycin, metronidazole and lansoprazole for eradication of Helicobacter pylori. The lansoprazole was thought to be the cause of her pancytopenia.
Four months later her RA started to flare, and at the patient's insistence azathioprine was restarted. Eight years later she is still taking the drug without problem.
Myelosuppression is a recognized complication of DMARD therapy, and patients should be counselled and monitored according to BSR guidelines [3]. When an adverse drug reaction (ADR) occurs it is critical to elucidate which drug is responsible, and this should be reported to the CSM. It is easy to ascribe causality to the more ‘toxic’ drug, but adverse events occur more commonly with drugs that have been recently introduced [4, 5]. The diagnostic processes underlying causality assessments have been well described, and include consideration of the time to onset of ADR, differential causes, a process of elimination, and the recurrence of the event on rechallenge [6]. In clinical practice, rechallenge after an ADR is not always possible.
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] - British National Formulary. Available at: www.bnf.org. Accessed 7 September 2004.
- National Guidelines for the Monitoring of Second Line Drugs produced by The British Society for Rheumatology. July 2000 https://www.msecportal.org/portal/editorial/PublicPages/bsr/536883013/3.doc.
- Clunie GR, Lennard L. Relevance of thiopurine methyltransferase status in rheumatology patients receiving azathioprine. Rheumatology 2004;43:13–8.
[Abstract/Free Full Text] - Grove ML, Hassell AB et al. Adverse reactions to disease-modifying anti-rheumatic drugs in clinical practice. Q J Med 2001;94:309–19.
- Shakir SAW. Causality and correlation in pharmacovigilance. In: Talbot J, Waller P, eds. Stephens’ Detection of new adverse drug reactions, 5th edn. John Wiley & Sons, 2004;329–43.
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