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Second course gold therapy in the treatment of rheumatoid arthritis.

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1071
SECOND COURSE GOLD THERAPY IN THE
TREATMENT OF RHEUMATOID ARTHRITIS
ANN E. EVERS and WALTER R. SUNDSTROM
Twenty-three rheumatoid arthritis patients who
had previously received gold therapy were selected for
second course gold. Eleven patients had developed complete remission during the first course of gold therapy.
Four of these had a complete response to second course
gold. Of the 10 nonresponders and 2 partial responders
to first course gold, none responded to second course
gold. We conclude that individuals in whom first course
gold is unsuccessful respond poorly to repeated gold
treatments. In addition, only 36% of the patients who
initially had a complete response sustained complete
remission with second course gold.
Gold salts are an important therapeutic modality in the treatment of rheumatoid arthritis (RA) (1-3).
Controlled studies of patients treated with a first
course of gold report decreases in functional disability
and active synovitis after therapy (43). However,
there is little evidence of the efficacy of a second
course of gold in the management of RA (6). W e
compared the clinical response and toxicity between
first and second courses of gold in 23 patients with
moderate to severe RA. These patients were followed
for a mean of 98.3 months. Both courses of gold were
From the William S. Middleton Memorial Veterans Administration Hospital, Medical Service and the University of Wisconsin-Madison, Department of Medicine, Madison, Wisconsin.
Supported in part by the Veterans Administration.
Ann E. Evers, MD: Assistant Professor, Department of
Medicine, University of Wisconsin-Madison; Walter R. Sundstrom,
MD: Chief, Medical Service, William S. Middleton Memorial VA
Hospital and Professor, Department of Medicine. University of
Wisconsin-Madison.
Address reprint requests to Walter R. Sundstrom, MD,
William S. Middleton Memorial VA Hospital, 2500 Overlook Terrace, Madison, WI 53705.
Submitted for publication August 31, 1982; accepted in
revised form March 31. 1983.
Arthritis and Rheumatism, Vol. 26, No. 9 (September 1983)
initiated at t he Rheumatology Clinics of the University
of Wisconsin Clinical Sciences Center or the William
S. Middleton Memorial VA Hospital.
PATIENTS AND METHODS
We conducted a retrospective chart review of all
patients with diagnosed RA, to select those patients who
started gold therapy at the University of Wisconsin Hospital
or the William S. Middleton Memorial V A Hospital during
the period 1970-1979. The diagnosis of RA was confirmed in
296 patients. Although 162 RA patients were treated with
gold salts, only 23 patients began 2 separate courses of gold
therapy. The rheumatologists following the patients were
unaware that their notes would form the basis of a study; all
data were analyzed retrospectively. Standardized records
for patient evaluation have been used at both institutions
since 1970 and form the basis of the study data.
All study patients fulfilled American Rheumatism
Association criteria for the diagnosis of definite or classic
RA (7). None of the patients had been previously treated
with gold. The mean duration of RA for the 23 patients prior
to initial gold therapy was 5.46 years. Three patients had had
RA for more than 20 years; the remaining 20 patients had had
the disease for 6 months to 5 years. (Duration of disease is
defined from date of diagnosis to initiation of gold therapy.)
Patients were excluded from the study if they were being
treated with D-penicillamine, cytotoxic drugs, or hydroxychloroquine.
Patients were included in the study if they were
receiving nonsteroidal antiinflammatory medication, or 10
mg or less daily of prednisone if the dose had been constant
over the preceding 4 months. The majority of patients were
treated with gold sodium aurothiomalate, beginning with a
test dose of 10 mg and increasing to 25 mg/week for the first 3
months of lherapy. Thereafter, the doses and maintenance
intervals of gold salt injections were adjusted according to
the clinical response of each patient. All 23 patients were
treated a minimum of 12 months with an initial course of
gold.
Entry into the study began at initiation of the first
course of gold. The clinical status of each patient was
EVERS AND SUNDSTROM
Table 1. Characteristics of patients at start of gold therapy
Characteristics*
No. of patients
Age (mean 2 SE)
Sex (MIF)
Duration of RA (years) (mean 2
SE)
Mean hours morning stiffness
Functional class (mean)
No. of inflamed joints (mean)
ESR, Westergren (mdhour)
(mean 2 SE)
Mean periarticular changes with
erosions (on joint radiograph)
No changes
* RA
=
rheumatoid arthritis; ESR
Complete
responders
to 1 year
gold
II
40.0
f
2.0
615
4.0 2 2.0
2.0
2.3
14.4
25.5 t- 3.2t
12
49.5 2 4.6
1111
6.6 2 3.6
2.8
2.7
15.0
41 2 3.61
6
RESULTS
3
erythrocyte sedimentation
rate.
tP
=
crease in the dose of aspirin, nonsteroidal antiinflammatory
drug, or prednisone; 6) mean improvement in grip strength
of 30 mm in each hand; 7) normal hematocrit level; 8) Westergren sedimentation rate below 20. To be in complete
remission, a patient must score 7 or 8 on the above scale.
Partial response was defined as 4-6 points and no response
as 0-3 points.
Using the assessment scale, we compared clinical
responses to first and second course gold therapy. Because
maximum response to gold salts appeared to occur by 12
months, the responses to each course of gold at 12 months
were carefully compared. Assessment continued, however,
throughout gold therapy. Overall, the 23 patients treated
with 2 separate courses of gold were followed a mean of 98.3
months.
7
L
=
Partial or
poor
responders
to 1 year
gold
0.05 (Student’s t-test).
determined by reviewing the chart entries at initiation of gold
therapy, at 6, 12, 18, and 24 months, and yearly thereafter
until the discontinuation of gold salts. The date of withdrawal from gold, reasons for withdrawal, total gold dose, duration of therapy, and clinical status of each patient were
noted. The range of duration of the initial course of gold
therapy was 1 to 7 years. The reasons for discontinuing gold
included toxicity, no response, and clinical remission.
After a minimum of 6 months from completion of the
initial gold course, the 23 patients were retreated with a
second course of gold varying from 2 months to 4 years. In
the interval between gold courses, the charts were reviewed
every 6 months and all medications were noted. Before
beginning a second course of gold, all patients were withdrawn from D-penicillamine or hydroxychloroquine therapy
for at least 6 months. During the second course of gold, the
clinical status of each patient was recorded from chart
entries at the initiation of gold therapy, at 6, 12, 18, and 24
months, and yearly thereafter until discontinuation of gold.
At withdrawal from the second course of gold, each patient
was reevaluated. Second course gold was discontinued
because of toxicity or lack of benefit.
At each evaluation, the following information was
recorded on a standard form: painful joints attributed to
inflammation rather than deformity; joint swelling, tenderness, warmth, redness, or limitation of motion; morning
stiffness; grip strength, with the best effort of 3 recorded;
medications; peripheral blood count; urinalysis findings;
latex titer; Westergren erythrocyte sedimentation rate; radiologic reports; side effects attributed to gold; and extraarticular manifestations of rheumatoid disease and other
illnesses.
Response to gold therapy was measured by an assessment scale with a maximum score of 8 points. One point
was assigned to each of the following 8 criteria: 1) absent
morning stiffness; 2) no pain on movement of ajoint, excluding fixed deformity; 3) no active synovitis on joint examination as characterized by the presence of 2 of the 3 following
signs: tenderness, swelling, or pain on motion; 4) improvement in functional capacity (8) by 1 or more classes; 5 ) de-
Clinical respoase. All 23 study patients completed a first year course of gold (Table 1). At the end of 1
year, 1 I patients (48%) were in complete remission, 2
patients (9%) had a partial response, and 10 patients
(43%) had a poor response to gold. Complete remission occurred by 24 weeks of gold therapy in 7 of the
11 patients (64%). Four of the 11 (36%) had remission
between 24 and 52 weeks. The differences in response
rates between the poor responders and the complete
responders are noted in Table 2.
Prior to gold treatment, the 11 complete responders had a mean score of 1.27 on the assessment
scale. After 1 year of gold, this score increased to a
mean of 7.45 (P < 0.005). In contrast, the nonresponders improved from a mean score of 0.70 prior to
gold therapy to a mean score of 2.40 following a I-year
course of gold ( P < 0.005).
Of the 1 I patients with a complete response t o a
first course of gold, 5 (45%) continued receiving gold a
mean of 4.0 ? 1.5 years. Eventually, all 11 complete
responders were withdrawn from gold. Skin rash occurred in 3 patients (27%) and complete remission in 8
patients (73%).
Withdrawal from the initial course of gold occurred at 1 year in 5 (42%) of the 12 nonresponders.
Reasons for withdrawal were toxicity in 3 patients
(60%) and flare in disease in 2 patients (40%). Because
Table 2.
First course gold: response after I year*
Patient group
Complete responders
( I 1 patients) (mean score f SE)
Minimal or poor responders
(12 patients) (mean score 2 SE)
Prior to
gold
treatment
1.27
f
0.19
0.70 f 0.12
After 1 year
first course
gold
7.45
f
0.16t
2.40 2 0.34
* Using 8-point assessment scale: 7-8 = complete remission. See
text for detailed explanation of scale.
t Paired t-test, P < 0.005.
1073
GOLD RETREATMENT IN RA
Table 3. Clinical characteristics of patients at the start of second course gold therapyCharacteristics
No. of patients
Sex (MIF)
Time between gold courses (years)
(mean r SE)
Mean hours morning stiffness
Functional class (mean)
No. of inflamed joints (mean)
Mean ESR (Westergren) (mm/hour)l
Mean initial gold dose (mg)
Complete responders
to both courses
Complete first responders:
poor second responders
Poor responders to
both courses
4
212
2.1 2 0.41
5
312
2.1 f 0.1
7
710
2.1 0.82
7.5
3.25
17.3
32.3
1.100
3.6
2.5
12.4
22.7
2.355
5.0
3.3
13.3
33
2.640
*
* The group initially consisted of 23 patients. Gold toxicity developed in 7 patients prior to 24 weeks, necessitating withdrawal of gold;
therefore, only 16 patients were analyzed.
t Erythrocyte sedimentation rate.
of possible delayed response to gold, 7 (58%) of the 12
nonresponders to initial gold continued to receive gold
injections an additional mean 3.3 ? 0.68 years. No
further benefit was obtained and gold injections were
terminated because of poor response in 5 patients
(71%) or minor toxicity in 2 patients (29%).
During a mean interval of 2.2 ? 0.28 years
between gold courses, all 23 patients developed a flare
in disease as measured by the assessment scale. All 23
were rechallenged with a second course of gold therapy. Toxicity developed in 7 patients (30%),necessitating withdrawal of gold prior to 24 weeks. Sixteen
patients were treated for a minimum of 12 months.
Four patients (17%) were in complete remission at the
end of I year. Twelve patients (52%) had a minimal or
poor response to a second course of gold.
Prior to a second course of gold, the complete
responders had a mean assessment score of 1.2; their
mean score at 12 months was 7.2 (P < 0.005). The
assessment score of minimal or poor responders prior
to second course gold was 1.3 0.26; the mean score
at 12 months was 2.2 0.28. The nonresponders had
only minimal improvement in assessment scores with
treatment.
Table 3 compares the clinical differences among
the complete responders to both courses of gold prior
to the start of second course gold. The first course
responders, second course nonresponders. and the
nonresponders to both courses showed no statistical
differences in the duration of time without gold, morning stiffness, grip strength, erythrocyte sedimentation
rate, functional class, or joint count. All 3 patient
groups had the same disease activity at the onset of the
second course of gold treatment as at the onset of the
first.
Table 4 compares the clinical response to first
and second course gold. Of the 11 patients with a
complete initial response to gold, only 4 developed a
complete response to second course gold. Two of the
*
*
other complete initial responders developed early toxicity, and 5 failed to respond to a second course of
gold. Overall, only 17% (4 of the 23 patients) responded to a second course of gold salts. Of the 11 initial
complete responders, 4 redeveloped remission. Of the
12 nonresponders to an initial course of gold, 5 developed early toxicity and 7 failed to respond to a second
treatment. Because of a possible partial response to
gold, 5 of the nonresponders to both courses of gold
and the 2 of the 5 patients who failed only the second
course of gold had their gold treatments continued a
mean of 2.5 2 0.19 additional years. No further benefit
was obtained.
Toxicity. During the initial treatment with gold
salts, 8 patients (35%) developed generalized dermatitis which led to the withdrawal of gold (Table 5). Of the
8 patients, 5 had to discontinue gold at 1 year, and 3
after 2 years. Generalized dermatitis, necessitating
termination of gold, developed in 3 patients in the
complete responder group and 5 patients in the nonresponder group.
Toxicity led to withdrawal of a second course of
gold in 11 patients (48%). Generalized dermatitis occurred in 8 patients, 5 of whom had had generalized
dermatitis during an initial course of gold. Those
Table 4. Comparison of clinical response to first and second
course gold at 1 year
Response to
second course
Complete second course
responders
Discontinued due to early
toxicity
Poor responders to second course
Totals
Complete first
course
responders
(1 1 patients)
4
2
S
I1
Partial or poor
first course
responders
(12 patients)
EVERS AND SUNDSTROM
1074
Table 5. Toxicity necessitating termination of gold ( n
patients)
First
course
gold
Dermatitis
Onset of new rash
Prior dermatitis with first
course of gold
Proteinuria
Thromboeytopenia
Hepatotoxicity
Onset of toxicity (months)
(mean 2 SE)
=
23
Second
course gold
3
5*
8
2
1
1
24
5
8.8
10.2 2 2.14
* Fisher’s exact test. P < 0.005
patients who developed generalized dermatitis during
first course gold had an increased risk of developing
generalized dermatitis with a second course of gold.
This risk was lower in patients who did not develop
dermatitis during a first course of gold (Fisher’s exact
test, P < 0.005).
Major toxicity during a second course of gold
developed in 3 patients. One patient developed nausea
and changes in liver enzymes consistent with hepatotoxicity after 2 months of gold treatment. Proteinuria
developed in 1 patient after 10 months of therapy. The
third patient was found to have both thrombocytopenia and proteinuria after 2 months of therapy.
Intermittent rashes and oral ulcers occurred
during both courses of gold, but did not necessitate
discontinuation of gold therapy. None of the patients
developed aplastic anemia, diarrhea, neutropenia, or
dysgeusia. One patient died of a cerebrovascular accident after 2 years of treatment with a second course of
gold. The remaining patients continue to be followed
in our clinic.
Termination of gold as a result of toxicity
tended to occur much earlier during the second course
of gold, compared with termination due to toxicity
during the initial treatment of gold (mean ? SE = 10.2
? 2.14 and 24 .t 8.8, respectively).
DISCUSSION
Long-term gold therapy has been shown to be
of benefit in the treatment of RA (7,9-13). A small
number of patients with RA develop complete remission during initial treatment with gold salts. Remission
during the first course of gold has been reported to
occur from 24 weeks to 2 years after initiation of
treatment (4-7,9-11).
The clinical response to a second course of gold
in RA patients has been less well characterized. The
British Empire Study allowed retreatment with gold in
RA patients based on the judgment of the patient’s
physician (6). Only patients who had responded poorly
to the initial course of gold were selected for retreatment. Their response to a second course of gold
treatment was as poor as the initial failure. Kean and
Anastassiades gave a second treatment to 2 complete
responders to first course gold who had subsequently
flared while off gold (10). Both these patients developed a remission after retreatment. A comparison of
response rates to second course gold has not been
reported for RA patients who either completely remitted or failed to respond during the first course of gold.
In this study, clinical remission developed in 11
of the 23 patients (48%) during the first year of gold
therapy. The high percentage of complete remissions
among patients treated for the first time with gold salts
reflects a selection bias for entry into the study.
Patients with an excellent initial response to gold salts
were more likely to be retreated with a second course
of gold. It is also possible that some of the study
patients developed a spontaneous complete remission
rather than a complete response to gold. Contrary to
the findings in earlier studies, the responder rate to an
initial course of gold did not improve with continued
administration of gold salts beyond 1 year (10).
Prior to a second course of gold salts, all study
patients developed active disease. Disease activity
was not significantly different in any one patient at the
onset of the second gold course compared with the
onset of the first. It is unlikely that any difference in
outcome between the 2 courses of gold therapy in an
individual patient could be attributed to more clinically
active disease. A mean interval of 2.2 5 0.28 years
(mean 2 SE) separated gold trials for the 23 patients
studied.
After 1-year retreatment with a second course
of gold salts, only 17% (4 of the 23 patients) entered a
complete remission. All 4 patients who developed a
clinical remission with a second course of gold salts
had been among the 11 complete responders to first
course gold. Excluding 2 patients who developed early
toxicity, the remaining 5 patients who had been complete responders to initial gold treatment failed to
respond to a second course of gold despite prolonged
therapy beyond 1 year. The 12 nonresponders to first
course gold either developed early toxicity or failed to
respond to a second course of gold salts. The difference in response rates to a second course of gold
among complete initial responders versus poor initial
responders was significant at P < 0.05.
Our results agree with those of the Empire gold
study (6) and suggest that poor responders to an initial
course of gold salts will have a poor response to a
GOLD RETREATMENT IN RA
second course of gold. It is unclear why a second
course of gold has a poorer response rate among initial
complete responders.
Reasons for withdrawal from the initial gold
course included complete remission, poor response,
and toxicity. Reasons for withdrawal from a second
course included only poor response and toxicity. Toxicity during the initial course of gold was limited t o
skin rashes (35%). T h e incidence of toxicity is similar
t o that reported in other studies, in which toxicity
ranged from 28-44% (14-18). No patients at this
medical center were retreated with gold salts if they
had developed significant major toxicity such as proteinuria, thrombocytopenia, or neutropenia during the
first course of gold salts.
In contrast, toxicity t o a second course of gold
included major toxicity: 2 patients developed proteinuria and 1 developed hepatotoxicity. Skin rash remained the most common form of toxicity during a
second course of gold and recurred in 5 patients who
had terminated first course gold because of a skin rash.
Sagrinsky and Greenwald retrospectively reviewed 25 responders t o gold therapy who flared while
on maintenance doses of gold. Upon “reinduction”
therapy, 20 of the 25 patients had a good t o excellent
response; 5 had a poor response (19). Our study
examines the “retreatment” of responders and nonresponders t o gold therapy after an average of 2.2 years
without gold. Although both reviews have a selection
bias, are retrospective, and used small numbers of
patients, we believe the data support a diminished
patient response t o reinduction or retreatment with
gold therapy.
Our findings suggest that R A patients with a
poor initial response t o gold salts a t the end of a year
are likely t o have a poor second response t o gold.
Further, it appears that R A patients in remission after
an initial year of therapy with gold salts have only a
36% likelihood of developing complete remission after
a year of second course gold. Skin rashes tend t o
terminate second course gold therapy if they terminated the first course of gold. Overall, toxicity occurs
earlier in second course gold treatment than in first
course gold.
REFERENCES
1. Empire Rheumatism Council: Gold therapy on rheuma’toid arthritis. Ann Rheum Dis 19:95-119, 1960
2. Rothermich NO, Philips VK, Bergen W, Thomas MH:
Chrysotherapy: a prospective study. Arthritis Rheum
19:1321-1327, 1976
1075
3. Cats A: Multicentre controlled trial of the effects of
different dosages of gold therapy, followed by a maintenance dosage. Agents Actions 6:355-363, 1976
4. Sigler JW, Blum GB, Duncan H, Sharp JT, Ehsiss DC,
McCrum WR: Gold salts in the treatment of rheumatoid
arthritis. Ann Intern Med 80:21-26, 1974
5. The Cooperating Clinics Committee of the American
Rheumatism Association: A controlled trial of gold salt
therapy in rheumatoid arthritis. Arthritis Rheum 16:353358, 1973
6. Empire Rheumatism Council: Gold therapy in rheumatoid arthritis: final report of a multiclinic controlled trial.
Ann Rheum Dis 20:315-334, 1961
7. Ropes MW, Bennett GA, Cobb S , Jacox R, Jessar RA:
1958 revision of diagnostic criteria for rheumatoid arthritis. Arthritis Rheum 2: 16-20, 1959
8. Rodnan GP,editor: Primer on the Rheumatic Diseases.
Seventh edition. JAMA (suppl) 224(5): 130, 1973
9. Lorber A, Simon TM, Leeb J, Carroll PE: Chrysotherapy: pharmacological and clinical correlates. J Rheumato1 2:401-410, 1975
10. Kean WF, Anastassiades TP: Long term chrysotherapy:
incidence of toxicity and efficacy during sequential time
periods. Arthritis Rheum 22:495-501, 1979
11. Srinivasan R, Miller BL, Paulus HE: Long-term chrysotherapy in rheumatoid arthritis. Arthritis Rheum
22: 105-1 10, 1979
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Followup study of chrysotherapy. Arthritis Rheum
22:423, 1979
13. Luukkainen R, Isomaki H, Kajander A: Effect of gold
treatment on the progression of erosion in RA patients.
Scand J Rheumatol6:123-127, 1977
14. Empire Rheumatism Council: Relation of toxic reactions
in gold therapy to improvement in rheumatoid arthritis.
Ann Rheum Dis 20:335-340, 1961
IS. Gottlieb NL, Bielle A: Gold compounds in rheumatoid
arthritis: a report of a symposium. Scand J Rheumatol
61225-230, 1977
16. Jalava S , Luukkainen R, Hameenkorpi R, Helve T,
Isomaki H: Some characteristics of RA patients with
and without side effects due to gold treatment. Scand J
Rheumatol 6:206-208, 1977
17. Huskisson EC, Gibson TJ, Balme HW, Berry H, Burry
HC, Grahame R, Hart FD, Henderson DRF, Wogtulewsk JA: Trial comparing d-penicillamine and gold in
rheumatoid arthritis: preliminary report. Ann Rheum
Dis 33:532-535, 1974
18. Makisara R, Nissila M, Kajander A, Marto J, von Essen
R, Anttila P, Makisara G: Comparison of penicillamine
and gold treatment in early rheumatoid arthritis. Scand J
Rheumatol 7: 166- 170, 1978
19. Sagrinsky DM, Greenwald RA: Efficacy and toxicity of
treatment with gold salts: a retrospective review of 25
cases. J Rheumatol 7:474-478, 1980
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