close

Вход

Забыли?

вход по аккаунту

?

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

код для вставкиСкачать
138
LONG-TERM PROSPECTIVE STUDY OF THE USE OF
METHOTREXATE IN THE TREATMENT OF
RHEUMATOID ARTHRITIS
Update After a Mean of 90 Months
JOEL M. KREMER and CARLTON T. PHELPS
Objective. To determine and describe the clinical,
radiographic, and toxicity profile in a cohort of rheumatoid arthritis patients receiving weekly oral methotrexate (MTX) over a mean period of 90 months, and to
compare and contrast these data with our previous data
on this cohort, reported after 53 months.
Methods. Prospective, open observational study
over a mean treatment period of 90 months (range
79-107 months). Standard clinical and laboratory measures of disease activity were assessed by the same
investigator at baseline, 1month, 3 months, and every 3
months thereafter.
Results. A significant improvement from baselie
was maintained in all clinical parameters but the number of tender joints. Toxic reactions were as common in
months 54-90 as during the first 53 months. The mean
dosage of MTX decreased from 14.6 mg/week at the
time of the last report to 11.7 mg/week, while the mean
prednisone dosage increased from 1.9 mg/day to 2.1
mg/day. Radiographic scores for erosive disease became
statistically significantly different from baseline at year
8, and scores for joint space narrowing differed significantly from baseline at years 5 and 8. Since study entry,
2 patients (6.9%) have experienced MTX pneumonitis.
From the Department of Medicine, Division of Rheumatology, Albany Medical College, and the Albany Medical Center
Hospital, Albany, New York.
Supported in part by grants from Lederle Laboratories and
the Arthritis Foundation.
Joel M. Kremer, MD: Professor, Department of Medicine,
Division of Rheumatology, Albany Medical College; Carlton T.
Phelps, MD: Assistant Professor, Department of Radiology, Albany
Medical Center Hospital.
Address reprint requests to Joel M. Kremer, MD, Division
of Rheumatology, Albany Medical College, Albany, NY 12208.
Submitted for publication May 3, 1991; accepted in revised
form September 19, 1991.
Arthritis and Rheumatism, Vol. 35,
No. 2 (February 1992)
Conclusion. We conclude that a majority of
rheumatoid arthritis patients are able to continue MTX
treatment with generally sustained efficacy, for intervals
that meaningfully exceed those reported previously.
Methotrexate (MTX) is an effective agent in the
short-term treatment of refractory rheumatoid arthritis
(RA) (1-3). Retrospective reviews (4-6) and prospective trials (7-10) have demonstrated sustained clinical
benefits from this therapy. Compared with other secondline drugs, a higher percentage of patients are able to
continue therapy with MTX over prolonged periods
(7-1 1). This is true in spite of the common occurrence of
minor toxicities, which can be made tolerable or alleviated with an adjustment of the weekly dosage of MTX.
Treatment with MTX must be sustained in
order to maintain clinical efficacy: Even after prolonged treatment intervals, the disease flares rapidly
when the drug is discontinued (12). Because therapy
with MTX must be continued, issues of long-term
toxicity logically assume potential significance. Experience with the drug in the treatment of psoriasis has
shown that significant hepatic toxicity is associated
with total cumulative dose and duration of MTX
therapy (13-15). However, both retrospective reviews
(1 6-1 8) and prospective investigations which have
included baseline and sequential liver biopsies of patients with RA receiving MTX (19,20) have now demonstrated that the long-term hepatic outcome appears
to be significantly more benign in this disease.
Because of its perceived effectiveness and tolerability, some are advocating that MTX treatment be
instituted earlier in the RA disease course, prior to or
in combination with traditional therapies such as gold
salts (21). Others have advocated a more conservative
139
90-MONTH MTX TRIAL
approach because of gaps in our understanding of the
effects of the drug on disease and because of certain
unanswered clinical questions: Can an optimum maintenance dosage of MTX be sustained for truly prolonged periods? Is clinical response sustained? Does
the incidence of toxic reactions change with truly
long-term usage? and finally, Does the drug affect
radiographic progression of disease?
We present herein an update of our experience
with a prospectively studied cohort of RA patients.
The patients were treated with MTX for a mean of 90
months. The issues noted above are discussed in light
of data obtained in this investigation.
PATIENTS AND METHODS
Patient population. The cohort of patients we have
been studying was drawn from a population of patients who
were seen at Albany Medical College from November 1980
through September 1984. The cohort has previously been
described in detail (7,9). The original cohort consisted of 29
patients. At the time of our last report, after a mean
treatment period of 53 months (9), 25 patients remained in
the study. Since that time, 7 patients discontinued the
protocol, leaving 18 patients in the group described herein
(62% of the original cohort).
Clinical assessments. Clinical disease variables were
evaluated by the same physician at baseline, 1 month, 3
months, and every 3 months thereafter. Assessments consisted of the evaluation of 66 diarthrodial joints for swelling
and tenderness on pressure or pain on passive motion (or
both), mean grip strength for both hands, duration of morning stiffness, physician’s assessment of pain and disease
activity (graded as 0 = asymptomatic, 1 = mild, 2 =
moderate, 3 = severe, and 4 = very severe), and patient’s
assessment of pain and disease activity (graded on the same
scale).
Laboratory assessments. The following laboratory
studies were performed at baseline and every 2 weeks
thereafter during the first year of MTX therapy (if no
abnormal values were found during that period of time, then
the studies were performed monthly): complete blood cell
count including platelet count, and measurements of serum
aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), alkaline phosphatase, albumin, total bilirubin,
total protein, and creatinine. At each clinical assessment
(see above), results of urinalysis and measurement of the
erythrocyte sedimentation rate (ESR)and rheumatoid factor
(by latex fixation) were obtained.
An elevation of the AST value to 2 3 times the
normal level, a decrease in the white blood cell (WBC) count
to <3,500/mm3,or a decrease in the platelet count to < I .5 x
105/mm3was considered cause for withholding MTX treatment until these values returned to normal, at which time the
drug would be restarted at the same dosage. Patients with
levels of AST or GGT that were elevated but were <3 times
the normal value were reevaluated weekly. An AST level
that remained elevated at 2 3 times the normal level for a period
of 1 month was considered reason for terminating the treatment
and performing a liver biopsy. Because patients took MTX on
different days of the week, sampling of blood varied from a
few hours to several days after ingestion of the MTX.
All of the initial 29 patients were typed for HLA-A,
B, C, and D polymorphisms at the Paternity Testing Laboratory of the Albany Medical College Department of Surgery. The reagents used included antiserum that was tested
during the 8th Histocompatibility Workshop.
Radiographic analysis. Anteroposterior radiographs
of the hands and wrists were analyzed by a radiologist who
specializes in musculoskeletal imaging (CTP), using the
methodology described by Fries et al (22). Seventeen joints
in each hand and wrist were graded for erosions and joint
space narrowing, by comparing each joint with a radiographic standard prepared for this study. The standard
consisted of a collection of joint radiographs demonstrating
erosive change or joint space narrowing on a scale ranging
from 0 to 5 points, as follows: for joint space narrowing, 0 =
no perceivable joint space narrowing; 1 = slightest perceivable narrowing; 2 = -50% narrowing; 3 = -75% narrowing;
4 = total loss of joint space; and 5 = ankylosis. For erosive
disease, 0 = no erosive disease; 1 = 1 or more tiny (1-2-mm)
erosions; 2 = 1 or more small (2-4-mm) erosions; 3 = 1 or
more moderate-to-large ( 2 5 mm) erosions without loss of
joint architecture; 4 = joint architecture partially destroyed
(i.e., >30% of articular surface involved); and 5 = joint
architecture completely destroyed. Scores for the 34 joints
were summed, so that the maximum possible erosion or joint
space narrowing score was 170.
In each of 15 patients, films obtained at baseline were
compared with films obtained after an average of 2 , 5 , and 8
years of MTX therapy. The reviewer was blinded as to the
chronological order of the films. In 2 additional patients,
radiographs were not obtained when MTX therapy was
initiated, but were obtained after an average of 2, 5, and 8
years.
RESULTS
Demographic features of the study population.
At the time of the last report, the mean duration of
MTX therapy was 52.8 months. At the time of this
reassessment, the mean (+SEM) duration of MTX
therapy was 90.0 f 18.3 months (range 79-107
months), and the mean (2SEM) .weekly dosage of
MTX had decreased from 14.6 f 4.2 mg (range 7.5-25
mg) at 53 months to 11.7 & 6.6 mg (range 7.5-22.5 mg)
(P= 0.027). At baseline, 21 of 29 patients were taking
prednisone, at a mean f SEM daily dosage of 7.8 f
1.4 mg. Of the 18 patients remaining on the protocol
after 90 months, 14 had been taking prednisone, at a
mean SEM dosage of 7.84 f 6.2 mg/day, at baseline.
At the current assessment after a mean of 90 months,
*
8 of the 14 had completely discontinued prednisone
and the mean dosage for the entire cohort had de-
140
KREMER AND PHELPS
Table 1. Characteristics of 18 rheumatoid arthritis patients who
received methotrexate therapy over a mean period of 90 months*
Mean age, years (range)
Mean disease duration, months (range)
No. malelno. female
No. whitelno. black
No. (%) taking prednisone
Mean 2 SEM prednisone dosage, mg/day
No. (%) DR4 positive
No. (%) DRI positive
No. (%) RF positivet
53.9 (30-78)
230.8 (140-338)
5/13
16/2
6 (33)
2.1 2 0.8
9 (50)
5 (28)
15 (83)
* Eighteen patients completed a mean of 90 months of therapy.
Efficacy and toxicity data in the text include up to 25 patients who
remained in the study at the time of the last update (mean treatment
period 53 months), with 7 dropouts occurring since then.
t As of 1991. RF = rheumatoid factor.
creased to 2.1 2 0.8 mg (P = 0.005 versus baseline).
Other demographic characteristics of the 18 patients
who remained in the study are shown in Table 1.
Seven patients have withdrawn from the study
since the time of the last report. Three of the 7 actually
continued to take methotrexate although they withdrew from the trial because of the inconvenience of
coming to the clinic for protocol evaluations. Two
patients (6.9% of the original 29) were withdrawn
because of lack of efficacy; they represent the first
withdrawals for this reason since the study was begun.
One patient was withdrawn for administrative reasons,
after he experienced a cerebrovascular accident which
impaired his judgment in assessing pain and disease
activity. Another patient was withdrawn after an episode of MTX pneumonitis. Information on the 11
withdrawals since the initiation of the study is summarized in Table 2.
Changes in clinical and laboratory parameters
compared with baseline. There were significant improvements in most of the clinical parameters of
disease activity after 90 months of MTX treatment
(Table 3). Compared with baseline values (prior to
initiation of MTX), the number of swollen joints
decreased from a mean SEM of 17.3 +- 7.5 to 9.5 2
5.3 (P = 0.0005). The duration of morning stiffness
decreased from 163.8 179.5 minutes (mean SEM)
to 66.5 2 76.0 minutes (P = 0.004). Grip strength
increased from 59.1 & 32.6 mm Hg to 81.4 46.2 mm
Hg (P = 0.003). Scores on the patients’ assessments of
pain and global disease activity decreased from 2.3 4
*
*
*
*
Table 2. Reasons for withdrawal from the prospective methotrexate (MTX) study among rheumatoid
arthritis patients treated over a mean period of 90 months*
Patient
Months of
MTX therapy
Reason for withdrawal
1
I
2
12
MTX pneumonitis
3
4
34
48
Headache, nausea
Died of cardiac arrest
5
45
MTX pneumonitis
6
55
7
60
8
73
Inconvenience of
clinic visits
Inconvenience of
clinic visits
Decreased efficacy
9
90
Administrative
10
95
Decreased efficacy
11
106
Nausea
Inconvenience of
clinic visits
Comment
Total cumulative
dose 17.5 mg
Resolved after
steroid therapy
Side effect resolved
Unrelated to MTX
therapy
Resolved after
steroid therapy;
subsequently died
of sepsis at
another hospital
Continues MTX
Continues MTX
Disease continues to
be poorly
controlled
CVA; continues
MTX
Disease continues to
be poorly
controlled
Continues MTX
* Patients 5-1 1 have withdrawn since the last update, at which time the mean treatment period was 53
months. CVA = cerebrovascular accident.
90-MONTH MTX TRIAL
14 1
Table 3. Clinical and laboratory parameters (mean f SEM) in rheumatoid arthritis patients who received methotrexate (MTX)therapy over
a mean period of 90 months*
Variable
No. of tender joints
No. of swollen joints
Morning stiffness
(minutes)
Grip strength (mm Hg)
Physician global assessment
(0-5 scale)
Patient pain assessment
(0-5 scale)
Functional class ( 1 4 )
ESR (mm hour)
AST (units/ml)
Platelets ( X I d )
Hemoglobin (gddl)
WBC ( X 103)
Rednisone (mg/day)
Weekly MTX dosage
(&week)
Cumulative MTX dose (mg)
* NS
=
Mean 90
months of
treatment
(range 79-104)
(n = 18)
Versus
baseline
Versus month
53
Baseline
(n = 29)
Mean 53
months of
treatment
(range 31-77)
(n = 25)
15.2 2 8.6
17.3 2 7.5
6.9 2 6.7
11.3 f 6.8
0.0001
0.05
12.0 f 9.6
9.5 f 5.3
NS
0.0005
0.007
NS
163.8 f 179.5
59.1 2 32.6
68.8 2 74.0
88.3 f 56.3
0.001
0.003
66.5 k 76.0
81.4 f 46.2
0.004
0.003
NS
0.05
2.4 2 0.68
1.6 f 0.7
0.0001
1.6 f 0.6
0.0007
NS
2.3 2 0.69
2.4 2 0.6
36.0 2 22.1
17.9 2 9.4
354.1 2 107.6
12.5 2 1.6
8.9 2 2.4
7.8 2 1.4
1.4 f 0.6
2.3 f 0.6
25.2 2 15.5
33.0 2 12.2
298.7 2 %.5
13.3 2 1.2
7.2 f 1.8
1.9 f 0.5
0.0002
NS
0.02
0.0001
0.10
0.02
0.002
0.0005
1.7 2 0.8
2.1 2 0.3
38.6 k 19.5
23.5 f 7.8
281.2 f 97.0
13.0 f 1.6
7.4 5 2.0
2.11 f 0.8
0.002
0.05
NS
0.02
0.02
0.06
0.0003
0.003
NS
0.05
NS
NS
12.8 2 3.3
0
14.6 f 4.2
2,915 f 1,099
0.01
11.7 f 6.6
6,020 2 1,560
NS
P versus
baseline
P
0.009
NS
0.02
0.005
0.03
not significant; ESR = erythrocyte sedimentation rate; AST = aspartate aminotransferase; WBC = white blood cells.
*
0.69 to 1.7 0.8 and from 2.3 2 0.81 to 1.7 2 0.6,
respectively (P = 0.002 for each). Moreover, scores on
the physicians’ evaluations of pain and global disease
activity in the patients studied decreased from 2.5
0.7 to 1.5 f 0.5 and from 2.4 2 0.7 to 1.6 2 0.6,
respectively (P = 0.0001 and P = 0.0007, respectively). The only clinical parameter in which a significant
improvement over baseline was not maintained after
90 months was the number of tender joints, which
decreased from 15.2 k 8.6 to 12.0 k 9.6. Functional
classification according to the Steinbrocker criteria
(23) decreased from a mean 2 SEM of 2.4 2 0.6 at
baseline to 2.1 f 0.3 at 90 months (P = 0.05).
The laboratory parameters that showed significant changes from baseline values included the platelet
count (mean f SEM 354,000 5 108,000/mm3at baseline, 281,000 97,000 at 90 months; P = 0.009), the
WBC count (8,900 f 2,400/mm3 at baseline, 7,400 2
2,000 at 90 months; P = 0.02), and the AST value (17.9
9.4 unitdm1 at baseline, 23.5 2 7.8 at 90 months; P
= 0.02) (Table 3). Although the hemoglobin level
increased from 12.5 & 1.6 g d d l to 13.0 f 1.6 gm/dl
and the ESR increased from 36.0 f 22.1 mmhour to
38.6
19.5 mmhour, neither of these changes was
statistically significant. The mean log titer of rheumatoid factor did not change significantly after 90 months
*
*
*
*
of MTX therapy compared with baseline. Clinical
response did not correlate with HLA haplotype.
Differences in clinical response at 90 months of
therapy versus 53 months of therapy. A continuation of
the overall plateau in clinical response that was seen
after the patients had received a mean of 29 months (7)
and 53 months of therapy (9) persisted through a mean
of 90 months. During this time the total cumulative
dose of MTX increased from a mean f SEM of 2,915
-t 1,099 mg to 6,020 % 1,560 mg. In our last report (9),
we compared clinical parameters at 53 months with
those recorded at 29 months and found no statistically
significant differences between any of the values from
these times. In contrast, when clinical and laboratory
parameters at 90 months were compared with those at
53 months (Table 3), there were statistically significant
changes in the mean k SEM number of tender joints
(6.9 2 6.7 at 53 months, 12.0 2 9.6 at 90 months; P =
0.007), grip strength (88.3 f 56.3 mm Hg at 53 months,
81.4 k 46.2 at 90 months; P = 0.05), and patient
scoring of pain (1.4 k 0.6 at 53 months, 1.7 2 0.8 at 90
months; P = 0.02). Comparison of laboratory parameters between month 53 and month 90 showed a
decrease in the hemoglobin level (13.3 1.2 g d d l at
53 months, 13.0 f 1.6 at 90 months; P = 0.05), an
increase in the ESR (25.2 f 15.5 mmhour at 53
*
KREMER AND PHELPS
142
Table 4. Adverse reactions among rheumatoid arthritis patients who received methotrexate therapy
over a mean period of 90 months*
Adverse reaction
GI tract (GI distress and/or
nausea)
CNS (headache, lightheadedness,
fatigue, feeling “out of sorts”)
Mouth sores or soreness
Leukopenia
Abnormally high AST value
Methotrexate pneumonitis
Total with toxic reaction
Months 1-29
(n = 29)
Months 3&53
(n = 25)
Months 54-78
(n = 24)
18 (62)
13 (52)
13 (54)
13 (65)
6 (21)
9 (36)
9 (38)
7 (35)
11 (38)
6 (21)
20 (69)
1 (3)
26 (90)
8 (32)
6 (24)
22 (88)
0
21 (84)
9 (38)
6 (25)
6 (25)
I (4)
19 (79)
I 1 (55)
4 (20)
3 (15)
0
Months 7!9-104
(n = 20)
17 (85)
* Values are the number (%) with the specific reaction. GI = gastrointestinal; CNS = central nevous
system; AST = aspartate aminotransferase.
months, 38.6 ? 19.5 at 90 months; P = 0.0003), and a
decrease in the AST level (33.0 & 12.2 unitdm1 at 53
months, 23.5 ? 7.8 at 90 months; P = 0.003).
Toxic reactions to MTX. Toxic reactions are
reported for 4 time intervals so that their prevalence in
relation to different durations of MTX therapy can be
more easily assessed. These time intervals are as
follows: baseline to mean of 29 months (period 1);
months 30-53 (period 2); months 54-78 (period 3);
months 79-104 (period 4). Toxicity during periods 1
and 2 has previously been reported (9).
Twenty-four patients continued MTX through
period 3 (Table 4). During this period, 13 patients
(54.2%) experienced 43 separate episodes of gastrointestinal symptoms of drug toxicity (gastrointestinal
discomfort or nausea), 9 patients (37.5%) reported 31
episodes of central nervous system toxicity (headaches, lightheadedness, fatigue, or feeling “out of
sorts”), and 9 patients (37.5%) reported 22 episodes of
mouth sores or soreness. During period 4, 13 of 20
patients (65%) experienced 29 episodes of gastrointestinal toxicity, 7 patients (35%)experienced 27 episodes
of central nervous system toxicity, and 1 1 patients
(55%) experienced 22 episodes of mouth sores or
soreness. Three patients (15%) experienced no toxicity during either period 3 or period 4; these same
individuals had no toxicity in periods 1 and 2.
Types of toxic reactions to MTX remained
remarkably consistent within individuals throughout
all 4 time intervals. HLA haplotypes were not useful in
predicting either the presence or the type of toxicity.
None of the toxicities mentioned above resulted in
discontinuation of MTX therapy.
One patient, a 66-year-old woman, developed
methotrexate pneumonitis after 45 months of MTX
therapy (10 mg/week, total cumulative dose 2.0 gm).
She was treated with prednisone (30 mg twice a day)
and improved over 2 weeks. She was discharged, but
3 weeks later she was admitted to a suburban community hospital, where she died of septicemia after a
5-week stay. Because she had recovered from the
pneumonitis, the death was not considered to be
directly linked to MTX therapy, although she was still
taking steroids at the time of the septicemia. An
autopsy was not performed.
Radiographic changes. Eight of the 17 patients
in whom sequential radiographs were obtained showed
no radiologic progression, while 9 did have progression. An examination of HLA markers in the group
with and the group without radiologic progression did
not reveal any significant differences. Scoring for
erosive disease in the entire cohort (17 patients)
changed from a mean 2 SD of 56.4 2 30.0 at baseline
to 63.2 ? 30.5 at year 2,67.1 2 33.3 at year 5, and 72.2
?Z 29.3 at year 8. Only the grading at year 8 was
significantly changed from baseline (P = 0.016). Scoring of joint space narrowing changed from a mean 5
SD of 87.7 k 22.3 at baseline to 94.1 ? 23.7 at year 2,
98.1 2 27.0 at year 5 (P= 0.023), and 105.5 & 21.9 at
year 8 (P = 0.007).
DISCUSSION
After a mean of 7% years of MTX therapy for
rheumatoid arthritis, 18 of 29 patients (62%) remained
in the study protocol. Three additional patients continue to receive MTX, although they are no longer part
of the formal study. Thus, a total of 21 of 29 patients
(72%) continue to take MTX. These figures are noteworthy in view of the fact that all subjects in this
cohort had longstanding active disease and had been
treated unsuccessfully with several slow-acting anti-
90-MONTH MTX TRIAL
rheumatic drugs prior to the initiation of MTX therapy. Statistically meaningful overall clinical response
was sustained through 90 months in the study cohort.
The plateau in clinical response after 6 months of MTX
therapy, which was first reported in this cohort (7) and
confirmed by other investigators (9,continues, although the number of tender joints has significantly
worsened in the interval between 53 months and 90
months. Measurement of semi-subjective clinical parameters such as joint counts, morning stiffness, and
grip strength may be problematic in an open, uncontrolled observational study such as this, since the
measurements may be subject to unconscious and
unavoidable bias. Of perhaps greater importance in
long-term studies are the changes described in the
ESR and joint radiographs as well as the number of
patients who are able to continue MTX therapy for
prolonged intervals.
Other long-term prospective investigations of
MTX therapy in RA patients treated with the drug for
shorter intervals have also shown that a majority are
able to continue MTX treatment. Weinblatt et al
reported that 16 of 26 patients (62%) continued MTX
for a mean period of 36 months (8). More recent
investigations by Weinblatt et al(24) and by Furst et al
(10) have demonstrated continuation rates for MTX
therapy of 78% and 56%, respectively, after 2 years
and 3.4 years. Wolfe et a1 also found that patients were
less likely to discontinue MTX than other slow-acting
drugs ( 1 1).
The major reason for discontinuation of MTX is
more likely to be toxicity, rather than lack of efficacy.
Only 2 of 29 patients in our study (7%) had to discontinue therapy with the drug because of lack of efficacy,
and these withdrawals occurred after 73 and 95 months
of treatment (Table 2). In the study by Furst et al in
which 20 of 45 patients receiving MTX discontinued
the drug within 3.4 years, no withdrawals were due to
lack of efficacy (10). Similarly, Weinblatt and colleagues found that in a 42-month study of 123 patients
who began MTX treatment, only 4 (3%) had discontinued the drug due to lack of response; the duration of
treatment in these 4 patients ranged from 9 months to
26 months (24). Alarc6n et al (25) observed that toxic
effects were the major factor in limiting long-term
treatment with MTX. Interestingly, whereas only 40%
of the patients in their study who began MTX treatment prior to 1984 continued the treatment €or 3 years,
60% of those who began after 1984 remained on the
drug regimen after 3 years. The authors suggested that
the improvement in the percentage of patients able to
143
continue MTX resulted from the fact that “physicians
became more familiar with the drug and its side
effects.”
The percentage of patients who are able to
continue therapy with MTX is noteworthy in view of
the frequency of toxic reactions noted in reports of
prospective investigations. Indeed, 27 of 29 patients
(93%) experienced toxicity at some time during our
study. This percentage is remarkably similar to that
reported by Furst et al, who reported a 96% incidence
of toxicity over 3.4 years (lo), and is higher than the
62% rate of toxicity over a period of 36 months
reported by Weinblatt et al (8).
The mean & SEM weekly dosage of MTX was
16.0 & 6.6 mg in the study by Furst et al (10). The
dosage of MTX in our study has decreased from 14.6
k 4.2 mg/week at 53 months to 11.7 t 6.6 mg/week at
90 months (P = 0.03). During this same period, the
overall incidence of toxicity has remained constant.
Twenty-one of 25 patients (84%) experienced some
toxicity through 53 months, 19 of 24 (75%) through 78
months, and 17 of 20 (85%) through 104 months of
therapy. Since the only reason the dosage of MTX was
decreased in this investigation was because of an
adverse effect that was unacceptable to the patient, the
significant lowering of the MTX dosage reflects less
tolerance to these effects over prolonged intervals.
The reasons for this are unclear, but may be partly
psychological and partly organic. Because the overall
incidence of toxicity remained constant, we are reluctant to ascribe these changes in tolerance to the folate
depletion which has been reported to occur over time
in patients receiving MTX (26,27).
Our finding that radiographic deterioration is
not halted over a period of almost 8 years extends the
body of available data gained from several previous
reports of the effects of MTX on radiographic changes
in disease over much shorter intervals (28-32). In
previous reports, we described an improvement in
erosive disease after 2 years of therapy (7), which was
lost at the time of the 53-month update of this cohort
(9). Others have reported some improvement in the
radiographic appearance of disease in a subset of
patients treated with MTX for 36 months (8).
We did note a statistically significant worsening
in the number of tender joints between 53 and 90
months of therapy with MTX, concurrent with the
significant decrease in the mean dosage from 14.6 mg
to 11.7 mg weekly. The Westergren ESR significantly
increased and grip strength significantly decreased
during this same interval. Thus, patients may need to
KREMER AND PHELPS
144
sustain higher weekly doses of MTX in order to
maintain optimal effects. This may have implications
for truly long-term treatment if patients feel the need
to have their MTX dosage lowered, as we observed. A
dose-related clinical response to MTX therapy has
been reported previously (33).
We have now observed pulmonary toxicity in 2
of 29 patients (6.9%). Although the 2 patients shared
the A2,24;DR4 HLA haplotype, with such small numbers it is not possible to determine whether this
association could be meaningful. A recent report described an abnormal result on pre-MTX chest radiography as a risk factor for the subsequent development
of MTX pneumonitis (34). Risk factors for the pulmonary reaction associated with MTX will need to be
better defined if physicians are to consider using this
drug as a first-line agent for significant numbers of
patients with RA. A previous report noted MTX
pneumonitis in 9 of 163 patients treated with the drug
(5.5%) (39, while no cases were reported in 2 recent
studies of a total of 136 patients (10,24). The true
incidence of MTX pneumonitis in the entire population
at risk is largely unknown.
In summary, we describe a continued response
to MTX therapy over a mean of 90 months in a cohort
of patients with previously refractory rheumatoid arthritis. Statistically significant worsening was noted in
the number of tender joints, grip strength, and Westergren ESR since the time of the last report, while the
mean weekly dose of MTX also decreased significantly. It is uncertain whether declining clinical effects, associated with a decreased weekly dose of
MTX, will be reflected by other clinical parameters
over longer periods than those described in this report.
In spite of these real and potential problems, at the
time of this writing MTX is the most effective and best
tolerated drug available for the treatment of patients
with RA.
REFERENCES
Weinblatt ME, Coblyn JS, Fox DA, Holdsworth DE,
Glass DN, Trentham DE: Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med 312:818822, 1985
Williams JH, Willkens RF, Samuelson CO Jr, Alarcon
GS, Guttadauria M, Yarboro C, Polisson RP, Weiner
SR, Luggen ME, Billingsley LM, Dahl SL, Egger MJ,
Reading JC, Ward JR: Comparison of low-dose oral
pulse methotrexate and placebo in the treatment of
rheumatoid arthritis: a controlled clinical trial. Arthritis
Rheum 28:721-730, 1985
Andersen PA, West SG, O’Dell JR, Via CS, Claypool
RG, Kotzin BL: Weekly pulse methotrexate in rheumatoid arthritis: clinical and immunologic effects in a
randomized, double-blind study. Ann Intern Med 103:
489-496, 1985
4. Weinstein A, Marlowe S, Korn J, Faronhar F: Low dose
methotrexate treatment of rheumatoid arthritis: longterm observations. Am J Med 79:331-337, 1985
5. Hoffmeister RT: Methotrexate therapy in rheumatoid
arthritis: 15 years experience. Am J Med 12:69-73, 1983
6. Willkens RF, Watson MA: Methotrexate: a perspective
of its use in the treatment of rheumatic diseases. J Lab
Clin Med 100:314-321, 1982
7. Kremer JM, Lee JK: The safety and efficacy of the use
of methotrexate in long-term therapy for rheumatoid
arthritis. Arthritis Rheum 29:822-831, 1986
8. Weinblatt ME, Trentham DE, Fraser PA, Holdsworth
DE, Falchuk KR, Weissman BN, Coblyn JS: Long-term
prospective trial of low-dose methotrexate in rheumatoid arthritis. Arthritis Rheum 31:167-175, 1988
9. Kremer JM, Lee JK: A long-term prospective study of
the use of methotrexate in rheumatoid arthritis: update
after a mean of fifty-three months. Arthritis Rheum
31:577-584, 1988
10. Furst DE, Erikson N , Clute L, Kochnke R, Burmeister
LF, Kohler JA: Adverse experience with methotrexate
during 176 weeks of long-term prospective trial in patients with rheumatoid arthritis. J Rheumatol 17:16281635, 1990
1 1 . Wolfe F , Hawley DJ, Cathey MA: Termination of slow
acting antirheumatic therapy in rheumatoid arthritis: a
14 year prospective evaluation of 1017 consecutive
starts. J Rheumatol 17:994-1002, 1990
12. Kremer JM, Rynes RI, Bartholomew LE: Severe flare of
rheumatoid arthritis after discontinuation of long-term
methotrexate therapy: double-blind study. Am J Med
82:781-786, 1987
13. Weinstein G, Roenigk HH, Maibach K, Cosmides J,
Halprin K, Millard M: Psoriasis-liver methotrexate interactions. Arch Dermatol 108:36-42, 1973
14. Nyfors A: Liver biopsies from psoriatics related to
methotrexate therapy: findings in post-methotrexate
liver biopsies from 160 psoriatics. Acta Pathol Scand
85:511-514, 1977
15. Zachariae H , Kragballe K, Sogaard H: Methotrexateinduced liver cirrhosis: studies including serial liver
biopsies during continued treatment. Br J Dermatol
102:407412, 1980
16. Shergy WJ, Polisson RP, Caldwell DS, Rice JR,
Pisetsky DS, Allen NB: Methotrexate-associated hepatotoxicity: retrospective analysis of 210 patients with
rheumatoid arthritis. Am J Med 85:771-774, 1988
17. Aponte J, Petrelli M: Histopathologic findings in the
liver of rheumatoid arthritis patients treated with longterm bolus methotrexate. Arthritis Rheum 31: 14571464, 1988
145
90-MONTH MTX TRIAL
18. Rau R, Karger T, Herborn G, Frenzel H: Liver biopsy
findings in patients with rheumatoid arthritis undergoing
long-term treatment with methotrexate. J Rheumatol
16:489-493, 1989
19. Kremer JM, Lee RG, Tolman KG: Liver histology in
rheumatoid arthritis patients receiving long-term methotrexate therapy: a prospective study with baseline and
sequential biopsy samples. Arthritis Rheum 32: 121-127,
1989
20. Brick JE, Moreland LW, Al-Kawas F, Chang WWL,
Layne RD,di Bartolomeo AG: Prospective analysis of
liver biopsies before and after methotrexate therapy in
rheumatoid patients. Semin Arthritis Rheum 19:31-44,
1989
21. Wilske K, Healey L: Remodeling the pyramid: a concept whose time has come. J Rheumatol 16565-567,
1989
22. Fries JF, Bloch DA, Sharp JT, McShane DJ, Spitz P,
Bluhm GB, Forrester D, Genant H, Gofton P, Richman
S , Weissman B, Wolfe F: Assessment of radiologic
progression in rheumatoid arthritis. a randomized, controlled trial. Arthritis Rheum 29:l-9, 1986
23. Steinbrocker 0, Traeger CH, Batterman RC: Therapeutic criteria in rheumatoid arthritis. JAMA 140:659-662,
1949
24. Weinblatt ME, Kaplan H, Germain BF, Meniman 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 18:33&338,
1991
25. Alarc6n GS, Tracy IC, Blackburn WD Jr: Methotrexate
in rheumatoid arthritis: toxic effects as the major factor
in limiting long-term treatment. Arthritis Rheum 32:671676, 1989
26. Kremer JM, Galivan J, Streckfuss A, Kremer JM,
Galivan J, Streckfuss A, Kamen B: Methotrexate metabolism analysis in blood and liver of rheumatoid arthritis patients: association with hepatic folate defi-
27.
28.
29.
30.
31.
32.
33.
34.
35.
ciency and formation of polyglutamates. Arthritis
Rheum 29:832-835, 1986
Morgan SL, Baggott JE, Vaughn WH, Young PK,
Austin JV, Krumdieck CL, Alarc6n GS: The effect of
folic acid supplementation on the toxicity of low-dose
methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 339-18, 1990
Boh L, Schuna A, Pitterle M, Adams E, Sundstrom W:
Long-term use of methotrexate in inflammatory arthritis: clinical and x-ray evaluation (abstract). Arthritis
Rheum 28 (suppl4):S46, 1985
Nordstrom DM, West SG, Andersen PA, Sharp JT:
Pulse methotrexate therapy in rheumatoid arthritis: a
controlled prospective 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: toxicity, efficacy and radiological progression. Br J Rheumatol28:147-153, 1989
L6pez-MCndez A, Tracy I, Alarc6n GS, Daniel WW:
Disease progression in rheumatoid arthritis during methotrexate (MTX) administration: a radiological study
(abstract). Arthritis Rheum 32 (suppl 1):R43, 1989
Sany J, Kaliski S, Couret M, Cuchacovich M, Daures
J-P: Radiologic progression during intramuscular methotrexate treatment of rheumatoid arthritis. J Rheumatol
17:163&1641, 1990
Furst DE, Koehnke R, Burmeister LF, Kohler J, Cargill
J: Increasing methotrexate effect with increasing dose in
the treatment of resistant rheumatoid arthritis. J Rheumatol 16:313-320, 1989
Golden MR, Katz RS, Balk RA, Neu J, Golden H: The
relationship of pre-existing lung disease to the occurrence of methotrexate pneumonitis in rheumatoid arthritis patients. Arthritis Rheum 33 (suppl 9):S40, 1990
Cannon GW, Ward JR, Clegg DO, Samuelson CO Jr,
Abbott TM: Acute lung disease associated with lowdose pulse methotrexate therapy in patients with rheumatoid arthritis. Arthritis Rheum 26:1269-1274, 1983
Документ
Категория
Без категории
Просмотров
0
Размер файла
754 Кб
Теги
prospective, treatment, terms, stud, long, arthritis, methotrexate, use, rheumatoid
1/--страниц
Пожаловаться на содержимое документа