186·1·93
`
`·Univ. of Minn.·
`· Bio-Medical.
`Librarv
`_,2 08 93
`
`1
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`4
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`Dermatologische Zeitschrift
`Dermatologica-Dermatology:
`A Centenary 1893-1993
`Holubar, K. (Vienna)
`In vivo Confocal Microscopy:
`A'New Paradigm in Dermatology
`Pierard, G.E. (Liege)
`·
`·--·:@~~~Bi~~l,~i[~~i~~~~~[~~f~~~
`6
`Clinical Investigation of Skin
`Microcirculation
`Bongard, 0.; Bounameaux, H. (Geneva)
`
`['
`
`Cutaneous Malignant Melanomas
`with Other Coexisting Neoplasms:
`A Tru.e Association?
`Schallreuter, K.U.; Levenig, Ch.; Berger, J.
`(Hamburg)
`Comparison of the Pathology of Fascia in
`Eosinophilic Myalgia Syndrome Patients
`and Idiopathic Eosinophilic Fasciitis
`Umbert, I.; Winkelmann, R.K.; Wegener, L.
`(Scottsdale, Ariz.)
`Severity Scoring of Atopic Dermatitis:
`The SCORAD Index. Consensus Report of the
`European Task Force on Atopic Dermatitis
`European Task Force on Atopic Dermatits
`(Bordeaux)
`Evolving Pattern of Drug-Induced Toxic
`Epidermal Necrolysis
`Correia, 0.; Chosidow, 0.; Saiag, Ph.;
`Bastuji-Garin, S.; Revuz, J.; Roujeau, J.-C.
`(Creteil)
`Effects of All-Trans-Retinoic Acid on
`Melanocyte Adhesion and Motility
`Situ, R.; Inman, D.R.; Fligiel, S.E.G.; Varani, J.
`(Ann Arbor, Mich./ Allen Park, Mich.}
`Soluble CD14 Monocyte Antigen in
`Suction Blister Fluid and Serum of
`Patients with Psoriasis
`Schopf, R.E.; Dobmeyer, J.; Dobmeyer, Th.;
`·
`Morsches, B. (Mainz)
`
`12
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`18
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`23
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`32
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`38
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`45
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`ISSN~1018-8665
`DERAEG
`186(1) 1-80 (1993)
`
`In vivo Vision of the Human Skin with the
`Tandem Scanning Microscope
`Corcuff, P.; Leveque, J.-L. (Aulnay-sous-Bois)
`
`50
`
`Azelaic Acid Has Antimycotic Properties
`in vitro
`Brasch, J.; Christophers, E. (Kiel)
`Onychomycosis: Successful Treatment
`with Once-Weekly Fluconazole
`Nahass, G.T.; Sisto, M. (Miami, Fla.)
`Therapeutic Efficacy of Oral Low-Dose
`Cyclosporin A in Severe Psoriatic
`Arthritis
`Wagner, S.A.; Peter, R.U.; Adam, 0.; Ruzicka, T.
`(Munich)
`
`Epidermolysis bullosa simplex
`Dowling-Meara: Troublesome Blistering
`and Pruritus in an Adult Patient
`McGrath, J.A.; Burrows, N.P.; Jones, R.R.;
`Eady, R.A.J. (London)
`Primary Infection by Human Parvovirus
`B19
`Veraldi, S.; Rizzitelli, G.; Lunghi, G.; Cardop.e, R.
`(Milano)
`·
`Acute Generalized Exanthematous
`Pustulosis due to Doxycycline
`Triieb, R.M.; Burg, G. (Ziirich)
`t~i~~~~rw:~.
`'••···········
`Topical Podophyllotoxin in Psoriasis
`vulgaris
`Wantke, F.; Fleisch!, G.; Gi:itz, M.; Jarisch, R.
`(Vienna)
`Positive Response to' 5.HT -2 Antagonists
`in a Family Affected by Epidermolysis
`bullosa Dowling-Meara Type
`Tadini, G.; Ermacora, E.; Cambiaghi, S.;
`Brusasco, A.; Cavalli, R. (Milan)
`
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`~=~d Scientific KA 1\ G E 1\
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`Publishers
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`Dr. Reddy's Laboratories, Ltd., et al.
`v.
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`IPR2015-__
`Exhibit 1038
`
`Exh. 1038
`
`

`

`Case Report
`
`Dermatology 1993;186:75-78
`
`R.M. Triieb
`G. Burg
`
`Department of Dermatology,
`University Hospital, Zurich, Switzerland
`
`Key Words
`Pustular drug rash
`Lymphocyte transformation test
`Rechallenge
`Allergy to doxycycline
`
`Abstract
`Sterile epidermal neutrophilic pustulation can be observed in a variety of dis-
`eases. Though drug hypersensitivity is an uncommon cause, it is yet a known
`entity to be considered in the differential diagnosis of generalized pustulosis. In a
`40-year-old woman, who developed a generalized pustular eruption after start-
`ing on doxycycline therapy of bronchitis, the rash was concluded to be drug
`induced after exclusion of other pustular dermatoses. Sensitization to doxycy-
`cline was demonstrated by in vitro lymphocyte testing and correlated with clin-
`ical drug hypersensitivity after recurrence of the pustular eruption on noninten-
`tional rechallenge with doxycycline.
`
`Pustular eruption is an uncommon manifestation of
`drug sensitivity [1]. A variety of dermatoses presenting with
`sterile epidermal neutrophilic pustulation must be con-
`sidered in its differential diagnosis. Toxic pustuloderma
`[2, 3] has been delineated as a clinical entity characterized
`by a single self-limiting pustular eruption and some degree
`of a vasculitic reaction pattern [4, 5]. It is most frequently
`precipitated by drugs, in particular antimicrobials [6, 7].
`The pathogenesis of toxic pustuloderma has remained sub-
`ject to speculation. A severe form of toxic erythema has
`been proposed [3], also a reaction pattern favored by a pso-
`riatic background has been suggested, though clinically and
`histologically different from pustular psoriasis [7]. We
`report a case in which drug allergy to doxycycline could be
`demonstrated by lymphocyte transformation testing.
`
`Case Report
`
`A 40-year-old woman suffering from allergic bronchial asthma was
`treated with doxycycline prior to the development of a pruritic ery-
`thematous rash, beginning in the flexural areas of the groin and elbows
`to subsequently spread over the trunk and limbs with a pustular erup-
`tion. Other medication at the time included acetylsalicylic acid, acet-
`aminophen, N-acetylcystein, theophylline and salbutamol. She had
`neither a personal nor a familia] history of any other skin disease. On
`admission to the hospital in June 1990 she exhibited a widespread
`patchy erythematopapular rash superimposed with several superficial
`pinhead-sized nonfollicular pustules (fig.1).
`The white cell count at the time was 11,200/mm3 with 84% neutro-
`phils, the erythrocyte sedimentation rate was 28 mm/h. Blood chemis-
`try was within normal limits. Cultures repeatedly taken from pustular
`lesions showed negative findings for bacterial or fungal organisms.
`Skin biopsy revealed subcorneal pustules with neutrophils and a
`perivascular infiltrate in the superficial dermis composed of polymor-
`
`Received:
`March 6, 1992
`Accepted:
`July 7, 1992
`
`Dr. R.M. Triieb
`Dermatologische UniversiUitsklinik
`Gloriastrasse 31
`CH-8091 ZUrich (Switzerland)
`
`© 1993 Karger AG, Basel
`1018-8665/93/1861--D075
`$ 2.75/0
`
`Exh. 1038
`
`

`

`phonuclear cells and lymphocytes (fig. 2). Direct immunofluorescence
`testing did not demonstrate any immunoglobulin or complement
`deposits in the skin or vessel walls.
`Patch-scratch testing was pedormed failing to reveal any hypersen-
`sitivity reaction to the implicated medicaments. A lymphocyte trans-
`formation test performed with doxycycline and acetylsalicylic acid in
`the Institute of Clinical Immunology of the University of Berne ( direc-
`tor: Prof. Dr. A.L. de Week) by Prof. Dr. W.J. Pichler demonstrated
`sensitization to doxycycline by a stimulation index of 13, whereas a
`stimulation index of up to 2 can be regarded as nonsignificant in regard
`to drug-specific hypersensitivity [pers. commun. of Prof. Dr. W.J.
`Pichler].
`All previous medication was stopped and prednisone administered
`at a dose of 40 mg daily. Within few days the rash cleared with subse-
`quent desquamation of the affected skin. In March 1991 the patient
`presented again with recurrence of the generalized pustular eruption
`after accidental ingestion of doxycycline. Other medication included
`theophylline, salbutamol and levomepromazine. After withdrawal of
`doxycycline and a short course of oral prednisone the pustular exan-
`thema resolved within a week. There has been no recurrence since
`then.
`
`Discussion
`
`There is a variety of dermatoses presenting with general-
`ized sterile epidermal neutrophilic pustulation. It is not an
`uncommon event. Any infectious cause of the pustules
`must first be excluded. Pustular eruption is a rather unusual
`manifestation of drug sensitivity [1], yet a known entity [7]
`to be considered. Its diagnosis is based on the temporal
`relationship incriminating the presumed causative agent,
`an often strikingly short intervall between administration of
`the drug and the skin reaction [7], and on the exclusion of
`other pustular dermatoses (table 1). Among drug-induced
`pustular dermatoses the acneiform eruptions (e.g. halogen
`acne) must be differentiated from nonfollicular pustulo-
`derma.
`In 1984, Staughton et al. [2] delineated toxic pustulo-
`derma as a new entity comprising a self-limiting syndrome
`presenting with an erythematous and pustular eruption
`associated with fever, peripheral blood leukocytosis and
`subcomeal pustules. The eruption is more frequently pre-
`cipitated by drugs [1-3, 6-19], although other causative
`agents [3, 7, 12, 17] have been incriminated (table 2).
`Three_ histological patterns to drug-induced pustular
`eruptions have recently been described: (a) one indistin-
`guishable from the changes in Sweet's syndrome, (b) leuko-
`cytoclastic vasculitis and (c) the subcomeal polymorphonu-
`clear microabscesses and upper dermal perivascular infil-
`trate composed of lymphocytes and neutrophils of toxic
`pustuloderma. It has been suggested to possibly consider
`these changes as a continuous spectrum in which neutro-
`
`Fig. 1. Generalized exanthematous pustulosis: superficial pin-
`head-sized nonfollicular pustules superimposed on a background of
`patchy erythema.
`
`Fig. 2. Histologic features of acute generalized exanthematous
`pustulosis: subcorneal pustule with polymorphonuclear leukocytes.
`Hematoxylin-eosin. x 200.
`
`76
`
`Trtieb/Burg
`
`Exanthematous Pustulosis
`
`Exh. 1038
`
`

`

`phils collect around the dermal blood vessels, form subepi-
`dermal pustules and are then eliminated transepidermically
`[5].
`The clinical identification of adverse drug reactions is
`largely based on subjective criteria [18]. Direct challenge
`provides the most definitive information on the relation-
`ship of a suspected drug to a given clinical syndrome but is
`usually not justified because of the potential morbidity
`involved. After implicating the causative agent, the clini-
`cian dealing with a drug reaction is faced with three issues:
`(1) immunologic versus nonimmunologic origin of the drug
`reaction, (2) detection of the responsible one of multiple
`drugs in case of an immunologic drug reaction, (3) risk of
`eliciting an allergic reaction to readministration of the drug
`[18]. To prove the immunologic origin of a given drug reac-
`tion, an immune response to the drug and a similar drug-
`initiated clinical reaction must be demonstrated. Because
`of the aforementioned difficulties associated with readmi-
`nistration of suspected drug allergens, in vitro tests have
`been devised to demonstrate a drug-specific immune
`response [20]. To detect drug-specific cellular immune
`response in drug hypersensitivity states, delayed tubercu-
`lin-type skin testing and the lymphocyte transformation test
`[21] have been used. The former is however of limited
`value with a possible risk of reexposing the sensitized
`patient to antigen, whereas with the latter in most instances
`it has not been possible to correlate the cell-mediated
`responses with clinical drug hypersensitivity. In our case
`the lymphocyte transformation test disclosed sensitization
`to doxycycline. Nonintentional rechallenge with doxycy-
`cline occurred. Recurrence of the rash on this occasion per-
`mitted the most clear-cut correlation of the in vitro demon-
`strated cell-mediated immune response with clinical hyper-
`sensitivity to doxycycline. We believe this has demon-
`strated a drug-specific cell-mediated immune response as
`causative in our case of an acute generalized exanthema-
`tous pustulosis.
`
`Table 1. Differential diagnosis of acute generalized exanthematous
`pustulosis
`
`Subcorneal pustular dermatosis
`Generalized pustular psoriasis
`Impetigo herpetiformis
`Pustulosis acuta generalisata
`Pustular necrotizing angitis
`Pustular erythema multiforme
`Intraepidermal immunoglobulin A· pustulosis
`
`Table 2. Causative agents in acute generalized exanthematous
`pustulosis
`
`Cause
`
`Drugs
`Acetaminophen
`Acetazolamide
`Amoxicillin
`Ampicillin
`Bufexamac
`Carbamazepine
`Carbutamide
`Cefaclor
`Cefazoline
`Cefradine
`Cefuroxime
`Cephalexin
`Chloramphenicol
`Clobazam
`Cyclines
`Diltiazem
`Erythromycin
`Furosemide
`Hydroxychloroquine
`Nifedipine
`Penicillin
`Phenytoin
`Pipemidic acid
`Piperazine
`Pristinamycin
`Pyrimethamine
`Quinidine
`Roxithromycin
`Spiramycin
`Streptomycin
`Sulbutiamine
`Vancomycin
`Other causes
`Viral infection
`Mercury
`Food poisoning
`
`Reference
`
`7
`16
`6, 7
`7
`7
`2, 7
`7
`16
`13
`10
`3
`12
`1
`7
`7, 11
`14
`7
`1
`15
`7
`7
`8
`7
`1
`7
`1
`7
`7
`7
`9
`7
`7
`
`7, 17
`7
`3
`
`77
`
`Exh. 1038
`
`

`

`ooooooooooooeooooeoooooooooooooooooooooooooooooooooooooooooooooooooooaQooooooooooooooooooooooooaooooooooooooooooeooooooaoooooo
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`Tri.ieb/Burg
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`Exh. 1038
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