Bulous Skin Lesions

8/11/2019 Bulous Skin Lesions

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case records of themassachusetts general hospital

T he n e w e n g l a n d j o u r n a l o f medicine

n engl j med 369;25 nejm.org december 19, 20132438

Founded byRichard C. CabotEric 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 EditorSally 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 andWomens 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 beguntaking citalopram, the development of oral erosions, tongue swelling, and urti-carial lesions, approximately 1 cm in diameter, on her torso occurred. Thesesymptoms were followed during the next several weeks by joint pain and swellingin her hands, fatigue, and low-grade fevers. Citalopram was stopped, and anti-histamines were prescribed, which the patient reported that she did not take forreligious reasons; during the next month, the lesions worsened. She was admittedto this hospital.

The patient reported difficulty eating because of oral ulcers; she also reportedpain on urination and defecation because of vaginal and anal lesions. She had ahistory of obesity, hypertension, and depression. Nine months before that admis-sion (27 months before the current admission), she had an episode of Streptococcuspneumoniaebacteremia associated with a tubo-ovarian abscess and complicated bybacterial 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 performedat that time. Medications included furosemide, metoprolol tartrate, aspirin (81 mgdaily), 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. Forreligious 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; herfather had died in an accident, her mother had hypertension, and an aunt hadbreast cancer.

On examination, the patient appeared uncomfortable because of oral lesions.The temperature was 38.7C. There were erosions on the inner lips and buccalmucosa, and there was edema of the lips. There were erythematous plaques withdusky centers on the abdomen; coalescent, erythematous, mildly scaly symmetricplaques on the back; and small oval erosions in the perianal area and vagina. Thewrist, metacarpal, and proximal interphalangeal joints were tender, without swell-

Case 39-2013: A 57-Year-Old Woman

with Painful Bullous Skin LesionsEllen K. Roh, M.D., Ruth Ann Vleugels, M.D., M.P.H., and Mai P. Hoang, M.D.

The New England Journal of Medicine

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case records of the massachusetts general hospital

n engl j med 369;25 nejm.org december 19, 2013 2439

ing or erythema. Pathological examination of acutaneous-biopsy specimen revealed interfacedermatitis (a finding consistent with erythemamultiforme) and a mild increase in dermal mucindeposition. Laboratory-test results are shown inTable 1. Broad-spectrum antibiotics and acyclovirwere 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 hydroxychloroquinewere prescribed, but she refused the medication.She was discharged on the 12th day. Dischargemedications included prednisone (40 mg daily),hydroxychloroquine (200 mg twice daily), di-phenhydramine (as needed), fluocinolone oint-ment (0.025%), and betamethasone dipropionateointment (0.05%).

Eighteen days later (17 months before this

admission), the patient was readmitted becauseof a persistent and increasingly painful erosive,pruritic rash on her back; the oral and anogeni-tal lesions had resolved. She reported not takingprednisone or hydroxychloroquine. Examinationrevealed erythematous scaly plaques with centralerosions on the back, chest, thighs, and buttocks.Laboratory results are shown in Table 1. A secondskin-biopsy specimen showed findings consis-tent with bullous lupus erythematosus. Hydroxy-chloroquine and prednisone were prescribed, butthe patient declined the medications. She wasdischarged on the seventh day.

Six weeks later, the patient was admitted toBrigham and Womens Hospital (BWH) becauseof worsening blistering and erosive skin lesionsduring the past week. The temperature was39.4C. Erythroderma of the face and torso waspresent (Fig. 1A and 1B); there were erosionsand large f lakes of desquamation and scattered,fragile flaccid bullae and open blisters coveringapproximately 70% of the body-surface area,predominantly on the upper chest and breasts,

with only a few plaques on the lower body andlegs, and no lesions on the palms, soles, oralmucosa, or genitalia. Pathological examinationof a third skin-biopsy specimen reportedly showedfindings consistent with pemphigus foliaceus.Methylprednisolone (125 mg daily) was admin-istered intravenously for 3 days, followed by atapering course of prednisone (60 mg daily for3 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. Theadministration of hydroxychloroquine was be-gun, and prednisone was tapered.

At a follow-up examination at BWH 10 daysafter discharge, there were no active skin lesions.After 3 months, the patient stopped keepingfollow-up appointments with the dermatologyservice at BWH and declined follow-up withrheumatology. Seven months before admission,at a follow-up appointment with her internist atthis hospital, she reported taking hydroxychlo-roquine (200 mg twice daily), prednisone (5 mgdaily), 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 patientreturned to her internist because of recurrentskin 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 betamethasonevalerate lotion (0.1%); the administration of vita-min A and D ointment was added. She declinedoral prednisone therapy because of concernabout diabetes mellitus and weight gain.

On the day of admission, the patient wasbrought to the emergency department at thishospital because of worsening skin lesions andincreasing pain (rated at 8 on a scale of 0 to 10,with 10 indicating the most severe pain). Onexamination, the vital signs and oxygen satura-tion were normal. There were multiple flaccidbullous lesions and superficial erosions, withcrusting 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 ofcoagulation and renal function; other results areshown in Table 1. A chest radiograph was nor-mal. Oxycodone (5 mg) was administered, andthe patient was admitted to this hospital.

A diagnostic procedure was performed.





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Th e n e w e n g l a n d j o u r n a l o f medicine


Table1.LaboratoryData.*

Variable

ReferenceRange,

Adults

ThisHospital

Brigham

andWomens

Hospital

ThisHospital

2

7MoEarlier,

1

stAdmission

18MoEarlier,

2ndAdmission

17M

oEarlier,

3rdAdmission

15MoEarlier

1Wkbefo

reThis

Admission

(Clinic)

OnThis

Admission

Hematocrit(%)

36.046.0

(women)

19.9

34.0

30.8

25.9

34.9

34.1

Hemoglobin(g/dl)

12.016.0

(women)

6.1

11.6

10.3

8.3

11.5

10.9

White-cellcount(permm

3)

450011,0

00

9900

2400

2300

6320

4500

4000

Differentialcount(%)

Neutrophils

4070

81

60

43

72

51

50

Bandforms

010

2

4

1

Lymphocytes

2244

15

27

40

17

26

25

Monocytes

411

4

9

5

5

6

5

Eosinophils

08

0

2

8

5

16

19

Basophils

03

0

0

0

0

1

1

Plateletcount(permm

3)

150,0

00400,0

00

437,0

00

178,0

00

1

86,0

00

371,0

00

254,0

00

280,0

00

Reticulocytes(%)

0.52.5

7.0

1.1

Meancorpuscularvolume(m

3)

80100

88

83

83

85

89

89

Red-celldistributionwidth(%)

11.514.5

17.2

14.5

15.9

16.6

15.3

15.7

Erythrocytecount(permm

3)

4,0

00,0

005,2

00,0

00

2,2

60,0

00

4,0

90,0

00

3,6

90,0

00

3,0

50,0

00

3,9

30,000

3,8

60,0

00

Erythrocytesedimentationrate(mm/hr)

020

83

71

75

25-HydroxyvitaminD(ng/ml)

>32

8

C-reactiveprotein(mg/liter)

1.5,positive

8.6

*ELISAdenotesenzyme-linkedim

munosorbentassay.Toconvertthevalue

sfor25-hydroxyvitaminDtonanomolesperliter,multiplyby2.4

96.

Referencevaluesareaffectedbymanyvariables,

includingthepatientpop

ulationandthelaboratorymethodsused.TherangesusedatMassachusettsGeneralHospitalareforadults

whoarenotpregnantanddonothavemedicalconditionsthatcouldaffec

ttheresults.

Theymaythereforenotbeap

propriateforallpatients.





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Erythema multiforme is often due to infections

(especially herpes simplex virus), although it can

be caused by medications.1Targetoid lesions be-

gin on acral skin and progress proximally, and

mucous membranes can be involved.1However,

this patient did not have classic targetoid lesions,

and the diagnosis does not explain the laborato-

ry findings. The StevensJohnson syndrome is ahypersensitivity 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.2Epi-

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 againstdesmoglein 1 and desmoglein 3 in pemphigusvulgaris. Typically, oral erosions precede f laccidcutaneous blisters, which develop into erosions.3Patients often respond well to systemic gluco-corticoids, as this patient did. However, thispatient 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 biopsyspecimens.The autoantibody target in pemphigus folia-

ceus is desmoglein 1. Most cases of pemphigusfoliaceus are idiopathic, but a type that is en-demic in Brazil is known as fogo selvagem. Pa-tients with pemphigus foliaceus do not havemucosal lesions but present with flaccid blisters,which develop into scaly, crusted erosions.4Thecondition also responds quickly to systemic glu-

cocorticoids. This patients third biopsy specimenshowed features consistent with pemphigus folia-ceus. She had flaccid blisters and erosions, whichresponded to treatment with prednisone. But thisdiagnosis does not explain the oral findingsduring the first admission, and it also does notexplain the laboratory-test results.

Patients with drug-induced pemphigus canpresent with pemphigus foliaceus or pemphigusvulgaris. Thiol-containing drugs, such as penicil-lamine, captopril, and enalapril, induce acan-tholysis directly, causing the more common fo-liaceus phenotype.5Nonthiol drugs (i.e., drugswith 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 noidentifiable cause of drug-induced pemphigus inthis 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.6Lesions 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-agedwomen. 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-





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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 foliaceusand SLE. Patients present with flaccid blisters

that evolve into crusted erythematous patches,

and lesions favor sun-exposed areas.8Typically,

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 involvementthat 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 toinvite Drs. Laura Winterfield and Daniela Kros-hinsky, who cared for this patient at BWH andMassachusetts 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 toMGH, the clinical findings were inconsistent

with the previous histopathological diagnoses oferythema 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): Atthe 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 picturewas most consistent with pemphigus erythema-tosus. In light of multiple different skin-biopsyresults, Drs. Aboutalebi and Alexander Marneros,who consulted from the dermatology service onthe day of admission, obtained additional skin-

biopsy specimens for routine histologic exami-nation and direct immunofluorescence studiesto confirm the diagnosis.

Clinical Di agnosis

Pemphigus erythematosus.

DR. ELLEN K. ROHS 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 atBWH 15 months before admission (Fig. 2E),showed acantholysis at the granular layer of the

epidermis. Direct immunofluorescence revealedstrong intercellular IgG in the stratum corneum,a finding consistent with pemphigus foliaceus.In addition, mild and discontinuous granular C3deposition was seen at the dermalepidermaljunction, which was interpreted as nonspecificstaining.

A skin-biopsy specimen from the left middleback, obtained on the patients admission to thishospital (Fig. 3A), showed similar features. Ac-





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antholysis was noted at the granular layer of theepidermis. Direct immunofluorescence revealedIgG and C3 granular and linear deposition at thebasement-membrane zone. In addition, weak

IgM and IgA deposition was also noted at thedermalepidermal junction, a finding consistentwith a lupus band.

Dr. Kroshinsky:Since we now had four different

A B

DC

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 abackground 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 ofDr. Scott Granter, Department of Dermatopathology, Brigham and Womens Hospital.)





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T h e n e w e n g l a n d j o u r n a l o f medicine


biopsy results, including a negative direct immu-nofluorescence assay on the most recent speci-men, additional testing was needed to confirmthe diagnosis of pemphigus erythematosus. Thepatients serum was sent to a reference labora-tory. Indirect immunofluorescence studies showed

intercellular IgG antibodies, and antibodies todesmoglein 1 were found by enzyme-linked im-munosorbent assay, features suggestive of pem-phigus foliaceus.

Dr. Hoang: After this result was reported, arepeat direct immunofluorescence assay showedintercellular 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 f irst describedin 1926 by Senear and Usher as a combination ofpemphigus 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 thedesmosomal cadherins desmoglein 1 and desmo-glein 3, respectively10), pemphigus erythemato-sus was classified as a variant of pemphigusfoliaceus that had features of both pemphigusand SLE. In pemphigus erythematosus, additionaldeposition of IgG and complement has beennoted at the epidermal basement-membranezone in up to 60% of biopsy specimens, as inthis case.11The differential diagnosis in this case

would be a concurrent manifestation of pemphi-gus and SLE.12

Discussion of M anagement

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.13Photoprotection 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 photoprotectionthat 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 inthe epidermis, as well as granular and linear IgG depo-sition at the basement-membrane zone.





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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 orrefractory disease, require systemic therapy. Thefirst-line systemic therapies that we considered

for this patient included systemic glucocorticoids,antimalarial therapy, and dapsone.14,15Both anti-malarial therapy and dapsone have the advantageof being effective in the treatment of cutaneousdisease without causing immunosuppression. Inthe United States, hydroxychloroquine is typi-cally the first-line antimalarial therapy, withchloroquine or combination antimalarial agents(hydroxychloroquinequinacrine or chloroquinequinacrine) as second-line options. This patientwould need routine monitoring for ocular ad-verse effects while receiving antimalarial therapy.

If she were to receive dapsone, she would needregular monitoring for such potential side effectsas hemolytic anemia, methemoglobinemia, agran-ulocytosis, the dapsone hypersensitivity syn-drome, and neuropathy. We would also performtesting for glucose-6-phosphate dehydrogenasedeficiency before the initiation of dapsone. Sinceit takes weeks to demonstrate therapeutic bene-fit from antimalarial agents and dapsone, wewould also need to treat this patient with anagent that would allow for rapid improvement ofthe extensive cutaneous disease. Treatment withsystemic glucocorticoids results in a rapid skin-disease response, and therefore these agents areoften initiated with the goal of tapering them asthe patients other glucocorticoid-sparing medi-cations take effect.

If these first-line therapies did not elicit aresponse in this patient, advanced systemic thera-peutic options for pemphigus erythematosuswould 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 wereadministered as adjunct therapy. After self-discon-tinuing these therapies, the patient presented with

a f lare of the cutaneous disease, which led to hercurrent hospital admission. At this time, I wouldrecommend systemic glucocorticoids, in additionto 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 twicedaily), and dapsone (50 mg twice daily). Dr. Tif-fany Angel provided follow-up care; the skin le-sions resolved, and the prednisone was taperedover a period of 2 months and then stopped. Tenmonths after discharge, we reduced the dose ofdapsone to 50 mg daily. Four months later, at thelast follow-up, the patient admitted that she had

discontinued both medications; she remains freeof cutaneous disease at this time.

Dr. Harris: A striking problem in caring forthis patient has been her distrust of the medicalsystem and her reluctance to take medication.Drs. Susan Mathai and Laura Myers, residents inMedicine who have been her primary care physi-cians, note that the patient refuses to believethat she has SLE, and in order to treat her, theyhave to agree to focus on her skin disease andthe medications necessary to treat it.

This woman is the only patient whom I haveconsidered as the subject of two clinicopatho-logical conferences (CPCs), for two illnesses. Weinitially considered discussing her presentationwith a tubo-ovarian abscess, which resulted inbacterial endocarditis, endophthalmitis, and myo-cardial infarction. We finally decided that thatstory was too complicated. Her case was thenproposed again a year later by our colleagues indermatopathology for this completely new set ofproblems. It is gratifying to learn that after allthis, she is well and living independently.

Are there any questions or comments for anyof our discussants?A Physician:These treatments can have severe

side effects. I used hydroxychloroquine to treat ayoung woman who had cutaneous lupus, and Iadded quinacrine because she insisted on sun-tanning. Irreversible pancytopenia developed, andthe patient required bone-marrow transplanta-tion. In a patient with bullous pemphigoid, whoalso had diabetic kidney disease, treatment with





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IVIG precipitated acute renal failure, which wasnearly fatal. In a patient with pyoderma gangreno-sum, a deep-vein thrombosis and pulmonaryembolus developed after treatment with thalido-mide; she turned out to have factor V Leiden.

Dr. Vleugels:We know that quinacrine can causepancytopenia, so our standard patient follow-up

includes regular complete blood counts. This isa very rare side effect; the most common sideeffect of quinacrine is reversible yellow pigmen-tation of the skin. Newer formulations of IVIGare sorbitol-based, rather than sucrose-based,which greatly reduces the risk of acute renalfailure. Although we do not routinely screen forhypercoagulability in patients before startingthalidomide, we take a careful history to assessclotting risk. For example, we would avoid treat-ment with thalidomide in a patient with SLE andthe antiphospholipid syndrome. These are all ex-

cellent points, reminding us that there are rarebut serious complications associated with theseagents.

Dr. Harris: In these Case Records, we havediscussed a patient with cardiomyopathy due tohydroxychloroquine use17 and a patient withmethemoglobinemia due to dapsone use,18fur-ther illustrating potential complications associ-ated with these agents.

A Physician:At this patients initial presenta-tion, paraneoplastic pemphigus could have beenconsidered, especially because of the mucous-membrane involvement. Also, age-appropriatecancer screening could have been part of theinitial workup.

Dr. Roh:Paraneoplastic pemphigus should al-ways be in the differential diagnosis when con-sidering a diagnosis of pemphigus. I did notconsider it strongly in this case because in thepatients I have seen who have paraneoplasticpemphigus, mucosal involvement has been byfar the predominant symptom. This patient hadsome mucosal involvement at the initial presen-

tation, but it was minor as compared with thecutaneous involvement.Dr. Harris:This patients SLE developed short-

ly after she started taking citalopram. She had apositive test for antihistone antibody, suggestingto 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 apatient presenting with signs of SLE, citalopram

is not one of the usual culprits. Furthermore, shereportedly had been taking it for only a week be-fore the onset of symptoms; onset usually requireslonger drug exposure. In addition to antihistoneantibodies, she had other autoantibodies moretypical of primary SLE. Finally, drug-inducedSLE usually resolves with removal of the offend-ing drug, in contrast to this patients course.

Dr. Vleugels:There is an important distinctionbetween drug-induced SLE, which classically isassociated with antihistone antibody positivity,and drug-induced subacute cutaneous lupus,

which typically is associated with anti-Ro anti-body positivity. Most patients with drug-inducedSLE do not have predominant cutaneous mani-festations; in 90% of patients, the primarysymptoms are arthralgias and systemic symp-toms. In contrast, patients with Ro-positive drug-induced subacute cutaneous lupus present todermatology with classic skin lesions, usuallyafter a month or more of using hydrochloro-thiazide, terbinafine, or another drug culprit.

Final Di agnosis


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 WorldCareClinical. No other potential conflict of interest relevant to thisarticle was reported.

Disclosure forms provided by the authors are available withthe full text of this article at NEJM.org.

We thank Dr. Eli Miloslavsky (Rheumatology) and Drs. Tif-fany Angel and Elena Hawryluk (Dermatology) for assistancewith the preparat ion of the case history.

References

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erythematosus associated with erythemamultiforme: Rowells syndrome. Int J Der-matol 2007;46:Suppl 3:30-2.8. Scheinfeld NS, Howe KL, DiCostanzoDP, 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

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Ranalli M. Treatment of refractory pem-phigus erythematosus with rituximab. IntJ Dermatol 2008;47:1317-8.16. Gupta MT, Jerajani HR. Control ofchildhood pemphigus erythematosus withsteroids and azathioprine. Br J Dermatol2004;150:163-4.17. Case Records of the MassachusettsGeneral Hospital (Case 7-2011). N Engl J

Med 2011;364:957-66. [Errata, N Engl JMed 2011;364:1281, 1682.]18. Case Records of the MassachusettsGeneral Hospital (Case 11-2011). N Engl JMed 2011;364:1450-60.Copyright 2013 Massachusetts Medical Society.

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