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Long-term prospective trial of low-dose methotrexate in rheumatoid arthritis.

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167
LONG-TERM PROSPECTIVE TRIAL OF LOW-DOSE
METHOTREXATE IN RHEUMATOID ARTHRITIS
MlCHAEL E. WEINBLATT, DAVlD E. TRENTHAM,
PATRICIA A. FRASER, DONALD E. HOLDSWORTH, KENNETH R. FALCHUK,
BARBARA N. WEISSMAN, and JONATHAN S. COBLYN
Twenty-six patients with severe rheumatoid arthritis who had completed a randomized crossover trial of
methotrexate elected to continue to receive the drug in a
long-term prospective study. At 36 months, 16 patients
remained in the study. Over this period of time, significant improvement was noted in the number of painful
and swollen joints, physician and patient global assessments, erythrocyte sedimentation rate, and prednisone
dose. Adverse reactions occurred in 16 patients (62%),
including nausea, alopecia, headache, stomatitis, herpes
zoster, and diarrhea. Mild leukopenia (3 patients),
thrombocytopenia (3 patients), and elevated transaminase levels (8 patients) resolved with temporary drug
discontinuation. No patient withdrew due to drug toxicity. Liver biopsy specimens in 17 patients after 24 months
of treatment showed no evidence of fibrosis or cirrhosis.
A significant increase in the percentage of T3 and T4
blood cells and increases in lymphocyte proliferation to
concanavalin A and purified protein derivative of tuberculin were found after 2 years of therapy. Our findings
From the Department of Medicine, Harvard Medical
School; The Department of Rheumatology and Immunology and the
Department of Radiology, Brigham and Women's Hospital; and the
Division of Rheumatology, Beth Israel Hospital, Boston, Massachusetts.
Supported in part by a research grant from Lederle Laboratories. by USPHS research grants AM-21490, AM-37239, AM20850, and RR-05669, by The Charles A. Dana Research Institute,
and by a grant from the New England Peabody Home Foundation.
Michael E. Weinblatt, MD; David E. Trentham, MD;
Patricia A. Fraser, MD, MPH; Donald E. Holdsworth, MD; Kenneth R. Falchuk. MD; Barbara N . Weissman. MD; Jonathan S.
Coblyn, MD.
Address reprint requests to Michael E. Weinblatt, MD,
Brigham and Women's Hospital, 75 Francis Street, Boston, MA
02115.
Submitted for publication June 22, 1987; accepted in revised form September 10, 1987.
Arthritis and Rheumatism, Vol. 31, No. 2 (February 1988)
indicate that methotrexate has remained effective over 36
months of therapy, with acceptable toxicity levels and no
evidence of systemic immunosuppression.
Methotrexate (MTX) has been used in the treatment of rheumatoid arthritis (RA) for more than 2
decades (1-7). It has been shown to be effective in
short-term randomized trials (8-1 1); however, its longterm effectiveness and toxicity in RA remain unclear.
In a 36-month prospective study of oral, low-dose,
weekly MTX treatment in patients with severe RA, we
have found a sustained clinical response, as well as a
relative lack of serious toxicity.
PATIENTS AND METHODS
Patients. Twenty-eight patients with classic or definite RA (12) who had completed a randomized, crossover
trial comparing MTX with placebo were eligible to enroll in a
long-term open study of MTX. Each patient remained under
the care of his or her personal rheumatologist during the
study, was advised to abstain from alcohol, and continued to
receive, if needed, aspirin or another nonsteroidal antiinflammatory drug (NSAID). Those patients who were receiving
prednisone at entry to the randomized crossover trial were
maintained at a dosage not exceeding 10 mg/day; adjustment
of the prednisone dosage was allowed during the open study.
Methotrexate tablets (2.5 mg) were ingested at 8 AM,
8 PM, and 8 AM, beginning on the same day, once a week.
Adjustments in the MTX dosage were allowed during the
open study. The maximum dose was 15 mg/week. Informed
consent was obtained every 12 months during the open
study.
Clinical assessments. Clinical evaluations were performed 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: 1) of 66 diarthrodial joints, the number
with swelling; 2) of 68joints, the number with tenderness on
LOW-DOSE MTX IN RA
168
pressure and/or pain on passive motion; 3) joint swelling
index, expressed as a sum, where each joint was graded for
swelling on a scale of 0 = none, 1 = mild, 2 = moderate,
and 3 = severe; 4) joint tendernesdpain index, representing
the sum for joints graded according to the above scale; 5)
duration of morning stiffness; 6) physician assessment of
disease activity on a scale of 0 = asymptomatic, 1 = mild,
2 = moderate, 3 = severe, and 4 = very severe; 7) patient
assessment of disease activity using the scale described for
physician assessment.
Overall responses to treatment were derived using
the following arbitrary designations: 1) therapeutic remission, defined by the preliminary criteria of the American
Rheumatism Association (ARA) (13); 2 ) marked improvement in the joint swelling index and in the joint tenderness/
pain index, defined as a decrease 3 0 % in the values
determined in the open study compared with values at entry
to the randomized trial (9); 3) worsening, signified by increases 230% in an index. Improvement and worsening in
the physician and patient assessment of disease activity
represented changes of at least 2 integers in the 5-point
scales. Patients who achieved a marked improvement in
both the joint swelling and joint tendernessipain index and in
the physician and patient assessment of disease activity at
the 12-, 24-, and 36-month visits were termed “substantial”
responders.
Laboratory assessments. Every 4 weeks for the duration of the study, a complete blood count and levels of serum
creatinine, serum glutamic oxaloacetic transaminase, serum
glutamic pyruvic transaminase, alkaline phosphatase, and
total bilirubin were obtained. Methotrexate was temporarily
discontinued if the white blood cell count decreased to
<3,500/mm’, the polymorphonuclear leukocyte count decreased to < I ,2W/mm3, the platelet count decreased to < I .5
Table 1.
x IO’/mm’, the serum creatinine level became >1.5 mg/dl,
or the hepatic enyzme values increased to greater than twice
the upper limit of normal. Patients with abnormal findings
that persisted for longer than 3 weeks were withdrawn from
the study.
Radiographic assessments. Hand and wrist radiographs were obtained at the baseline visit of the randomized
trial. Followup radiographs were obtained after a minimum
of 28 months of therapy. The radiographs were evaluated by
the bone radiologist participating in the study, who had no
knowledge of the proper chronologic sequence of the radiographs or the patient’s clinical response to MTX. Radiographs were evaluated for number and size of erosions,
healing of erosions, and joint spacq narrowing.
Liver biopsy. After 24 mon’ths of MTX therapy, informed consent was obtained and a percutaneous liver biopsy
was performed in an outpatient surgical unit by the hepatologist participating in the study. Histologic sections of liver
were prepared with hematoxylin and eosin, trichrome, and
reticulum stains, and were interpreted by the same pathologist and the hepatologist using the classification described by
Roenigk et al (14): class 1 = normal, mild fatty infiltration,
mild nuclear variability, mild portal inflammation; class 11 =
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 IllB or IV led to discontinuation of the drug.
Immunologic assessment. At the entry visit and after
24 months of MTX therapy, 80 ml of blood was obtained for
immunologic studies. Serum aliquots were analyzed for rheumatoid factor titers by nephelometry and for immune complex
concentrations by Clq binding ( 10). Cytofluorographic enumeration of blood mononuclear cells by surface antigens was
Changes in clinical and laboratory parameters in a 36-month study of methotrexate*
Study
month?
No. of
patients
No. painful
joints
No. swollen
joints
Joint pain/
tenderness
index
Joint
swelling
index
Morning
stiffness
(mins.)
Physician
Patient
ESR
Entry
6 mos.
Difference
P
12 mos.
Difference
P
18 mos.
Difference
26
21
38.5 f 2.3
12.1 2 3.3
25.3 -t 3.8
0.0001
I1.1t3.6
26.1 f 3.9
0.0001
11.6 ? 3.7
25.6 2 3.7
0.0001
7.7t3.3
28.4 t 3.9
0.0001
9.4 f 3.8
25.1 f 4.1
0.0001
7.9 f 3.7
26.5 f 4.2
0.0001
32.2 t 1.9
14.8 2 2.9
18.9 c 2.2
0.0001
13.0f3.1
21.4 f 2.1
0.0001
13.0 f 3.3
21.4 f 2.1
o.oO01
11.3?2.1
21.9 c 1.5
0.OoOl
10.4 2 1.8
21.3 c 1.6
0.0001
8.9 f 1.9
23.1 f 1.6
0.0001
58.3 2 4.9
14.6 2 4.1
41.2 c 4.3
0.0001
12.4t3.9
42.1 f 4.4
0.0001
13.5 t 4.4
41.0 f 4.1
0.0001
9.1a3.7
43.9 t 4.4
0.0001
10.0 2 4.2
41.6 ? 4.8
0.0001
8.5 f 4.0
44.1 -t 4.8
0.0001
47.0 2 3.4
17.7 t 4.0
30.9 t 4.1
0.0001
14.8f4.1
35.2 c 3.8
O.O(H)I
15.1 t 4.3
34.9 t 3.7
0.0001
13.123.2
35.6 2 3.4
0.0001
11.3 f 2.2
3 4 . 9 k 4.0
0.0001
9.9 2 2.4
37.0 t 3.9
0.0001
150.0 f 37
51.0 2 24.2
96.8 ? 51.0
0.07
35.8211.0
117.0 ? 49.0
0.03
31.0 2 11.5
131.0 ? 50.0
0.02
24.028.0
132.2 2 47.7
0.01
30.9 t 12.0
l 3 0 . 9 t 50.0
0.02
24.0 t 9.0
143.4 t 56.0
0.02
2.6 f 0.1
1.12 2 0.2
1.7 f 0.2
0.0001
1.0?0.2
1.7 ? 0.2
0.0001
1.2 ? 0.22
1.5 f 0.3
0.0001
1.0?0.2
1.7 2 0.2
o.OoO1
0.9 2 0.1
1.7 2 0.3
0.OoOI
0.9 f 0.2
1.7 t 0.3
0.OoOl
2.8 f 0.1
1.2 f 0.3
1.5 t 0.3
0.0001
1.1c0.2
1.6 2 0.3
0.0001
1.2 f 0.25
1.5 c 0.3
0.0001
0.920.2
1.8 f 0.2
0.0001
1.0 f 0.2
1.7 2 0.3
0.0001
1.0 2 0.2
1.7 i 0.3
0.0001
64.2 f 6.0
ND
ND
ND
41.0k5.2
33.4 f 7.7
0.0003
ND
ND
ND
55.2k6.8
21.1 t 9.1
0.03
ND
ND
ND
52.7 f 6.7
28.9 k 9.8
0.01
19
19
P
24 mos.
Difference
18
P
30 mos.
Difference
16
P
36 mos.
Difference
P
16
Global assessment$
* Values are the mean f SEM. ESR = erythrocyte sedimentation rate; ND = not done.
t Entry data are the baseline measurements obtained at the initial visit of the randomized trial for all 26 patients who were enrolled in the
long-term study. The difference represents the change in the respective data at the study visit versus at entry. 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.
WEINBLATT ET AL
performed as described (10). Anti-T3 reacted with all mature
T cells, whereas anti-T4 and anti-T8 identified functionally
distinct T cell subsets. Tritiated thymidine incorporation
responses by blood mononuclear cells to an optimal quantity
of the mitogens phytohemagglutinin (PHA) and concanavalin
A (Con A) and the antigens Candida and purified protein
derivative of tuberculin (PPD) were also measured (15). A
thymidine incorporation response is expressed as a stimulation index, which is equal to the amount of tritiated thymidine
incorporated in cultures with mitogen or antigen divided by
the amount of thymidine incorporated in unstimulated cultures (both represented as mean counts per minute).
Statistical analysis. Disease variables were analyzed
as the difference in group means between the open study
visits and the entry (baseline) visit to the randomized trial,
by Student's 2-tailed t-test. Other parameters were analyzed
in terms of their group means, by Student's 2-tailed t-test.
RESULTS
Patients and study course. Of the 28 patients
who completed the randomized trial, 26 (16 women, 10
men) enrolled in this long-term extension study. Their
average age was 59 years (range 45-73), and the
average duration of disease was 106 months (range
21-320). Rheumatoid factor titer was ?1:160 in 25 of
the patients, and 14 patients were receiving prednisone
(510 mglday) at study entry.
Ten patients withdrew during the open study.
Seven of the patients withdrew within the first 9 months
of entry, including 1 who died from complications after
open heart surgery and 6 who were withdrawn for
administrative reasons (visit noncompliance, relocation).
One patient withdrew at 18 months due to continued lack
of drug efficacy. Two patients withdrew after 24 months
of therapy: 1 because of apprehension about drug toxicity and 1 due to a desire to consume alcohol; both of
these patients had experienced sustained improvement
while receiving the drug. Of the 6 patients who withdrew
from the trial for administrative reasons, 4 have continued to receive MTX from their rheumatologist.
One patient had an intraarticular injection of
corticosteroid at month 6 of the study and 1 had an
injection for carpal tunnel syndrome at month 19.
Seven patients underwent reconstructive joint surgery
or surgeries during the open study, including 2 total
hip replacements, 5 total knee replacements, 1 metacarpophalangeal arthroplasty , l metatarsal resection,
1 wrist arthroplasty, and 1 ankle arthrodesis. All
patients tolerated surgery without complications. Methotrexate was temporarily discontinued during the
immediate postoperative period.
Disease effects. In the 19 patients who completed 12 months of the extension study, significant ( P
= 0.0001) improvement occurred in the number of
169
painfulhender joints, number of swollen joints, joint
paidtenderness index, joint swelling index, and patient and physician global assessments (Table l). Significant improvement also occurred in the duration of
morning stiffness (P = 0.03) and erythrocyte sedimentation rate ( P = 0.0003).
Among the 18 patients who completed 24
months of the study, significant improvement was
noted in the duration of morning stiffness ( P = 0.01)
and erythrocyte sedimentation rate ( P = 0.03), as well
as all the other clinical parameters ( P = 0.0001).
At the 36-month visit, 16 patients remained in
the study, and significant improvement was still seen
in all parameters. No significant difference occurred in
these parameters between the 36-month visit and the
24- or 12-month visit. This sustained clinical response
is noted by the improvement in selected parameters
illustrated in Figure 1.
The number of individual patients who responded to MTX therapy was determined by using the
a.
NUMBER OF PAINFUL JOINTS
%
CHANGE
FROM
BASELINE
"
"
1
VISIT (months)
100
b.
6
12
18
24
30
36
NUMBER OF SWOLLEN JOINTS
Oh
40
CHANGE
FROM
BASELINE 60
"1
-I'-
1004
VISIT (months)
d
6
12
18
24
30
36
Figure 1. Mean percent change from baseline in a, number of painful
joints and b, 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.
LOW-DOSE MTX IN RA
170
A
B
Figure 2. Comparison posteroantenor radiographs of the hand and wrist. A, At study entry, showing extensive erosion of the proximal
interphalangealjoints, metacarpophalangealjoints, and wrist, with diffuse cartilage narrowing. B, After 42 months of methotrexate therapy,
showing sclerosis of the subchondral bone at the metacarpophalangeal,intercarpal, and radiocarpal joints.
previously described arbitrary definitions. There were
no remissions as defined by ARA criteria (13). Of the
26 patients enrolled in the study, marked improvement
in the joint paidtenderness index occurred in 18 (69%)
at 12 months, 16 (62%) at 24 months, and 16 (62%) at
36 months. Marked improvement in the joint swelling
index occurred in 17 (65%) at 12 months, 16 (62%) at
24 months, and 16 (62%) at 36 months. Definite improvement in the physician assessment of disease
activity occurred in 10 of the patients (38%) at the
12-month visit, 9 patients (35%) at the 24-month visit,
and 7 patients (25%) at the 36-month visit. Similar
improvement in the patient assessment of disease
activity was noted in 11 patients (42%) at the 12-month
visit, 10 patients (38%) at the 24-month visit, and 9
patients (35%) at the 36-month visit.
Five of the 26 patients (19%) who entered the
open study exhibited the most “substantial” response
to MTX, achieving marked improvement in the joint
paidtenderness index, joint swelling index, and physician and patient assessments of disease activity at the
12-month, 24-month, and 36-month visits. There was no
significant difference in disease variables, demographic
features, or prednisone therapy at study entry in these
5 patients compared with the other 21 patients.
The mean weekly dose of h4TX for the 26 patients
was 13.8 mg (range 2.5-15.0) at entry into the open study,
10.3 mg (range 2.5-15.0) at the 12-month visit, 9.2 mg (range
2.5-15.0) at the 24-month visit, and 8.6 mg (range 2.5-15.0)
at the 36month visit. In 9 of the patients, the dosage of MTX
was reduced, without a flare of arthritis activity. Two patients had their MTX dosage increased during the trial, to
171
WEINBLATT ET AL
A
B
Figure 3. Comparison coned radiographic views of the right thumb metacarpal joint shown in Figure 2. A, At study entry, showing extensive
bare area erosion and cartilage space narrowing. B, After 42 months of methotrexate therapy, showing remodeling of bony surfaces and filling
of erosions.
maintain clinical response. No patient was allowed a dosage
>I5 Wweek.
Fourteen patients who entered this study were
receiving prednisone therapy at a mean +- SEM dosage
of 7.1 & 0.8 mg/day. A significant reduction in the
prednisone dosage (reduction of 2.9 ? 1.1 mg/day; P
< 0.02) was noted at the 12-month visit; the reductions
were 3.0 & 0.9 mg/day and 3.2
1.1 mg/day at the
24-month and 36-month visits, respectively. Two patients stopped taking prednisone completely, without
an increase in disease activity, and the dosage was not
increased in any patient during the study. Four patients completely discontinued the use of NSAIDs and
another 4 had a 50% reduction in NSAID dosage,
without a flare of arthritis activity.
Fourteen patients had radiographic evaluations
of the hand and wrist after at least 28 months (range
*
28-42 months) of MTX therapy. Six of the patients
had a definite global worsening, including an increase
in the size and number of erosions and joint space
narrowing. Three patients had no change in their
radiographs. Five patients had an improvement in the
number and size of the erosions with evidence of
healing (Figures 2 and 3); however, an overall increase
in joint space narrowing was seen. Of the 5 patients
who demonstrated this improvement in erosions, 3
were also among those who showed the most substantial clinical response in the long-term study.
Liver biopsy. Of the 18 patients who completed
24 months of the study, 17 underwent a liver biopsy at
24 months. One patient was not biopsied because of
refusal to consent to potentially necessary blood transfusions. There were no complications, and no patient
required overnight hospitalization.
LOW-DOSE MTX IN RA
172
Table 2.
Adverse response to methotrexate in 26 patients
Type of response
No. (%)
of patients*
Clinical
Nausea
Alopecia
Headache
Stomatitis
Infections?
Herpes zoster
Rectal furuncle
Cellulitis
Urinary tract infection
Nodulosis
Diarrhea
Laboratory$
Transaminitis
Leukopenia
Thrombocytopenia
~~~~
* A total of
~
~
16 patients had adverse reactions.
t One patient had 2 separate infectious episodes (cellulitis and
a
urinary tract infection).
$ Transaminitis was arbitrarily defined as a greater than twofold
elevation of normal values for serum transaminases (serum glutamic
oxaloacetic transaminase andlor serum glutamic pyruvic transaminase). Leukopenia was defined as a white blood cell count
<3,500/mm3. Thrombocytopenia was defined as a platelet count
<i.s x 105/mm3.
At the time of biopsy, the mean cumulative
dose of MTX was 1,082 +- 104 mg (range 695-2,088).
Of the 17 biopsies, 1 had normal findings and 16
exhibited variable degrees of pathology, including
minimal to moderate fatty infiltration, nuclear size
variability, hepatocyte necrosis, and periportal inflammation. No evidence of fibrosis or cirrhosis was found
on any biopsy specimen. Fifteen specimens were
categorized as class I, and 2 were judged to have class
I1 changes.
Adverse occurrences. During this study, 16 of
the 26 patients (62%) had clinical or laboratory evidence of l or more adverse reactions that were considered to be attributable to the drug (Table 2). No
patient withdrew from the extension study because of
toxicity. Fifteen patients experienced more than 1
adverse effect from the drug. In none of these patients
was the toxicity assessed as severe. Gastrointestinal
toxicity (in particular, nausea) was found most frequently. Clinical toxicity was unrelated to the duration
of MTX therapy and occurred throughout the study.
Several of the adverse reactions required temporary
drug discontinuation and/or dosage reduction.
Bacterial infections, including a rectal furuncle,
superficial cellulitis, and a urinary tract infection,
occurred in 4 patients; 1 patient had 2 separate infections. These infections all responded to oral antibiot-
ics. Two patients receiving prednisone developed localized herpes zoster; neither of the patients was
leukopenic at the time of the infection. Three patients
noted the development of new rheumatoid nodules and
an increase in size of preexisting rheumatoid nodules;
this increase was seen only after 12 months of MTX
therapy. All of the reactions, except the nodulosis,
resolved.
Mild thrombocytopenia (1.16-1.20 x 105/mm3)
developed in 3 patients, and 2 of these patients also
developed concurrent mild leukopenia (2,800/mm3and
3,200/mm3).Mild leukopenia (3,400/mm3)was noted in
1 additional patient. A viral illness occurred in 1 of the
patients concurrently with leukopenia and thrombocytopenia; otherwise, no risk factors could be identified.
All of these abnormalities resolved with temporary
discontinuation of MTX.
Eight patients (31%) had 16 episodes of transaminitis, defined as increases greater than twice the
normal values for serum transaminase levels. In all
patients, this elevation was less than 5 times the upper
limit of normal. In all 8 patients, the elevation occurred exclusively in the first 18 months of drug
administration and was not seen thereafter. In all
instances, the hepatic enzyme elevation resolved
within 3 weeks of temporary drug discontinuation.
Immunologic effects. Significant phenotypic alterations in the T cell populations were evident after 24
months of MTX therapy. The percentages of T3 and
T4 cells were significantly ( P < 0.00005) increased
compared with the baseline values, with no significant
change in either the T8 cell subpopulation or the mean
T4:T8 ratio (Table 3). Lymphocyte function, as measured by thymidine incorporation in unstimulated cultures or after stimulation with the mitogen Con A and
the antigen PPD, was significantly (P < 0.005) enhanced after 24 months of therapy. There was also an
increased response to PHA and Candida, but these
changes were not statistically significant. There was
no significant alteration in the total lymphocyte count,
mean rheumatoid factor titer, or immune complex
concentration after MTX therapy.
DISCUSSION
Both in open (1-7) and short-term randomized
(8-1 1) trials, low-dose, weekly MTX has been reported
to be effective in the treatment of active RA. Several of
the open studies (3,7,16) showed continued efficacy with
long-term administration. In contrast, it was observed in
another study that the beneficial response found with
MTX dissipated after 16 months of therapy (17). Kremer
WEINBLATT ET AL
173
Table 3. Immunologic effects of methotrexate in 18 patients who had received 24 months of
therapy*
Baseline
Rheumatoid factor titer
Immune complexes (pg/ml)t
Absolute lymphocytes/mm3
Phenotypes+
T3
T4
T8
T4:T8 ratio
Thymidine incorporation
(background cpm)
Mitogen
Antigen
Stimulation index
Mitogen
Concanavalin A
Phytohemagglutinin
Antigen
Purified protein derivative
of tuberculin
Candida
2 years
3,699 f 1,238
1,009 f 578
1,326 f 156
2,569
273
1,228
2
2
2
483
94
130
P
NS
NS
NS
58 f 3
35 ? 3
21 f 2
2.2 t 0.3
73 f 2
50 f 2
21 2 2
2.8 2 0.4
194
264
f
f
31
42
575
782
85
420
f
f
12
48
163 f 27
455 f 69
<0.005
NS
19.5 t 5.7
20.3 f 7.5
<0.005
NS
3.9 f 0.8
13.7 f 3.5
f
f
127
152
<0.00005
<0.00005
NS
NS
<0.005
<0.005
* Values are the mean r SEM. NS = not significant.
t Normal range 0-23 pg/ml, determined by Clq binding assay.
f Percentage of cells, determined by cytofluorographic analysis.
and Lee (18) reported a significant improvement in
disease-related parameters in a prospective long-term
trial of 29 patients. The clinical response occurred early
and reached a plateau after 6 months of therapy. This
improvement was generally maintained for an additional
18 months of observation.
The results of our open extension study are
similar to those of Kremer and Lee (18). A rapid
improvement in disease activity was noted in our randomized trial (lo), with a sustained level of improvement persisting over the next 36 months of therapy.
There was no greater improvement over time, but the
clinical response was maintained. Even though 8 patients withdrew from the study, only l patient did so for
lack of drug efficacy. Individual patient responses in
both joint pain and joint swelling were highly favorable
with long-term administration. This sustained efficacy
was achieved despite a lowering in the mean weekly
dosage of MTX, a significant reduction in mean daily
prednisone dosage, and in several patients, discontinuation of NSAIDs. There were, however, no remissions
as defined by ARA criteria (13).
The improvement in erosive disease that was
seen on hand radiographs in 5 of 14 patients is consistent with the earlier observation by Kremer and Lee
(18). This improvement in erosive disease with remodeling was noted primarily in the patients with the most
impressive and sustained clinical response. Healing of
erosions has also been observed with parenteral gold
salts (19), cyclophosphamide (20), and the combination of cyclophosphamide, azathioprine, and hydroxychloroquine (21). It should be noted, however,
that despite the improvement in erosive disease, a
further narrowing in the joint space was observed. The
long-range significance of this cartilage space narrowing needs to be evaluated.
Toxicity attributable to MTX occurred commonly: 62% of the patients developed a drug-related
reaction demonstrated in either a clinical or a laboratory parameter. In no patient, however, was the
adverse experience serious enough to warrant permanent drug discontinuation. Gastrointestinal toxicity
occurred most frequently. Clinical toxicity occurred
irrespective of the duration of therapy. The development of new rheumatoid nodules after 12 months of
MTX therapy, despite an improvement in articular
disease, was observed in another long-term study (18),
but not in a short-term randomized trial (9). Hematologic toxicity, primarily mild thrombocytopenia and
leukopenia, was also noted, and the only identifiable
contributory factor was a concomitant viral illness.
Serum transaminase elevations of greater than
twice normal levels occurred in 3 1% of the patients and
developed exclusively within the first 18 months of
therapy. Perhaps the subsequent reduction in enzyme
abnormalities represents hepatic adaptation to the drug.
Nonspecific histologic abnormalities, including
periportal inflammation and fatty infiltration, were
174
noted in the majority of the liver biopsy specimens.
These findings are not specific for MTX toxicity and
have been previously observed in RA patients who
were not receiving MTX therapy (18,22). The characteristic hepatic pathology with MTX is fibrosis or cirrhosis, which was not noted in this study. The absence
of significant pathology has been reported in other RA
patients receiving MTX for a similar duration of treatment (7,16,18). In all of these studies, however, relatively short-term therapy and low cumulative doses of
the drug were used. Whether the incidence of toxicity
increases with a greater duration of therapy and higher
cumulative doses remains to be studied.
The mechanism for the efficacy of MTX in RA
remains unknown. This drug has classically been
designated as an immunosuppressive agent. With the
low doses given in RA, however, evidence of systemic
immunosuppression has not been observed using standard immunologic techniques. No significant change in
T cell subset populations or in vitro proliferative
responses to selected antigens and mitogens occurred
with MTX therapy in our short-term randomized trial
(10). Another short-term study produced the same
result (1 1). In the present study, the observation that
the percentage of circulating T helper cells was significantly increased after long-term MTX administration,
as well as the augmented thymidine incorporation
responses, are evidence against a profound systemic
immunosuppressive effect with this dose of MTX. It is
uncertain whether the improvement of in vitro function and the increase in the T helper population can be
ascribed directly to the action of MTX or, more likely,
reflect the reduction in systemic corticosteroid requirements and the overall improvement in disease
activity that occurred during this long-term study.
Although uncontrolled, this prospective study
provides additional evidence for the effectiveness of
MTX in RA. The sustained clinical response and the
lack of serious adverse reactions are encouraging.
Interpretation of these favorable results should be
balanced by the small size of our sample and the open
study design. Important issues that remain unanswered about MTX include the frequency of toxicity
(particularly hepatic and pulmonary disease); the appropriate methods to monitor for hepatic disease;
whether the clinical response can be maintained, and if
the radiographic observations in open studies can be
confirmed in randomized trials; and finally, the mechanism(s) of action of MTX in RA. The position of
MTX among the choices for treatment of active RA
will require that these questions be answered.
LOW-DOSE MTX IN RA
ACKNOWLEDGMENTS
The authors thank Agnes Maier for administrative
support, Kathleen Benfell and the Investigational Drug
Service for drug distribution, Donna Rowland and Roselynn
Dynesius-Trentham for technical assistance. and the staff of
the Robert B. Brigham Arthritis Center for their assistance.
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