British Journal of Rheumatology l995;34(suppl. 2):43—48
`
`EFFICACY OF METHOTREXATE IN RHEUMATOID ARTHRITIS
`
`M. E. WEINBLA'I'I‘
`
`Department of Rheumalology and Immunology, Brigham and Women '3 Hospital. Harvard Medical School,
`Boston, MA, USA
`
`SUMMARY
`
`Methotrexate (MTX), an antifolate agent, has been used in the treatment of rheumatoid arthritis (RA) for over two decades.
`Open clinical studies and short-term. randomized, placebo-controlled studies demonstrate the efficacy of MTX in active RA.
`Long-term prospective studies, including two of over 7yr duration, report a sustained response and a corticosteroid-sparing
`effect. Comparative studies demonstrate superior eficacy to auranofin, amthioprine and mlosporin A. A highly favourable
`retention rate with the drug has been noted in large studies from academic and community-based practices. Radiographic studies
`suggest a slowing of radiographic progression with the compound. MTX has become an accepted and widely used treatment
`for active RA.
`
`KEY worms: Methotrexatc, Rheumatoid arthritis, Antifolate, Comparative study.
`
`mom, a folic acid antagonist and parent com-
`pound of methotrexate (MTX), was initially developed
`for the treatment of acute childhood leukaemia. The
`
`use of folic acid antagonists followed the isolation of
`folic acid from the liver in 1943. The molecular formula
`
`of folic acid, and two methods for its synthesis, were
`described in 1946. It was appreciated that folic acid was
`important in haematological function, and this led to
`a series of experiments with folic acid in the treatment
`of leukaemia and solid tumours. Administration of
`
`folic acid to patients with chronic myeloid leukaemia
`resulted in haematological and clinical relapse. In one
`patient, an improvement was associated with the with-
`drawal of folic acid, and in another patient, a haem-
`atological response occurred when the patient was
`started on a diet low in folic acid. In 1948, Farber er a1.
`[1] reported their classic study on the use of amino-
`pterin in the treatment of childhood leukaemia. This
`study established the role of folic acid antagonists in
`the therapy of malignancy.
`In 195], Gubner er a]. [2] reported an open study of
`aminoptcrin in patients with psoriasis, rheumatoid
`arthritis (RA) and psoriatic arthritis. Refinement of the
`aminopterin compound led to the development of
`MTX. MTX was extensively studied as a therapy for
`psoriasis in the 19603. Weinstein and Frost [3] de-
`veloped an oral regimen in which MTX was adminis-
`tered at 12-h intervals in three doses, once a week. This
`dosing regimen was based on the difference between the
`maturation time of psoriatic skin vs normal skin. This
`weekly cycled regimen produced less toxicity than daily
`therapy and was as good as single, larger dose, par-
`enteral injections. A natural progression with MTX
`was
`from the treatment of psoriasis to psoriatic
`arthritis. In I964, Black er al.
`[4] reported a double-
`blind study of MTX vs placebo in patients with active
`psoriatic arthritis. An improvement in both the psori-
`asis and arthritis occurred in the treatment group.
`Responses were detectable within a Few weeks of drug
`initiation.
`In I984. Willkens er
`a1.
`[5]
`reported a
`double-blind study with MTX at a maximum dose of
`
`15 rug/week. In this small study of psoriatic arthritis,
`MTX was no better
`than placebo at
`improving
`joint swelling or joint tenderness. MTX was superior
`to placebo, however,
`in the physician assessment
`of arthritis activity and in improving the amount of
`psoriatic skin surface area. The lack of greater im-
`provement in this particular study may have been due
`to the low dose of MTX utilized and the small sample
`Size.
`
`RHEUMATOID ARTHRITIS: OPEN STUDIES
`
`Following the observation that MTX was of value in
`psoriatic arthritis,
`in [972, Hofl'meister [6] reported
`beneficial effects with i.m. MTX in 29 patients with
`RA. The dose of MTX was 10—15 mg/week. Over the
`next 15 yr, several open studies confirmed Hofl'meister's
`initial observations of the beneficial effects of low-dose,
`weekly treauncnt with MTX in active RA. Willkens
`and Watson [7] reported their experience with low-
`dose oral MTX in 67 patients with RA who had failed
`gold therapy. A one-step response was observed in 33
`patients (49%) and a two-step response was observed
`in 18 (27%) of the patients. The duration of therapy
`was from 3 months to 10 yr and the dose of MTX
`ranged from 7.5 to 22.5 mg/week.
`Hoffmeister [8] expanded his initial series to include
`78 patients with a treatment duration as long as l5 yr.
`Forty-five of his patients (58%) were observed to have
`had a marked improvement, with 28% judged to be in
`complete remission. The dose of MTX ranged from
`10.0 to 15.0 mg/week.
`Steinsson er a1. [9] observed a significant improve-
`ment in an open study, involving 2| patients, with a
`mean treatment duration of 38 weeks. The dose of
`
`MTX ranged from 7.5 to 25.0 mg/week given either
`orally or by i.m.
`injection. Fifty-two per cent of the
`patients were noted to be responders. A follow-up
`report of 18 of these patients noted a sustained clinical
`response after a mean of 42 months of treatment [10].
`Michaels er al. [ll] reported the use of i.v. MTX in
`l4 patients at a dose as high as 50.0 mg/week, with a
`
`© I995 British Society for Rheumatology
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`44 RADICAL INTERVENTION IN EARLY RA
`
`duration of treatment that ranged from 7 to 20 weeks.
`An improvement was observed within 4 weeks of drug
`initiation. Seventy-nine per cent of the patients showed
`an objective improvement within 2 months; however, at
`this dose. 35% of the patients discontinued therapy due
`to toxicity.
`
`RANDOMIZED TRIALS
`
`Based on these open studios. randomized placebo-
`controllcd trials were initiated to determine the short-
`
`term effimcy of MTX in active RA. All of the
`randomized, placebo-controlled trials were similar with
`regard to the severity of disease, duration of disease
`and prior second-line therapy usage. All patients in
`these studies had failed to respond to or had developed
`toxicities to second-line therapies, including gold salts
`and p—penicillamine. Thompson et al. [12] reported a
`placebo-controlled, randomized trial of 48 patients
`with RA. The dose of parenteral MTX was either 10.0
`or 25.0 nag/week. After 6 weeks, a significant improve-
`ment was noted in RA activity parameters in the MTX
`group compared with the placebo group. This improve-
`ment included the number of painful joints, swollen
`joints, global assessment and erythrocyte sedimenta-
`tion rate.
`
`In 1985, Weinblatt er a1. [13] reported the results of
`a placebo—controlled, 24-week, randomized crossover
`study involving 35 patients. All patients had previously
`received gold therapy and 80% had previously received
`D-penicillamine. The initial dose of MTX in this study
`was 7.5 mg/wcek, taken in a cycled oral regimen. The
`dose was increased to six tablets per week or 15.0 mg/
`week if a clinical response was not noted after 6 weeks.
`A significant improvement was observed at l2 weeks in
`the MTX group compared with the placebo group
`in all clinical variables, with the exception of grip
`strength.
`In the MTX group,
`the mean number of
`painful joints decreased from 37 at baseline to ll at 12
`weeks, and the number of swollen joints decreased
`from 34 at baseline to 20 at 12 weeks. The improvement
`with MTX was noted as early as 3 weeks after drug
`initiation. Individual patient response, defined as a
`50%, or greater, improvement in the joint tenderness
`index or joint swelling index, occurred in 54 and 34%
`of the MTX-treated patients. During the second half of
`the study (weeks l2—24), an increase in disease activity
`occurred in those patients who initially received MTX
`and were then randomiwd to the placebo group.
`in an l8 week, randomized, multicentre trial, 189
`patients received either placebo or low-dose weekly
`MTX {M}. In this study, MTX was administered as a
`weekly, oral cycled regimen at doses of 7.5 or
`ISO mg/week. At 18 weeks, a significant improvement
`in all disease variables was observed in the MTX group
`compared with placebo. The mean number of painful
`joints decreased from 27 to 13 and the number of
`swollen joints decreased from 22 to I4 in the MTX
`group, with no change in the placebo-treated patients.
`Individual patient
`improvement. defined as a 50%
`improvement in the joint pain index and joint swelling
`index, was observed in 32 and 2 l % of the MTX-treated
`
`Page 2 of 6
`
`patients compared with 11 and 4% of the patients who
`received placebo.
`A fourth randomized, placebo-controlled trial also
`utilized a crossover dsign [IS]. A similar improvement
`with MTX was observed during the treatment phase
`with MTX. A flare of disease activity was also noted
`when patients were randomized from MTX to placebo
`therapy in the second half of the study.
`A meta-analysis was performed of the four random-
`ized trials; 8. significant improvement was noted in the
`MTX-treated patients in all clinical parameters, with
`the exception of the 50’ wall:
`time [16]. A pooled
`estimate of clinical benefit was defined as the improve-
`ment observed in the MTX-treated patients above that
`observed in the patients who received placebo. By this
`definition, a 44% reduction in duration of morning
`stiffness, a 27% reduction in the number or painful
`joints and a 26% reduction in the number of swollen
`joints was achieved in the MTX-treated patients.
`The four randomized trials and the meta-analysis
`confirm the short-term efiicacy of MTX in patients who
`have failed other standard second-line therapies, in-
`cluding gold salt therapy. Two of the randomized trials
`[13, 14] were the pivotal studies for the review by the
`United States Food and Drug Administration for the
`approval of MTX as a therapy for active RA.
`A flare of arthritis follows MTX discontinuation.
`This was noted first in short-tenn crossover studies
`[[3, 15], and was confirmed in two longer treatment
`studies [[7, 18]. In one of the longer term studies,
`l0
`patients received 36 months of MTX and were then
`rte-randomized to receive either placebo or MTX [17].
`A flare of arthritis activity occurred in all of the
`patients randomized to the placebo group; this flare
`occurred within 4 weeks of discontinuing MTX.
`
`COMPARISON STUDIES
`
`The next step in the development programme of
`MTX was a comparison of MTX with other standard
`second-line therapies,
`including azathioprine, par-
`enteral gold salts, oral gold and, most
`recently,
`cyclosporin A.
`Three trials have compared MTX with azathioprine.
`All three of the studies utilized patients who had had
`prior treatment with either gold salts or o-penicil-
`lamine. A study involving 42 patients compared MTX
`with azathioprinc for 24 weeks [19]. The maximum
`dose of MTX in this study was lSmg/week and the
`maximum dose of azathioprine was ISO mg/day. An
`improvement
`in all clinical outcome variables was
`noted in both treatment groups; there was no statistical
`difference in response between treatment groups. There
`was, however, a trend towards a more marked and
`rapid improvement
`in the MTX-treated population.
`In a second trial, 53 patients were randomized to
`receive either MTX, at an initial dose of IO rug/week,
`or azathioprine, at an initial dose of mo mg/day [20].
`Alter 24 weeks, both groups showed a significant
`improvement from baseline in the pain score and
`functional capacity score, but there was no difference
`in response between the two groups. Fifty per cent of
`
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`WEINBLATT: METHOTREXATE lN RHEUMATOID ARTHRITIS 45
`
`the patients withdrew from the study either due
`to toxicity or lack of drug efficacy. A 48-week,
`randomized trial of 64 patients compared MTX, at a
`maximum dose of 15 mg/week, with azathioprine, at
`a maximum dose of 150 mg/day [21]. At week 24, a
`significant
`improvement
`in clinical disease variables
`was observed in both treatment youps. An area
`under the curve of analysis noted a significantly greater
`improvement in the MTX-treated group in the number
`of swollen joints, pain score, erythrocyte sedimentation
`rate and disease activity score compared with the
`azathioprine group. Clinical reSponse was faster and
`more sustained with MTX compared with azathio-
`prine. Patient improvement, using a composite disease
`activity score, noted that 60% of the patients receiving
`MTX and 35% of the patients receiving azathioprine
`improved significantly after 24 weeks of therapy. At
`wcelt 48, 50% of the patients on azathioprine and 76%
`of the patients receiving MTX had improvement in this
`patient response index.
`Several studies have compared MTX with parenteral
`gold salts. In one double-blind trial, 40 patients en-
`rolled in a study lasting 26 weeks, which compared
`aurothiomalate with parenteral MTX [22]. The dose of
`MTX was 10 mg/week and the dose of aurothiomalate
`was 50 rug/week. Both drugs were found to be cfi'ective
`with no difference noted between groups. In a 26-week
`study of 35 patients, again no difference in eficacy was
`noted between MTX at a dose of I25 mg/week or gold
`sodium thiomalate [23]. A third study of 57 patients
`compared gold sodium thiomalate (50 mg/week) with
`MTX (l5 mg/weelt) for 6 months [24]. An improve-
`ment
`in standard clinical variables and erythrocyte
`sedimentation rate was observed with both treatment
`
`groups and, again, there was no difference in response
`between groups. Because of the small sample size in all
`of these studies, conclusions regarding relative efficacy
`between drugs may not be accurate due to the pos-
`sibility of a type II statistical error.
`In a 9 month trial involving 281 patients and com-
`paring MTX with auranofrn, MTX was found to be
`superior to auranofin in improving all measures of
`disease activity, including the erythrocyte sedimenta-
`tion rate [25]. Twenty-five per cent of the patients in the
`MTX group and 34% of the patients in the auranofin
`group did not complete the 36 week study. Only four
`of the patients in the MTX group compared with 13 in
`the auranofin group withdrew because of a lack of
`efficacy. Seventy per cent of the patients receiving MTX
`exhibited a marked improvement, defined as a 50%
`improvement in the joint/pain and tenderness index,
`and 64% had a similar level of improvement in the
`joint
`swelling index. This degree of improvement
`was significantly greater with MTX than seen with
`auranofin.
`
`MTX was recently compared with cyclosporin A
`in a 34-week, multicentre. double-blind study of 264
`patients [26]. All patients failed at least one prior
`second-line therapy. The dose of MTX ranged from 7.5
`to l5.0 rug/week and the dose of cyclospcrin A was
`2.5-5.0 mg/kg/day. Both cyclosporin A and MTX were
`
`Page 3 of 6
`
`found to be statistically superior to placebo. MTX was
`noted to be superior to cyclosporin A in the improve-
`ment in the physician and patient global assessments,
`Health Assessment Questionnaire score, and the tender
`joint counts.
`Felson er a1. performed a meta-analysis of placebo-
`controlled and comparative clinical trials to examine
`the relative efiieacy and toxicity of standard second-line
`therapies used to treat RA. In the initial meta-analysis
`[27], MTX was found to be similar in clficacy to
`injectable gold, Dpenicillamine and sulphasalazine.
`An update in 1992 included studies of azathiopiine,
`and noted that MTX had scored among the most
`efficacious of the drugs with a favourable toxicity
`profile [28].
`
`LONG-TERM STUDIES
`
`There have been several long-term prospective stud-
`ies of MTX in RA. Kramer and Phelps [29] reported a
`sustained clinical response after 90 months of MTX
`therapy. Of the original 29 patients enrolled in the
`study, 18 remained in the trial at 90 months. The dose
`of MTX ranged from 7.5 to 22.5 mg/weelt. At 90
`months, eight of 14 patients had completely discon-
`tinued their prednisone dose; a significant reduction in
`the mean dose of prednisone was seen for the entire
`group. All standard clinical parameters improved, with
`the exception of the number of tender joints.
`Similar results were observed in another long-term
`prospective trial [30]. After completion of a 24-week,
`placebo—controlled crossover study of MTX [13], 26
`patients enrolled in a long-term prospective study.
`Alter 84 months of therapy. 12 patients (46%) re-
`mained in the study [30]. A significant improvement in
`all standard arthritis disease parameters, including the
`number of painful and swollen joints, was still ob-
`served. The maximum clinical benefit was achieved by
`6 months. Eighty-three per cent of the patients demon-
`strated a marked improvement, defined as a 50%
`improvement in the joint pain index, and 92% had a
`marked improvement
`in the joint swelling index. A
`sustained clinical response was observed throughout
`the study. There was no difference in the degree of
`improvement noted at 12 months vs the improvement
`noted at 84 months. Fifty per cent of the patients were
`able to discontinue their background prednisone
`therapy and 33% of the patients were also able to
`discontinue
`their background non-steroidal
`anti-
`inflamrnatory drugs. These two studies are the longest
`prospective studies of any therapy in the treatment of
`RA.
`
`In a third prospective study, 128 patients received
`i.m. MTX at a dose that
`ranged from 5.0 to
`25.0 mg/week [3i]. Forty-nine patients received treat-
`ment
`for 3yr. Clinical parameters improved with
`therapy, although 43 patients witde from the study.
`One hundred and ninety-one patients enrolled in a
`prospective study of M11 treatment at a dose that
`ranged from 5.0 to 15.0 mg/week [32]. The mean
`duration of MTX therapy was 3—58 months. A signi‘
`ficant improvement
`in all clinical variables and the
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`46
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`RADICAL INTERVENTION IN EARLY RA
`
`erythrocyte sedimentation rate was observed A defin-
`ite reduction in background corticosteroid therapy was
`also noted. In this study,
`it was projected that the
`probability of remaining on MTX was 65% at 2 yr and
`46% at 5 yr.
`Following completion of a 9-month randomized
`trial, comparing MTX with auranofin [25], 123 patients
`enrolled in a Syr open study of oral MTX [33]. At
`year 5, 64% of the patients still remained on drug
`treatment. A significant improvement was observed in
`all clinical parameters and the erythrocyte sedimenta-
`tion rate. There was also a significant improvement
`noted in the functional status, as assessed by the
`Modified Health Assessment Questionnaire. A marked
`improvement, defined as a 50% reduction in the joint
`pain index and joint swelling index, was observed in
`71 and 69% of the patients, respectively. Sixty-two
`per cent of the patients achieved the Paulus criteria
`for response [34]. Of the 78 patients with an elevated
`erythrocyte sedimentation rate at baseline, 51% nonmal-
`ized their sedimentation rate while on treatment. Of the
`
`44 patients who withdrew from the study, only eight
`withdrew due to a lack of drug efficacy. This high
`retention rate is highly favourable and is similar to
`those reported in other prospective studies.
`Several retrospective studies have also reported a
`high retention rate with MTX. Of 124 patients treated
`with MTX. 60 (48%) continued to receive MTX for
`2 yr [35]. Adverse drug reactions were the major reason
`for drug withdrawal. In a study of 152 patients with
`RA, 71% of the patients remained on drug at 1 yr; it
`was projected that, at 6 yr, 49% of the patients would
`remain on drug treatment [36]. The major reason for
`withdrawal in this study was also drug toxicity. Studies
`from community-based rheumatologists from the USA
`and Australia reported similar high retention rates.
`Pincus er a1.
`[37] reported that
`the rate of MTX
`continuation was approximately double that seen with
`other second-line treatments. Wolfe er a!. [38] prospect-
`ively followed 671 RA patients over a l4—yr observation
`period. The mean duration of MTX treatment was
`approximately double that seen with other second-line
`therapies. In a report from Australia of 596 patients,
`managed over a decade in community-based practices,
`it was projected that at 5 yr, 62% of the patients would
`remain on MTX [39]. This was significantly longer
`than seen with all other second-line therapies.
`In
`another Australian study of 587 patients who received
`'MTX, 76% remained on the drug at 70 months [40].
`The majority of terminations were again due to drug
`toxicity.
`
`utilized doses that ranged from 7.5 to 20.0 mg/week. In
`the randomized trial comparing auranofin with MTX.
`43% of the MTX patients increased their MTX dose
`from 7.5 to 15.0 mg/week [25]. Furst er a1. [4l] per-
`formed a dose—response study in which the 10mg/mz
`dose was clinically and statistically superior to placebo.
`There was a suggestion that this dose was better than
`the 5.0 mg/m1 dose. As a result of decreased oral
`bioavailability, MTX doses >20 mg/week should be
`administered parenterally. A pilot study evaluated i.v.
`MTX at an initial dose of 40mg/m’ in 10 patients who
`had failed oral MTX [42]. The final dose in this 12 week
`study was 26 mg/m’. This higher dose was associated
`with an improvement in clinical parameters, and side-
`effeCts were mild.
`
`Once a satisfactory clinical response occurs, the dose
`of MTX may be slowly reduced; however, some
`patients may require higher doses over time to maintain
`a positive benefit. It has also been observed that some
`patients can be maintained on therapy every other
`week without a flare of disease activity.
`
`RADIOGRAPHIC STUDIES
`
`The efi'ect of MTX on radiographic progression has
`been reported in several studies.
`In an open study
`without a control group, a healing of erosions was
`observed within the first 29 months of MTX therapy
`[43]. However. in this same population. after a mean of
`54 months of treatment, new erosions were noted [44].
`In another prospective study, after a mean of 28
`months of therapy, a worsening of the radiographs was
`noted in six of 14 patients [45]. In five patients, an
`improvement in the number and size of erosions was
`observed, but a marked narrowing of the joint space
`was also seen. Two other studies suggested a slowing
`of radiological progression in a small number of
`patients [31,46].
`In a multicentre study comparing
`MTX with azathioprine,
`the rate of radiographic
`progression was less in the MTX group than in the
`mthioprine group [47].
`In the 9-month MTX vs
`auranofin study, a decrease in the rate of radiographic
`progression, as defined by joint erosions and joint space
`narrowing, was observed with MTX compared with
`auranofin [48].
`In a trial comparing auranofin and
`MTX alone with the combination of MTX and aura-
`
`nofin, a worsening in the erosion score and joint
`narrowing score occurred in all three treatment groups
`[49]. The worsening of erosions and joint narrowing
`score was statistically significant, however, only in the
`auranofin group. This study suggested that the rate of
`progression was also slower with MTX.
`
`DOSING AND DRUG ADMINISTRATION
`
`CONCLUSIONS
`
`MTX should not be given more frequently than
`1 day/week. More frequent administration is associated
`with a greater incidence of acute and chronic toxicity,
`particularly liver disease. MTX can be administered
`either orally or by parenteral injection. The initial dose
`of MTX is generally 7.5 mg/weelt. If a positive result
`has not been noted within 4-8 weeks and there is no
`
`toxicity, the dose may be increased. Most clinical trials
`
`In summary. open prospective studies. short-term
`randomized placebo-controlled
`trials,
`comparison
`studies of MTX with other second-line therapies and
`long-term prospective trials all demonstrate the efficacy
`of low-dose weekly MTX in the treatment of active
`RA. The high proportion of patients remaining on
`drug therapy in the prospective studies, and the high
`retention rate observed from studies by academic and
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`WEINBLATI‘: METHOTREXATE IN RHEUMATOID ARTHRITIS 47
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`community-based rheumatologists confirm the long-
`term efficacy of the compound. MTX has now become
`a standard therapy in the USA for the treatment of
`active RA, with increasing enthusiasm for this drug
`worldwide.
`
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