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D-penicillamine in the treatment of rheumatoid arthritis.

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666
D-PENICILLAMINE IN THE
TREATMENT OF RHEUMATOID
ARTHRITIS
IAN K . T S A N G , C A R O L I N E A . PATTERSON, H O W A R D B. STEIN, H A R O L D S. ROBINSON, and
D E N Y S K. F O R D
Forty-four patients with definite or classic rheumatoid arthritis and failure to tolerate or respond to gold
therapy were treated with D-penicillamine on a so-called
go-slow, go-low regime. Seventeen patients tolerated the
drug and had a 3-13 month follow-up assessment; 8 were
markedly improved, 6 moderately or slightly improved,
and 3 unimproved. Penicillamine had to be discontinued in
9 patients because of toxic side effects.
Since the first report of Jaffe ( I ) , the therapeutic
efficacy of D-penicillamine in the treatment of active
rheumatoid arthritis ( R A ) has been supported in various centers with both controlled (2) a n d uncontrolled
(3-6) studies. The toxicity of D-penicillamine has also
been defined (7). However, with the so-called go-slow,
go-low regimen (8,9), the incidence of toxicity has been
reduced while the therapeutic efficacy has been maintained.
From the Division of Rheumatology. Department of Medicine, University of British Columbia. and the Arthritis Centre. Vancouver. British Columbia. Canada.
Supported in part by the Canadian Arthritis and Rheuniatism Society.
Ian K . Tsang. M.B.: Fellow in Rheumatology: Caroline A.
Patterson, M.B.: Clincial Instructor: Howard B. Stein, M.D.: Clinical Instructor: Harold S . Robinson. M.D.: Clinical Professor: Denys
K . Ford. M.D.: Professor.
Address reprint requests to Harold S . Robinson, M.D.. The
Arthritis Centre. 895 West 10th Avenue, Vancouver. B.C.. Canada.
Submitted for publication July 30. 1976: accepted October 5 ,
1976.
Arthritis and Rheumatism, Vol. 20, No. 2 (March 1977)
At the Arthritis Centre in Vancouver, British
Columbia, between April 1975 a n d June 1976, 44 patients with R A were treated with D-penicillamine. The
purpose of this paper is to report that experience with
special reference both to toxicity in the 44 patients and
to the therapeutic effectiveness in 17 patients followed
more than 3 months. I n view of the consensus in England regarding t h e therapeutic efficacy (2,7,9), a randomized comparison was considered inappropriate.
MATERIALS AND METHODS
Patients. Every patient had definite or classic adult
rheumatoid arthritis by A R A criteria (10); 25 were women and
19 were men. They were all under supervision by one of the
consulting rheumatologists at the Centre, who was responsible
f o r the Penicillamine Clinic. The patients all had active disease, despite adherence to the basic regime for R A . All
patients had received chrysotherapy in the past, but the gold
treatment was discontinued in 37 patients because of side
effects and in 7 patients because of failure to respond. At the
start of the study all patients had clinical and laboratory
evidence of active disease.
Treatment Schedule. All patients began treatment
with 250 mg of D-penicillamine (Merck, Sharp and Dohrne)
daily. given orally after meals. The dose was increased by
adding 250 mg to the daily dose every 2 weeks early in the
study, and every 4 weeks later in the study. A maintenance
dose of 500-750 rng/day in divided dosage was generally
achieved in 12-16 weeks. A higher daily dosage was given in
exceptional cases. but the dose was reduced to 750 mg daily as
soon as clinical improvement took place. Nonsteroidal anti-
667
Table 1. Sutiittiary of rhe Outcotne
UJ
a Penicillatnine Program in the 44 Patients
Duration of Disease at
Onset of Penicillamine
Treatment
Follow-~p
Category
Removal from study
Stopped on account of
toxicity
Less than 3 months
More than 3 months
No. of
Patients
Results of
Treatment
Average Age
(years)
9
Table 2
50
9
9
50
(6)
Table 3
Not assessed
Table 4
Markedly improved
Slightly to moderately
(3)
Not improved
17
(8)
improved
inflammatory agents were prescribed in the same dosage as that
in which they were given before the penicillamine. Glucocorticoids were reduced in response to improvement. N o patients
received antimalarials, gold salts, o r immunosuppressants during the study.
Monitoring for Toxicity. Patients were regularly questioned about skin rash, loss of taste, diarrhea, and other possible side effects. Hemoglobin, white blood cell count, platelet
estimate, erythrocyte sedimentation rate (ESR) by the Westergren method, and urinalysis were monitored every 2 weeks
until the penicillamine dosage was stabilized, and then every 4
weeks. When signs of toxicity appeared, penicillamine was
decreased or discontinued according to the clinical situation.
D-penicillamine was restarted at 250 mg daily after complete
disappearance of the suspected toxic manifestation. The dose
was then increased cautiously and, if the toxic manifestation
recurred, penicillamine was discontinued permanently.
Assessment of Disease Activity. Eight parameters were
measured to assess the patient’s progress during therapy: hemoglobin. ESR, duration of morning stiffness, Lansbury’s
articular index, grip strength measured by the mean of three
grips by each hand, time to walk 25 yards, time to ascend and
descend nine steps, and reduction of prednisone intake, i f
applicable. Patients were regularly questioned about their
sense of well-being, changes in the severity of their joint pain.
and alterations in their level of function.
RESULTS
T a b l e I s u m m a r i z e s t h e o u t c o m e o f t h e penicillamine p r o g r a m in t h e 44 patients studied. N i n e patients
were removed f r o m t h e study f o r reasons unrelated t o
penicillamine toxicity ( T a b l e 2). Patient 13, a 54-yearold w o m a n , h a d h a d r h e u m a t o i d arthritis for 21 years;
her t r e a t m e n t h a d included c o n t i n u o u s prednisone at 100
mg daily a n d j o i n t replacements f o r t h e left h i p a n d t h e
right knee. N e u r o p a t h y a n d episcleritis h a d complicated
t h e course of her previous disease. I n O c t o b e r 1975 a left
f o o t d r o p suddenly developed a n d .vasculitis w a s diag-
Average
(years)
I2
8.7
Range
(years)
3-22
9
1-16
1-20
49
6
4-16
57
61
14.5
6.3
9-22
3-8
nosed. S h e w a s started on penicillamine a t 250 m g daily,
a n d 2 weeks later t h e d o s e w a s increased t o 500 m g
daily. A t t h e end of t h e t h i r d week on penicillamine, a
s p o n t a n e o u s perforation o f t h e colon resulted in d e a t h
within 2 days.
Penicillamine w a s discontinued temporarily in 3
patients: 1 h a d d i a r r h e a a t 3 m o n t h s , 1 h a d proteinuria
a t 3 months, a n d 1 h a d a perforation of a d u o d e n a l ulcer
t h a t pre-dated t h e initiation of t h e therapy. All 3
patients h a d penicillamine restarted after their s y m p t o m s h a d subsided, a n d each remained free o f adverse
effects when continued on t h e penicillamine p r o g r a m .
Table 2. Patient.r Rettioced ,/rotti Stud!,
Duration
of
Patient Treatment
No.
(weeks)
Reason for Removal
I
4
9
II
13
24
8
4
3
21
24
31
I2
34
I
38
8
Refused to continue after discovery of 1-2 R B C /
HPF in a single urinanalysis.
Died from bronchogenic carcinoma.
Left town while improving.
Left town while improving.
Died from perforation of the bowel, presumed to
result from vasculitis, for which the patient was
put on penicillamine 3 weeks before.
Although patient improved, evaluation was
obscured by Yttrium-90 synovectomy and by
revision of right below-knee amputation slum p
for pre-existing osteomyelitis.
Unable to obtain the medication because of
supply shortage.
Refused to continue after development of blurred
vision. unexplained by ophthalmologic consultation.
Left town while improving.
10
TSANG ET A L
I n 9 patients penicillamine was discontinued permanently because of toxic side effects (Table 3). Patient
4 had an itchy, erythematous, macular rash over the
anterior aspect of her lower leg after 1 month of therapy.
The rash disappeared within 5 days of discontinuation
of penicillamine, but recurred 2 days after the drug was
restarted. Penicillamine was finally discontinued permanently. The rash in patient 19 was a single itchy,
eczematous. scaly patch approximately 3 cm in diameter
on the back of the neck. Patient 26 had a generalized
pruritic urticaria1 skin rash with palpitations a n d general malaise; the symptoms subsided within 72 hours
after the discontinuation of penicillamine. T h e oral ulcers in patients 2 and 25 were painful but subsided
within 2 weeks after the discontinuation of penicillamine. Patients 20 and 23 had proteinuria of more than 2
g/24 hours, but this fell to 178 a n d 153 mg/24 hours
respectively in 3 months. T h e microscopic hematuria of
patient 37 subsided with the discontinuation of penicillamine but recurred with reinstitution of the drug.
Leukopenia developed in patient 3 after 6 months of
therapy while she was taking 1.5 g of penicillamine
daily. Her initial leukocyte count was 4000 WBC/mm3.
Although penicillamine was discontinued when the leukocyte count dropped to 2800 WBC/mm3, it continued
t o d r o p t o 800 WBC/mm3 (31% neutrophils, 20% band
cells, and 43% lymphocytes) over the next week, before
gradually increasing to 4000 WBC/mm3 in the second
week after the drug was stopped. T h e hemoglobin and
platelet count were unaffected in this patient.
Twenty-six of the initial 4 4 patients remained on
penicillamine continuously. At the time of this report
the duration of therapy ranged from I month to 13
months with a n average of 5 months. Seventeen of the
patients received penicillamine for 3 months or longer
and 10 patients for 6 months or longer. T h e subsequent
observations on the efficacy of penicillamine are based
on these 17 patients (Table 4). Eight patients were considered t o have shown a marked improvement, 6 a moderate or slight improvement, a n d 3 patients no improvement. The hemoglobin, ESR, a n d articular index were
considered to be the most useful criteria for assessing
improvement of active disease. G r i p strength, the 25yard walk time, a n d the stair climb time were considered
t o be affected, not only by active inflammation, but also
by pre-existing joint damage. T h e remaining two criteria, duration of morning stiffness a n d prednisone intake, were not applicable t o all the patients.
The 8 patients in the marked improvement class
all had a rise of hemoglobin, a fall of ESR, a n d a fall in
articular index. Patient 18 had an ESR of only 20 on
admission to the study, but she was on 10 mg prednisone
daily at that time. After 7 months of therapy her ESR
was 7 and she was no longer taking prednisone. The 6
patients in the moderate or slight improvement class
were thought to have clinically demonstrated definite
improvement, but the objective assessment of their response was not uniform, as shown by the data in the
hemoglobin, ESR, a n d articular index columns of Table
4. Three patients were designated a s not improved on
the basis of their objective assessment. There were no
differences in the duration of rheumatoid arthritis between the above three groups of patients, but Table 4
shows that a larger proportion of the patients who responded poorly to penicillamine were on prednisone
therapy.
Table 3. Tosic Murii/esraiions Requiring Pernianeni Cessaiion oJ Pmicillaniine Therapy
Treatment Data
Pa ti en t
No.
4
19
26
2
25
20
23
37
3
Duration
(months)
Toxic Manifestation
from Penicillamine
Final Daily
Dosage
(mg)
Type
500
750
250
500
500
750
750
500
1500
Skin rash
Skin rash
Skin rash
Oral ulcer
Oral ulcer
Proteinuria
Proteinuria
Hematuria
Leukopenia
Duration after
Withdrawal
(wks)
Toxic
Manifestation
from Gold
I
None
Skin rash
Oral ulcer
Oral ulcer
Oral ulcer
Proteinuria
Leukopenia
Skin rash
Skin rash
3
0.5
2
I
I2
I2
7
2
D-PENICILLAMINE FOR RA
669
Table 4. Assessment of Improvement from Clinical and Laboratory Data in 17 Patients Treated Longer than 3 Months
~~~
~
~
~~
~
Hemoglobin
(g%1
Pt. Rx
No. (mos) Pre-
Post-
ESR
(mm/hr)
Pre-
Post-
Hand
Grip
(mmHg)
Articular
Index
Pre-
Post-
Pre-
Post-
25-Yard
Walk
(set)
Pre-
Duration
Morning
Stiffness
(hours)
Stair
Test
(set)
Prednisone
Intake
(mg/d)
Post-
Pre-
Post-
Pre-
Post-
Pre-
Post-
60
19
19
17
17
17
18
15
UN*
49
75
57
52
46
39
29
UN
36
35
37
4
.25
0
0
0
0
0
0
0
42
32
26
8
.5
8
0
0
0
2
I
0
0
10
0
2.5
0
0
0
0
0
0
0
2.5
0
0
34
UN
20
29
20
28
UN
UN
ND
101
36
57
UN
UN
34
83
34
UN
0
8
0
2
1
2
0
8
0
0
5
2
2.5
0
7.5
5.0
7.5
0
5.0
0
2.5
5.0
7.5
0
69
19
34
UN
33
ND
75
39
69
8
0
0
2
0
0
2.5
2.5
5.0
0
0
0
Marked Improvement
8
12
14
18
29
30
35
36
13
9
7
7
5
4
4
3
10.4
13.5
12.0
13.8
13.2
11.3
13.4
12.5
12.5
15.1
13.6
15.2
14.5
12.2
15.4
13.5
83
58
78
20
81
60
82
40
21
17
40
7
20
33
12
17
166
36
112
58
114
123
138
153
110
8
80
0
24
82
58
4
52
120
131
97
73
71
102
190
61
129
169
130
116
68
94
207
66
22
25
28
20
18
20
15
40
Moderate or Slight Improvement
6
15
16
22
24
28
13
5
7
6
6
4
11.7
11.2
13.5
11
12.6
11.9
12.8
11.3
13.7
10.3
13.2
11.7
90
116
36
Ill
45
82
20
35
58
65
45
25
82
138
118
74
118
166
88
124
54
12
66
202
56
UN
136
87
72
67
70
48
155
90
91
60
65
UN
ND
40
18
26
No Improvement
5 13
7 1 1
33
4
* UN:
7.1
9.1
14.114.8
11.1 11.9
114
33
90
95
30
59
114
44
ND
130
50
77
52
145
55
68
105
74
59
16
ND
unable to perform test.
t ND: not done.
DISCUSS10 N
The 25% incidence of mucocutaneous, renal, and
hematologic toxic side effects requiring discontinuat ion
of therapy in this study is similar to that of other reported studies (23). However the incidence of “indigestion” and alterations of taste is lower, and no
patient discontinued the penicillamine because of these
two latter side effects. It was thought that this lower
incidence might have been a result of the go-slow, golow policy. Thrombocytopenia was not observed, in
contrast to a 13% incidence in a previous study (6).
Albuminuria in 2 of the patients and leukopenia in
another proved to be reversible.
In this uncontrolled open study, 17 patients were
followed for longer than 3 months after starting penicillamine; 8 were markedly improved and 6 moderately
or slightly improved. Improvement in 14 of 17 patients
who had severe rheumatoid arthritis and who were
chrysotherapy failures is impressive, particularly in view
of the long duration of disease in all the patients.
There was no close correlation between the toxic
manifestations of gold and penicillamine, although both
patients who discontinued penicillamine on account of
oral ulcers had similar ulcers caused by gold, and another patient had albuminuria on both medications. In 1
patient the type and location of the rash were the same
with both drugs. Only 1 of the 7 patients who had failed
to respond to gold was followed long enough t o allow a
satisfactory assessment of penicillamine therapy, and
this patient was classed as moderately improved.
This study not only supports the view that penicillamine is useful in managing patients with rheumatoid
arthritis, but also indicates that it may be used successfully in patients who have reacted adversely to gold. It is
clear that it is necessary to assess patients over a longer
period before the full evaluation of efficacy and toxicity
can be established. The authors propose t o continue the
670
TSANG ET A L
Penicillamine Clinic a n d to extend gradually t h e use of
t h e drug, while maintaining a careful monitoring of t h e
treated patients.
ACKNOWLEDGMENTS
The authors thank Ms. A. Teufel for her administrative and nursing assistance in the Penicillamine Clinic, and
they are also grateful to the occupational therapists of The
Arthritis Centre for performing the functional tests. The
Penticton Kiwanis Club contributed toward the cost of the
penicillamine.
REFERENCES
Jaffe I A : Rheumatoid arthritis with arteritis: report of a
case treated with penicillamine. Ann Intern Med
6 I 15 56-563. 1964
Multicenter Trial Group: Controlled trial of D(-)penicillamine in severe rheumatoid arthritis. Lancet 1:275-280.
1973
Golding JR. Wilson JV. Day AT: Observations on the
4.
5
6.
7.
8.
9.
10.
treatment of rheumatoid disease with penicillamine. Postgrad Med J 46599-605, 1970
Day AT, Golding J R , Lee PN, et al: Penicillamine in
rheumatoid disease: a long term study. Br Med J 1:180183. 1974
Zuckner J, Ramsey RH, Dorner RW, et al: D-penicillamine in rheumatoid arthritis. Arthritis Rheum 13:131-138,
1970
Huskisson EC, Gibson TJ, Balme HW. et al: Trial comparing D-penicillamine and gold in rheumatoid arthritis.
Preliminary report. Ann Rheum Dis 33532-535, 1974
Editorial: D-penicillamine in rheumatoid arthritis. Lancet
I:I 123-1 125, 1975
Jaffe IA: The technique of penicillamine administration in
rheumatoid arthritis. Arthritis Rheum 18513-514, 1975
Dixon AStJ, Davies J. Dormandy TL, et al: Synthetic
D(-)penicillamine in rheumatoid arthritis. Double-blind
controlled study of a high and low dosage regimen. Ann
Rheum Dis 34:416-421, 1975
Ropes MW. Bennett GA, Cobb S, et al: 1958 revision of
diagnostic criteria for rheumatoid arthritis. Bull Rheum
Dis 9:175-176, 1958
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