Methotrexate is now the most commonly used slow acting antirheumatic drug for rheumatoid arthritis.^1,2 In contrast to anticancer treatment, very low doses are given weekly (7.5 to 25 mg/week) by the oral, intramuscular, or subcutaneous route.³ Intramuscular administration is desirable because there is better absorption than by the oral route, the peak concentrations are similar to the intravenous (IV) route, and there is slower drug absorption and more prolonged exposure to the drug than with IV administration.⁴ Conversely, oral methotrexate may be associated with reduced gastrointestinal tolerance.⁵ Previous studies have shown better efficacy of intramuscular than oral methotrexate, based on pharmacokinetic indices of absorption and bioavailability,⁴ but to our knowledge clinical variables were evaluated in only one study.⁶ This latter study showed better efficacy with intramuscular methotrexate and a low incidence of adverse events.

There is at present no clear consensus on the route of choice for methotrexate administration, which differs between countries according to the prevailing medico-social systems and legislation. In the USA, methotrexate is mostly given orally, whereas in countries such as France, intramuscular administration is more common, although not yet legally approved.

From June to September 2001, the injectable form of methotrexate was out of stock in several European countries. Patients treated with intramuscular methotrexate thus had to be switched to the oral form. This transient shortage of the product gave us an opportunity to compare intramuscular and oral administration for efficacy and tolerance to the drug. A group of 143 patients switched from intramuscular to oral methotrexate was analysed in a retrospective and longitudinal study. When the supply problem was solved a few months later, some could be switch back to the intramuscular form, allowing a crossover comparison.

METHODS

We selected 213 patients from a computer database of the patients followed at the rheumatology unit of the Hôpital Edouard Herriot, Lyon, France. To be included, patients had to have rheumatoid arthritis, to be on a stable dose of intramuscular methotrexate as of June 2001, and to have been switched to oral methotrexate from June to September 2001 only because of a shortage of the intramuscular form. Methotrexate dosage was kept identical. We excluded patients already on the oral preparation, those stopping methotrexate because of side effects or lack of efficacy, those for whom intramuscular methotrexate was already insufficient, and those refusing injections. Patients already on folic acid were maintained on the same dose.

A multiple choice questionnaire was created, first tested on 10 eligible patients and sent by mail on January 2002. The aim was to evaluate the following:

• 11 clinical criteria (joint pain, morning pain, joint swelling, hand morning stiffness, duration of morning joint swelling, consumption of analgesic drugs and its duration, eye and mouth dryness, nausea after taking methotrexate);

• one biological criterion (transaminase levels).

In those in whom intramuscular methotrexate was reintroduced in September 2001 the same criteria were evaluated three months after the switch from the oral to the intramuscular route. For each question, possible answers were an increase, a decrease, or no change.

RESULTS

DISCUSSION

Several studies have compared the various modes of methotrexate administration.^4,5 Oral methotrexate is rapidly but incompletely absorbed (approximately 15% less than intramuscular), although with large interindividual variability.⁹ For doses above 25 mg/day, oral administration is associated with lower bioavailability because of absorption saturation.¹⁰ Conversely, intramuscular administration results in rapid and complete absorption and higher serum concentrations.⁷

Although these pharmacological studies have shown that intramuscular methotrexate should work better, few studies have examined the clinical implications of such a switch.^6,10–,¹² As revealed here, a relapse in the clinical symptoms of rheumatoid arthritis may be observed after switching from intramuscular to oral administration.¹⁰ A recent open study comparing oral with intramuscular methotrexate also showed increased efficacy with fewer adverse events with intramuscular administration.⁶ Such findings imply that a switch to the intramuscular route could be useful in patients not responding adequately to the oral drug.¹¹

To evaluate the effect of switching from intramuscular to oral administration, we took advantage of the fact that between June and September 2001 intramuscular methotrexate was out of stock in France. In our study of 143 patients with rheumatoid arthritis initially treated with intramuscular methotrexate, each patient remained their own control. All the clinical symptoms of rheumatoid arthritis were exacerbated by the change. As an internal control, oral and eye dryness did not change, neither did transaminase values.

As the hiatus in supply of intramuscular methotrexate was brief, 47 patients could be switched back to the intramuscular preparation, allowing a crossover analysis. When comparing the two modes of administration, most patients showed an increase in disease activity on the oral preparation, followed by a decrease on the intramuscular preparation. With respect to toxicity, although there was no significant overall change in liver transaminases, the values increased in nearly a quarter of the patients when they were on oral methotrexate and decreased again when they were re-established on intramuscular methotrexate, suggesting reduced liver toxicity with the intramuscular preparation.^5,12 A reduction in side effects permits higher doses to be used, leading in turn to better efficacy. However, an increase in the treatment burden and cost is associated with intramuscular methotrexate.