Arthritis 8C Rheumatism
`
`
`
`Official Journal of the American College of Rheumatology
`
`LONG-TERM PROSPECTIVE STUDY OF
`
`METHOTREXATE IN THE TREATMENT OF
`
`RHEUMATOID ARTHRITIS
`
`84-Month Update
`
`MICHAEL E. WEINBLATT. BARBARA N. WEISSMAN, DONALD E. HOLDSWORTH,
`PATRICIA A. FRASER. AGNES L. MAIER, KENNETH R. FALCHUK, and JONATHAN S. COBLYN
`
`Objective. To determine the long-term eflicacy
`and safety of low-dose methotrexate (MTX) in rheuma-
`toid arthritis (RA).
`Methods. Eighty-four-month open prospective
`trial at a single academic rheumatology center.
`Results. Twenty-six patients were enrolled in a
`prospective study of the long-term eilicacy of MTX in
`RA; a significant improvement had been demonstrated
`after 36 months of therapy. Twelve patients remained in
`the study at the 84-month visit; the mean weekly dosage
`of MTX was 10.2 mg. A significant improvement was
`still noted at 84 months in the number of painful joints,
`number of swollen joints, joint pain index, joint swelling
`index, and phycian and patient global assessrneuts. A
`50% improvement in the joint pain index and joint
`swelling index was observed In more than 80% ofthe 12
`
`From the Department of Rheumatology and Immunology.
`the Department of Radiology. and the Department of Medicine.
`Brigham and Women's Hospital, Harvard Medical School. Boston.
`Massachusetts.
`Supported in part by a research grant from Lederle Labo-
`
`ralories.
`
`Michael E. Weinblatt, MD: Department of Rheumatology
`and Immunology; Barbara N. Weissman. MD: Department of Ra-
`diology; Donald E. Holdsworth. MD: Department of Rheumatology
`and immunology; Patricia A. Fraser. MD. MPH: Department of
`Rhcumatology and Immunology; Agnes L. Meier, BA: Department
`of Rheumatology and Immunology; Kenneth R. Falchuk. MD:
`Department of Medicine; Jonathan S. Coblyn. MD: Department of
`Rheumatology and Immunology.
`Address reprint requests to Michael E. Weinblatt, MD.
`Department of Rheumatology and Immunology, Brigham and Wo-
`men's Hospital, 75 Francis Street, Boston. MA 02115.
`Submitted for publication May 3! . I99] ; accepted in revised
`form September 3, I99].
`
`Arthritis and Rheumatism. Vol. 35, No. 2 (February I992)
`
`patients still enrolled. A significant reduction in pred-
`nisone dosage was achieved; of 14 patients taking pred-
`nisone at entry, 7 had discontinued prednisone com-
`pletely. Fourteen patients withdrew from the study: 10
`between 0 and 36 months, and 4 between 36 and 84
`months. Toxicity in 3 patients and visit noncompliance
`in 1 patient were the reasons for withdrawal between 36
`and 84 months. At 84 months, 46% of the patients
`remained in the study; 11.5% had discontinued due to
`MTX toxicity.
`Conclusion. The eflectiveness of MTX in the
`treatment of RA continues to be demonstrated in this
`
`prospective study, after 84 months of treatment.
`
`Methotrexate (MTX) has become an estab-
`lished treatment in patients with active rheumatoid
`arthritis (RA). The eflicacy of this drug has been
`demonstrated in short-term placebo-controlled studies
`(1-4), comparative trials (5-8), and open prospective
`studies (9-I2). We have previously reported the re-
`sults of a 36-month prospective study of low-dose
`weekly MTX in patients with severe RA (10). This
`study. which began in 1984, now comprises 84 months
`of treatment observation. A sustained clinical re-
`
`sponse with an acceptable toxicity profile has been
`observed in the cohort of study patients, who have
`received MTX treatment for more than 7 years.
`
`PATENTS AND METHODS
`
`Patients. Twenty-six patients with classic or definite
`RA (13) who completed a 24-week randomized crossover
`
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`130
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`WEINBLATT ET AL
`
`trial comparing MTX with placebo (I) enrolled in a long-term
`open study of MTX. Each patient remained under the care of
`his or her personal rheumatologist during the study. and
`each continued to take aspirin or another nonsteroidal
`antiinllammatory drug (NSAID). if needed. All patients were
`advised to abstain from alcohol consumption. In patients
`who were taking prednisone at entry into the randomized
`trial. this treatment was maintained at a dosage not exceed-
`ing l0 mg/day; adjustment in the prednisone dosage was
`allowed during the open study.
`Methotrexate tablets (2.5 mg) were ingested at 8 AM,
`8 PM, and 8 AM once a week, always beginning on the same
`day. Adjustments in the dosage were allowed during the
`open study. but
`the maximum weekly dosage of MTX
`allowed in this study was IS mg. Informed consent was
`obtained every I2 months during the open study.
`Clinical assessments. Clinical evaluations were per-
`formed by the same physician-investigator every 2 months
`for the first 2 years of the study and every 6 months
`thereafter. The clinical disease variables determined at each
`visit were as follows: I) of 66 diarthrodial joints. the number
`with swelling; 2) Of 68 joints. the number with tenderness on
`pressure and/or pain on passive motion; 3) A joint swelling
`index, expressed as a sum. where each joint was graded for
`swelling on a scale of 0 = none, I = mild, 2 = moderate, and
`3 = severe; 4) A joint tendemess/pain index, expressed as a
`sum. where each joint was graded according to the above
`scale; 5) Duration of morning stifiness; 6) Physician assess-
`ment of disease activity, on a scale of 0 = asymptomatic, I
`= mild, 2 = moderate, 3 = severe. and 4 = very severe; 7)
`Patient assessment of disease activity, using the same scale
`as described for physician assessment.
`Overall response to treatment was derived using the
`following arbitrary designations: l) Therapeutic remission as
`defined by the preliminary criteria of the American College
`of Rheumatology (ACR; formerly, the American Rheuma-
`tism Association) (14); or 2) Marked improvement in the
`joint swelling index and in the joint tenderness/pain index,
`defined as a >50% decrease in the values determined in the
`
`open study compared with values at entry into the random-
`ized trial, and improvement in physician and patient assess-
`ment of disease activity representing changes of at least 2
`integers in the 5-point scale, or from mild to asymptomatic.
`Patients who had achieved a “marked improvement" in the
`joint swelling index. the joint tendemess/pain index, and the
`physician and patient assessments of disease activity at their
`last visit were termed "substantial" responders.
`Laboratory assessments. Every 4 weeks for the initial
`60 months of the study and every 8 weeks thereafter, a
`complete blood cell count and measurements of serum
`creatinine, serum aspartate aminotransferase, serum alanine
`aminotransferase, alkaline phosphatase, bilirubin, and albu-
`min were obtained. MTX was temporarily discontinued if
`the white blood cell count decreased to <3,500lmm’, the
`polymorphonuclear leukocyte count decreased to <1,2oo/
`mm’, the platelet count decreased to <l.5 x l0’lmm’, the
`liver enzyme values increased to greater than twice the
`upper limits of normal, or the serum creatinine level became
`abnormal. Patients with abnormal laboratory values persist-
`ing for longer than 3 weeks were withdrawn from the study.
`
`Liver biopsy. Afier 24, 48. and 72 months of MTX
`therBPY. a percutaneous liver biopsy was performed at an
`outpatient surgical unit. The same hepatologist performed all
`biopsies on all patients. The histologic sections were pre-
`pared with hematoxylin and eosin, trichrome, and reticulum
`stains. The findings were interpreted by the same pathologist
`and hepatologist in all cases, using the classifications de-
`scribed by Roenigk et al (15): class I = normal: mild fatty
`infiltration, mild nuclear variability, mild portal inflamma-
`tion; class II = moderate to severe fatty infiltration. moder-
`ate to severe nuclear variability, portal tract inflammation,
`and moderate to severe portal tract expansion; class IIIA =
`mild fibrosis; class IIIB = moderate to severe fibrosis; class
`IV = cirrhosis. A score of IIlB or IV prompted discontinu-
`ation of the drug.
`Radlographic assessments. Standard posteroanterior
`and oblique radiographs of the hands and wrists were
`obtained at the baseline visit in the randomized trial, and
`after a minimum of 28 months and 70 months of therapy.
`Radiographs were evaluated by an experienced bone radiol-
`ogist. for the number and size of erosions. healing of
`erosions. and joint space narrowing.
`Statistical analysis. Disease variables were analyzed
`as the difference in group means between the entry (baseline)
`visit in the randomized trial and the open study visit. by
`Student's 2-tailed I-test. An intent-to-treat analysis was
`performed for the patients who discontinued the trial. Group
`means for other parameters were compared by Student's
`2-tailed I-test.
`
`RESULTS
`
`Patient course in the study. Of the 28 patients
`who had completed the randomized trial (l), 26 en-
`rolled in the long-tenn extension study. Their average
`age at entry into the randomized trial was 59 years.
`with a mean duration of disease activity of 106 months
`(range 21-320 months). Twenty-five of the 26 patients
`were seropositive (rheumatoid factor titer 2l:l60).
`and [4 were receiving prednisone (510 mg/day) at
`study entry.
`Ten patients withdrew from the study within
`the lirst 36 months (10). Since that time, an additional
`4 patients withdrew from the study. Three of these 4
`patients withdrew due to an adverse reaction and l
`withdrew due to visit noncompliance. Twelve patients
`remain in the open study and have received MTX
`therapy for at least 84 months.
`Disease elects. For the patients who remained
`in the study, significant (P s 0.002) improvement was
`noted at all study visits during months 36-84, com-
`pared with baseline, in the mean number of painful
`joints, number of swollen joints, physician global
`assessment, patient global assessment, joint pain in-
`dex, and joint swelling index. Significant improvement
`
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`

`
`84—MONTH UPDATE OF MTX TRIAL
`
`131
`
`Table 1. Changes in rheumatoid arthritis disease parameters. months 36-84 of methotrexste study
`versus baseline‘
`
`Value
`No. of
`Value st
`during
`
`Variable
`patients
`baseline
`therapy
`Ditference
`P
`
`No. of painfiiljoints
`36 months
`48 months
`60 months
`72 months
`84 months
`
`No. of swollen joints
`36months
`48 months
`60 months
`72 months
`84 months
`
`Joint pain index
`36 months
`48 months
`60 months
`72 months
`84 months
`
`Joint swelling index
`36 months
`48 months
`60 months
`72 months
`84 months
`
`Morning stifl'ness
`(minutes)
`36 months
`48 months
`60 months
`72 months
`84 months
`
`MD global assessment?
`36 months
`48 months
`60 months
`72 months
`84 months
`
`Patient global assessment?
`36 months
`48 months
`60 months
`72 months
`84 months
`
`Erythrocyte sedimentation
`rate (mmlhour)
`36 months
`48 months
`60 months
`72tnonths
`84months
`
`16
`16
`15
`13
`12
`
`16
`16
`15
`13
`12
`
`16
`16
`15
`13
`12
`
`16
`16
`15
`13
`12
`
`16
`16
`15
`13
`12
`
`15
`16
`15
`13
`12
`
`15
`16
`15
`13
`12
`
`13
`16
`13
`11
`10
`
`34.4 1 2 8
`34.4 1 2.8
`35.4 1 2.9
`37.5 1 2.1
`38.1 1 2 4
`
`32.0 1 19
`32.0 1 1 9
`32.4 1 2 0
`32.5 1 2 I
`32.0 1 2 8
`
`52.6 1 4 8
`52.5 1 4 8
`54.1 1 49
`57.6 1 4 1
`58.9 1 4 9
`
`46 9 1 3.7
`46 9 1 3.7
`47 9 1 3.9
`48 2 1 4.5
`49 5 1 5.7
`
`7.9 1 3.7
`11.1 1 4.5
`9.7 1 4.4
`11.5 1 5.0
`12.5 1 6.6
`
`8.9 1 1 9
`12.6 1 2 4
`11.3 1 2.0
`11.4 1 24
`13.7 1 1 9
`
`8.5 1 4.0
`12.0 1 4.9
`10 5 1 4.7
`12.5 1 5.4
`13.3 1 5.7
`
`9.9 1 2 4
`13.8 1 26
`12.5 1 2 2
`13.4 1 2 7
`16.4 1 2 3
`
`26.5 1 4.2
`23.3 1 4.6
`25.7 1 4.6
`25.9 1 5.1
`25.6 1 6.6
`
`23 1 1 16
`19 4 1 2.2
`21.1 1 1.7
`21 1 1 2.1
`18 3 1 2 1
`
`44 1 1 4.8
`40 6 1 5.2
`43 6 1 5.1
`45 l 1 5.4
`45 6 1 7.0
`
`37 0 1 3.4
`33 2 1 4.2
`35 5 1 3.9
`34 8 1 4.]
`33 1 1 5.2
`
`167 0 1 56.1
`167 0 1 56.1
`164 0 1 59.9
`155.0 1 68.5
`178.0 1 88.4
`
`24 0 1 9.0
`32 8 1 11 1
`23 7 1 10 6
`20.7 1 10.3
`14.7 1 5.9
`
`.
`143.4 1 56.0
`135.0 1 57.7
`141.0 1 61.0
`134.6 1 68.8
`163.3 1 82.6
`
`2 7 1 0.2
`2 6 1 0.2
`2 5 1 0.2
`2 5 1 0.2
`2 6 1 0.2
`
`2.7 1 0.2
`2.7 1 0.2
`2.6 1 0.2
`2.5 1 0.2
`2.6 1 0.2
`
`0.9 1 0 2
`0.9 1 0 2
`0.9 1 0.2
`0 8 1 0.2
`1 0 1 0.3
`
`1.0 1 0.2
`1.0 1 0.3
`0.9 1 0.2
`0.7 1 0.2
`0.9 1 0.3
`
`1 7 1 0.3
`I 7 1 0.2
`1 6 1 0.2
`1 7 1 0.3
`1 6 1 0.3
`
`1.7 1 0.3
`1.7 1 0.3
`1.7 1 0.3
`1.8 1 0.3
`1.7 1 0.4
`
`0.0001
`0.0001
`0.0001
`0.0003
`0.(IJ03
`
`0.0001
`0.0001
`0.0001
`0.01111
`0.0001
`
`0.0001
`0.0001
`0.0001
`0.0001
`0.0001
`
`0.01111
`0.0001
`0.01111
`0.01111
`0.01111
`
`0.02
`0.03
`0.04
`0.07
`0.07
`
`.
`0.0001
`0.01111
`0.0%!
`0.0001
`0.001
`
`0.0001
`0.0002
`0.0003
`0.1110]
`0.002
`
`84.3 1 9 6
`78.9 1 8 7
`72.8 1 9 7
`79.41105
`72.4 1 116
`
`52.7 1 6.7
`47 9 1 8.2
`48.2 1 6.8
`47816.4
`58 5 1 8.8
`
`28 9 1 9.8
`31 0 1 12.3
`24 5 1 10.5
`2651110
`139 1 131
`
`0.01
`0.02
`0.03
`0.03
`0.3
`
`' Values on the mean 1 SEM. Baseline data are the measurements obtained at the initial visit of the
`randomized trial. Difierence represents the degree of change at the study visit versus baseline, for
`those patients evaluated.
`1 Scored on a scale ot'0-4. whereo = none nnd4 = very severe. See Patients and Methods for details.
`
`Page 3 of 9
`
`Page 3 of 9
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`

`
`NUMBER OF PAINFUI. QINTS
`
`132
`
`oak:
`no»
`main
`
`too
`
`5
`
`1:
`
`:4
`
`as
`
`as
`vtstr month)
`
`so
`
`72
`
`as
`
`NUMBER OF SWOLLEN IOINTS
`
`no
`
`*
`CIMNII
`mom
`BASED!
`
`too
`
`6
`
`12
`
`:4
`
`as
`
`as
`vlstr «mum
`
`so
`
`72
`
`an
`
`Figure I. Mean change from baseline in number of painful joints
`and number of swollen joints. The number of patients at each visit
`was as follows: I2 months, I9 patients; 24 months. 18 patients; 36
`months, 16 patients; 48 months. 16 patients: 60 months. 15 patients;
`72 months, 13 patients; 84 months. 12 patients.
`
`also occurred in the duration of morning stillness from
`month 36 to month 60 (P s 0.04). An improvement
`from baseline in the mean erythrocyte sedimentation
`rate was observed and was statistically significant (P s
`0.03) at the assessments between month 36 and month
`72 (Table 1).
`A similar degree of improvement was observed
`in the patients who discontinued the study. Significant
`(P < 0.005) improvement was noted at the last visit,
`compared with baseline,
`in the number of painful
`joints (mean : SEM 40.7 : 4.2 at baseline versus 19.8
`2 4.6), number of swollenjoints (33.1 : 3.3 at baseline
`versus 17.1 t 3.7), physician global assessment (2.9 1
`0.2 at baseline versus 1.7 t 0.3), and patient global
`assessment (3.0 I 0.2 at baseline versus 1.5 I 0.3). in
`
`Page 4 of 9
`
`WEINBLATT ET AL
`
`patients who withdrew from the study. There was no
`significant ditference in the response between the
`patients who remained in the study and those who
`withdrew.
`
`There was a sustained clinical response in the
`disease parameters throughout the study. There was
`no significant difference in the degree of improvement
`noted at 12 months versus improvement at 84 months.
`The number of painful and swollen joints remained
`substantially improved between 36 months and 84
`months (Figure 1).
`The number of individual patients who re-
`sponded to MTX therapy was determined using the
`arbitrary definitions described above. There were no
`remissions as defined by the ACR criteria (14). Of the
`12 patients who remained in the study at 84 months, 10
`(83%) demonstrated a “marked” improvement in the
`joint pain index, 11 (92%) in the joint swelling index, 5
`(42%) in the physician assessment, and 6 (50%) in the
`patient assessment of disease activity. Five of these 12
`patients exhibited the most “substantial” response to
`MTX at their last visit, achieving a marked improve-
`ment in the joint pain index. joint swelling index, and
`physician and patient assessments of disease activity.
`There was no unique dilference in demographic pro-
`file, prednisone therapy, or disease activity at entry in
`the patients who achieved a “response" compared
`with the other patients. Of the 14 patients who with-
`drew from the study, 9 (64%) demonstrated a
`“marked" improvement
`in the joint pain index, 7
`(50%) in the joint swelling index, 3 (21%)
`in the
`physician assessment, and 6 (43%) in the patient
`assessment of disease activity at their last study visit.
`The mean 1- SEM weekly dosage of MTX was
`8.9 2 0.99 mg (range 2.5-15) at 48 months, 9.5 : 1.!
`mg (range 5.0—15.0) at 60 months, 10.0 : 1.1 mg (range
`5.0—15.0) at 72 months, and 10.2 1 1.1 mg (range
`5.0—15.0) at 84 months. Fourteen patients were receiv-
`ing prednisone at study entry, at a mean : SEM
`dosage of 7.1 1 0.8 mg/day. At the last study visit, the
`mean dosage of prednisone in these 14 patients was 2.7
`2 0.9 myday. which was a significant reduction (P =
`0.0005). Seven of the 14 patients had been able to
`discontinue prednisone completely, with no increase
`in disease activity. Of the 12 patients who remained in
`the study, 5 of the 12 were taking prednisone (5.5 2 1.2
`mg/day) at study entry. At 84 months,
`the mean
`dosage of prednisone in these 5 patients was 2.8 1- 1.1
`mg/day (P = 0.09). Two of the 5 patients discontinued
`prednisone therapy, and no patient required an in-
`crease in prednisone dosage, or initiation of pred-
`
`Page 4 of 9
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`

`
`84-MONTH UPDATE OF MTX TRIAL
`
`133
`
`
`
`Figure 2. Comparison posteroanterior radiographs of the second
`and third metacarpophalangeal joints. A, Baseline. The radiograph
`shows erosion of the index and middle metacarpophalangeal joints
`and cartilage space narrowing. B. After 42 months of methotrexate
`therapy, new bone formation from the margins of the third meta-
`carpophalangeal joint and from the metacarpal erosion (arrows) is
`noted. C, After 84 months of methotrexate therapy, additional new
`bone formation has developed at the third (arrow) and probably the
`second metacarpal erosion sites. There is further subluxation of the
`second metacarpophalangeal joint. No new erosions are present.
`
`with joint space narrowing. The 4 patients who did
`not demonstrate progression over the 84 months of
`therapy had a “substantial“ clinical response with
`MTX therapy.
`Findings on liver biopsy. Liver biopsies were
`performed in 17 patients at 24 months, in 15 patients at
`48 months, and in 10 patients at 72 months. There were
`no complications, and no patient required overnight
`hospitalization or blood transfusion. At the time of the
`first biopsy, after 24 months of therapy and a mean :
`SEM cumulative dose of MTX of 1,082 : 104.0 mg
`(range 695—2,088), there was no evidence of fibrosis or
`cirrhosis. In the 15 patients who underwent a second
`biopsy after 48 months of therapy. the cumulative dose
`of MTX at the time of this biopsy was 2,006 = I93 mg
`(range l,152—3,572). Results on 13 of the biopsies were
`graded as class I, 1 as class II, and 1 as class llIA (mild
`fibrosis). At the time of the third liver biopsy, per-
`formed in 10 patients after 72 months of therapy, the
`cumulative dose of methotrexate was 3,095 i 315 mg
`(range 1,597-4,635). Seven specimens were graded as
`class I, 2 as class II, and 1 as class IIIA. Three patients
`exhibited a change in classification: 2 from class I to
`class II, and 1 from class I to class lllA (Table 2). The
`
` C
`
`nisone therapy, during the study. Of the 12 patients
`who remained in the study, 4 were able to stop taking
`NSAIDs and another 3 had the NSAID dosage re-
`duced by 50% without an increase in disease activity.
`In 1 additional patient, NSAID treatment was discon-
`tinued due to an adverse reaction.
`
`Ten patients had radiographic evaluations of
`the hand and wrist perfonned at entry to the random-
`ized trial, after a mean : SEM of 41 t 1.4 months
`(range 28-42 months) of MTX therapy. and again after
`81 1 1.7 months (range 70-84 months) of MTX. Six of
`these patients exhibited disease progression on this
`latest radiograph compared with the earlier radiograph
`(mean 40 months of therapy), with an increase in the
`number and size of erosions, deformity, and joint
`space narrowing. Three patients showed no progres-
`sion with no new erosions, and 1 patient continued to
`demonstrate erosion healing with associated joint
`space narrowing (Figure 2). All 5 of the patients who
`exhibited progression on the first series of radiographs
`continued to show progression on this latest set of
`radiographs. Of the 3 patients who exhibited healing of
`erosions on the earlier radiographs. 2 did not develop
`new erosions and 1 continued to show erosion healing
`
`Page 5 of 9
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`

`
`134
`
`WEINBLATT ET AL
`
`Table 2. Histologic findings on liver biopsy‘
`
`Of the adverse events that occurred between 36
`
`Patient
`
`24 months
`
`48 months
`
`72 months
`
`I
`2
`3
`4
`5
`6
`7
`8
`9
`I0
`I I
`I2
`I3
`I4
`I5
`I6
`I7
`
`I
`II
`I
`I
`II
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`II
`IIIA
`I
`I
`I
`withdrew
`Withdrew
`
`I
`I
`I
`II
`1
`I
`I
`I
`II
`[HA
`Withdrew
`withdrew
`withdrew
`Refused
`Pending
`withdrew
`Withdrcw
`
`’ Biopsy findings were scored according to the Roenigk classifica-
`tion (I5), where class I = normal: rru'ld fatty infiltration. mild nuclear
`variability, mild portal inflammation; class II = moderate to severe
`fatty infiltration. moderate to severe nuclear variability. portal tract
`inflammation, and moderate to severe portal tract expansion; class
`IIIA = mild fibrosis; class [113 = moderate to severe fibrosis; and
`class IV = cirrhosis.
`
`patient with the class IIIA biopsy at 72 months under-
`went another biopsy at 84 months, which again
`showed mild fibrosis (class IIIA). All biopsy speci-
`mens exhibited variable degrees of abnormality, which
`included minimal to moderate fatty infiltration, nuclear
`size variability, hepatocyte necrosis, and periportal
`inflammation. No specimens showed moderate to se-
`vere fibrosis or cirrhosis.
`
`Adverse experiences. Between 36 months and 48
`months, 12 of the 16 patients still enrolled in the study
`(75%) had at least 1 adverse reaction. During this time
`period, 4 of these patients had adverse events that
`were believed to be related to MTX therapy. including
`a viral syndrome, disseminated cutaneous zoster re-
`quiring hospitalization and antiviral treatment, urinary
`tract infection, stomatitis, and alopecia. Between 48
`months and 60 months, 9 of 16 patients (56%) had 1 or
`more adverse events; in 4 of the patients, reactions
`were believed to be drug related. This included a
`urinary tract infection, headaches, alopecia leading to
`drug discontinuation, and pneumonitis leading to drug
`discontinuation. Between 60 months and 72 months, 9
`of 13 patients (69%) experienced I or more adverse
`events, including 4 patients who had reactions that
`were believed to be drug related. This included an
`episode of diarrhea, viral pneumonia, rash, and 1 case
`of interstitial pneumonitis leading to the patient’s
`withdrawal from the study. Between 72 months and 84
`months, there were no adverse events reported.
`
`months and 84 months, 3 required hospitalization,
`including 2 cases of pneumonitis and 1 case of dissem-
`inated cutaneous zoster. The zoster occurred in a
`
`patient who had non-insulin-dependent diabetes and
`was receiving regular low-dose prednisone. Three
`patients who had noted an increase in the size and the
`number of rheumatoid nodules within the first 36
`
`months of therapy continued to observe this reaction
`throughout the study.
`One patient developed 2 episodes of mild
`thrombocytopenia (1.4-1.47 x 1051mm’) between
`months 72 and 84 of therapy. One patient developed
`mild leukopenia (2,600/mm’) after 70 months of ther-
`apy. Between 36 months and 84 months of therapy,
`only 1 patient had a 2-fold or greater elevation in
`serum transaminase levels; liver biopsies did not show
`fibrosis over 72 months in this patient.
`Two patients developed pneumonitis during
`this time period. Both patients were men who had
`underlying restrictive lung disease. One, a 72-year-old
`nonsmoker, had chronic interstitial fibrosis on a base-
`line chest radiograph with a stable carbon monoxide
`diffusing capacity of 53% of predicted prior to the
`institution of MTX. He developed acute dyspnea,
`fever, and increasing interstitial
`infiltrates after 66
`months of MTX therapy. Bronchoalveolar lavage was
`nondiagnostic; an open lung biopsy showed advanced
`pulmonary fibrosis,
`interstitial
`lymphocytic infiltra-
`tion, macrophages, occasional giant cells, pleuritis,
`and vasculitis. Histologic findings in the lung were
`interpreted as showing advanced rheumatoid lung dis-
`ease, though superimposed MTX toxicity could not be
`excluded. MTX was discontinued and high-dose cor-
`ticosteroids were instituted, with stabilization in pul-
`monary symptoms.
`Another patient. a 65-year-old man who was a
`heavy cigarette smoker, had chronic interstitial basilar
`fibrosis shown on chest radiograph, prior to the initi-
`ation of MTX. Pulmonary function studies at the time
`of that radiographic evaluation showed an obstructive
`and restrictive pattern. with a forced expiratory vol-
`ume in I second of 2.09 liters, aforced vital capacity of
`3.72 liters, and a carbon monoxide dilfusing capacity
`of 56% of predicted. This patient developed acute
`dyspnea after 48 months of MTX therapy. Chest
`radiography showed chronic severe interstitial bibasi-
`lar disease. Pulmonary function testing showed a
`severe restrictive defect, with a dilfusing capacity of
`31% of predicted. MTX was discontinued, the pres-
`ence of infection was niled out. and high-dose cor-
`
`Page 6 of 9
`
`Page 6 of 9
`
`

`
`84-MONTH UPDATE OF MTX TRIAL
`
`135
`
`Table 3. Patients who withdrew from the study
`
`Reason for
`withdrawal
`
`No. (96) of
`patients
`
`Lack of elllcacy
`Adverse experience
`Pneumonitis
`Alopecia
`lntercurrent medical problem
`Administrative‘
`
`Total
`
`1 (4)
`3 (I2)
`2 (8)
`I (4)
`1 (4)
`9 (35)
`
`I4 (54)
`
`Month
`
`I8
`
`48. 66
`60
`2
`0-24 (8 patients),
`46 (l patient)
`
`' Withdrawals due to visit noncompliance, patient relocation, pa-
`tient apprchension. alcohol consumption.
`
`ticosteroids were administered, with stabilization
`
`of the symptoms.
`Withdrawals. Since the last update at 36
`months, 4 patients have withdrawn from the study
`(Table 3). One patient was withdrawn at month 46 due
`to visit noncompliance. One patient withdrew at 60
`months due to progressive alopecia which did not
`stabilize with reduction of the MTX dosage, and 2
`patients withdrew, at months 48 and 66, due to pneu-
`monitis.
`
`DISCUSSION
`
`After 84 months of therapy, methotrexate re-
`mained an effective treatment among the rheumatoid
`arthritis patients enrolled in this open prospective
`study. The study population comprised patients who
`had "refractory“ RA and had received prior second-
`line therapies including gold salts, hydroxychlono-
`quine, D-penicillamine, and azathioprine, which had
`been discontinued due to lack of efiicacy or to toxicity.
`A rapid improvement in disease activity was observed
`in this population in our initial 24-week randomized,
`placebo-controlled crossover study (1) and was sus-
`tained over the initial 36 months of the open prospec-
`tive study (l0). This update, after 84 months of ther-
`apy, continues to show a sustained clinical response
`with MTX therapy. There was no greater improve-
`ment in disease parameters observed over this time
`period, and no patient met the ACR criteria for remis-
`sion (14). However, individual patient responses in the
`joint pain and joint swelling index were highly favor-
`able with long-term MTX administration. The plateau
`elfect in clinical response that was observed after 6
`months of therapy has continued over 84 months.
`These observations are similar to those reported by
`Kremer and Lee after a mean of 29 months, 53
`months, and 89 months of observation (9,l6,l7).
`In addition to the clinical improvement, there
`
`was a significant reduction in mean prednisone dosage,
`and 50% of the patients were able to discontinue their
`prednisone therapy during the trial. Several patients
`were also able to discontinue NSAIDS. This cortico-
`
`steroid sparing elfect with MTX has been noted in
`other studies (12,16).
`The radiographic findings noted in this followup
`study are consistent with previously published reports
`in which radiographic progression has generally been
`observed, but with a small number of patients showing
`stabilization (I l , I8-20). Progression was noted in most
`of our patients; however, in several patients the dis-
`ease did not progress radiographically, and 1 patient
`continued to show erosion healing. This lack of pro-
`gression was observed in the patients who achieved
`the most impressive clinical response. This is similar
`to the observations in a study by Nordstrom and
`colleagues (18), in which radiographic progression was
`noted in all but 2 patients; these 2 patients met criteria
`for remission. Kremer and Lee noted erosion healing
`after a mean of 29 months of therapy (9), but in their
`followup study afier a mean of 53 months of therapy,
`new erosions were noted (16). It should be empha-
`sized, as noted in our earlier report (10), that the
`healing of erosions was associated with further joint
`space narrowing.
`The dosage of MTX utilized from months 36 to
`84 ranged from 2.5 to 15.0 mg/week. Frequent dose
`titrations were required to adjust for eflicacy and
`toxicity. The maximum dosage of MTX allowed in this
`study was [5 mglweek. In several patients, higher
`doses might have been utilized in an attempt
`to
`achieve greater clinical eflicacy, but the protocol did
`not allow for this.
`
`Drug-related toxicities occurred throughout the
`study. Between 36 months and 84 months, there were
`3 adverse events that necessitated hospitalization.
`These included 2 cases of pneumonitis and 1 case of
`disseminated cutaneous zoster. The overall incidence
`
`of adverse events (both drug-related and non-drug-
`related) remained constant over the 84-month period
`of observation. Clinical toxicity occurred throughout
`the study irrespective of the duration of therapy.
`Of the 2 patients who developed pneumonitis
`during MTX thel‘8PYa both had underlying restrictive
`lung disease. This was a noteworthy finding: 2 studies
`have suggested that underlying pulmonary disease is a
`potential risk factor for MTX-associated pneumonitis
`(21,22). To date, risk factors for this toxicity have not
`been comprehensively defined, however. The clinical
`course, histopathologic findings, and response to cor-
`ticosteroids in these 2 patients were similar to pub-
`lished experiences with other patients (23).
`
`Page 7 of 9
`
`Page 7 of 9
`
`

`
`136
`
`WEINBLATI‘ ET AL
`
`The development of new rheumatoid nodules
`despite an improvement in articular disease continued
`to be observed between 36 and 84 months of treat-
`
`ment. Hematologic toxicity, primarily mild thrombo-
`cytopenia, was also noted during this long-tenn up-
`date, emphasizing the need for regular monitoring of
`these laboratory parameters even after long-tenrr ad-
`ministration of the drug. Serum transaminase eleva-
`tions of greater than twice the normal level were rarely
`observed between months 36 and 84 of therapy. This
`diflers from the results reported by Kremer et al (24)
`and might be explained by our definition of elevated
`enzymes (2-fold over normal) and by the fact that the
`frequency of laboratory monitoring was decreased to
`every 8 weeks afier month 60.
`Results from the liver biopsies obtained at 24,
`48, and 72 months in this study population are reas-
`suring. There have been no cases of either moderate
`fibrosis or cirrhosis in this cohort. The hepatic his-
`tologic features are similar to those reported by other
`investigators (24-26). Serious liver disease (on both
`clinical and pathologic grounds) has, however, been
`observed in other RA patients receiving MTX (27-30);
`risk factors for this toxicity have not yet been identified.
`Of the 26 patients who enrolled in the open
`prospective study, 12 (46%) remain in the trial. Of the
`I4 patients who were withdrawn from the study, the
`reason for withdrawal was toxicity (alopecia, pneumo-
`nitis) in 3, lack of eflicacy in I, an intercurrent medical
`problem in l, and administrative factors in 9. The
`withdrawal rate of 54% over 7 years is similar to rates
`reported by other investigators. Fehlauer et al (31)
`reported a withdrawal rate of 52% over 24 months in
`I24 patients receiving methotrexate. Alarcon et al (32)
`projected that of I52 patients followed at a university
`center, the probability of continuing MTX at 6 years
`was 49%; toxicity was the most common reason for
`drug discontinuation. This favorable withdrawal rate
`for MTX in patients with relatively chronic and refrac-
`tory disease has also been observed in patients receiv-
`ing MTX for less chronic and refractory RA (12).
`The eflicacy results observed in any open pro-
`spective study must be interpreted with some caution
`due to the open, unblinded nature of the study, enthu-
`siasm by patient and investigator, and economic in-
`centives such as free medication, ofiice visits, and
`laboratory tests. In studies of patients with “refracto-
`ry” disease, the paucity of other available therapies
`must also be considered when interpreting withdrawal
`rate data. In our study, however, the individual patient
`response data suggest that a beneficial response did
`occur with MTX.
`
`The results of this open prospective study pro-
`
`vide evidence that the elfectiveness of methotrexate
`
`has been maintained over 7 years in this select popu-
`lation of rheumatoid arthritis patients. Interpretation
`of the favorable results must be balanced by the open
`study design and small sample size. Toxicity remains
`constant,