Bulous Skin Lesions

case records of the massachusetts general hospital
The new engl and journal o f medicine

n engl j med 369;25 nejm.org december 19, 2013
2438
Founded by Richard C. Cabot
Eric S. Rosenberg, m.d., Editor Nancy Lee Harris, m.d., Editor
Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor
Sally H. Ebeling, Assistant Editor Emily K. McDonald, Assistant Editor
From the Departments of Dermatology
(E.K.R.) and Pathology (M.P.H.), Massa-
chusetts General Hospital, the Depart-
ment of Dermatology, Brigham and
Womens Hospital (R.A.V.), and the De-
partments of Dermatology (E.K.R., R.A.V.)
and Pathology (M.P.H.), Harvard Medi-
cal School all in Boston.
N Engl J Med 2013;369:2438-49.
DOI: 10.1056/NEJMcpc1215967
Copyright 2013 Massachusetts Medical Society.
Presentation of Case
Dr. Amir Aboutalebi (Dermatology): A 57-year-old woman was admitted to this hospi-
tal because of recurrent painful bullous and erosive skin lesions.
Approximately 19 months before admission, 1 week after the patient had begun
taking citalopram, the development of oral erosions, tongue swelling, and urti-
carial lesions, approximately 1 cm in diameter, on her torso occurred. These
symptoms were followed during the next several weeks by joint pain and swelling
in her hands, fatigue, and low-grade fevers. Citalopram was stopped, and anti-
histamines were prescribed, which the patient reported that she did not take for
religious reasons; during the next month, the lesions worsened. She was admitted
to this hospital.
The patient reported difficulty eating because of oral ulcers; she also reported
pain on urination and defecation because of vaginal and anal lesions. She had a
history of obesity, hypertension, and depression. Nine months before that admis-
sion (27 months before the current admission), she had an episode of Streptococcus
pneumoniae bacteremia associated with a tubo-ovarian abscess and complicated by
bacterial endocarditis, infectious endophthalmitis (causing near-total blindness),
and a myocardial infarction due to a septic embolus from valvular vegetation.
Total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed
at that time. Medications included furosemide, metoprolol tartrate, aspirin (81 mg
daily), diphenhydramine (as needed for itching), and a multivitamin. She was di-
vorced and lived alone; she did not smoke, drink alcohol, or use illicit drugs. For
religious reasons, she was reluctant to take medications and was distrustful of the
medical system. She was of African-American descent and had one adult child; her
father had died in an accident, her mother had hypertension, and an aunt had
breast cancer.
On examination, the patient appeared uncomfortable because of oral lesions.
The temperature was 38.7C. There were erosions on the inner lips and buccal
mucosa, and there was edema of the lips. There were erythematous plaques with
dusky centers on the abdomen; coalescent, erythematous, mildly scaly symmetric
plaques on the back; and small oval erosions in the perianal area and vagina. The
wrist, metacarpal, and proximal interphalangeal joints were tender, without swell-
Case 39-2013: A 57-Year-Old Woman
with Painful Bullous Skin Lesions
Ellen K. Roh, M.D., Ruth Ann Vleugels, M.D., M.P.H., and Mai P. Hoang, M.D.
The New England Journal of Medicine
Downloaded from nejm.org by gita mutiara on July 10, 2014. For personal use only. No other uses without permission.
Copyright 2013 Massachusetts Medical Society. All rights reserved.
2439
ing or erythema. Pathological examination of a
cutaneous-biopsy specimen revealed interface
dermatitis (a finding consistent with erythema
multiforme) and a mild increase in dermal mucin
deposition. Laboratory-test results are shown in
Table 1. Broad-spectrum antibiotics and acyclovir
were administered; acyclovir was stopped when
cultures for herpes simplex virus were negative.
Screening for cold agglutinins was negative.
When the course of antibiotics was completed,
prednisone (40 mg daily) and hydroxychloroquine
were prescribed, but she refused the medication.
She was discharged on the 12th day. Discharge
medications included prednisone (40 mg daily),
hydroxychloroquine (200 mg twice daily), di-
phenhydramine (as needed), fluocinolone oint-
ment (0.025%), and betamethasone dipropionate
ointment (0.05%).
Eighteen days later (17 months before this
admission), the patient was readmitted because
of a persistent and increasingly painful erosive,
pruritic rash on her back; the oral and anogeni-
tal lesions had resolved. She reported not taking
prednisone or hydroxychloroquine. Examination
revealed erythematous scaly plaques with central
erosions on the back, chest, thighs, and buttocks.
Laboratory results are shown in Table 1. A second
skin-biopsy specimen showed findings consis-
tent with bullous lupus erythematosus. Hydroxy-
chloroquine and prednisone were prescribed, but
the patient declined the medications. She was
discharged on the seventh day.
Six weeks later, the patient was admitted to
Brigham and Womens Hospital (BWH) because
of worsening blistering and erosive skin lesions
during the past week. The temperature was
39.4C. Erythroderma of the face and torso was
present (Fig. 1A and 1B); there were erosions
and large flakes of desquamation and scattered,
fragile flaccid bullae and open blisters covering
approximately 70% of the body-surface area,
predominantly on the upper chest and breasts,
with only a few plaques on the lower body and
legs, and no lesions on the palms, soles, oral
mucosa, or genitalia. Pathological examination
of a third skin-biopsy specimen reportedly showed
findings consistent with pemphigus foliaceus.
Methylprednisolone (125 mg daily) was admin-
istered intravenously for 3 days, followed by a
tapering course of prednisone (60 mg daily for
3 days, then 50 mg daily) and topical clobeta-
sol, with rapid improvement in the skin lesions.
The patient was discharged on the eighth day
(first to a rehabilitation hospital, then home),
and she indicated that she would adhere to hy-
droxychloroquine and prednisone therapy. The
administration of hydroxychloroquine was be-
gun, and prednisone was tapered.
At a follow-up examination at BWH 10 days
after discharge, there were no active skin lesions.
After 3 months, the patient stopped keeping
follow-up appointments with the dermatology
service at BWH and declined follow-up with
rheumatology. Seven months before admission,
at a follow-up appointment with her internist at
this hospital, she reported taking hydroxychlo-
roquine (200 mg twice daily), prednisone (5 mg
daily), furosemide, metoprolol, aspirin, diphen-
hydramine, and topical glucocorticoid ointments,
and she had no active skin lesions. Sometime
thereafter, she stopped taking hydroxychloro-
quine and prednisone.
Eight days before this admission, the patient
returned to her internist because of recurrent
skin lesions and alopecia. There were tender,
pruritic skin lesions on her scalp that were ulcer-
ated and excoriated and in the periumbilical area.
She declined admission but resumed using hy-
droxychloroquine and topical betamethasone
valerate lotion (0.1%); the administration of vita-
min A and D ointment was added. She declined
oral prednisone therapy because of concern
about diabetes mellitus and weight gain.
On the day of admission, the patient was
brought to the emergency department at this
hospital because of worsening skin lesions and
increasing pain (rated at 8 on a scale of 0 to 10,
with 10 indicating the most severe pain). On
examination, the vital signs and oxygen satura-
tion were normal. There were multiple flaccid
bullous lesions and superficial erosions, with
crusting and mild oozing on the chest, back,
abdomen, and both arms and shoulders (Fig. 1C
and 1D). Blood levels of electrolytes, glucose,
magnesium, calcium, phosphorus, total and di-
rect bilirubin, total protein, albumin, and globu-
lin were normal, as were the results of tests of
coagulation and renal function; other results are
shown in Table 1. A chest radiograph was nor-
mal. Oxycodone (5 mg) was administered, and
the patient was admitted to this hospital.
A diagnostic procedure was performed.
2440
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2442
Differential Diagnosis
Dr. Ellen K. Roh: This woman presented with recur-
ring painful erosions and flaccid blisters, with
mucosal involvement during one episode. Her
condition responded quickly to prednisone. Lab-
oratory testing was positive for multiple markers
of rheumatologic diseases. Three skin biopsies
were performed, and examination of each speci-
men was suggestive of a different diagnosis
erythema multiforme, bullous lupus erythemato-
sus, and pemphigus foliaceus.
Hypersensitivity reactions
Patients with blistering skin lesions and mucosal
involvement should first be evaluated for a hyper-
sensitivity reaction, such as erythema multiforme,
the StevensJohnson syndrome, and toxic epider-
mal necrolysis. This patients first biopsy speci-
men was consistent with erythema multiforme.
A B
D C
Figure 1. Clinical Photographs of the Patient.
Approximately 15 months before admission, erythroderma involving the face (Panel A) and torso (Panel B) were
present, with erosions and large flakes of desquamation and scattered, fragile flaccid bullae and open blisters cover-
ing approximately 70% of the body-surface area. On admission, there were multiple flaccid bullous lesions and su-
perficial erosions, with crusting and mild oozing on the back (Panel C), chest (Panel D), abdomen, and both arms
and shoulders (not shown). (Panels A and B courtesy of Drs. Elena Hawryluk and Lily Uhlein, Department of Der-
matology, Massachusetts General Hospital and Brigham and Womens Hospital. Panels C and D courtesy of Drs.
Amir Aboutalebi and Sabina Bis, Department of Dermatology, Massachusetts General Hospital.)
2443
Erythema multiforme is often due to infections
(especially herpes simplex virus), although it can
be caused by medications.
1
Targetoid lesions be-
gin on acral skin and progress proximally, and
mucous membranes can be involved.
1
However,
this patient did not have classic targetoid lesions,
and the diagnosis does not explain the laborato-
ry findings. The StevensJohnson syndrome is a
hypersensitivity reaction most commonly caused
by medications. Affected patients present with a
painful blistering erythema, purpuric macules,
atypical targetoid lesions, and hemorrhagic ero-
sions affecting at least two mucosal sites.
2
Epi-
dermal detachment is limited to less than 10% of
body surface area, since cases with more than
30% involvement are classified as toxic epider-
mal necrolysis (cases between 10% and 30% are
considered to be an overlap of the two condi-
tions). This patient had painful blisters and ero-
sions, but she did not always have mucosal in-
volvement. These two diagnoses also do not
explain the laboratory findings and are not sup-
ported by the biopsy findings. In addition, pa-
tients with the StevensJohnson syndrome or toxic
epidermal necrolysis typically have a slow recov-
ery, whereas this patients condition appeared to
improve quickly with treatment.
Acquired autoimmune blistering disorders
Acquired autoimmune disorders must also be
considered. In these disorders, autoantibodies
are responsible for the clinical manifestations.
Acquired autoantibodies are directed against
desmoglein 1 and desmoglein 3 in pemphigus
vulgaris. Typically, oral erosions precede flaccid
cutaneous blisters, which develop into erosions.
3

Patients often respond well to systemic gluco-
corticoids, as this patient did. However, this
patient had inconsistent mucosal involvement;
furthermore, the diagnosis of pemphigus vul-
garis does not explain her positive rheumatologic-
disease markers, and features diagnostic of the
condition were not seen in any of the biopsy
specimens.
The autoantibody target in pemphigus folia-
ceus is desmoglein 1. Most cases of pemphigus
foliaceus are idiopathic, but a type that is en-
demic in Brazil is known as fogo selvagem. Pa-
tients with pemphigus foliaceus do not have
mucosal lesions but present with flaccid blisters,
which develop into scaly, crusted erosions.
4
The
condition also responds quickly to systemic glu-
cocorticoids. This patients third biopsy specimen
showed features consistent with pemphigus folia-
ceus. She had flaccid blisters and erosions, which
responded to treatment with prednisone. But this
diagnosis does not explain the oral findings
during the first admission, and it also does not
explain the laboratory-test results.
Patients with drug-induced pemphigus can
present with pemphigus foliaceus or pemphigus
vulgaris. Thiol-containing drugs, such as penicil-
lamine, captopril, and enalapril, induce acan-
tholysis directly, causing the more common fo-
liaceus phenotype.
5
Nonthiol drugs (i.e., drugs
with a masked thiol group), such as penicillin,
cephalosporins, and piroxicam, induce autoanti-
body formation, which in turn causes acantholy-
sis and vulgaris-like findings.
5
There was no
identifiable cause of drug-induced pemphigus in
this patients history.
Systemic Lupus Erythematosus
Bullous Lupus Erythematosus
Bullous lupus erythematosus is a rare subtype of
systemic lupus erythematosus (SLE) that is char-
acterized by the production of autoantibodies to
type VII collagen. It occurs predominantly in
young black women; patients present with tense
blisters and erythematous macules.
6
Lesions fa-
vor sun-exposed areas but can occur anywhere.
Mucosal involvement is variable, and patients
often have no response to prednisone. This pa-
tients second biopsy specimen was suggestive of
bullous lupus, and the laboratory findings also
supported the diagnosis; however, the blisters
were flaccid.
Rowells Syndrome
Another rare variant of SLE is Rowells syndrome,
a condition in which patients have features of
both SLE and erythema multiforme. Patients pre-
sent with recurring erythema multiforme, often
with mucosal lesions and chilblains.
7
Rowells
syndrome predominantly affects middle-aged
women. Laboratory tests are positive for anti-
nuclear antibody (ANA) with a speckled pattern,
Ro and La antibodies, and rheumatoid factor.
Histologic examination shows erythema multi-
formelike findings with mucin. This patients
first biopsy specimen had features consistent
with erythema multiforme with a small amount
of mucin; testing was positive for ANA and Ro and
La antibodies, and she had a response to predni-
2444
sone. However, Rowells syndrome does not ex-
plain the erosions and flaccid blisters that char-
acterized her presentations.
Pemphigus Erythematosus
Pemphigus erythematosus, otherwise known as
the SenearUsher syndrome, is a disorder with
characteristics of both pemphigus foliaceus
and SLE. Patients present with flaccid blisters
that evolve into crusted erythematous patches,
and lesions favor sun-exposed areas.
8
Typically,
mucous membranes are spared. ANA and lupus
band tests are positive, and patients often re-
spond well to treatment with systemic glucocorti-
coids. This patients third biopsy specimen was
consistent with pemphigus foliaceus, and tests
for markers of rheumatologic diseases were pos-
itive. In addition, she had a good response to
prednisone. However, the first two biopsy speci-
mens and the mucous-membrane involvement
that was seen during her first admission do not
support this diagnosis.
Summary
In view of the history of flaccid blisters, the pos-
itive tests for rheumatologic-disease markers,
and a third biopsy, which was suggestive of
pemphigus foliaceus, I would consider pemphi-
gus erythematosus as the most likely diagnosis.
I would recommend obtaining another biopsy
specimen and performing additional tests, such
as indirect immunofluorescence assays, to con-
firm this diagnosis.
Dr. Nancy Lee Harris (Pathology): I would like to
invite Drs. Laura Winterfield and Daniela Kros-
hinsky, who cared for this patient at BWH and
Massachusetts General Hospital (MGH), respec-
tively, to comment on their thinking.
Dr. Laura S. Winterfield (Dermatology, BWH):
When the patient presented to our institution,
15 months before her most recent admission to
MGH, the clinical findings were inconsistent
with the previous histopathological diagnoses of
erythema multiforme and bullous lupus. An ad-
ditional biopsy specimen, studied with direct im-
munofluorescence, suggested pemphigus folia-
ceus. In the context of the patients known SLE,
we made the diagnosis of pemphigus erythema-
tosus.
Dr. Daniela Kroshinsky (Dermatology, MGH): At
the time of her most recent admission to MGH,
the patients lesions were clinically most consis-
tent with pemphigus foliaceus. She met the clini-
cal criteria for SLE, and thus her clinical picture
was most consistent with pemphigus erythema-
tosus. In light of multiple different skin-biopsy
results, Drs. Aboutalebi and Alexander Marneros,
who consulted from the dermatology service on
the day of admission, obtained additional skin-
biopsy specimens for routine histologic exami-
nation and direct immunofluorescence studies
to confirm the diagnosis.
Clinical Diagnosis
Pemphigus erythematosus.
DR. ELLEN K. ROH S DIAGNOSIS
Pathological Discussion
Dr. Mai P. Hoang: I will begin by reviewing the pa-
tients previous skin-biopsy specimens. A biopsy
specimen of the left side of the abdomen ob-
tained at this hospital 19 months before admis-
sion showed interface dermatitis, evidenced by
necrotic keratinocytes at the dermalepidermal
junction, focal dermal mucin deposition, and fol-
licular plugging (Fig. 2A and 2B). Another biopsy
specimen, from the left side of the back, obtained
here 17 months before admission (Fig. 2C and
2D), showed complete dermalepidermal separa-
tion, with a prominent dermal lymphocytic in-
filtrate and nuclear debris in a background of
mucin deposition. Although the initial biopsy
specimen suggested a diagnosis of erythema
multiforme, in retrospect, both specimens have
features consistent with SLE and associated sub-
epidermal vesiculation.
Another skin-biopsy specimen, obtained at
BWH 15 months before admission (Fig. 2E),
showed acantholysis at the granular layer of the
epidermis. Direct immunofluorescence revealed
strong intercellular IgG in the stratum corneum,
a finding consistent with pemphigus foliaceus.
In addition, mild and discontinuous granular C3
deposition was seen at the dermalepidermal
junction, which was interpreted as nonspecific
staining.
A skin-biopsy specimen from the left middle
back, obtained on the patients admission to this
hospital (Fig. 3A), showed similar features. Ac-
2445
antholysis was noted at the granular layer of the
epidermis. Direct immunofluorescence revealed
IgG and C3 granular and linear deposition at the
basement-membrane zone. In addition, weak
IgM and IgA deposition was also noted at the
dermalepidermal junction, a finding consistent
with a lupus band.
Dr. Kroshinsky: Since we now had four different
A B
D C
E
Figure 2. Skin-Biopsy Specimens Obtained before Admission (Hematoxylin and Eosin).
A skin-biopsy specimen from the left side of the abdomen obtained 19 months before admission (Panels A and B)
shows necrotic keratinocytes at the dermalepidermal junction, follicular plugging, and dermal mucin deposition.
A biopsy specimen from the left side of the back obtained 17 months before admission (Panels C and D) shows
complete dermalepidermal separation, with a prominent dermal lymphocytic infiltrate and nuclear debris in a
background of mucin deposition. A third skin-biopsy specimen, obtained 15 months before admission, shows acan-
tholysis at the granular layer of the epidermis, as well as within the epidermis (Panel E, arrows). (Panel E courtesy of
Dr. Scott Granter, Department of Dermatopathology, Brigham and Womens Hospital.)
2446
biopsy results, including a negative direct immu-
nofluorescence assay on the most recent speci-
men, additional testing was needed to confirm
the diagnosis of pemphigus erythematosus. The
patients serum was sent to a reference labora-
tory. Indirect immunofluorescence studies showed
intercellular IgG antibodies, and antibodies to
desmoglein 1 were found by enzyme-linked im-
munosorbent assay, features suggestive of pem-
phigus foliaceus.
Dr. Hoang: After this result was reported, a
repeat direct immunofluorescence assay showed
intercellular IgG and C3 deposition in the epi-
dermis and at the basement-membrane zone
(Fig. 3B). The histologic findings of the skin-
biopsy specimens, together with the findings on
direct and indirect immunofluorescence assays,
support the diagnosis of pemphigus erythema-
tosus.
Pemphigus erythematosus was first described
in 1926 by Senear and Usher as a combination of
pemphigus vulgaris and lupus erythematosus.
9
When the distinction between pemphigus folia-
ceus and pemphigus vulgaris was solidified (i.e.,
when pemphigus foliaceus and pemphigus vul-
garis were characterized by antibodies to the
desmosomal cadherins desmoglein 1 and desmo-
glein 3, respectively
10
), pemphigus erythemato-
sus was classified as a variant of pemphigus
foliaceus that had features of both pemphigus
and SLE. In pemphigus erythematosus, additional
deposition of IgG and complement has been
noted at the epidermal basement-membrane
zone in up to 60% of biopsy specimens, as in
this case.
11
The differential diagnosis in this case
would be a concurrent manifestation of pemphi-
gus and SLE.
12
Discussion of Management
Dr. Ruth Ann Vleugels: The diagnosis of pemphigus
erythematosus was made on the patients admis-
sion to BWH, in view of the biopsy findings of
pemphigus foliaceus and the clinical features of
SLE. The management of this rare disease can
present several challenges, which are similar to
those encountered when treating patients who
have cutaneous manifestations of SLE. To my
knowledge, no randomized, controlled trials have
been performed specifically to evaluate the re-
sponse of skin disease to treatment, and existing
data are predominantly in the form of case re-
ports. Initial therapy mandates careful photopro-
tection, because exposure to ultraviolet radiation
leads to disease flares.
13
Photoprotection includes
sunscreen with a sun protection factor of 50 or
more and sun-protective clothing, including
wide-brimmed hats; behavioral modification is
also important. The degree of photoprotection
that is necessary to prevent disease exacerbations
is difficult to achieve and often affects patients
quality of life. In addition, vitamin D supplemen-
tation is typically required. The application of
topical glucocorticoids, topical tacrolimus, or
both can be helpful in patients with limited dis-
ease or as an adjunct therapy in patients who are
receiving systemic therapy. In pemphigus erythe-
matosus, as in SLE with other cutaneous mani-
A
B
Figure 3. Skin-Biopsy Specimen Obtained on Admission.
A skin-biopsy specimen from the left middle back shows
intraepidermal acantholysis at the subcorneal region
(Panel A, hematoxylin and eosin). Examination with
direct immunofluorescence (Panel B, immunofluores-
cence for IgG) shows intercellular IgG deposition in
the epidermis, as well as granular and linear IgG depo-
sition at the basement-membrane zone.
2447
festations, therapeutic agents have variable effi-
cacy for skin and systemic disease manifestations,
mandating careful selection of a therapeutic
regimen, as well as a team approach.
Patients such as this one, with widespread or
refractory disease, require systemic therapy. The
first-line systemic therapies that we considered
for this patient included systemic glucocorticoids,
antimalarial therapy, and dapsone.
14,15
Both anti-
malarial therapy and dapsone have the advantage
of being effective in the treatment of cutaneous
disease without causing immunosuppression. In
the United States, hydroxychloroquine is typi-
cally the first-line antimalarial therapy, with
chloroquine or combination antimalarial agents
(hydroxychloroquinequinacrine or chloroquine
quinacrine) as second-line options. This patient
would need routine monitoring for ocular ad-
verse effects while receiving antimalarial therapy.
If she were to receive dapsone, she would need
regular monitoring for such potential side effects
as hemolytic anemia, methemoglobinemia, agran-
ulocytosis, the dapsone hypersensitivity syn-
drome, and neuropathy. We would also perform
testing for glucose-6-phosphate dehydrogenase
deficiency before the initiation of dapsone. Since
it takes weeks to demonstrate therapeutic bene-
fit from antimalarial agents and dapsone, we
would also need to treat this patient with an
agent that would allow for rapid improvement of
the extensive cutaneous disease. Treatment with
systemic glucocorticoids results in a rapid skin-
disease response, and therefore these agents are
often initiated with the goal of tapering them as
the patients other glucocorticoid-sparing medi-
cations take effect.
If these first-line therapies did not elicit a
response in this patient, advanced systemic thera-
peutic options for pemphigus erythematosus
would be selected from the therapeutic arma-
mentarium for pemphigus foliaceus and SLE.
Options include mycophenolate mofetil, azathio-
prine, methotrexate, tetracycline and nicotina-
mide, intravenous immune globulin (IVIG), ritux-
imab, cyclophosphamide, and plasmapheresis.
14-16
We initially treated this patient with a combi-
nation of systemic glucocorticoids and hydroxy-
chloroquine, with an excellent clinical response.
Strict photoprotective measures were emphasized,
and high-potency topical glucocorticoids were
administered as adjunct therapy. After self-discon-
tinuing these therapies, the patient presented with
a flare of the cutaneous disease, which led to her
current hospital admission. At this time, I would
recommend systemic glucocorticoids, in addition
to hydroxychloroquine and dapsone. After im-
provement in the skin disease, systemic gluco-
corticoids would be tapered and discontinued.
Dr. Kroshinsky: Since the disease had flared in
the past while the patient was receiving predni-
sone and hydroxychloroquine, dapsone was add-
ed to a regimen of prednisone and hydroxychlo-
roquine. She was discharged taking prednisone
(25 mg daily), hydroxychloroquine (200 mg twice
daily), and dapsone (50 mg twice daily). Dr. Tif-
fany Angel provided follow-up care; the skin le-
sions resolved, and the prednisone was tapered
over a period of 2 months and then stopped. Ten
months after discharge, we reduced the dose of
dapsone to 50 mg daily. Four months later, at the
last follow-up, the patient admitted that she had
discontinued both medications; she remains free
of cutaneous disease at this time.
Dr. Harris: A striking problem in caring for
this patient has been her distrust of the medical
system and her reluctance to take medication.
Drs. Susan Mathai and Laura Myers, residents in
Medicine who have been her primary care physi-
cians, note that the patient refuses to believe
that she has SLE, and in order to treat her, they
have to agree to focus on her skin disease and
the medications necessary to treat it.
This woman is the only patient whom I have
considered as the subject of two clinicopatho-
logical conferences (CPCs), for two illnesses. We
initially considered discussing her presentation
with a tubo-ovarian abscess, which resulted in
bacterial endocarditis, endophthalmitis, and myo-
cardial infarction. We finally decided that that
story was too complicated. Her case was then
proposed again a year later by our colleagues in
dermatopathology for this completely new set of
problems. It is gratifying to learn that after all
this, she is well and living independently.
Are there any questions or comments for any
of our discussants?
A Physician: These treatments can have severe
side effects. I used hydroxychloroquine to treat a
young woman who had cutaneous lupus, and I
added quinacrine because she insisted on sun-
tanning. Irreversible pancytopenia developed, and
the patient required bone-marrow transplanta-
tion. In a patient with bullous pemphigoid, who
also had diabetic kidney disease, treatment with
2448
IVIG precipitated acute renal failure, which was
nearly fatal. In a patient with pyoderma gangreno-
sum, a deep-vein thrombosis and pulmonary
embolus developed after treatment with thalido-
mide; she turned out to have factor V Leiden.
Dr. Vleugels: We know that quinacrine can cause
pancytopenia, so our standard patient follow-up
includes regular complete blood counts. This is
a very rare side effect; the most common side
effect of quinacrine is reversible yellow pigmen-
tation of the skin. Newer formulations of IVIG
are sorbitol-based, rather than sucrose-based,
which greatly reduces the risk of acute renal
failure. Although we do not routinely screen for
hypercoagulability in patients before starting
thalidomide, we take a careful history to assess
clotting risk. For example, we would avoid treat-
ment with thalidomide in a patient with SLE and
the antiphospholipid syndrome. These are all ex-
cellent points, reminding us that there are rare
but serious complications associated with these
agents.
Dr. Harris: In these Case Records, we have
discussed a patient with cardiomyopathy due to
hydroxychloroquine use
17
and a patient with
methemoglobinemia due to dapsone use,
18
fur-
ther illustrating potential complications associ-
ated with these agents.
A Physician: At this patients initial presenta-
tion, paraneoplastic pemphigus could have been
considered, especially because of the mucous-
membrane involvement. Also, age-appropriate
cancer screening could have been part of the
initial workup.
Dr. Roh: Paraneoplastic pemphigus should al-
ways be in the differential diagnosis when con-
sidering a diagnosis of pemphigus. I did not
consider it strongly in this case because in the
patients I have seen who have paraneoplastic
pemphigus, mucosal involvement has been by
far the predominant symptom. This patient had
some mucosal involvement at the initial presen-
tation, but it was minor as compared with the
cutaneous involvement.
Dr. Harris: This patients SLE developed short-
ly after she started taking citalopram. She had a
positive test for antihistone antibody, suggesting
to some caregivers that she had drug-induced SLE.
Dr. Kroshinsky: I was not involved in this pa-
tients initial presentation, but although drug-
induced SLE should always be considered in a
patient presenting with signs of SLE, citalopram
is not one of the usual culprits. Furthermore, she
reportedly had been taking it for only a week be-
fore the onset of symptoms; onset usually requires
longer drug exposure. In addition to antihistone
antibodies, she had other autoantibodies more
typical of primary SLE. Finally, drug-induced
SLE usually resolves with removal of the offend-
ing drug, in contrast to this patients course.
Dr. Vleugels: There is an important distinction
between drug-induced SLE, which classically is
associated with antihistone antibody positivity,
and drug-induced subacute cutaneous lupus,
which typically is associated with anti-Ro anti-
body positivity. Most patients with drug-induced
SLE do not have predominant cutaneous mani-
festations; in 90% of patients, the primary
symptoms are arthralgias and systemic symp-
toms. In contrast, patients with Ro-positive drug-
induced subacute cutaneous lupus present to
dermatology with classic skin lesions, usually
after a month or more of using hydrochloro-
thiazide, terbinafine, or another drug culprit.
Final Diagnosis
This case was presented at the Harvard Medical School post-
graduate course Dermatopathology Update with Mini-Sympo-
siums on Inflammatory Dermatoses and New Diagnostic Test-
ings for Melanocytic Lesions (directed by Drs. Lyn M. Duncan,
Mai P. Hoang, Martin C. Mihm, Jr., George F. Murphy, and Ste-
ven R. Tahan). The course was sponsored by the Harvard Medi-
cal School Department of Continuing Education.
Dr. Roh reports receiving consulting fees from WorldCare
Clinical. No other potential conflict of interest relevant to this
article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Dr. Eli Miloslavsky (Rheumatology) and Drs. Tif-
fany Angel and Elena Hawryluk (Dermatology) for assistance
with the preparation of the case history.
References
1. Lamoreux MR, Sternbach MR, Hsu
WT. Erythema multiforme. Am Fam Phy-
sician 2006;74:1883-8.
2. Mockenhaupt M. The current under-
standing of Stevens-Johnson syndrome
and toxic epidermal necrolysis. Expert Rev
Clin Immunol 2011;7:803-13.
3. Venugopal SS, Murrell DF. Diagnosis
and clinical features of pemphigus vul-
garis. Dermatol Clin 2011;29:373-80.
4. James KA, Culton DA, Diaz LA. Diag-
nosis and clinical features of pemphigus
foliaceus. Dermatol Clin 2011;29:405-12.
5. Goldberg I, Kashman Y, Brenner S.
The induction of pemphigus by phenol
drugs. Int J Dermatol 1999;38:888-92.
6. Sebaratnam DF, Murrell DF. Bullous
systemic lupus erythematosus. Dermatol
Clin 2011;29:649-53.
7. Shadid NH, Thissen CA, van Marion
AM, Poblete-Gutirrez P, Frank J. Lupus
2449
erythematosus associated with erythema
multiforme: Rowells syndrome. Int J Der-
matol 2007;46:Suppl 3:30-2.
8. Scheinfeld NS, Howe KL, DiCostanzo
DP, Craig E, Cohen SR. Pemphigus erythe-
matosus associated with anti-DNA anti-
bodies and multiple anti-ENA antibodies:
a case report. Cutis 2003;71:303-6.
9. Senear FE, Usher B. An unusual type
of pemphigus combining features of lu-
pus erythematosus. Arch Derm Syphilol
1926;13:1761-81.
10. Hacker-Foegen MK, Janson M, Am-
agai M, Fairley JA, Lin MS. Pathogenicity
and epitope characteristics of anti-desmo-
glein-1 from pemphigus foliaceus patients
expressing only IgG1 autoantibodies.
J Invest Dermatol 2003;121:1373-8.
11. Chorzelski T, Jabloska S, Blaszczyk
M. Immunopathological investigations in
the Senear-Usher syndrome (coexistence
of pemphigus and lupus erythematosus).
Br J Dermatol 1968;80:211-7.
12. Malik M, Ahmed AR. Dual diagnosis
of pemphigus vulgaris and connective tis-
sue disease. J Am Acad Dermatol 2006;55:
699-704.
13. Deschamps P, Pedailles S, Michel M,
Leroy D. Photo-induction of lesions in a
patient with pemphigus erythematosus.
Photodermatol 1984;1:38-41.
14. Amerian ML, Ahmed AR. Pemphigus
erythematosus: presentation of four cases
and review of literature. J Am Acad Der-
matol 1984;10:215-22.
15. Diab M, Bechtel M, Coloe J, Kurtz E,
Ranalli M. Treatment of refractory pem-
phigus erythematosus with rituximab. Int
J Dermatol 2008;47:1317-8.
16. Gupta MT, Jerajani HR. Control of
childhood pemphigus erythematosus with
steroids and azathioprine. Br J Dermatol
2004;150:163-4.
17. Case Records of the Massachusetts
General Hospital (Case 7-2011). N Engl J
Med 2011;364:957-66. [Errata, N Engl J
Med 2011;364:1281, 1682.]
18. Case Records of the Massachusetts
General Hospital (Case 11-2011). N Engl J
Med 2011;364:1450-60.
Copyright 2013 Massachusetts Medical Society.
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material is now eligible to receive a complete set of PowerPoint slides, including digital images, with identifying legends,
shown at the live Clinicopathological Conference (CPC) that is the basis of the Case Record. This slide set contains all of the
images from the CPC, not only those published in the Journal. Radiographic, neurologic, and cardiac studies, gross specimens,
and photomicrographs, as well as unpublished text slides, tables, and diagrams, are included. Every year 40 sets are produced,
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