Download Pompholyx and eczematous reactions associated with intravenous

Pompholyx and eczematous reactions associated
with intravenous immunoglobulin therapy
Meg R. Gerstenblith, MD, Ashley K. Antony, BA, Jacqueline M. Junkins-Hopkins, MD, and Rachel Abuav, MD
Baltimore, Maryland
Introduction: Intravenous immunoglobulin (IVIG) is used to treat many inflammatory and autoimmune
disorders and although generally well tolerated, cutaneous side effects occur.
Objective: We reviewed reports of pompholyx and eczematous reactions associated with IVIG.
Methods: A literature search was performed using the PubMed and MEDLINE databases with the search
terms ‘‘intravenous immunoglobulin pompholyx,’’ ‘‘intravenous immunoglobulin eczema,’’ ‘‘intravenous
immunoglobulin cutaneous adverse effects,’’ ‘‘intravenous immunoglobulin cutaneous effects,’’ ‘‘intravenous immunoglobulin skin effects,’’ and ‘‘intravenous immunoglobulin adverse effects.’’ Relevant Englishlanguage articles or articles in other languages cited in English-language articles were included.
Results: We identified 64 cases of eczematous reactions associated with IVIG therapy, including a patient
treated on our inpatient consult service. In reported cases, the majority of patients (62.5%) had pompholyx
alone or a combination of pompholyx on the hands or feet and two or fewer additional body surfaces
involved. The majority of reported cases (75%) experienced the eczematous reaction after their first IVIG
treatment. Neurologic conditions were the most common (85.9%) diseases for which IVIG was used. Most
patients responded well to topical steroids or did not require treatment.
Limitations: Some reported cases had insufficient descriptions to be included in this review. A literature
review may underestimate the frequency of eczematous reactions to IVIG because these reactions are often
limited and may not be reported.
Conclusions: With the use of IVIG increasing, it is important for dermatologists to recognize this cutaneous
side effect of IVIG. ( J Am Acad Dermatol 2012;66:312-6.)
Key words: adverse skin reactions; dyshidrotic eczema; eczema; intravenous immunoglobulin;
pompholyx.
I
ntravenous immunoglobulin (IVIG) was developed more than 30 years ago and is currently used
on- and off-label for several dermatologic, neurologic, hematologic, and immunologic disorders.1 As
From the Department of Dermatology, Johns Hopkins School of
Medicine.
Funding sources: None.
Conflicts of interest: None declared.
Presented at the Gross and Microscopic Symposium at the Annual
American Academy of Dermatology Meeting in March 6, 2009,
San Francisco, California (Abstract #261).
Reprint requests: Meg R. Gerstenblith, MD, Department of
Dermatology, Case Western Reserve University, Lakeside
3500, 11100 Euclid Ave, Cleveland, OH 44106. E-mail: meg.
[email protected].
Published online May 23, 2011.
0190-9622/$36.00
Ó 2011 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2010.12.034
a blood product consisting of only IgG antibodies
pooled from at least 1000 different human donors,
IVIG must be manufactured using viral inactivation
measures and screened for infections to ensure its
safety. Minor adverse effects occur in about 30% to
40% of patients and include headache, chills, fatigue,
nausea, arthralgias, myalgias, and back pain.1,2 Rarely,
more serious reactions may occur, including aseptic
meningitis, renal failure, anaphylactic shock, hemolytic anemia, and thromboembolic complications.1-7
Although minor adverse effects may be related to the
rate of infusion, some of the serious reactions may be
related to the particular osmotic and sodium loads of
the IVIG preparation, the rate of infusion, and host
factors.2 For example, the risk of renal failure with
IVIG is related not only to the sucrose content of the
IVIG preparation and rate of infusion, but also host
factors such as pre-existing renal disease, diabetes,
312
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Gerstenblith et al 313
J AM ACAD DERMATOL
VOLUME 66, NUMBER 2
and hypertension. Cutaneous adverse effects may
were obtained in only 13 patients; therefore, eczeoccur and vary in presentation from localized to
matous reactions were classified largely on a morgeneralized reactions and are estimated to occur in
phologic basis. Typical findings of pompholyx are
0.4% to 6% of treated patients.6,8,9 There are several
shown in Fig 1, A and B, with multiple, grouped
reports of urticaria and isolated reports of alopecia,
pinpoint clear and erythematous vesicles occurring
erythema multiforme, lichenoid dermatitis, purpuric
on the palms and soles bilaterally. Representative
erythema, vasculitis, and morbilliform eruptions
histopathology reveals a loculated, spongiotic vesiassociated with IVIG10-16;
cle, typical of dyshidrosis; a
however, an underappreciperivascular infiltrate conCAPSULE SUMMARY
ated cutaneous reaction is ecsisting of lymphocytes and
zema, often localized to the
eosinophils; and exocytosis
The use of intravenous immunoglobulin
palms and soles as the vesicof lymphocytes into the epi(IVIG) to treat multiple inflammatory and
ular variant, pompholyx.
dermis (Fig 1, C ).
autoimmune disorders is increasing.
Forty of the reported cases
Pompholyx is an important cutaneous
METHODS
(62.5%) presented with pomside effect of IVIG.
We conducted a literature
pholyx alone or a combinareview using the PubMed and
tion of pompholyx (hands or
Pompholyx occurring after IVIG
MEDLINE databases and the
feet) and fewer than two
treatment typically wanes over time but
search terms ‘‘intravenous imbody surfaces involved; 8
can recur and become more extensive
munoglobulin pompholyx,’’
(12.5%) had pompholyx in
with subsequent IVIG treatments.
‘‘intravenous immunoglobuassociation with a generalDermatologists should recognize this
lin eczema,’’ ‘‘intravenous
ized, widespread eczematous
cutaneous side effect of IVIG.
immunoglobulin cutaneous
eruption; 3 (4.7%) had wideadverse effects,’’ ‘‘intravenous
spread eczematous erupimmunoglobulin cutaneous effects,’’ ‘‘intravenous imtions; and 13 (29.7%) had other unspecified
munoglobulin skin effects,’’ and ‘‘intravenous immueczematous reactions. The majority of eczematous
noglobulin adverse effects,’’ for English-language
reactions occurred during the first IVIG treatment
articles. Relevant English-language articles or articles
course (75.0%). Most patients (85.9%) were being
in other languages cited in English-language articles
treated with IVIG for neurologic conditions.
were included. We reviewed the titles and abstracts
Interestingly, only 3 cases are reported of pompholyx
identified in the literature searches. We also reviewed
occurring in patients treated with IVIG for dermatoreferences from bibliographies of pertinent articles.
logic conditions, including one patient with StevensJohnson syndrome and two patients with chronic
urticaria.31,40 Another patient with Stevens-Johnson
RESULTS
syndrome developed vesicles on the palms after IVIG
We identified 64 cases to date of eczematous
treatment, with histopathology showing an intracorreactions associated with IVIG therapy, including a
neal vesicle without inflammatory cells in the epiderpatient treated on our inpatient consult service.17-40
mis or dermis, findings not entirely consistent with
Two articles were non-English-language articles; one
pompholyx.29
could be translated and one included a table in
There are no known risk factors for developing
English with enough detail to be included in our
cutaneous adverse effects with IVIG therapy. When
analysis.26,36 Few additional cases were reported but
assessed, the majority of affected individuals did not
without the demographic and clinical data needed to
have a personal history of atopy, eczema, allergic
be included.41,42
reactions, or another dermatologic condition
Table I summarizes the clinical characteristics of
(83.0%). In our review, eczematous reactions and
the identified patients, including age; sex; history of
pompholyx were reported with multiple IVIG prepatopy, including hand eczema, childhood asthma,
arations but occurred most frequently with
and seasonal allergies; the underlying disease being
Sandoglobulin (Novartis, East Hanover, NJ), which
treated with IVIG; the type of IVIG preparation and
may reflect its widespread use. Interestingly, switchits dose and treatment course if reported; the type of
ing the type of IVIG in 5 patients resulted in variable
eczematous reaction; the time for the reaction to
responses. One patient with pompholyx developed
appear and resolve; the treatments for the reaction
an identical reaction, one patient with pompholyx
if any; and the response to subsequent IVIG courses.
developed noneczematous skin eruptions of inNoneczematous skin reactions or reactions not specreased severity (Baboon syndrome and a morbillicifically described as pompholyx or eczematous
form rash),17 one patient with no prior cutaneous
were excluded from our analysis. Biopsy specimens
d
d
d
d
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314 Gerstenblith et al
J AM ACAD DERMATOL
FEBRUARY 2012
Table I. Reported cases to date of pompholyx and
eczematous reactions occurring in association with
intravenous immunoglobulin treatment
Demographic information
Age (n = 33)
Mean, y
Median, y
Range, y
Male:female (n = 42)
Underlying disease and atopic history
information
Underlying disease
Neurologic diseases
Multiple sclerosis
Chronic inflammatory demyelinating
polyneuropathy
Guillain-Barre syndrome
Multifocal motor neuropathy
Other neurologic
Dermatologic diseases
Chronic urticaria
Stevens-Johnson syndrome
Hematologic diseases*
Immunologic diseasesy
Ophthalmologic diseasesz
History of atopy (n = 23)
Hand eczema
Childhood asthma
Seasonal allergies
Not specified
IVIG treatment information
Initial IVIG type (n = 38)
Sandoglobulin
Gammagard
Tegelin
IVIG dose (n = 53)
0.4-0.5 g/kg/d 3 3-5 d
1 g/kg/d 3 2 d
2 g/kg/d 3 1 d
Days to first eruption (n = 44)
\8
8-14
>14
Skin reaction characteristics (n = 64)
Pompholyx primarily with # 2 body
surfaces involved in addition to hands/feet
Pompholyx with simultaneous,
preceding, or subsequent
generalized eczema (>2 body
surfaces involved in addition to hands/feet)
Widespread, generalized eczematous
eruption
Other, unspecified eczematous
eruptions
Biopsy specimens taken
50.6
55
7-75
33:9
N (%)
(n = 64)
55 (85.9)
14 (25.5)
9 (16.4)
9
8
15
3
2
1
3
2
1
4
1
1
1
1
(16.4)
(14.5)
(27.3)
(4.7)
(66.7)
(33.3)
(4.7)
(3.1)
(1.6)
(17.4)
(25)
(25)
(25)
(25)
18 (47.4)
11 (28.9)
9 (23.7)
35 (66.0)
16 (30.2)
2 (3.8)
34 (77.3)
6 (13.6)
4 (9.1)
40 (62.5)
8 (12.5)
3 (4.7)
Table I. Cont’d
Time to resolution, wk (n = 27)
\3
$3
Treatment for first or subsequent reaction
(n = 45)x
Topical steroids
Spontaneous resolution
Antihistamines
Systemic steroids
Hospitalization
Subsequent IVIG courses (n = 29)
No. of patients with subsequent reaction
Improved reaction
Same reaction
Worse reaction
IVIG preparation changed after rash
development (n = 5)
No further reaction
Same reaction
Worse reaction
Morphology of reaction changed
7 (26.0)
20 (74.1)
27
11
7
6
2
(60.0)
(24.4)
(15.6)
(13.3)
(4.4)
24
3
5
16
(82.8)
(12.5)
(20.8)
(66.7)
2
1
1
1
(40)
(20)
(20)
(20)
Available data were extracted from reported cases for this table;
therefore, numbers used vary for categories presented.
IVIG, Intravenous immunoglobulin.
*There were two cases of thrombocytopenic purpura and one
case of idiopathic systemic capillary leak syndrome.
y
Includes one patient with dermatomyositis and the patient we
treated who had an initial diagnosis of immunodeficiency that was
not confirmed on subsequent testing.
z
Birdshot retinochoroidopathy.
x
Total number and percentages do not add up to 45 and 100%,
respectively, because some individuals received more than one
treatment.
reaction developed a new vesicular facial eruption,20
and two patients with pompholyx or eczema improved with no subsequent reaction after a change in
IVIG formulation.20
Most of the patients responded well to topical
steroids or did not require therapy, although oral
steroids were occasionally necessary. In 74.1% of
reported cases, the reaction subsided in 3 or more
weeks. For all reported cases, the eczematous reactions improved, although in one case, pruritus
occurred for several months after IVIG treatment.20
There were no mortalities reported in these patients
with eczematous reactions to IVIG; however, for
many patients, IVIG was not continued because of
these eczematous reactions.
13 (29.7)
13
Continued
DISCUSSION
IVIG use is becoming more widespread as the
numbers of both indications and patients with
autoimmune and inflammatory disorders increase.
IVIG has several proposed mechanisms of action;
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Gerstenblith et al 315
Fig 1. A and B, Multiple grouped pinpoint vesicles, which were present on palms and soles
bilaterally. C, Biopsy specimen from foot demonstrating dyshidrotic intraepidermal spongiotic
vesicle with eosinophils and lymphocytes. (Hematoxylin and eosin stain; original magnification: 310.)
however, there is no clear mechanism that can explain
the association with eczema. Interestingly, we were
unable to identify any cases of pompholyx or
eczematous reactions occurring in patients being
treated with IVIG for an underlying immunodeficiency. There are two potential hypotheses to explain
the near absence of eczematous reactions in the
immunodeficient population treated with IVIG. First,
this type of reaction may not occur in association with
IVIG in individuals with true immune deficiency.
Alternatively, the dose used to treat immunodeficiency
is typically lower than that used in neurologic, hematologic, and dermatologic conditions described here
(0.4 and 2 g/kg, respectively), which could suggest
that pompholyx and eczematous reactions occur only
when high-dose IVIG is used. This may reflect a
possible dose response for eczematous reactions.
Although eczematous reactions to IVIG are reported to wane over time, in our review we found
that the reaction was likely to recur with subsequent
treatments, and, in the majority of patients, the
reaction worsened. Because pompholyx is treatable,
the general recommendation is for IVIG treatment to
be continued for patients experiencing clinical benefit. In the case of severe cutaneous reactions, IVIG
should be discontinued.
Dermatologists should be aware that pompholyx
and eczema are common cutaneous adverse effects
of IVIG that can occur alone or in combination, and
that these effects may worsen upon subsequent IVIG
treatments. However, these effects can be successfully treated, allowing continuation of IVIG therapy if
warranted.
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