Journal of the

Robinson American Academy of

Dermatology

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5. Guthrie TH, Porubsky ES. Successful chemotherapy of
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7. Jacobs GH, Rippey JJ, Altini M. Prediction of aggres-
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533-7.
8. Lang PG, Maize JC. Histologic evolution of recurrent
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9. Hartman R, Hartman S, Green N. Long-term survival
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Arch Derrnatol 1986; 122:912-4.
I0. Weiman TJ, Shively EH, Woodcock TM. Responsive-
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IIIII III I

Oral hyposensitization in nickel allergy

Peter Sjrvall, M.D., Ole B. Christensen, M.D., and Halvor Mrller, M.D.
Malrnii, Sweden

In two controlled studies, each including 24 patients with contact allergy to

nickel, different p m t o c o i s were designed in an attempt to diminish the
patients' hypersensitivity by oral administration o f the antigen. With doses of
5.0 mg nickel sulfate taken once a week for 6 weeks, but not with 0.5 mg
daily, the degree of contact allergy was significantly lowered, measured as
patch test reactions before and after nickel administration. (J AM ACAD
DERMATOL 1987; 17:774-8.)

Since we introduced oral provocation with
nickel to study the pathogenesis of nickel hand
eczema, ~ this technique has been widely used in
clinical and experimental work. 2"a It is now a com-
mon experience that even if a standardized nickel
dose is used for provocation, there is a great range
in extension and intensity of clinical reactions.
From the Department of Dermatology, Lund University.
Preliminary data presented to the Eighth IntemationaI Symposium
on Contact Dermatitis, Cambridge, United Kingdom, March 2l,
1986.
Supported by grants from the Edvard Welander Foundation and the
Inez Bergstrand Foundation.
Accepted for publication ApriI 21, 1987.
Reprint requests to: Dr. Peter Sjrvall, Department of Demaatology,
General Hospital, S-214 01 Malmr, Sweden.
774
Thus some patients show a strong and widespread
eczematous flare-up, including a macular or even
urticarial rash, and others show a weak and limited
reaction or none at all.
After positive oral provocations, some of our
nickel patients have reported improvement of their
hand eczema, diminished metal sensitivity, or
both. It is our impression that such reports emanate
from patients who had vigorous flare-up reactions
in particular. This experience encouraged us to
conduct the following oral hyposensitization ex-
periments.
MATERIAL
Patients with patch t e s t - p r o v e d contact allergy to
nickel were invited to the studies, and informed consent
was obtained. The studies were approved by the ethical
Volume 17
Number 5, Part 1
November 1987
board of the medical faculty. All patients were female
and between the ages of 15 and 63 years (mean, 37
years), Two controlled studies were carried out, with
24 patients participating in each.
METHODS
Two studies were conducted consecutively. The pa-
tients were tested epicutaneously (Finn Chamber on
Scanpor surgical tape) with a dilution series of nickel
sulfate in distilled water. Before and after ingestion of
nickel, the skin tests were performed on the left and
right sides of the back, respectively. The patch tests
were applied for 48 hours and read after a further 24
hours. The individual test reactions were scored as fol-
lows: 0 = no reaction; 1.0 = erythema and infiltra-
tion; 2.0 = erythema, infiltration, and papules; and
3.0 = erythema, infiltration, papules, and vesicles
with exudation. When the tests were read at the second
occasion (after ingestion of nickel), the results from the
first test were kept in files not available to the reader.
The sum of test scores before and after ingestion of
nickel was determined for each patient.
Ingestion of nickel was carried out by means of
capsules containing nickel sulfate (NiSo4 • 6 H20),
2.2 mg ( = 0 . 5 mg nickel) in sucrose; nickel sulfate,
22.4 mg ( = 5.0 mg nickel) in sucrose; or placebo (su-
crose). To mask the nickel sulfate color which was
apparent with the high nickel dose, these capsules and
those containing placebo were supplemented with 4 mg
methylene blue. During the studies the patients were
self=observant in regard to symptoms of flare=up and
kept a diary.
Study I
In study I, a double-blind study, 24 patients were
randomly assigned to two groups, one obtaining cap-
sules with 0.5 mg nickel and one obtaining placebo
capsules. The patients took one capsule a day for 6
weeks. The skin tests were performed 1 to 3 weeks
before oral intake and within 1 week afterward. In the
patch test series with nickel sulfate, the compound was
applied in the following concentrations: 2.7%, 0.9%,
0.3%, and 0.1%. The patients were also tested intra-
cutaneously before and after ingestion of nickel with
tuberculin, 2 TU purified proteiri derivative (Statens
Seruminstitut, Copenhagen). The reactions were read
after 72 hours and graded by measuring two right-
angled diameters of the infiltration.
One week after the last capsule, a serum sample and
a 24-hour urine sample were collected in acid-washed
pI~istic containers for determination of nickel concen-
trations.4
Oral hyposensitization in nickel allergy 775
Pilot study
We conducted an open pilot study of five patients
who obtained one capsule of 3.5 mg nickel once a week
for 6 weeks. In the patch test series with nickel sulfate,
the compound was applied in the following concentra-
tions: 0.8%, 0.2%, 0.05%, and 0.0125%. Seventeen
microliters of the nickel solution was transferred by
micropipette onto each Scanpor filter. The reason for
choosing lower test concentrations than in study I was
to obtain weaker reactions that might more readily dis-
close any changes in the patients' reactivity. Tuberculin
reactivity was determined as in study I.
S t u d y II
Study II was also a double-blind study of 24 patients
randomly assigned to two groups, one obtaining cap-
sules with 5.0 mg nickel and one obtaining pqacebo
capsules. The patients took one capsule a week for
6 weeks. The skih tests were performed within 1 week
before ingestion of nickel and within one week after-
ward. The patch test series with nickel sulfate was the
same as that used in the pilot study.
In patch tests before and/after ingestion of nickel,
venous blood samples were taken from the participating
patients to investigate whether the ratio between
T-helper lymphocytes and T-suppress0r lymphocytes
differed between the group obtaining nickel and the
group obtaining placebo. Two patients refused to give
blood samples. Mononuclear cells were separated and
stored in liquid nitrogen. T lymphocyte subpopulations
were quantitated in direct immunofluorescence by
means of antihuman Leu-3a and Leu-2a (Becton Dick-
inson Immunocytometty Systems, Mountain View,
CA) on a fluorescence-activated cell sorter~ (model 50-
H, Ortho Diagnostic Systems, Inc., Raritan, NJ).
Statistics
For each patient the sum of test scores before and
after ingestion of nickel or placebo was compared and
used for statistical analysis. The Wilcoxon rank sum
test was used in studies I and II, and the Wilcoxon
signed-rank test was used for the pilot study.
RESULTS
Study I
When the code was broken, it was found that
13 patients had received nickel and 11 patients
placebo. Two patients dropped out of the study,
one (taking nickel) because of a strong flare-up of
her contact dermatitis and one (taking placebo)
because of neurologic symptoms of a functional
 Journal of the
776 SjOvall et al American Academy of
Dermatology

STUDY I PILOT 8 T U D Y S T U D Y II

10 0 0 e9 O0 @@

0 9 000 @@

I9 0 0 000
0 el O0 9 O O0
O9 9149 ~ lie 0 eeo 0
5 -. 9 ...... O9 0 oe 0 @g
o
OO 9 eo 9 OI

oo ~o O

O 00 9 @ O0 ee
ee
0 I A I .L _.l I I .I- I I
B A B A 13 A B A B A
Nickel Placebo Nickel Nickel Placebo

Fig. 1, Nickel sensitivity before (B) and after (A) oral nickel provocation.

nature. In the remaining 22 patients there were no
flare-up reactions in either of the two groups apart
from what could be expected of the regular base-
line activity o f their disease.
The individuaI sums of patch test scores before
and after oral ingestion of nickel or placebo are
presented in Fig. 1. There was no significant dif-
ference between the groups before and after the
oral intake.
There was no change in the strength of the tu-
berculin reactions before and after the ingestion
of nickel. The assay of nickel in serum and urine,
as studied 1 week after the study, did not disclose
higher nickel levels in patients receiving nickel
than in those taking placebo.
Pilot study
Five patients obtained 3.5 m g nickel once
weekly for 6 weeks. Of these, three patients had
a flare-up of their eczematous eruptions. The other
two patients did not react to the nickel capsules.
In all five patients the sum of test scores was lower
after nickel ingestion than before, and the me-
dian value diminished significantly (p < 0.05)
(Fig. 1). The tuberculin reactions, however, were
not affected.
Study II
In this study, 12 patients received nickel and 12
received placebo. No patient dropped out of the
study. In the nickel group, one patient had urti-
carial swelling after the third and fourth capsules,
seven other patients had mild flare-ups of their
eczema, and the remaining four patients had no
signs or symptoms. In the placebo group, two pa-
tients had a diffuse itching during the study, one
patient had a flare-up of her pompholyx after the
third capsule, and the remaining nine patients had
no signs or symptoms.
The individual sums of patch test scores before
and after oral ingestion of nickel or placebo are
presented in Fig. 1. In the patients receiving
nickel, the test score was significantly lowered in
comparison with that of the p l a c e b o group
(p < 0.05).
The total amount of circulating T lymphocytes,
the number of T helper and T suppressor cells,
and the ratio between these subpopulations did not
change in any of the two patient groups.
DISCUSSION
Once acquired, contact allergy in man usually
is a lifelong state. Spontaneous disappearance oc-
curs as individual exceptions that have been doc-
umented when patch tests have been repeated in
the same patients. 6'7 Unresponsiveness to specific
low-molecular-weight antigens, or so-called hard-
ening, has been reported to develop in industrial
workers, perhaps because of continuous low-dose
exposure, s
Specific immune tolerance in man, that is, in-
hibition of contact sensitization by low-dose buc-
cal pretreatment with the sensitizer, has been dem-
onstrated. 9 The much greater clinical problem of
desensitizing or hyposensitizing patients with es-
tablished contact allergy has been approached in
some experimental studies with varying success.
In a 1958 article dealing with hyposensitization
Volume 17
Number 5, Part I
November 1987
against thus dermatitis, Kligman 1~concluded that
oral or intramuscular administration of Rhus al-
lergens caused a definite but limited decrease in
Rhus sensitivity. Urbach and Gottlieb" reported
on two female patients with nickel allergy who
were given increasing subcutaneous doses of
nickel sulfate. Clinical and patch test sensitivity
diminished after the treatment 9 Wilson 1~described
six nurses with contact allergy to streptomycin 9
Desensitization with subcutaneous, and later in-
tramuscular, injections was successful, with just
one recurrence. Van Scott and Kalmanson 13 ran
into problems of contact allergy in the treatment
of mycosis fungoides patients with topical nitrogen
mustard. Different techniques for desensitization
were attempted. Most successful were intravenous
injections or infusions of the antigen, whereas
experiments with oral administration did not
succeed.
Systematic studies with oral hyposensitization
were performed by Epstein et a114'~5 on North
American healthy subjects sensitized to the ubiq-
uitoias poison ivy and poison oak antigen, urushiol.
Increasing oral doses of urushiol or placebo were
given over a protracted period and resulted in a
lowered degree of patch test sensitivity. Rashes
and anal pruritus were the main complications, not
urticaria. In the second study the authors used a
higher total dose and were more successful, par-
ticularly in highly sensitized individuals. It was
concluded that a low initial dose did not prevent
side effects; furthermore, some type of mainte-
nance therapy was recommended.
In the first of our three studies the patients were
given a low nickel dose of 0.5 mg. This dose is
p r e s u m e d to equalize the mean daily dietary intake
and should generally not provoke a flare-up of
contact dermatitis. It did so, however, in one of
our patients, who thereafter dropped out of the
protocol. As a matter of fact, Cronin et a116 ob-
tained some positive provocations when admin-
istering a nickel dose as low as 0.6 rag. The degree
of contact allergy did not change during study I,
in itself a sign of the stability of the registration
technique.
The design of the pilot study was based on our
anecdotal experience of clinical improvement in
nickel dermatitis after a positive oral provocation.
In this open study the degree of contact allergy
Oral hyposensitization in nickel allergy 777
in all five patients diminished significantly. Since
reactivity to tuberculin was unaffected, the low-
ered sensitivity seems to be specific to nickel.
The outcome of the pilot study encouraged us
to design a controlled study with even higher nickel
doses. The results in this study II confirmed those
from the pilot study: the nickel allergy diminished
after 6 weeks with weekly doses of 5 nag nickel
sulfate. The majority of the patients in the nickel
group had a flare-up of their derinatitis. These
eruptions were not, however, individually corre-
lated with a decrease of contact allergy.
Although high doses are inconvenient to the pa-
tients, it is possible that high doses are more prone
to succeed in influencing the allergy state. Giainea
pigs sensitized to chromate were Successfully de-
sensitized by a double-shot technique combiriing
a high intravenous antigen dose with a carefully
timed epicutaneous one. 17 In a recent report of
urushiol-sensitized guinea pigs, the animals were
hyposensitized with oral antigen, particularly with
high doses. 18
The mechanism behind suppression of a contact
allergy reaction can only be speculated on. It is
possible that antigen excess may stimulate or ini-
tiate the production of T suppressor cells, With
the methods available to us, this production was,
however, not possible to demonstrate.
In conclusion, we believe that our study has
shown that oral hyposensitization is possible in
patients with allergic contact dermatitis to nickel.
At present we do not know the duration of the
lowered hypersensitivity. Further studies are re-
quired to evaluate this hyposensi~ization procedure
in clinical practice.
We thank Dr. Anna Johnson and Ms. Marie Billgren,
University Hospital of Lund Department of Oncol6gy,
for performing the lymphocyte studies. We also thank
Verner Lagesson, Ph.D., Link6ping, for determining
nickel concentrations in blood and urine by atomic ab-
sorption spectrophotometry.
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1. Christenson OB, M611erH. External and internal expo-
sure to the antigenin the hand eczema of nickel allergy.
Contact Dermatitis 1975;1:136-41.
2. Menn6 T, Hjorth N. Reactions from systemic exposure
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778 SjOvaIl e t aI
old patch sites in nickel allergy. Acta Derrn Venereol
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ABSTRACTS
Infection with human parvovirus (B19), aplasia of the
bone marrow and a rash in hereditary spherocytosis
Nunoue T, Koike % Koike R, et al: J Infect 1987;14:67-70
Does everyone know that human parvovirus (B19) can cause a
severe bone marrow aplasia as well as the usual rash? The worst
effects occur in adults, even those without spherocytosis.
Philip C. Andersoli, M.D.
Long-term griscofulvin treatment for progressive
systemic sclerosis
Ferri C, Bernini L, Bombardieri S, etal: Scand J
Rheumatol 1986;15:356-62
Readers need to be alert to very inaccurate methods, as shown
here in a wholly uncontrolied, unselected, uncritical study of the
benefits of griseofulvinin treating scleroderma. No rational reviewer
can still believe that controls and double biindiag are not really
needed. Of course, 28 of 33 patielats with scleroderma improved
nicely as they always do in the control group, probably due to good
implementation of physical therapy and improved mental attitude.
Let the reader beware when the reviewers fall asleep on the job.
Philip C. Anderson, M.D.
Journal of the
American Academy of
Dermatology
13. Van Scott EJ, Kalmanson JD. Complete remissions of
mycosis fungoides lymphoma induced by topical nitrogen
mustard (HN2): control of delayed hypersensitivity to
HN,. desensitization and by induction of specific immu-
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oak hyposensitization: evaluation of purified urushiol.
Arch Dermatol 1974;109:356-60.
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specific hyposensitization to poison oak in sensitized
adults. Arch Dermatol 1982;118:630-3.
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in nickel-sensitive women with hand eczema. In:
Brown SS, Sundennan FW Jr, eds. Nickel toxicology.
New York: Academic Press, 1980:149.
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Persistent adrenal insufficiency secondary to low-dose
ketoconazole therapy
Best TR, Jenkins JK, Murphy FY, et al: Am J Med
1987;82:676-80
A single case is not persuasive, but we should be alert to this
possible side effect of ketoconazole. The adrenal failure was very
prolonged. More cases need more study.
Philip C. Anderson, M.D.
Absence of congenital infection and teratogenesis in
three chilren born to mothers with blastomycosis and
treated with amphoteriein B during pregnancy
Cohen I: Pediatr Infect Dis J 1987;6:76-7
For these three fetuses, exposure to large-dose amphotericinB
was not harmful. Remain cautious, however.
Philip C. Anderson, M.D.