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Neurotoxicity following a very high dose of oral gold auranofin.

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1316
LETTERS
Bartholomew LE: Ophthalmologic safety of long-term hydroxychloroquine treatment. Arthritis Rheum 22:832-836,
1979). No reports of controlled trials with hydroxychloroquine had been published since 1962. At that time, Mainland
and Sutcliff reported that with doses of 800 mg per day, their
patients suffered significant side effects including 58% with
pruritus, 43% with blurred vision, and 40% with diarrhea
(Mainland D, Sutcliff MI: Hydroxychloroquine sulfate in
rheumatoid arthritis: a six month double-blind trial. Bull
Rheum Dis 12:287-290, 1962).
One gets the feeling that in rheumatology at times
there are more opinions than facts. Although Dr. Kovarsky
says “. . .many accomplished rheumatologists would argue. . .,” there are in fact no data from prospective controlled trials indicating that 6 mg/kg/day of hydroxychloroquine sulfate, for example, is better than 2.2 mg/kg/day of
base. Twenty-two percent of our patients had side effects
with this dose, and we would suspect that in a long-term
followup the incidence of toxicity would be even higher with
6 mg/kg/day. Perhaps larger doses of hydroxychloroquine
are therapeutically better than lower doses, but until such
evidence is shown, we would side with the little lady in the
commercial and ask. “Where’s the data?”
Thomas W. Bunch, MD
J. D. O’Duffy, MD
Mayo Clinic
Rochester, MN
Neurotoxicity following a very high dose of oral gold
(auranofin)
To the Editor:
Schlumpf et a1 recently reported the clinical, laboratory, histologic, and structural findings in 2 patients who
presented with Guillain-BarrC-like syndrome during treatment with gold sodium thiomalate. The same paper also gave
the clinical and laboratory data of a third patient who was
treated with gold and developed peripheral neuropathy and
myokymia (1).
Although gold is widely used in the therapy of
rheumatoid arthritis (RA), neuropathy continues to be a rare
complication of such treatment. According to Endtz, who
reviewed 72 documented cases of gold-induced neuropathy ,
the prominent features of this complication are: 1) painful
neuropathy associated with insomnia and anxiety, 2) peripheral motor neuropathy, including a Guillain-Barr&like syndrome, and 3) encephalopathy with exogenous psychosis,
depression, and delirium (2). The type of injectable gold
compound, its vehicle, the cumulative dose, and the rate of
dosage increase did not seem to influence the development
of neuropathy .
We recently observed a patient who presented with
severe neurologic symptoms while she was taking a very
high dose of a new oral gold compound, (triethylphosphine
gold, auranofin) (3). A 50-year-old woman, affected with RA
since March 1982, started treatment with auranofin (6 mg/
day, 2 tablets) in addition to nonsteroidal antinflammatory
drugs in November 1982. Because of the unsatisfactory
effect of this therapeutic regimen, a dosage increase to 9 mg/
day of auranofin (3 tablets) was prescribed in June 1983.
Fifteen days later, the patient was hospitalized in a neurology unit because of the sudden appearance of diffuse multifocal myoclonus, mental derangement with impaired consciousness, and restlessness. Hypertonus in 4 limbs with
choreoathetoid movements and a dystonic attitude of both
hands were also observed. A bilateral foot drop was noted
after a few days. Facial dyskinesias (stereotyped movements
of lips, tongue, and mouth) and dysarthria were present from
the very beginning of the syndrome. Fecal and urinary
incontinence were also present.
Cerebrospinal fluid was examined twice and the
results were normal, as were the results of an electroencephalogram and cerebral angiography. Computerized tomography showed a slight cerebral atrophy which was considered
within normal limits for the patient’s age. Electromyography
demonstrated partial denervation of the right radial nerve,
marked axonal neuropathy of both lower limbs, along with
complete unexcitability of the common peroneal nerves. The
clinical picture and laboratory tests were not in keeping with
an inflammatory, vascular, or neoplastic disease of the
nervous system. Central nervous system involvement and
peripheral neuropathy due to heavy metals was instead
suspected.
A careful investigation among her relatives revealed
that after 5 days of therapy with 3 tabletdday of auranofin (9
mg), for unknown reasons, the patient started to take 9
tabletslday (27 mg). Such a toxic dosage was maintained for
10 days and immediately preceded the acute development of
the neurologic syndrome. Auranofin was then withdrawn
and therapy with D-penicillamine (750 mglday) was started.
A progressive clinical improvement was noted, and complete
recovery from the neurologic symptoms became evident
after about 3 months.
The case suggests that oral gold (auranofin), like
other gold compounds, may be a potential neurotoxic agent.
Our patient showed a serious neuropathy 10 days after
taking a dose which was 3 times the advised maximum
therapeutic dosage. The neurologic syndrome included both
peripheral motor neuropathy and encephalopathy , while
there was no evidence of inflammatory, vascular, or neoplastic central nervous system involvement. The withdrawal
of auranofin and the administration of D-penicillamine,
which some (4) consider to be effective in the treatment of
gold toxicity, resulted in a slow but progressive and complete recovery. Since the symptoms arose within 10 days of
taking a very high dosage, the severe neurologic side effect
of the oral gold therapy seems to be dose-related rather than
LETTERS
1317
an allergic dose-independent reaction. Therefore, if the
efficacy of auranofin is confirmed in RA, neurotoxicity
should not hinder the proper use of the drug.
Pierfranca Gambari, MD
Pierantonio Ostuni, MD
Paolo Lazzarin, MD
Bruno Tavolato, MD
Silvano Todesco, MD
University of Padova
Policlinico Universita
Padova, Italy
I . Schlumpf U, Meyer M, Ulrich J, Friede RL: Neurologic complications induced by gold treatment. Arthritis Rheum 26:825-83 I ,
1983
2. Endtz W :Complications nerveuses du traitement aurique. Rev
Neurol (Paris) 99:395-410, 1958
3. Finkelstein AE, Walz DT, Batista VM, Mizzaji M, Roisman F,
Mischer A: New oral gold compound for treatment of rheumatoid
arthritis. Ann Rheum Dis 35:251-257, 1976
4. Lyle WH: Penicillamine in metal poisoning. J Rheumatol 8:%99. 1981
HLA-DR4 and rheumatoid arthritis in Mexican
mestizos
To the Editor:
An association of HLA-D4 and DR4 in seropositive
adult patients with classic rheumatoid arthritis (RA) has
been established in whites, Japanese, blacks, and in a group
of Latin Americans consisting of Mexicans and Venezuelans
Table 1. HLA antigen frequencies of patients in comparison with
controls*
Antigen frequencies
Specificity
A1
A2
A3
A9
A10
A25
A26
All
Awl9
A28
Aw29
Aw32
B5
B7
B8
B12
B13
B I4
B15
B17
Bw21
Bw22
B27
Bw35
B37
B40
BS 1
B52
DR 1
DR2
DR3
DR4
DR5
DR7
Patients
(n = 52)
0.057
0.692
0.019
0.442
0.038
O.Oo0
0.076
0.076
0.OOo
0.096
0.000
O.Oo0
0. I15
0.096
0.115
0.0%
0.038
0.038
0.019
0.OOo
0.038
0.019
0.038
0.519
0.000
0.OOo
0.019
0.019
0.077
0.019
0.115
0.384
0.038
0.077
Controls
(n = 301)
Corrected
P values
0.060
27.16
5.50
32.00
I .24
1S O
4.41
4.70
0.57
21.21
32.00
22.08
2 1.92
21.76
0.28
1.56
27.39
24.64
6.17
5.05
21.40
2.14
21.21
32.00
6. I7
22.08
3.04
21.92
21.92
0.06
20.86
27.52
4.76
19.07
3.10
0.581
0.030
0.30
0.150
0.013
0.019
0.060
0.026
0.086
0.033
0.033
0.183
0.280
0.040
0.120
0.020
0.066
0.086
0.036
0.140
0.017
0.026
0.412
0.066
0.070
0.000
0.000
0.295
0.063
0.140
0.300
0.070
0.180
* Statistical analysis performed by Dr. Jose de Jesus ManriqueOrtega.
(1).
We studied 49 female and 3 male patients with a
diagnosis of “definitive” or “classic” RA according to
criteria of the American Rheumatism Association (2). All
patients had positive agglutination tests for rheumatoid
factor. The patients were Mexican mestizos whose ages
ranged from 31-72 (mean 46.9). The control group consisted
of 301 healthy, unrelated Mexican mestizos, who had the
same socioeconomic and ethnic background as that of the
patients and who ranged in age from 15-65.
HLA typing of the lymphocytes isolated in a FicollHypaque gradient was performed using a modification of the
technique of the National Health Institutes (3). The typing
sera for both the control group and the patient group were
obtained from the NIH serum bank. All subjects were typed
for the specificities listed in Table 1, by using 2 or more
antisera for each specificity. The established frequency of
HLA antigens was compared statistically between groups by
the x2 test with Yates’ correction. The P value was corrected
by multiplying by the number of antigens tested (34 anti-
gens). Table 1 shows the antigen frequencies which were
found for the patients and for the control group with their
respective corrected P values.
In contrast with previous studies on patients with RA
(l), a higher frequency of HLA-DR4 was not demonstrated.
In studies of other ethnic groups, such as Jews (nonAshkenazi) and Asian Indians, an increase of D4 and DR4
was also not associated with RA (1). It is striking that in a
Latin American group (Mexicans and Venezuelans) (l), the
DR4 antigen frequency of patients (n = 41) and controls (n =
19) was shown to be 0.57 and 0.05, respectively. The
frequency of HLA-DR4 in our patients was 0.384, and in
controls it was 0.300. The latter value is similar to that
encountered in Mexican American groups typed in the
United States (4).
Since considerable variations exist in antigen frequencies between populations even within the same country,
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auranofin, neurotoxicity, dose, following, high, gold, oral
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