Clinical dermatology ¯ Concise report
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`]
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`Clinical and Experimental Dermatology
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`Dapsone hypersensitivity syndrome with circulating 190-kDa and
`2 3 0-kDa autoantibodies
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`I. S. Chun, S. I. Yun, S. I. Kim, S. C. Lee, Y. H. Won and I. B. Lee
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`Department of Dermatology, Brain Korea 21 Project, Chonnam National University Medical School, Gwangju, Korea
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`doi: 10.1111/j. 1365-2230.2009.03527.x
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`Summary
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`Dapsone has potent anti-inflammatory effects, and is used in the treatment of leprosy,
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`cutaneous vasculitis, neutrophilic dermatoses, and dermatitis herpetiformis and other
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`blistering disorders. However, it may cause severe adverse reactions such as
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`hypersensitivity syndrome, which is characterized by fever, skin rash, hepatitis and
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`lymphadenopathy. We report a 44-year-old female Korean patient with dapsone
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`hypersensitivity syndrome (DHS) that presented as a bullous skin eruption. The patient
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`had a 1-year history of urticarial vasculitis, treated with antihistamines, prednisolone
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`and dapsone. Although the skin lesions improved, she reported fever, nausea,
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`abdominal pain, jaundice, fatigue and skin rashes. On physical examination, there
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`were generalized erythematous macules and purpura with facial oedema that
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`developed into vesicles on the upper limbs. Histological examination of a skin biopsy
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`of a vesicular lesion found subepidermal oedema with a mixed inflammatory cell
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`infiltrate, including eosinophils in the dermis. Indirect immunofluorescence testing
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`using normal foreskin as substrate revealed IgG deposits in the basement membrane
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`zone. Circulating autoantibodies against antigens of 190 and 230 ld)a were found by
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`immunoblotting analysis using epidermal extracts. This case illustrates DHS with the
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`formation of circulating autoantibodies.
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`Dapsone (4,4’-diaminodiphenyl sulfone), a potent anti-
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`immunoblotting studies showed circulating auto-
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`inflammatory and antiparasitic compound, is used for a
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`antibodies targeting epidermal antigens in the patient.
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`variety of dermatological conditions including leprosy,
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`autoimmune bullous diseases, leucocytoclastic disorders
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`and other forms of vasculitis. Dapsone may cause a
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`Report
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`severe idiosyncratic reaction known as dapsone hyper-
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`In December 2004, a 44-year-old Korean woman
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`sensitivity syndrome (DHS), which presents with a triad
`of fever, rash and internal organ involvement.1 We
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`visited the emergency department with pruritic, ery-
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`thematous generalized oedematous patches associated
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`report a case of DHS in a patient with urticarial
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`vasculitis, who had diffuse generalized erythema over
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`with vesicles and bullae on the limbs, which had been
`present for 3 days. The patient reported fever and
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`the entire body surface associated with tense vesicles
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`tenderness on the right upper abdomen. She had been
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`and bullae on the limbs. The immunofluorescence and
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`treated for urticarial vasculitis with 100 mg of dapsone,
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`Correspondence: Professor Jee Bum Lee, Department of Dermatology,
`Chonnam National University Medical School, 501-746 Dong gu Hak Dong
`8, Gwangju, Korea
`E-mail: jbmlee@chonnam.ac.kr
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`Conflict of interest: none declared,
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`Accepted for publication 6 March 2009
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`l0 mg of prednisolone and l0 mg of ebastine, a
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`nonsedating H1 antihistamine. She had been taking
`the medications for l month, and had then developed
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`generalized skin rash with fever. The patient’s family
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`history was noncontributory.
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`On physical examination, generalized oedema with
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`diffuse erythema was seen over the entire body surface,
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`and tense vesiculobullous lesions were present on the
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`e798
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`© 2009 The Author(s)
`Journal compilation © 2009 British Association of Dermatologists ¯ Clinical and Experimental Dermatology, 34, e798-e801
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`Almirall EXHIBIT 2047
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`DHS with circulating 190-kDa and 230-1d)a autoantibodies ¯ J. S. Chun et al.
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`forearms (Fig. 1). The oral and genital mucosae were
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`(10-15%) and eosinophilia (14%; 14%). Viral markers
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`intact. Multiple enlarged cervical lymph nodes were
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`for acute hepatitis were negative. Abdominal ultrasono-
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`palpable. The patient had a persistent fever (> 38°C).
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`graphy found parenchymal liver disease.
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`Laboratory investigations revealed leucocytosis (white
`blood cell count 16.2 x 10V/L; normal range 4-10 x
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`Histopathological examination of a vesicle from
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`forearm found subepidermal bullae due to marked
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`l O9/L), abnormalliver function [asparatate aminotrans-
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`oedema in the upper dermis and perivascular lympho-
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`ferase 248 U/L (normal range 10-35 U/L); alanine
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`cytic infiltrates with eosinophils (Fig. 2a). To exclude
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`transferase (ALT) 196 U/L (10-40 U/L); gamma glu-
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`the possibility of drugqnduced autoimmune bullous
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`tamyl transferase 214 U/L (5-41 U/L); total bilirubin
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`disease, we performed indirect immunofluorescence
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`3.8 mg/dL (0.22-1.2 mg/dL] and raised lactate
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`(IIF) and immunoblotting analyses of the patient’s
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`dehydrogenase (1741 U/L; normal range 270-530
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`serum. IIF on normal human foreskin showed deposi-
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`U/L). After admission, the leucocytosis worsened to
`22 x lO9/L, aggravated by atypical lymphocytosis
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`tion of immunoglobulin G linearly along the basement
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`membrane zone (BMZ) (Fig. 2b). Immunoblotting using
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`Figure 1 (a) Generalized oedematous ery- ~f~_~
`thema on the face and (b) erythematous~- .,,
`patches with tense vesiculobullae on the ~
`forearms. ~.
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`Figure 2 (a) Subepidermal bullae due to marked oedema in the upper dermis, and moderately dense mixed inflammatory cell infltrates
`with lymphocytic predominance (haematoxylin and eosin, original magnification x 40). (b) Indirect immunofluorescence revealed linear
`IgG deposits along the basement membrane zone (original magnification x 400).
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`© 2009 The Author(s)
`Journal compilation © 2009 British Association of Dermatologists ¯ Clinical and Experimental Dermatology, 34, e798-e801
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`DHS with circulating 190-1d)a and 230-1d)a autoantibodies ¯ J. S. Chun et al.
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`human epidermal extracts demonstrated IgG antibodies
`bound to polypeptides of 190 and 230 ld)A (Fig. 3).
`ELISA using antidesmoglein (Dsg)-l, anti-Dsg-3, anti-
`bullous pemphigoid (BP)180NC16a and anti-BP230
`was performed at 1 : 100 dilution; the results were
`negative. To exclude viral activation, especially human
`herpesvirus (HHV)-6 which is implicated in drug-
`induced hypersensitivity syndrome, we performed
`HHV-6 gene nested PCR (GenBank accession No.
`$57540) using the patient’s serum, but no PCR product
`was found,
`Dapsone was discontinued and the patient was
`treated with antihistamines and prednisolone
`25 rag/day. Subsequently, the skin rash became dusky
`exfoliative patches and the laboratory results normal-
`ized without fever. The patient was diagnosed with DHS.
`DHS is a severe idiosyncratic drug reaction charac-
`terized by the clinical triad of fever, rash and systemic
`involvement. Various types of rashes develop in DHS,
`such as maculopapular/pustular/vesiculobullous erup-
`tion, exfoliative dermatitis, erythroderma and Stevens-
`Johnson syndrome (SJS)/toxic epidermal necrolysis
`(TEN). The pathophysiology of DHS remains unclear,
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`Figure 3 Immunoblotting assay using human foreskin epidermal
`extracts. Lane 1, patient’s serum; lane 2, paraneoplastic pemphi-
`gus serum with autoantibodies to 190-1d)a and 2 lO-id)a
`antigens; lane 3, bullous pemphigoid serum with autoantibodies
`to 180-1d)a and 230-1d)a antigens; lane 4, pemphigus vulgaris
`serum with autoantibodies to 160-1d)a and 130-1d)a antigens,
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`but it may be caused by dapsone metabolites forming
`haptens, resulting in the formation of antidapsone
`antibodies.1
`Because our patient with DHS had multiple vesiculo-
`bullous lesions, we tested for autoimmune bullous
`diseases using histopathology, IIF test, immunoblotting,
`and ELISA. We found deposition of IgG antibodies
`along the BMZ using IIF. The immunoblotting assay
`revealed that the autoantibodies from the patient’s
`serum were bound to antigens of 190 and 230 ld)a in
`size, which were compatible with the molecular weight
`of periplakin and BP230, respectively. The ELISA did
`not detect antibodies against 230-1d)a antigens. Our
`findings suggest a difference in the sensitivity of the
`ELISA compared to the immunoblotting assay, which
`resulted in inconsistent data. In assessing the index
`value for ELISA, the final absorbance obtained might
`not necessarily represent an accurate estimate of the
`concentration of the autoantibodies.2 Another consid-
`eration is that the target antigens that caused antibody
`production in this patient may be heterogeneous. In
`addition, the autoantibodies found by IIF and immuno-
`blotting might not have been specific for periplakin or
`BP230, even though the molecular weight of the
`autoantibodies were similar. Moreover, there are several
`studies about the association of drug-induced bullous
`dermatosis with positive IF findings and negative IIF and
`ELISA, with no clear explanation for these results.3’4
`These results suggest that circulating autoantibodies
`might be produced after dapsone exposure, which
`trigger DHS. Formation of autoantibodies to the 190-
`kDa and 230-1d)a antigens in our patient with DHS was
`unrelated to autoimmune bullous disease, a finding that
`is of particular interest. There are reports of auto-
`antibody formation associated with administration of
`carbamazepine,s’6 The exact role of the autoantibodies
`found in drug-induced hypersensitivity syndrome
`remains unknown. Dapsone is metabolized primarily
`via N-acetylation and N-hydroxylation (oxidation). The
`N-hydroxylation pathway is thought to be the initial
`step in the formation of toxic intermediate metabolites,
`1
`including hydroxylamine. These metabolites covalently
`bind to or modify various molecules, including major
`histocompatibility complex peptides, so that drug-
`specific T-cell recognition contributes to DHS. Reactive
`metabolites act as haptens and bind to endogenous
`proteins to form a compound that triggers an immune
`reaction. Haptenated compounds may also be directly
`toxic to cells. 7 Thus, the autoantibodies detected in
`our case might be a secondary phenomenon during
`the immune reaction, not the primary pathogenic
`event.
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`© 2009 The Author(s)
`Journal compilation © 2009 British Association of Dermatologists * Clinical and Experimental Dermatology, 34, e798-e801
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`DHS with circulating 190-1d)a and 230-1d)a autoantibodies ¯ J. S. Chun et al.
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`Recent studies have shown that HHV-6 and HHV-7
`might also be involved in drug rash with eosinophilia
`and systemic symptoms (DRESS) syndrome, although
`the precise role and preceding order in the pathogenesis
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`remains unclear? However, we found no evidence of
`HHV-6 activation in our patient with DHS. The patho-
`genesis of DHS is likely to involve complex immune
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`interactions,
`Whether we consider our case as DHS or bullous drug
`eruption is another controversial question. DHS is
`regarded as a form of DRESS syndrome induced by
`dapsone. The current definition of DRESS does not
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`characterize and describe the nature of rash, but some
`authors suggest that all drug eruptions should be
`classified according to the cutaneous lesions of the most
`pronounced pathology?’1° SIS/TEN are also regarded
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`as DRESS with severe skin reaction, but they show
`different characteristics, treatment and prognosis com-
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`pared with DRESS. There are still arguments for and
`against the current definition and classification of
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`DRESS.
`In conclusion, the detection of circulating autoanti-
`bodies might provide another clue towards understand-
`ing the pathogenesis of DHS.
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`References
`
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`2 Cheng SW, Kobayashi M, Tanikawa A et al. Monitoring
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`3 Billet SE, Kortuem KR, Gibson LE, E1-Azahary R. A mor-
`billiform variant of vancomycin-induced linear IgA bullous
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`8 Descamps V, Valance A, Edlinger C et al. Association of
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`9 Wolf tl, Mats H, Marcos B, Orion E. Drug rash with
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`10 Wolf tl, Davidovici B, Matz H et al. Drug rash with eosin-
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`308-10.
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`© 2009 The Author(s)
`Journal compilation © 2009 British Association of Dermatologists ,, Clinical and Experimental Dermatology, 34, e798-e801
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