J o u r n a l o f R h e u m a t i c D i s e a s e sV o l . 2 0 , N o . 6 , D e c e m b e r , 2 0 1 3http://dx.do i.org/10.4078/jrd .2013.20.6 .374

□ Case Report □

374

＜Received：September 26, 2012, Revised (1st: December 21, 2012, 2nd: January 10, 2013), Accepted：January 10, 2013＞Corresponding Yeon-Sik Hong, Division of Rheumatology, Department of Internal Medicine, School of Medicine, The Catholic

University of Korea, Incheon St. Mary’s Hospital, 56, Dongsuro, Bupyeong-gu, Incheon 403-720, Korea. E-mail：rhcow1@yahoo.co.kr

pISSN: 2093-940X, eISSN: 2233-4718Copyright ⓒ 2013 by The Korean College of RheumatologyThis is a Free Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.

Toxic Epidermal Necrolysis by Ceftriaxone in Patient with Newly Diagnosed Systemic Lupus Erythematosus

Jae Ho Lee, Il Nam Ju, Hyung Jun Cho, Hong Ki Min, Yeon-Sik Hong

Division of Rheumatology, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, Incheon, Korea

Toxic epidermal necrolysis (TEN) is a rare disease in abso-

lute numbers with an incidence of 2 cases per million peo-

ple per year. Most cases of TEN are caused by drugs, but

certain infectious diseases may have an impact on the risk.

There are rare reports of TEN occurring without history

of drug ingestion in systemic lupus erythematosus (SLE),

appearing similar to cutaneous lupus and early TEN mani-

festations, such as erythema multiforme. This report de-

scribes a patient with SLE who presented with manifes-

tations of TEN after ceftriaxone treatment. The patient was

newly diagnosed with SLE and TEN occurring eight days

after cessation of ceftriaxone. Considering possible etiol-

ogies, we could not exclude ceftriaxone as the cause of

TEN. After intravenous immunoglobulin with glucocorti-

coid, clinical symptoms improved.

Key Words. Systemic lupus erythematosus, Toxic epi-

dermal necrolysis, Ceftriaxone, Hydroxychloroquine, IV

immunoglobulin

Introduction

Toxic epidermal necrolysis (TEN) is an acute, rapidly evolv-

ing mucocutaneous reaction, frequently associated with medi-

cation use characterized by extensive painful cutaneous and

mucosal exfoliation, and systemic involvement that may be

life-threatening (1). Common triggers of TEN are anti-

epileptic drugs such as carbamazepine. Also, allopurinol is

the most common cause of Stevens- Johnson syndrome

(SJS)/TEN in Europe and Israel (2). However, several drugs

except the following drugs can be a cause of TEN (3). One

of them is cephalosporin, such as ceftriaxone. Moreover, SLE

can present as SJS and TEN, too (4-6). The mortality of TEN

approximates 30%. Therefore, differential diagnosis about the

cause of TEN is important in SLE patients. We experienced

a case presenting TEN in a new diagnosed SLE patient after

ceftriaxone administration.

Case Report

A 37 year-old female patient who had facial rash, febrile

sense for 2 weeks was admitted to the emergency room. The

patient was treated by local dermatologic clinic regarding fa-

cial rash using steroid ointment. There was no facial rash im-

provement; therefore, laboratory tests were checked. She was

transferred to our hospital because the test showed elevated liv-

er enzymes. At that time, blood pressure was within normal

limit, but the pulse rate 119 bpm and body temperature 38.1oC

were increased. In past history, it was non-specific except

herbal medication for 4 days before 2 weeks. Nothing unusual

was found in familial history. Oral ulcer and mild abdominal

tenderness without rebound tenderness were observed.

Complete blood count showed decreased white blood cell

(WBC) 1,560/mm3 (absolute neutrophil count (ANC) 790), he-

moglobin 10.4 g/dL and platelet count 113 K, pancytopenia.

It was showed an increased aspartate transaminase/alanine

transaminase (AST/ALT) 457/238 (0∼40) U/L, γ-GTP 44 (0

Toxic Epidermal Necrolysis in a Systemic Lupus Erythematosus Patient 375

Figure 1. It shows blistered skin

lesions in back (A) and upper

abdomen (B).

Figure 2. It shows skin detach-

ment and new epidermis regenera-

tion. Skin detachment start in back

at hospital day 22 (A). Around

hospital day 30, almost skin de-

tachment is over and new epide-

rmis go into new regeneration (B).

∼38) U/L, and LDH 1,607 (208∼450) IU/L in blood chem-

istry, but otherwise within normal limit, including urine

analysis. The patient was hospitalized in the division of hep-

atology for evaluation and treatment about hepatitis. Empirical

ceftriaxone was started considering infectious fever, and raniti-

dine, ornithine oxoglurate, and oral prednisolone 10 mg were

administered in the light of autoimmune diseases. However,

AST/ALT was on the increase continuously. The results of

hepatitis viral examination (HAV, HBV, HCV, EBV, and

CMV) and autoimmune hepatitis (anti-liver kidney microsomal

antibody, anti-smooth muscle antibody, anti-mitochondrial anti-

body) were all negative. In immunologic test, rheumatoid fac-

tor was negative, but anti-nuclear antibody 1：640 homoge-

neous, anti SS-A antibody was positive and anti-dsDNA anti-

body was over 600 IU/mL. Complements were both decreased:

C3 was 20.3 (90∼180 mg/dL) and C4 12.2 (14∼50 mg/dL).

At hospital day 7, ceftriaxone was stopped since fever is not

infectious origin. Liver biopsy showed focal macrovesicular

steatosis with intralobular degeneration and focal necrosis.

Moreover, Masson-Trichrome stain was positive in collagen

tissue of the portal tract and reticulin was positive in reticulin

framework, too. The result of liver biopsy may be present in

SLE. She was diagnosed SLE based on clinical symptoms and

laboratory test, and transferred to the division of rheumatology

on hospital day 12. At that time of transfer, ANC was de-

creased to 330/mm3, therefore an increase of prednisolone dos-

age of up to 50 mg was decided. Three days later, although

reduction of AST/ALT was not significant, ANC was elevated

to 3,330/mm3. A dose of 400 mg of hydroxychloroquine

(HCQ) was prescribed. Confluent erythematous plaques with

target lesions developed on the whole abdomen and back with

itching sense on the same evening. The rash extended to the

extremities, face and neck over 4 days, and then multiple blis-

ters arose on the patient’s abdomen and back (Figure 1). This

376 Jae Ho Lee et al.

Figure 3. It shows skin pathology

stained haematoxylin eosin. Epi-

dermis separate from subepidermal

layer (A, ×100). Several vacuo-

lization were observed in subepi-

dermal layer (B, ×400). Because

total seperat-ion from dermal-

epidermal junction, it is difficult to

observe the vacuolar alteration and

solitary necrotic kerati-nocyte. How-

ever, it is not observed that

moderate to dense periadnexal and

perivascular lymphocyte infiltration

consistent with SLE.

was also associated with injected conjunctivae and oral ulcers.

Thus, we quitted HCQ administration on the following day and

maintained prednisolone 50 mg only. Because the lesions were

suspected toxic epidermal necrolysis (TEN), a skin biopsy of

the back and daily dressing was performed. IV im-

munoglobulin was started 50 g/day (1 g/kg/day) for 4 days by

dermatology consultation on hospital day 19. At hospital day

22, Skin detachment occurred on the abdomen, whole back and

face (Figure 2). Skin histopathology was found detachment for

the whole epidermal layer with subepidermal vacuolization and

immunofluorescence was negative, consistent with TEN

(Figure 3). At hospital day 28, WBC, platelet count and

AST/ALT were normalized, except anemia. New epidermis re-

generated (Figure 2). Skin lesion was improved consistently

without skin and soft tissue infection. Laboratory findings were

stabilized, so prednisolone was tapered to 30 mg. Then, the

patient discharged without other complications at hospital day

38.

Discussion

SLE presents various cutaneous manifestations, including

blistering condition. The diagnosis of bullous SLE can be dif-

ficult since several primary blistering disorders, such as pem-

phigus vulgaris, bullous pemphigoid, SJS and TEN. Moreover,

it is not clear whether patients with SLE have an increased

risk for TEN over that of the general population (7). Probably,

TEN without causality in SLE should come from keratinocyte

apoptosis, common pathology. We considered two possibilities

causing TEN in this patient. First, SLE itself can be a cause.

Second considerations are drugs, ceftriaxone or HCQ. Aisha

et al. have reported a case of TEN and acute generalized ex-

anthematous pustulosis (AGEP) induced by HCQ in a SLE

patient (8). Although there is other report about TEN related

HCQ (9), times of starting HCQ in both cases differ from our

report. Commonly, TEN occurs some days after drug

administration. Therefore, one of SLE or ceftriaxone might in-

duce TEN. Unfortunately, there are no definite foci for differ-

ential diagnosis, which one is the cause of TEN in SLE or

drugs. Pathophysiology of SJS/TEN is still unknown. CD8+

lymphocyte have been identified to play an important role in

the process. It seems that ceftriaxone-specific MHC molecule

induce specific TCR activation. Cytotoxic T-cells killed autol-

ogous lymphocyte and keratinocytes in a drug-specific, perfor-

in/granzyme-mediated pathway restricted to MHC class I. On

the other hand, immune-complex and complement infiltration

are key factors in skin manifestation of SLE. In our case, there

is nothing to observed immune-complex or complement in

immunofluorescence. Although we could not find junctional

vacuolar alteration or solitary necrotic keratinocyte at lower

epidermal level due to epidermal peeling off, HE stain is not

suitable SLE-origin TEN because there are no moderate to

dense periadnexal and perivascular lymphocytic infiltration,

with the presence of melanophage (10). According to a report,

the onset of TEN-like lupus was insidious, with an initial pho-

todistribution and absence of genital/perianal erosions com-

pared with drug-induced. The mean duration between the on-

set of the initial rash and epidermal detachment was sig-

nificantly longer than that of the conventional drug induced

TEN (6). In this case, skin lesion occurred acutely with mu-

cosal involvement and distribution of detachment was not lim-

ited in photodistribution. Given the acute onset of symptoms,

rapid cutaneous progression, prominent mucosal involvement,

recent moderate-risk drug exposure, no vasculitic lymphocyte

and immunoglobulin infiltration in tissue pathology; therefore,

we favored TEN secondary to ceftriaxone.

There is an algorithm for assessment of drug causality in SJS

and TEN (ALDEN). It is divided 5 categories by using ALDEN,

very unlikely, unlikely, possible, probable, and very probable in

Toxic Epidermal Necrolysis in a Systemic Lupus Erythematosus Patient 377

turn. Data from the report showed lower etiologic fraction of

cephalosporin related epidermal necrolysis, 4.3% (11).

TEN remains a potentially fatal disorder. The typically quot-

ed mortality rate of 20% and 30% was confirmed (12).

Established therapies are controversial up to now, and treat-

ments are not different regardless of the etiology. In aspect

of the topical treatment, appropriately placed wet dressing

may help to avoid adhesion or stricture and infection via skin

or mucosa. Also, supportive care in intensive unit is im-

portant, such as maintain room temperature, avoiding dehy-

dration and electrolyte imbalance. In addition, various im-

munomodulating therapies are discussed for SJS/TEN, includ-

ing IVIG. It is unclear IVIG mechanism to improve SJS/TEN

survival. Antibodies in pooled human IVIG block in vitro

FAS-mediated keratinocyte necrosis, which is why IVIG is

used in the treatment of SJS and TEN (13). Nothing has been

decided yet regarding proper dosage of IVIG. The dose has

varied from one author to the next (1). There have been argu-

ments against systemic glucocorticoid treatment due to in-

creased mortality related infection (13,14). On the other hand,

some reports have shown effects of steroid pulse therapy, pre-

venting ocular complication or not increased mortality (15).

We administered prednisolone 1 mg/kg to control SLE activity

not TEN. IVIG was prescribed by 50 g/day (1 g/kg/day). We

considered ethnic distinctions to decide the dose. Otherwise,

there are many immunomodulators to treat TEN, TNF antago-

nist, thalidomide, cyclophophamide, cyclosporine A, and etc.

Summary

Our patient recovered rapidly after IVIG treatment. We are

following her for 6 months, and she takes HCQ before several

months without adverse effects.

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