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Long-Term Prospective Study of Methotrexate in the Treatment of Rheumatoid Arthritis.

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Arthritis & 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
patients still enrolled. A significant reduction in prednisone dosage was achieved; of 14 patients taking prednisone at entry, 7 had discontinued prednisone completely. 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 effectiveness of MTX in the
treatment of RA continues to be demonstrated in this
prospective study, after 84 months of treatment.
Objective. To determine the long-term efficacy
and safety of low-dose methotrexate (MTX) in rheumatoid arthritis (RA).
Method&. 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 efficacy 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 swollenjoints, joint pain index, joint swelling
index, and physician and patient global assessments. A
50% improvement in the joint pain index and joint
swelling index was observed in more than 80% of the 12
Methotrexate (MTX) has become an established treatment in patients with active rheumatoid
arthritis (RA). The efficacy of this drug has been
demonstrated in short-term placebo-controlled studies
( I d ) , comparative trials ( 5 4 , and open prospective
studies (9-12). We have previously reported the results 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 response with an acceptable toxicity profile has been
observed in the cohort of study patients, who have
received MTX treatment for more than 7 years.
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 Laboratories.
Michael E. Weinblatt, MD: Department of Rheumatology
and Immunology; Barbara N. Weissman, MD: Department of Radiology; Donald E. Holdsworth, MD: Department of Rheumatology
and Immunology; Patricia A. Frasei, MD, MPH: Department of
Rheumatology and Immunology; Agnes L. Maier, 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 Women’s Hospital, 75 Francis Street, Boston, MA 02115.
Submitted for publication May 31, 1991; accepted in revised
form September 3, 1991.
PATIENTS AND METHODS
Patients. Twenty-six patients with classic or definite
RA (13) who completed a 24-week randomized crossover
Arthritis and Rheumatism, Vol. 35, No. 2 (February 1992)
129
130
trial comparing MTX with placebo (1) 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
antiinflammatorydrug (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 exceeding 10 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 A M 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 15 mg. Informed consent was
obtained every 12 months during the open study.
Clinical assessments. Clinical evaluations were performed by the same physician-investigatorevery 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: 1) 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 tendernesdpain index, expressed as a
sum, where each joint was graded according to the above
scale; 5) Duration of morning stiffness; 6) Physician assessment 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: 1) Therapeutic remission as
defined by the preliminary criteria of the American College
of Rheumatology (ACR; formerly, the American Rheumatism Association) (14); or 2) Marked improvement in the
joint swelling index and in the joint tendernesslpain index,
defined as a >SO% decrease in the values determined in the
open study compared with values at entry into the randomized trial, and improvement in physician and patient assessment 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 tenderness/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 albumin were obtained. MTX was temporarily discontinued if
the white blood cell count decreased to <3,500/mm3, the
polymorphonuclear leukocyte count decreased to < 1,200/
mm3, the platelet count decreased to C1.5 x 10’/mm3, 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 persisting for longer than 3 weeks were withdrawn from the study.
WEINBLATT ET AL
Liver biopsy. After 24, 48, and 72 months of MTX
therapy, a percutaneous liver biopsy was performed at an
outpatient surgical unit. The same hepatologist performed all
biopsies on all patients. The histologic sections were prepared with hematoxylin and eosin, trichrome, and reticulum
stains. The findings were interpreted by the same pathologist
and hepatologist in all cases, using the classifications described by Roenigk et al (15): class I = normal: mild fatty
infiltration, mild nuclear variability, mild portal inflammation; class I1 = 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 IIIB = moderate to severe fibrosis; class
IV = cirrhosis. A score of IIIB or IV prompted discontinuation of the drug.
Radiographic 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 radiologist, 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 1-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 r-test.
RESULTS
Patient course in the study. Of the 28 patients
who had completed the randomized trial (I), 26 en-
rolled in the long-term 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 2 1: 160),
and 14 were receiving prednisone (110 mg/day) at
study entry.
Ten patients withdrew from the study within
the first 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 1
withdrew due to visit noncompliance. Twelve patients
remain in the open study and have received MTX
therapy for at least 84 months.
Disease effects. For the patients who remained
in the study, significant (P I0.002) improvement was
noted at all study visits during months 36-84, compared with baseline, in the mean number of painful
joints, number of swollen joints, physician global
assessment, patient global assessment, joint pain index, and joint swelling index. significant improvement
131
84-MONTH UPDATE OF MTX TRIAL
Table 1. Changes in rheumatoid arthritis disease parameters, months 36-84 of methotrexate study
versus baseline*
No. of
patients
Value at
baseline
16
16
15
13
12
34.4 f 2.8
34.4 f 2.8
35.4 2 2.9
37.5 f 2.1
38.1 f 2.4
No. of swollen joints
36 months
48 months
60 months
72 months
84 months
16
16
15
13
12
32.0
32.0
32.4
32.5
32.0
Joint pain index
36 months
48 months
60 months
72 months
84 months
Value
during
therapy
Difference
P
9.7 f 4.4
11.5 f 5.0
12.5 f 6.6
26.5 f 4.2
23.3 f 4.6
25.7 4.6
25.9 f 5.1
25.6 f 6.6
*
0.0001
0.0001
0.0001
0.0003
0.0003
1.9
f 2.0
f 2.1
f 2.8
8.9 f 1.9
12.6 f 2.4
11.3 f 2.0
11.4 f 2.4
13.7 f 1.9
23.1 f 1.6
19.4 f 2.2
21.1 f 1.7
21.1 f 2.1
18.3 2 2.1
0.0001
0.0001
0.0001
0.0001
0.0001
16
16
I5
13
12
52.6 f 4.8
52.5 f 4.8
54.1 f 4.9
57.6 f 4.1
58.9 f 4.9
8.5 f 4.0
12.0 f 4.9
10.5 f 4.7
12.5 f 5.4
13.3 5.7
44.1 f 4.8
o.oO01
0.0001
0.0001
Joint swelling index
36 months
48 months
60 months
72 months
84 months
16
16
15
13
12
46.9 f 3.7
46.9 f 3.7
47.9 f 3.9
48.2 f 4.5
49.5 f 5.7
9.9 +. 2.4
13.8 f 2.6
12.5 f 2.2
13.4 2.7
16.4 f 2.3
37.0 +. 3.4
33.2 f 4.2
35.5 f 3.9
34.8 f 4.1
33.1 f 5.2
Morning stiffness
(minutes)
36 months
48 months
60 months
72 months
84 months
16
16
15
13
12
167.0 f 56.1
167.0 & 56.1
164.0 f 59.9
155.0 f 68.5
178.0 f 88.4
24.0 f 9.0
32.8 f 11.1
23.7 f 10.6
20.7 f 10.3
14.7 f 5.9
143.4 f 56.0
135.0 f 57.7
141.0 f 61.0
134.6 f 68.8
163.3 f 82.6
MD global assessmentt
36 months
48 months
60 months
72 months
84 months
15
16
15
13
12
2.7 f 0.2
2.6 f 0.2
2.5 f 0.2
2.5 f 0.2
2.6 f 0.2
0.9 f 0.2
0.9 f 0.2
0.9 f 0.2
0.8 f 0.2
1.0 f 0.3
1.7 f 0.3
1.7 f 0.2
1.6 2 0.2
1.7 f 0.3
1.6 f 0.3
o.mi
15
2.7 2 0.2
2.7 f 0.2
2.6 f 0.2
2.5 f 0.2
2.6 f 0.2
1.0 f 0.2
1.0 f 0.3
0.9 f 0.2
0.7 f 0.2
0.9 f 0.3
1.7 f 0.3
1.7 f 0.3
1.7 0.3
1.8 f 0.3
1.7 f 0.4
0.0001
0.0002
0.0003
o.oO01
0.002
84.3 f 9.6
78.9 f 8.7
72.8 f 9.7
79.4 -C 10.5
72.4 f 11.6
52.7 f 6.7
47.9 f 8.2
48.2 f 6.8
47.8 f 6.4
58.5 f 8.8
28.9 2 9.8
31.0 f 12.3
24.5 f 10.5
26.5 f 11.0
13.9 f 13.1
Variable
No. of painful joints
36 months
48 months
60 months
72 months
84 months
Patient global assessmentt
36 months
48 months
60 months
72 months
84 months
16
15
13
12
Erythrocyte sedimentation
rate (mmhour)
36 months
48 months
60 months
72 months
84 months
13
16
13
11
10
~~
f 1.9
f
7.9
f 3.7
11.1 f 4.5
*
*
40.6
43.6
45.1
45.6
5.2
5.1
5.4
f 7.0
f
f
*
*
o.Ooo1
0.0001
0.0001
0.0001
o.Ooo1
0.0001
0.0001
0.02
0.03
0.04
0.07
0.07
o.oO01
0.0001
0.0001
0.001
0.01
0.02
0.03
0.03
0.3
~
* Values are the mean f SEM. Baseline data are the measurements obtained at the initial visit of the
randomized trial. Difference represents the degree of change at the study visit versus baseline, for
those patients evaluated.
t Scored on a scale of 0-4, where 0 = none and 4 = very severe. See Patients and Methods for details.
132
WEINBLATT ET AL
NUMBER OF PAINFUL lOlNTS
n
CHANGE
FROM
6%5EUNE
. . . . . . . . . . . . .
100
6 1 2
24
36
60
48
R
i
M
VISIT hlmnths)
NUMBER OF SWOLLEN 10INTS
20
O
h
”1
l
o
6 1 2
24
o
36
48
m
60
R
M
VISIT months)
Figure 1. Mean change from baseline in number of painful joints
and number of swollen joints. The number of patients at each visit
was as follows: 12 months, 19 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 stiffness from
month 36 to month 60 (P I0.04). An improvement
from baseline in the mean erythrocyte sedimentation
rate was observed and was statistically significant (P 5
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 2 SEM 40.7 2 4.2 at baseline versus 19.8
4.6), number of swollenjoints (33.1 & 3.3 at baseline
versus 17.1 ? 3.7), physician global assessment (2.9 &
0.2 at baseline versus 1.7 ? 0.3), and patient global
assessment (3.0 & 0.2 at baseline versus 1.5 ? 0.3), in
*
patients who withdrew from the study. There was no
significant difference 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
Eubstantially improved between 36 months and 84
months (Figure 1).
The number of individual patients who responded 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 improvement in the joint pain index, joint swelling index, and
physician and patient assessments of disease activity.
There was no unique difference in demographic profile, prednisone therapy, or disease activity at entry in
the patients who achieved a “response” compared
with the other patients. Of the 14 patients who withdrew 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 & SEM weekly dosage of MTX was
8.9 0.99 mg (range 2.5-15) at 48 months, 9.5 f 1.1
mg(range5.0-15.0)at 60months, 1 O . O k 1.1 mg(range
5.CLl5.0) at 72 months, and 10.2 -t 1.1 mg (range
5.s15.0) at 84 months. Fourteen patients were receiving prednisone at study entry, at a mean ? SEM
dosage of 7.1 k 0.8 mg/day. At the last study visit, the
mean dosage of prednisone in these 14 patients was 2.7
& 0.9 mg/day, 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 f 1.2
mg/day) at study entry. At 84 months, the mean
dosage of prednisone in these 5 patients was 2.8 f 1.1
mg/day (P= 0.09). Two of the 5 patients discontinued
prednisone therapy, and no patient required an increase in prednisone dosage, or initiation of pred-
*
84-MONTH UPDATE OF MTX TRIAL
A
133
B
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 thud metacarpophalangeal 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.
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 reduced by 50% without an increase in disease activity.
In 1 additional patient, NSAID treatment was discontinued due to an adverse reaction.
Ten patients had radiographic evaluations of
the hand and wrist performed at entry to the randomized trial, after a mean
SEM of 41 5 1.4 months
(range 2 8 4 2 months) of MTX therapy, and again after
81 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 progression 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
*
*
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 2,006 193 mg
(range 1,152-3,572). Results on 13 of the biopsies were
graded as class I, 1 as class 11, and 1 as class IIIA (mild
fibrosis). At the time of the third liver biopsy, performed in 10 patients after 72 months of therapy, the
cumulative dose of methotrexate was 3,095 % 315 mg
(range 1,5974,635). Seven specimens were graded as
class I, 2 as class 11, and 1 as class IIIA. Three patients
exhibited a change in classification: 2 from class I to
class 11, and 1 from class I to class IIIA (Table 2). The
*
WEINBLATT ET AL
134
Table 2. Histologic findings on liver biopsy*
~~~~~~~~~~~
~~
Patient
24 months
48 months
72 months
1
I
I1
I
I
I
I
I
I
I
I
I
I
I
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
I1
I
I
I
I
I
I
I
I
1
I
I
1
I
I
I
I
I1
IIIA
I
I
I
Withdrew
Withdrew
I1
1
I
I
I
I1
IIIA
Withdrew
Withdrew
Withdrew
Refused
Pending
Withdrew
Withdrew
* Biopsy findings were scored according to the Roenigk classification (IS), where class I = normal: mild fatty infiltration, mild nuclear
variability, mild portal inflammation; class I1 = moderate to severe
fatty infiltration, moderate to severe nuclear variability, portal tract
idammation, and moderate to severe portal tract expansion; class
IIIA = mild fibrosis; class IIIB = moderate to severe fibrosis; and
class IV = cirrhosis.
patient with the class IIIA biopsy at 72 months underwent another biopsy at 84 months, which again
showed mild fibrosis (class IIIA). All biopsy specimens 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 severe 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 requiring 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 1 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.
Of the adverse events that occurred between 36
months and 84 months, 3 required hospitalization,
including 2 cases of pneumonitis and 1 case of disseminated 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 105/mm3) between
months 72 and 84 of therapy. One patient developed
mild leukopenia (2,600/mm3)after 70 months of therapy. 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 baseline 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 infiltration, macrophages, occasional giant cells, pleuritis,
and vasculitis. Histologic findings in the lung were
interpreted as showing advanced rheumatoid lung disease, though superimposed MTX toxicity could not be
excluded. MTX was discontinued and high-dose corticosteroids were instituted, with stabilization in pulmonary 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 initiation of MTX. Pulmonary function studies at the time
of that radiographic evaluation showed an obstructive
and restrictive pattern, with a forced expiratory volume in 1 second of 2.09 liters, a forced vital capacity of
3.72 liters, and a carbon monoxide diffusing capacity
of 56% of predicted. This patient developed acute
dyspnea after 48 months of MTX therapy. Chest
radiography showed chronic severe interstitial bibasilar disease. Pulmonary function testing showed a
severe restrictive defect, with a diffusing capacity of
31% of predicted. MTX was discontinued, the presence of infection was ruled out, and high-dose cor-
84-MONTH UPDATE OF MTX TRIAL
Table 3. Patients who withdrew from the study
Reason for
withdrawal
No. (%) of
patients
Lack of efficacy
Adverse experience
Pneumonitis
Alopecia
Intercurrent medical problem
Administrative*
1 (4)
3 (12)
2 (8)
1 (4)
1 (4)
Total
9 (35)
Month
18
%66
60
2
0-24 (8 patients),
46 (1 patient)
14 (54)
* Withdrawals due to visit
noncompliance, patient relocation, patient apprehension, 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 pneumonitis.
DISCUSSION
After 84 months of therapy, methotrexate remained 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 secondline therapies including gold salts, hydroxychloroquine, D-penicillamine, and azathioprine, which had
been discontinued due to lack of efficacy 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 sustained over the initial 36 months of the open prospective study (10). This update, after 84 months of therapy, continues to show a sustained clinical response
with MTX therapy. There was no greater improvement in disease parameters observed over this time
period, and no patient met the ACR criteria for remission (14). However, individual patient responses in the
joint pain and joint swelling index were highly favorable with long-term MTX administration. The plateau
effect 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 (9,16,17).
In addition to the clinical improvement, there
135
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 corticosteroid sparing effect 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 (1 I , 18-20). Progression was noted in most
of our patients; however, in several patients the disease did not progress radiographically, and 1 patient
continued to show erosion healing. This lack of progression 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 after a mean of 53 months of therapy,
new erosions were noted (16). It should be emphasized, as noted in our earlier report (lo), 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 mglweek. Frequent dose
titrations were required to adjust for efficacy and
toxicity. The maximum dosage of MTX allowed in this
study was 15 mg/week. In several patients, higher
doses might have been utilized in an attempt to
achieve greater clinical efficacy, 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-drugrelated) 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 therapy, 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 corticosteroids in these 2 patients were similar to published experiences with other patients (23).
WEINBLATT ET AL
136
The development of new rheumatoid nodules
despite an improvement in articular disease continued
to be observed between 36 and 84 months of treatment. Hematologic toxicity, primarily mild thrombocytopenia, was also noted during this long-term update, emphasizing the need for regular monitoring of
these laboratory parameters even after long-term administration of the drug. Serum transaminase elevations of greater than twice the normal level were rarely
observed between months 36 and 84 of therapy. This
differs 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 after month 60.
Results from the liver biopsies obtained at 24,
48, and 72 months in this study population are reassuring. There have been no cases of either moderate
fibrosis or cirrhosis in this cohort. The hepatic histologic 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
14 patients who were withdrawn from the study, the
reason for withdrawal was toxicity (alopecia, pneumonitis) in 3, lack of efficacy in 1, an intercurrent medical
problem in 1, 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
124 patients receiving methotrexate. Alarc6n et al(32)
projected that of 152 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 refractory disease has also been observed in patients receiving MTX for less chronic and refractory RA (12).
The efficacy results observed in any open prospective study must be interpreted with some caution
due to the open, unblinded nature of the study, enthusiasm by patient and investigator, and economic incentives such as free medication, office visits, and
laboratory tests. In studies of patients with “refractory” 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 effectiveness of methotrexate
has been maintained over 7 years in this select population of rheumatoid arthritis patients. Interpretation
of the favorable results must be balanced by the open
study design and small sample size. Toxicity remains
constant, and serious reactions, though rare, can occur any time during drug treatment. Regular monitoring and patient education are required even after years
of therapy. Because of the chronic nature of this
disease and the variable response to drug therapy over
time, long-term open prospective studies are needed
for all therapies under development for RA.
ACKNOWLEDGMENTS
The authors thank Kathleen Benfell and John Fanikos (Investigational Drug Service) for drug distribution, Drs.
Ronald Anderson, William Docken, Matthew Liang, and
Jean Jackson for referring patients to this study, and members of the staff of the Robert B. Brigham Arthritis Center
for their assistance.
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