Caveats to the use of parenteral methotrexate in the treatment of rheumatic disease

R. K. Moitra, J. M. Ledingham, R. G. Hull, F. C. McCrae, A. L. Thomas, R. Shaban and K. R. MacKay

Rheumatology Department, Portsmouth Hospitals NHS Trust, Portsmouth, Hampshire, UK

Correspondence to: R.K. Moitra, Department of Rheumatology, North Hampshire Hospital, Aldermaston Road, Basingstoke RG24 9NA, UK. E-mail: rkmoitra{at}doctors.org.uk

Sir, methotrexate (MTX) remains the most widely prescribed of the disease-modifying anti-rheumatic drugs (DMARDs), but its clinical benefit is limited by gastrointestinal side-effects and a marked inter-individual variability in efficacy [1]. Parenterally administered MTX produces higher serum concentrations and more complete absorption than the orally administered drug at the top end of the dose range [2]. A recent open prospective study suggested improved efficacy with no reduction in safety on switching from oral to intramuscular (i.m.) administration in patients with active rheumatoid arthritis [3]. The parenteral route is well tolerated and there are no significant differences in bioavailability between MTX administered subcutaneously and I.M., making the two routes interchangeable [4]. On the downside, parenteral MTX costs more than seven times [5] as much as the oral preparation even before one takes associated expenses such as equipment, nurse and clinic time into account. It is imperative, therefore, that all reasonable steps are taken to ensure that patients are given an adequate trial of the oral drug before switching to the parenteral form.

We analysed the notes of 102 of the 115 patients receiving parenteral MTX for a variety of conditions in the 3 months leading up to and including June 2002. Ninety-one patients were using the subcutaneous as opposed to the i.m. route and of these, 77 had successfully been taught to self-inject.

All of the patients had received oral MTX prior to being switched and all had been receiving the parenteral drug for at least 3 months (mean duration 22.9 months). We documented the reasons prompting the switch and whether or not appropriate alternative measures had been tried beforehand. Each patient's perception of the ‘efficacy’ and ‘tolerability’ of the parenteral as compared with the oral preparation was gleaned from the notes, in clinic or over the telephone. A simple three-point scale was used: ‘no difference’, ‘better’ and ‘worse’. The erythrocyte sedimentation rate (ESR) (mean of three) was noted in the 3 weeks prior to the switch and at the time of analysis. The same three-point scale was used, with ‘better’ being defined as a 20% fall and ‘worse’ as a 20% rise in the baseline ESR. Disease control measures employed subsequent to switching, such as corticosteroid administration (via any route), were recorded.

Prior to switching, patients had taken oral MTX for a mean duration of 30.35 months (range 3 to 135 months). Of the 44 patients (43.1%) switched purely due to lack of efficacy, only 27 (61.4%) had received an oral dose of 17.5 mg/week or higher. Twenty-one of the 44 (47.7%) said they ‘felt better’ on the equivalent parenteral dose and the same number noticed no change. There was an improvement in the mean ESR in 32 of the 44 patients (72.7%) but in 26 of these (81.3%) other disease control measures had been employed.

Twenty-nine patients (28.4%) were switched following the advent of nausea. Twenty-one (72.4%) of these reported improved symptoms on the parenteral drug but only 14 (48.3%) had received an anti-emetic and only seven (34.5%) had been advised to try splitting their oral MTX dose prior to the switch. Three of the four patients switched after developing mucositis reported an improvement; only one of these had been advised to use increased folate supplementation and none of them had tried splitting the oral dose.

Other reasons for switching included non-specific malaise (five patients), abdominal pain (four patients) and weight gain.

A significant number of patients on suboptimal doses of oral MTX are switching to the parenteral form (and presumably other DMARDs or biologics) without adequate attempts at dose escalation. Similarly, simple symptom control measures are not routinely being employed to deal with common side-effects. Parenterally administered MTX is generally better tolerated and there is a suggestion that it is more efficacious but firm conclusions cannot be drawn due to the retrospective nature of this analysis and the lack of an appropriate control.

We would like to thank our audit coordinator, Mrs Angela Wood, for her help with tracing the notes and analysing the data.

The authors have declared no conflicts of interest.

References

  1. Godfrey C, Sweeney K, Miller K, Hamilton R, Kremer J. The population pharmacokinetics of long-term methotrexate in rheumatoid arthritis. Br J Clin Pharmacol 1998;46:369–76.[CrossRef][ISI][Medline]
  2. Hamilton RA, Kremer JM. Why intramuscular methotrexate may be more efficacious than oral dosing in patients with rheumatoid arthritis. Br J Rheumatol 1997;36:86–90.[CrossRef][ISI][Medline]
  3. Bingham SJ, Buch MH, Lindsay S, Pollard A, White J, Emery P. Parenteral methotrexate should be given before biological therapy. Rheumatology 2003;42:1009–10.[Free Full Text]
  4. Brooks PJ, Spruill WJ, Parish RC, Birchmore DA. Pharmacokinetics of methotrexate administered by intramuscular and subcutaneous injections in patients with rheumatoid arthritis. Arthritis Rheum 1990;33:91–4.[ISI][Medline]
  5. Mehta DK, ed. British National Formulary, Vol. 47. London: British Medical Association and Royal Pharmacological Society of Great Britain, 2004.
Accepted 8 October 2004





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