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`5 and 25 mg of oral MTX per week. Another review of
`a group of 24 patients with a mixture of diagnoses
`found that i.m. MTX was effective and well tolerated,
`and most patients were either very or extremely satis-
`fied with their therapy w5x. In addition, the same group
`found that the majority of patients preferred to receive
`their injections in the monitoring clinic rather than at
`the general practice surgery or at home despite the
`inconvenience.
`We have conducted an open prospective safety and
`efficacy study of switching to parenteral administration
`in a group of patients with active RA despite high-dose
`oral MTX who had not experienced any toxicity. The
`patients in this study had severe RA and had been
`referred for assessment for biological therapies in our
`‘Resistant RA’ clinic. Consecutive patients who had
`least 17.5 mguweek of oral MTX without
`failed at
`toxicity were enrolled; parenteral MTX was commenced
`at 7.5 mguweek and increased by 2.5 mg in alternate
`weeks up to 25 mguweek, unless limited by toxicity. A
`relatively low initial dose was used because of concern
`that increased bioavailability may lead to increased toxi-
`city. The doses of any concomitant disease-modifying
`agents (usually sulphasalazine or hydroxychloroquine)
`were stable for the preceding 4 weeks and were continued
`unchanged. The prednisolone dose was reduced when
`clinically indicated. All patients received concomitant
`folic acid (5 mguday except on the day of the MTX dose).
`Blood test monitoring was performed at 2 weeks and
`then 4-weekly. In most cases the MTX was administered
`by our clinical nurse practitioners (AP and JW). All
`patients who entered the study were assessed at 12 weeks
`and all those who continued beyond 12 weeks were asses-
`sed at 24 weeks. Disease activity was assessed using the
`modified disease activity score (DAS28) and C-reactive
`protein (CRP). The incidence of therapy discontinuation
`and the reason for discontinuation were noted.
`Therapy was switched in 33 patients (mean age 51 yr,
`range 29–70 yr; mean disease duration 8 yr, range 1–26 yr),
`and the mean number of previous disease-modifying
`anti-rheumatic drugs (DMARDs) was 4 (range 1–7). The
`mean baseline dose of oral MTX was 21 mguweek (range
`17.5–25 mguweek). Patients had active disease with a
`mean baseline DAS28 of 6.4 (range 3.79–8.49) (Table 1).
`After 12 weeks of parenteral MTX, the mean DAS28
`had decreased to 5.8 (P=0.015) and at 24 weeks mean
`DAS28 was 5.7 (P=0.014). Mean CRP also decreased,
`although this only reached significance at 24 weeks
`(P=0.022). The mean dose of MTX was comparable at
`each time point (Table 1), whereas the mean dose of
`prednisolone had decreased by 24 weeks (P=0.108;
`Table 1). At 12 weeks, 29 (88%) patients continued
`therapy, two stopped due to toxicity (one with systemic
`symptoms and one with oral–pharyngeal malignancy)
`and two stopped due to inefficacy. In four patients the
`dose escalation of MTX was limited by toxicity (one
`each with nausea, abnormal
`taste, and systemically
`unwell and itchy rash), but
`the patients continued
`therapy. At 24 weeks, 19 patients continued therapy
`(58% of those studied), four stopped due to toxicity (one
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`Rheumatology 2003;42:1009–1010
`doi:10.1093/rheumatology/keg246
`
`Parenteral methotrexate should be given before
`biological therapy
`
`Methotrexate (MTX) is the most commonly used disease-
`modifying agent and is considered to be the gold stan-
`dard treatment for therapy of rheumatoid arthritis (RA).
`The British Society for RheumatologyuNational Institute
`for Clinical Excellence guidelines stipulate that patients
`must have failed therapy with MTX for at least 6 months
`(unless limited by toxicity) in order to be considered for
`anti-tumour necrosis factor a therapies w1x. In many
`cases MTX is efficacious and in general is well tolerated
`w2x. However, some patients do not respond to high-dose
`oral MTX. The absence of systemic side-effects in many
`of these patients suggests that this might be due to
`impaired gastrointestinal absorption, and Hamilton
`and Kremer showed increased bioavailability of MTX
`following switching from oral to intramuscular (i.m.)
`MTX w3x. Previous small studies have shown increased
`efficacy of i.m. MTX. A retrospective case-note review
`showed an improvement in 20 of 24 patients (mainly
`with RA) who switched from oral to i.m. administration
`w4x. The patients in this study were receiving between
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`10101010
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`Letters to the EditorLetters to the Editor
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`TABLE 1. Comparison of disease activity, MTX dose and prednisolone dose between baseline and 12 and 24 weeks of i.m. MTX
`
`DAS28
`CRP (mgul)
`MTX dose (mguweek)
`Prednisolone dose (mguday)
`
`Baseline (n=33)
`Mean
`
`6.43
`47.9
`20.8
`4.1
`
`12 weeks (n=33)
`
`24 weeks (n=29)
`
`Mean
`
`5.84
`34.4
`19.6
`4.1
`
`P*
`
`0.015
`0.200
`0.169
`0.945
`
`Mean
`
`5.67
`26.0
`19.4
`2.9
`
`P**
`
`0.014
`0.022
`0.313
`0.108
`
`*Paired t-test between baseline and week 12 data.
`**Paired t-test between baseline and week 24 data.
`
`each with rash, systemic symptoms, upper respiratory
`tract infections and mouth ulcers) and five stopped
`due to inefficacy. One patient was lost to follow-up.
`In this open prospective study, switching to i.m.
`administration in patients with active disease despite
`high-dose oral therapy was safe and efficacious. Disease
`activity was reduced and 58% of patients continued
`therapy for more than 24 weeks. A low incidence of
`adverse events was seen and no serious toxicity occurred.
`It is unlikely that the malignancy seen at 12 weeks can be
`attributed to the switch in the route of MTX adminis-
`tration. We feel
`that a trial of parenteral MTX
`is warranted in patients with severe RA prior to
`commencing biological therapies.
`
`1,
`S. J. BINGHAM, M. H. BUCH, S.LINDSAY, A. POLLARD
`1, P. EMERY
`J. WHITE
`
`Rheumatology Research Unit, University of Leeds and
`1Rheumatology Department, Leeds General Infirmary,
`Leeds, UK
`Accepted 11 December 2002
`Correspondence to: S. J. Bingham, Old Nurses Home,
`Leeds General Infirmary, Great George Street, Leeds
`LS1 3EX, UK. E-mail: s.bingham@leeds.ac.uk
`
`1. British Society for Rheumatology. Guidelines for prescribing TNF-a
`blockers in adults with RA. London: British Society for Rheuma-
`tology, 2001.
`2. Kremer JM, Lee JK. A long-term prospective study of the use of
`methotrexate in rheumatoid arthritis: update after a mean of
`53 months. Arthritis Rheum 1988;31:577–84.
`3. 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.
`4. Osman A, Mulherin D. Is parenteral methotrexate worth trying? Ann
`Rheum Dis 2001;60:432.
`Intramuscular methotrexate in
`5. Burbage G, Gupta R, Lim K.
`inflammatory rheumatic disease. Ann Rheum Dis 2001;60:1156.
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