J Neurol (2001) 248:625–626 © Steinkopff Verlag 2001
M.J. Craner J.P. Zajicek
Immunosuppressive treatments in MS – side effects from azathioprine Received: 20 November 2000 Received in revised form: 5 February 2001 Accepted: 14 February 2001
regular full blood count and liver function tests. Precise information was obtained using questionnaire, telephone contact, and analysis of medical records. Three patients have been excluded from the results as we were unable to clarify the reason for intolerance in two and one voluntarily withdrew due to pregnancy. Azathioprine intolerance occurred in 21 (55 %) of our patients, of whom 66 % were intolerant due to hypersensitivity reactions with nausea, myalgia, and arthralgia being the predominant complaints. Furthermore we found drug intolerance manifested early in the course of therapy with 66 % of patients withdrawing within two months of initiation. Azathioprine intolerance is re-
ported to range from 11–15 % in disease states such as rheumatoid arthritis (RA) and myasthenia gravis (MG) but has not been specifically examined before in the context of MS [2–3]. We propose several reasons for the higher intolerance rate that seems specific to MS patients. Severe myelosuppressive reactions are seen in patients with lowered thiopurine methyltransferase levels determined by genetic polymorphism [4]. A recent paper has identified the same process with glutathione-S-transferase levels that may underlie severity of disability in MS [5]. This enzyme plays a key role in the metabolism of azathioprine to 6-mercaptopurine (6-MP). The varying pool of metabolites released may be re-
Tab. 1 Number of patients reporting severe side effects resulting in drug withdrawal in relation to duration of therapy Therapy Duration (Months)
General (Systemically unwell ± rash)
Gastrointestinal
Musculo-skeletal Hair loss (Arthralgia/ myalgia/fevers)
Abnormal liver function tests
Bone marrow suppression
1 2 3 4 5 6
2
5 2 3
3 1
2 1 1
2
1
1 1
1
These data represent information from 18 patients intolerant of azathioprine. 6 patients had multiple side effect groups; 4 patients with deranged liver function tests experienced gastro-intestinal disturbances, the remaining 2 patients experienced general side effects with gastro-intestinal disturbances one of whom had additional musculo-skeletal complaints. The 3 patients excluded from this table owing to inadequate data on treatment duration had pure gastro-intestinal side effects
Fig. 1 Summary of the metabolism of azathioprine
JON 482
Sirs: There is currently considerable interest in immunosuppressive treatments for multiple sclerosis (MS); the UK National Institute for Clinical Excellence have convened an appraisal of new treatments for MS (including beta interferon and glatiramer), which has led to a re-assessment of older and cheaper therapies as alternatives or adjuncts to newer treatments. Azathioprine is a non-specific immunosuppressant with a disease modifying action in MS, having a modest benefit both in terms of relapse rate reduction, and decreased rate of disease progression [1]. Although withdrawal due to adverse effects in these studies was in the order of between 9–12 % above placebo [1], it has been our experience that use in the outpatient setting resulted in a far higher level of intolerance. We therefore reviewed our own patients to quantify the frequency of intolerance as defined by drug withdrawal due to adverse side effects. Two hundred and seventy two patients with MS were identified under regular follow up from January 1996 to February 2000. Fortyone patients (15 %) received azathioprine that was started at a low dose and titrated up in 4-weekly intervals to a maximum dose of 2.0–2.5 mg/kg/day. All patients were warned of potential side effects of azathioprine prior to treatment and were monitored with
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sponsible for the higher intolerance rate in MS patients, and for this reason 6-MP is potentially a better choice of drug for the treatment of MS. Furthermore, azathioprine appears to be better tolerated in MG although this may be related to the frequent co-prescription of oral steroids leading to a dampening effect on the hypersensitivity reactions seen in our MS group. It is also possible that patients with MS may perceive a less tangible benefit from azathioprine treatment than those with, for example, MG who are witness to a reduction in symptoms and steroid dose. The observed difference in the few azathioprine trials examining its use in MS may be accounted for by the fact that patient groups within trials are highly motivated and as such, more likely to tolerate potential side effects.
Our experience with azathioprine in MS shows it is poorly tolerated, but may have an equivalent level of efficacy to beta-interferon. In the search for a well-tolerated, cost-effective and efficacious disease-modifying drug for MS, there is a desperate need for large, wellconducted randomised controlled trials of long duration in this difficult area.
References 1. Yudkin PL, Ellison GW, Ghezzi A, et al. (1991) Overview of azathioprine treatment in multiple sclerosis. Lancet 338:1051–5 2. Singh G, Fries JF, Spitz P, et al. (1989) Toxic effects of azathioprine in rheumatoid arthritis. Arthritis Rheum 32:837–843
3. Hohlfeld R, Michels M, et al. (1988). Azathioprine toxicity during longterm immunosuppression of generalised myasthenia gravis. Neurology 38:258–261 4. Kryetski EY, Evans WE (1999) Pharmacogenetics as a molecular basis for individualised drug therapy: The thiopurine S-methyltransferase paradigm. Pharm Res 16:342–349 5. Mann CLA, Davies MB, et al. (2000) Glutathione S-transerfase polymorphisms in MS: Their relationship to disability. Neurology 54:552–57 M. J. Craner () · J. P. Zajicek Department of Neurology Level 10 Derriford Hospital Derriford Road Plymouth, Devon, PL6 8DH, UK Tel.: +44-17 52-77 71 11 Fax: +44-17 52-76 89 76 e-Mail:
[email protected]
