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 s V o l . 2 0 , N o . 6 , D e c e m b e r , 2 0 1 3
http://dx.doi.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：
[email protected] pISSN: 2093-940X, eISSN: 2233-4718
Copyright ⓒ 2013 by The Korean College of Rheumatology
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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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