1492
`
`ARTHRITIS & RHEUMATISM Volume 37
`Number 10, October 1994, pp 1492-1498
`0 1994, American College of Rheumatology
`
`METHOTREXATE IN RHEUMATOID ARTHRITIS
`
`A Five-Year Prospective Multicenter Study
`
`MICHAEL E. WEINBLATT, HERBERT KAPLAN, BERNARD F. GERMAIN, SIDNEY BLOCK,
`SHELDON D. SOLOMON, RICHARD C. MERRIMAN, FREDERICK WOLFE, BRUCE WALL,
`LARRY ANDERSON, ERIC GALL, DENNIS TORRETTI. and BARBARA WEISSMAN
`
`Objective. To evaluate the efficacy and tolerabil-
`ity of oral methotrexate (MTX) in rheumatoid arthritis
`(RA) in a long-term prospective trial.
`Methods. One hundred twenty-three patients
`with RA who completed a 9-month multicenter random-
`ized trial comparing MTX and auranofin enrolled in this
`5-year prospective study of MTX.
`Results. Significant (P = 0.OOOl) improvement
`compared with baseline was noted in all clinical disease
`variables, functional status, and the Westergren erythro-
`cyte sedimentation rate (ESR). “Marked improvement”
`occurred in 87 (71%) and 85 (69%) of the patients,
`respectively, in the joint paidtenderness index and the
`joint swelling index at the last evaluable visit. Forty-four
`patients (36%) withdrew during the study. Eight (7%)
`withdrew due to lack of efficacy, and 8 (7%) due to
`adverse experiences, including 1 patient with cirrhosis.
`At 5 years, 64% of patients were still taking MTX and
`completed the study.
`
`Supported by a research grant from Lederle Laboratories,
`Pearl River, New York.
`Michael E. Weinblatt, MD: Brigham and Women’s Hospi-
`tal, Boston, Massachusetts; Herbert Kaplan, MD: Denver Arthritis
`Clinic, Denver, Colorado; Bernard F. Germain, MD: University of
`South Florida College of Medicine, Tampa; Sidney Block, MD:
`Bangor, Maine; Sheldon D. Solomon, MD: Arthritis, Rheumatic,
`and Back Disease Associates, Cherry Hill, New Jersey; Richard C.
`Merrirnan, MD: Baylor University Medical Center, Dallas, Texas;
`Frederick Wolfe, MD: The Arthritis Center, Wichita, Kansas;
`Bruce Wall, MD: Columbus Medical Center, Columbus, Ohio;
`Larry Anderson, MD: Rheumatology Associates, Portland, Maine;
`Eric Gall, MD: Arizona Health Sciences Center, Tucson; Dennis
`Torretti, MD: Geisinger Medical Center, Danville, Pennsylvania;
`Barbara Weissman, MD: Brigham and Women’s Hospital.
`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 November 30, 1993; accepted in
`revised form May 10, 1994.
`
`Conclusion. This large prospective study of long-
`term MTX treatment demonstrates sustained clinical
`response and improvement in the Westergren ESR and
`functional assessment scores, with an acceptable toxicity
`profile.
`
`Small long-term prospective studies of low-
`dose methotrexate (MTX) have demonstrated sus-
`tained clinical response in patients with active rheu-
`matoid arthritis (RA) (1,2). The patients in these
`studies had had either lack of response to, or intoler-
`able side effects with, standard second-line therapies
`including gold salts. Reported herein are the findings
`of a 5-year prospective study of MTX treatment in 123
`patients who had not received prior gold salt therapy.
`
`PATIENTS AND METHODS
`One hundred twenty-three patients with RA who had
`successfully completed a 9-month multicenter randomized
`trial comparing MTX and auranofin (3) enrolled in a 5-year
`open study of MTX. Patients were not eligible to enroll in the
`initial randomized trial (3) if they had ever received therapy
`with gold salts, D-penicillamine, MTX, or azathioprine.
`Patients were allowed to continue, if needed, treatment with
`aspirin or another nonsteroidal antiinflammatory drug andlor
`prednisone at a dosage not to exceed 10 mg/day. MTX
`tablets (2.5 mg) were ingested once a week. During the open
`study, adjustments in the MTX dosage were allowed; the
`maximum dosage was 20 mglweek. Clinical evaluations were
`performed every 12 weeks and included determinations of
`the number of painful joints, number of swollen joints, joint
`tendernesdpain index, joint swelling index, duration of
`morning stiffness, and patient and physician global assess-
`ments (3). A modified Stanford Health Assessment Ques-
`tionnaire (MHAQ) (4) was completed at baseline, yearly,
`and at the last study visit.
`Overall response to treatment was designated using
`the following arbitrary criteria: 1) Therapeutic remission,
`defined by the preliminary criteria of the American College
`
`Page 1 of 7
`
`Frontier Therapeutics Exhibit 1023
`
`

`
`LONG-TERM MTX TREATMENT IN RA
`
`1493
`
`89/34
`
`51.6 f 1.0
`26-81
`
`Table 1. Demographic and clinical characteristics of the 123
`rheumatoid arthritis patients studied
`No. from MTX groupho.
`from AUR group*
`Age, years
`Mean t SEM
`Range
`Disease duration, months
`Mean rt SEM
`Median
`Range
`No. (%) receiving prednisone
`(510 mg/day)
`No. (%) rheumatoid factor
`positive
`* Patients had previously been enrolled in a 36-week randomized
`trial comparing methotrexate (MTX) and auranofin (AUR) (ref. 3).
`
`76 f 9.7
`30
`6-612
`
`27 (22)
`95 (77)
`
`of Rheumatology (ACR; formerly, the American Rheuma-
`tism Association) (5); 2) Marked improvement in the joint
`swelling index and the joint tendernesslpain index, defined
`as a decrease of >50% in the values determined in the open
`study compared with values at baseline; 3) Improvement in
`physician and patient assessments of disease activity repre-
`senting changes of at least 2 integers in the 0-4 scale, or from
`mild to asymptomatic; and 4) Paulus criteria for response,
`defined as improvement in 4 of 6 selected parameters (6)
`(improvement defined as 220% improvement in morning
`stiffness, joint paidtenderness index, joint swelling index,
`and Westergren erythrocyte sedimentation rate [ESR] and
`r2-grade improvement in physician global and patient as-
`sessments).
`Every 4 weeks for the first 12 months of the study,
`and every 6 weeks thereafter, a complete blood cell count
`
`Table 2. Changes in clinical and laboratory Dammeters over the 60 months of the studv*
`Mean value
`at baseline Mean Mean f SEM
`visit
`value
`change
`
`Parameter,
`visit (month)
`
`n
`
`Pt
`
`95% CI
`
`12.10-27.59
`0.0001
`19.85 2 3.00
`21.98
`41.83
`66
`60
`* No. of painful joints is the number
`with tenderness on pressure and/or pain on passive motion of a
`t i e number of diarthroidial joints with swelling, of a possible 66.
`possible 68. No. of swollen joints is
`
`Page 2 of 7
`
`

`
`1494
`
`WEINBLATT ET AL
`
`was performed. Every 12 weeks, serum alkaline phos-
`phatase, serum aspartate and alanine aminotransferase, total
`bilirubin, and serum albumin and creatinine levels and
`Westergren ESR were measured.
`MTX was temporarily discontinued if the white
`blood cell (WBC) count decreased to <3,300/mm, the plate-
`let count decreased to <1.5 x 10s/mm, the hepatic enzyme
`values increased to greater than twice the upper limit of
`normal, or a significant clinical adverse experience occurred.
`Abnormal findings that persisted longer than 3 weeks follow-
`ing discontinuation of MTX led to withdrawal from the
`study. Patients were also withdrawn from the study if the
`WBC count fell to <1,500/mm, the platelet count fell to
`<1.O X 1OS/mm, the serum creatinine level increased to >1.5
`mg/dl, the hemoglobin and hematocrit values showed a
`progressive decline, or a serious adverse effect occurred.
`Radiographs of the hands and wrists were obtained at
`baseline and after 18 months and 36 months of MTX therapy.
`A standardized protocol for obtaining and scoring these
`radiographs was used in this study (7), and radiographs were
`evaluated by 4 radiologists who were blinded with regard to
`their sequence.
`A completer analysis was performed, in which dis-
`ease variables were analyzed, by Student’s 2-tailed t-test, for
`the significance of the difference in group means between the
`final study visit and the baseline visit for all patients who
`completed the study. The 4 primary disease variables were
`defined as the number of painful joints, number of swollen
`joints, and patient and physician global assessments. The
`baseline visit was defined as the visit immediately prior to
`initiation of MTX treatment. For those patients who re-
`ceived MTX in the randomized trial (3) and subsequently
`enrolled in the open study, the baseline visit was the initial
`visit in the randomized trial. For the patients who received
`auranofin in the randomized trial and subsequently enrolled in
`the open study of MTX, the baseline visit was the last visit in
`the auranofin study. We computed P values for the intermedi-
`ate visits to indicate when changes were first apparent; how-
`ever, these were considered to be of secondary importance.
`Efficacy parameters were also analyzed using an end-point
`analysis according to the intent-to-treat principle. The end
`point was defined as the @-month visit in patients who com-
`pleted the study and as the last visit in the study for patients
`who withdrew prior to study completion. Comparison be-
`tween groups was done by chi-square analysis.
`
`RESULTS
`One hundred twenty-three patients (36 men, 87
`women) enrolled in this long-term study. The charac-
`teristics of the study population are described in Table
`1. Seventy-nine patients (64%) successfully completed
`the 60-month study. Among the patients who received
`60 months of MTX therapy, there was a significant
`(P = 0.0001) improvement compared with baseline in
`the number of painfulkender joints, number of swollen
`joints, patient and physician global assessments, and
`Westergren ESR (Table 2). A significant improvement
`
`b
`
`?R
`
`50 -
`6 0 -
`70-
`
`:
`
`:
`
`I
`
`,
`
`,
`
`,
`
`,
`
`- Painful Joints
`- -. Swollen Joints
`
`,
`
`<
`
`
`
`100
`
`0
`
`6mo
`
`12mo 24mo 36mo 48mo 60mo
`Time
`Figure 1. Mean percent change from baseline in the number of
`painful joints and the number of swollen joints, in rheumatoid
`arthritis patients treated with methotrexate. The number of patients
`at each visit was as follows: 120 patients at 12 months, 109 patients
`at 24 months, 98 patients at 36 months, 88 patients at 48 months, and
`70 patients at 60 months.
`
`was also noted in the joint paidtenderness index, joint
`swelling index, and duration of morning stiffness (data
`not shown but available on request).
`A significant improvement in these disease vari-
`ables was observed at each visit over the entire course
`of the study. At the last visit at 60 months, there was
`a mean 2 SEM improvement of 13.6 k 1.5 in the
`number of painful joints, an improvement of 11.7 -+ 1.2
`in the number of swollen joints, a 0.85 f 0.1-grade
`improvement in the physician global assessment,
`improvement in the pa-
`and a 0.77 f 0.1-grade
`tient global assessment. The mean number of painful
`joints and swollen joints had decreased by 64% at
`month 60 (Figure 1); there was no significant differ-
`ence noted between the improvement at month 6 and
`that at month 60. Of the 79 patients who finished the
`study, the MHAQ was completed by 64. A significant
`improvement (P < 0.001) was observed between
`the mean 2 SEM baseline score of 0.71 ? 0.05 and the
`60-month score of 0.46 * 0.05. MHAQ data from
`the last study visit (end-point analysis) were available
`for 95 of the 123 patients who enrolled in the study,
`and similar improvement was observed (0.57 * 0.05 at
`the last visit, compared with 0.79 f 0.05 at baseline; P
`< 0.001).
`A significant improvement in disease variables
`was also noted in the end-point analysis (Table 3). All
`123 patients returned for at least 1 followup visit and
`thus were included in this analysis.
`A categorical assessment of marked improve-
`ment, determined as described in Patients and Meth-
`ods, was performed for each patient at the last evalu-
`
`Page 3 of 7
`
`

`
`LONG-TERM MTX TREATMENT IN RA
`
`1495
`
`Table 3. Changes in disease parameters: intent-to-treat analysis*
`Last
`Baseline
`n
`study visit
`visit
`Parameter
`18.57 * 0.99
`8.79 2 1.0
`21.93 2 1.07
`123
`No. of painful joints
`7.36 2 0.6
`No. of swollen joints
`123
`1.23 2 0.1
`2.10 2 0.05
`123
`Physician global assessment
`1.37 f 0.1
`2.27 f 0.07
`123
`Patient global assessment
`ESR
`27.8 f 2.2
`42.13 & 2.62
`123
`* Values are the mean ? SEM. See Table 2 for explanations and abbreviations.
`
`Mean
`change
`13.15 2 1.20
`11.21 f 1.04
`0.85 2 0.07
`0.89 2 0.10
`14.38 +- 2.8
`
`P
`
`0.001
`0.001
`0.001
`0.001
`0.001
`
`95% CI
`10.3-16.0
`8.8-1 3.6
`0.69-1.01
`0.69-1.09
`7.7-21 .O
`
`able visit (mean 48 months). Marked improvement in
`the joint paidtenderness index and the joint swelling
`index occurred in 87 (71%) and 85 (69%) of the
`patients, respectively. Marked improvement in the
`physician and patient assessments of disease activity
`occurred in 25 (20%) and 35 (28%) of the patients,
`respectively. Seventy-six patients (62%) met the Pau-
`lus criteria for response (6). Three patients (2%) met
`ACR criteria for remission during MTX therapy.
`Seventy-eight patients had an elevated ESR
`(>28 mdhour) at baseline. The ESR returned to
`normal levels during MTX therapy in 40 (51%) of these
`patients (P < 0.007).
`Thirty-seven patients received prednisone dur-
`ing the study; 27 were taking prednisone at study entry
`and 10 began the therapy during the study. Eleven of
`the 37 patients discontinued prednisone; 9 of these
`patients were receiving prednisone at study entry. In 2
`of the 37 patients, the prednisone dosage was in-
`creased during the study. Overall, there was a reduc-
`tion in prednisone dosage from a mean +- SEM initial
`dosage of 6.7 * 0.4 mglday to a final dosage of 3.7 f
`0.5 mg/day (P < 0.01). The mean weekly dosage of
`MTX was 10.1 mg (range 7.5-20 mg) at month 12, 10.4
`mg (range 2.5-20 mg) at month 24, 11.3 mg (range 5-20
`mg) at month 36, 11.3 mg (range 5-20 mg) at month 48,
`and 11.3 mg (range 2.5-20 mg) at month 60.
`Radiographs were available on 36 patients who
`received MTX in the initial 9-month randomized study
`and also completed the 60-month open study. The
`mean * SEM erosion score was 13.89 & 13.6 at
`baseline, 15.78 -+ 13.2 at month 18, and 17.21 +- 15.1 at
`month 36. The change in erosion score between base-
`line and month 18 (1.89 & 6.5) was not significantly
`different (P = 0.80) from the change between month 18
`and month 36 (1.44 * 5.4). The joint space narrowing
`score was 6.2 2 7.5 at baseline, 7.9 f 8.8 at month 18,
`and 8.7 -+ 9.7 at month 36. The change in narrowing
`score between baseline and month 18 was not signifi-
`
`cantly different from the change between month 18 and
`month 36 (1.6 +- 5.1 versus 0.7 f 3.5; P = 0.40).
`Forty-four patients (36%) withdrew during the
`open study. Eight (7%) withdrew due to a lack of drug
`efficacy, 8 (7%) due to adverse experiences, 10 (8%)
`due to intercurrent illness, and 18 (15%) for adminis-
`trative reasons including visit noncompliance and re-
`location. All 8 of the patients who withdrew due to
`lack of drug efficacy had received at least 9 months of
`MTX therapy at doses that ranged from 15 mg/week to
`20 mg/week.
`Adverse events occurred frequently during the
`study. Figure 2 shows the frequency of drug- and
`non-drug-related adverse occurrences throughout the
`study period. Within the first 6 months of therapy, 74%
`of the patients had 1 or more adverse reactions,
`whereas between months 48 and 60, 46% of the
`patients had an adverse experience. Adverse experi-
`ences that were considered by the investigator to be
`related to MTX were less frequent. Between months 0
`and 6, 52% of the patients had an adverse event
`attributed to MTX, and between months 48 and 60,
`16% of the patients had an adverse experience attrib-
`
`0 All adverse events
`I Drug related adverse events
`
`% Adverse
`Events
`
`100
`
`60
`50
`40
`30
`20
`10
`
`0-6
`
`6-12 12-18 18-24 24-30 30-36 36-48 48-60
`Time (months)
`Figure 2. Frequency of adverse experiences, including methotrexate-
`related and non-drug-related experiences, over the course of the study.
`
`Page 4 of 7
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`

`
`1496
`
`WEINBLATT ET AL
`
`uted to MTX. The adverse events included gastroin-
`testinal toxicity (nausea, vomiting, diarrhea, anorexia,
`and stomatitis), headaches, rash, alopecia, and fa-
`tigue. Gastrointestinal intolerance occurred most fre-
`quently and occurred irrespective of the duration of
`therapy. Neither folic acid nor folinic acid was admin-
`istered prophylactically in this study. During the
`course of the study, however, 15 patients received
`folic acid (1-2 mg/day) for a variety of adverse events
`ascribed to MTX, including stomatitis, anemia, alope-
`cia, and an elevated mean corpuscular volume.
`Eight patients withdrew from the study due to
`adverse experiences, including headache (1 patient),
`nausea (1 patient), hematologic toxicity (3 patients),
`and hepatic toxicity (3 patients). Three patients with-
`drew due to laboratory abnormalities (leukopenia in 2
`and leukopenia with thrombocytopenia in l), which
`resolved with drug discontinuation.
`Three patients withdrew due to hepatic toxi-
`city. One of these patients withdrew after 3 years of
`therapy due to recurrent elevations ( 2 4 times normal)
`in serum transaminase levels. A liver biopsy was
`recommended but the patient refused. The second
`patient developed persistent elevations in serum
`transaminase levels (3 times normal) and a low serum
`albumin level after 3 years of MTX. A liver biopsy
`showed moderate to severe hepatic necrosis. This
`patient denied alcohol intake, and results of hepatitis B
`and C serologic studies were negative. The third
`patient, a 52-year-old man, developed ascites after 4
`years of therapy. Liver biopsy results were interpreted
`as indicative of cirrhosis. There was a history of
`moderate alcohol ingestion prior to MTX therapy, but
`the patient denied alcohol ingestion after initiation of
`MTX. Results of hepatitis B and C serologic studies
`were negative. MTX was withdrawn and the patient
`was treated with mild diuretics, with improvement in
`the ascites. A retrospective review of the records
`identified that the patient had had recurrent elevations
`in serum transaminase levels (1-2 times normal) and a
`low serum albumin level (2.8-3.4 gddl) for the 10
`months prior to the development of ascites. Two years
`after discontinuation of MTX, the ascites had resolved
`with spironolactone treatment. Blood tests continued
`to show a low serum albumin level at 2.9 gm/dl, with
`elevations above the upper limit of normal in the
`serum transaminase levels.
`Intercurrent medical problems led to with-
`drawal in 10 patients. These included malignancy
`(lung, esophagus, and pelvis) in 3 patients, and peri-
`carditis, peripheral vascular disease, corneal ulcers,
`
`asthma, hilar adenopathy , pyoderma, and cerebral
`vascular accident in 1 patient each. There were no
`cases of MTX-associated pulmonary toxicity over the
`60 months of study.
`
`DISCUSSION
`This long-term open study was an extension of
`our previous study comparing MTX and auranofin, in
`which MTX was found to be not only more effective,
`but also less toxic than auranofin over a 36-week
`period (3). Following completion of the randomized
`trial, 123 patients were enrolled in this 5-year open
`extension study of MTX. The present report is an
`update of our earlier publication on the trial status
`after a mean of 26 months of treatment (8). With the
`conclusion of the 60-month prospective study of MTX,
`this is the final report. A sustained improvement in the
`standard parameters of RA activity was noted over the
`60 months of therapy. Only 36% of the patients with-
`drew from the study, and only 8 (7%) withdrew due to
`lack of efficacy. Individual patient responses were
`highly favorable, with 71% and 69% of patients achiev-
`ing at least a 50% reduction in the painful and swollen
`joint indexes, respectively. An improvement in func-
`tional status as assessed by a standardized health
`assessment questionnaire (the MHAQ) was observed.
`A significant improvement in the Westergren ESR was
`also achieved, with normalization of previously ele-
`vated levels occurring in 51% of the patients.
`Efficacy conclusions from open prospective
`studies must be viewed with some caution due to the
`lack of a control group, the continued investigator-
`patient interaction, and the various incentives for
`patients to be maintained on the treatment regimen.
`Irrespective of this, the clinical response appears to be
`quite favorable with MTX in this group of patients.
`This large long-term study confirms the obser-
`vations of several other long-term prospective studies
`of MTX treatment (1,2,%11). In those studies the
`mean duration of disease activity was in excess of 10
`years and patients had been treated unsuccessfully
`(lack of response and/or toxicity) with gold salts or
`D-penicillamine. The majority of these patients had
`received 2 or more second-line therapies prior to the
`institution of MTX. The patients enrolled in the
`present study were a group with less chronic and
`refractory disease. The mean duration of disease was
`76 months, and patients were not eligible for the study
`if they had received any prior second-line therapy
`other than hydroxychloroquine. In this large study,
`
`Page 5 of 7
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`

`
`LONG-TERM MTX TREATMENT IN RA
`
`1497
`
`64% of the patients completed the protocol and re-
`ceived MTX for 5 years. This high rate of retention
`with MTX is similar to that reported with other groups
`of patients (12,13). In a study from the University of
`Alabama it was projected that of 152 patients who
`began taking MTX, 50% would still be receiving this
`therapy at 5 years (14).
`Adverse experiences were noted frequently and
`occurred throughout the study. All adverse experi-
`ences were reported, regardless of their relationship to
`MTX therapy. Adverse events attributable to the drug
`were, however, much less frequent, with fewer than
`20% of patients having a drug-related adverse event
`after 6 months of therapy. Only 7% of the patients
`withdrew due to either a clinical adverse experience or
`a laboratory abnormality. The potential value of folk
`or folinic acid supplementation in reducing side effects
`was not addressed in this study.
`Since our initial report (8), 3 patients were
`withdrawn from the study due to hepatic abnormali-
`ties: 1 patient was withdrawn due to recurrent eleva-
`tions in serum transaminase levels, 1 due to an abnor-
`mal biopsy result in the setting of recurrent elevations
`in serum transaminase levels, and 1 due to ascites and
`cirrhosis. The patient who developed cirrhosis had
`received MTX for 4 years. There was an earlier history
`of moderate alcohol ingestion but no history of alcohol
`ingestion while he was receiving MTX. Ten months
`prior to the development of ascites and the diagnosis
`of cirrhosis the patient had recurrent elevations in
`serum transaminase levels (1-2 times normal) and a
`low serum albumin value, despite an improvement in
`the arthritis. In this protocol, only elevations >2 times
`normal necessitated treatment interruption. These
`findings are consistent with our recent observations
`about the predictive importance of persistent abnor-
`malities in serum transaminase and serum albumin
`levels in identifying patients at risk for serious liver
`disease (15).
`Throughout this study, there was not a single
`case of MTX-associated pneumonitis. Based on earlier
`reports from several centers in which the incidence of
`this toxicity ranged from 1% to 3% (16,17), we antici-
`pated at least 2 cases over the 5-year study period.
`Risk factors for this toxicity have not yet been identi-
`fied, but underlying lung disease has been suggested as
`one risk factor (18,19). Significant pulmonary disease
`as defined by chest radiograph and pulmonary function
`testing was an exclusion criterion for enrollment in this
`study (3). It is also possible that the incidence of
`MTX-associated pulmonary toxicity is lower than ini-
`
`tially reported, which might account for the lack of
`cases in our study.
`The results of earlier, smaller studies indicate
`that methotrexate is an effective drug in the treatment
`of rheumatoid arthritis. The present findings confirm
`the efficacy, and acceptable toxicity profile, of MTX
`given over a period of several years.
`
`ACKNOWLEDGMENTS
`The authors thank Ralph Small, PharmD, Robert
`Irby, MD, Richard Polisson, MD, Jon Coblyn, MD, and our
`many colleagues and study coordinators for their contribu-
`tions and support of this study. We also thank Nancy Baker,
`MD, Piran Alibadi, MD, and Carl Winalski, MD of the
`Department of Radiology, Brigham and Women’s Hospital,
`for interpretation of radiographs, Steven Blotner, MS for
`statistical expertise, and Michael Vieira, Richard Ryan, and
`Damien Quinn for their assistance in this study.
`
`REFERENCES
`I. Kremer JM, Phelps CT: Long-term prospective study of the use
`of methotrexate in rheumatoid arthritis: update after a mean of
`90 months. Arthritis Rheum 35:138-145, 1992
`2. Weinblatt ME, Weissman BN, Holdsworth DE, Fraser PA,
`Maier AL, Falchuk KR, Coblyn JS: Long-term prospective
`study of methotrexate in the treatment of rheumatoid arthritis:
`84-month updatc. Arthritis Rheum 35: 129-137, 1992
`3. Weinblatt ME, Kaplan H, Germain BF, Merriman RC, Solomon
`SD, Wall B, Anderson L, Block S, Irby R, Wolfe F, Gall E,
`Torretti D, Biundo J, Small R, Coblyn J, Polisson R: Low-dose
`methotrexate compared with auranofin in adult rheumatoid
`arthritis: a thirty-six-week, double-blind trial. Arthritis Rheum
`33:330-338, 1990
`4. Pincus T, Summey JA, Soraci SA Jr, Wallston KA, Hummon
`NP: Assessment of patient satisfaction in activities of daily
`living using a modified Stanford Health Assessment Question-
`naire. Arthritis Rheum 26:134&1353, 1983
`5. Pinals RS, Masi AT, Larsen RA, and the Subcommittee for
`Criteria of Remission in Rheumatoid Arthritis of the American
`Rheumatism Association Diagnostic and Therapeutic Criteria
`Committee: Preliminary criteria for clinical remission in rheu-
`matoid arthritis. Arthritis Rheum 24:1308-1315, 1981
`6. Paulus HE, Egger MJ, Ward JR, Williams HJ, and the Cooper-
`ative Systematic Studies of the Rheumatic Diseases Group:
`Analysis of improvement in individual rheumatoid arthritis
`patients treated with disease-modifying antirheumatic drugs,
`based on the findings in patients treated with placebo. Arthritis
`Rheum 33:477-484, 1990
`7. Weinblatt ME, Polisson R, Blotner SD, Sosman JL, Aliabadi P,
`Baker N, Weissman BN: The effects of drug therapy on
`radiographic progression of rheumatoid arthritis: results of a
`36-week randomized trial comparing methotrexate and aurano-
`fin. Arthritis Rheum 36:613419, 1993
`8. Weinblatt ME, Kaplan H, Germain BF, Merriman RC, Solomon
`SD, Wall B, Anderson L, Block S, Small R, Wolfe F, Gall E,
`Torretti D, Polisson R: Methotrexate in rheumatoid arthritis:
`effects on disease activity in a multicenter prospective study. J
`Rheumatol 18:334-338, 1991
`9. Nordstrom DM, West SG, Andersen PA, Sharp JT: Pulse
`methotrexate therapy in rheumatoid arthritis: a controlled pro-
`
`Page 6 of 7
`
`

`
`1498
`
`WEINBLATT ET AL
`
`spective roentgenographic study. Ann Intern Med 107:797-801,
`1987
`Hanrahan PS, Scrivens GA, Russell AS: Prospective long term
`follow-up of methotrexate therapy in rheumatoid arthritis: toxi-
`city, efficacy and radiological progression. Br J Rheumatol
`28:147-153, 1989
`Sany J, Anaya JM, Lussiez V, Couret M, Combe B, Daures J-P:
`Treatment of rheumatoid arthritis with methotrexate: a prospec-
`tive open longterm study of 191 cases. J Rheumatol 18:1323-
`1327, 1991
`Wolfe F, Hawley DJ, Cathey MA: Termination of slow acting
`antirheumatic therapy in rheumatoid arthritis: a 14-year pro-
`spective evaluation of 1017 consecutive starts. J Rheumatol
`17:994-1002, 1990
`Pincus T, Marcum SB, Callahan LF: Long-term drug therapy
`for rheumatoid arthritis in seven rheumatology private prac-
`tices. 11. Second line drugs and prednisone. J Rheumatol
`19: 1885-1894, 1992
`Alarcon GS, Tracy IC, Blackburn WD Jr: Methotrexate in
`
`10.
`
`11.
`
`12.
`
`13.
`
`14.
`
`rheumatoid arthritis: toxic effects as the major factor in limiting
`long-term treatment. Arthritis Rheum 32:671476, 1989
`15. Walker AM, Funch D, Dreyer NA, Tolman KG, Kremer JM,
`Alarcon GS, Lee RG, Weinblatt ME: Determinants of serious
`liver disease among patients receiving low-dose methotrexate
`for rheumatoid arthritis. Arthritis Rheum 36:329-335, 1993
`16. Carson CW, Cannon GW, Egger MJ, Ward JR, Clegg DO:
`Pulmonary disease during the treatment of rheumatoid arthritis
`with low dose pulse methotrexate. Semin Arthritis Rheum
`16:18&195, 1987
`17. St Clair EW, Rice JR, Snyderman R: Pneumonitis complicating
`low-dose rnethotrexate therapy in rheumatoid arthritis. Arch
`Intern Med 145:2035-2038, 1985
`18. Golden MR, Katz RS, Balk RA, Neu J, Golden H: The
`relationship of pre-existing lung diseaase to the occurrence of
`methotrexate pneumonitis in rheumatoid arthritis patients (ab-
`stract). Arthritis Rheum 33 (suppl 9):S40, 1990
`19. Searles G, McKendry RJ: Methotrexate pneumonitis in rheu-
`matoid arthritis: potential risk factors; four case reports and a
`review of the literature. J Rheumatol 14: 1164-1 171, 1987
`
`Page 7 of 7