Syndrome de Lyell Approche diagnostique. seminaires iris. Veronique del Marmol Alexandre Chamoun Service de Dermatologie Hôpital Erasme.

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1 Syndrome de Lyell Approche diagnostique Veronique del Marmol Alexandre Chamoun Service de Dermatologie Hôpital Erasme Serge Jennes Hôpital Militaire

2 Rash benign

3 Pustulose exanthematique Aigue et généralisée AGEP Benign versus severe DRESS

4 Benign versus severe?

5 Versus severe rash

6 Drug induced Rash The skin is one of the most common targets for adverse drug reactions To determine the cause of the eruption, a logical approach based on clinical characteristics, chronologic factors and a literature search is required Exanthematous eruptions and urticaria are the two most common forms of cutaneous drug reactions

7 Viral versus Drug induced exantheme Viral infection is the most important differential diagnosis. Drugs were responsible for 25% of the exanthems (more commonly in adults) of which antibiotics and NSAIDs were most frequently implicated. It is useful in differentiating exanthematic drug eruptions from viral exanthems to remember that viral rashes tend to start on the face and acral sites with subsequent progression to involve the trunk, and are more often accompanied by fever, sore throat, gastrointestinal symptoms, conjunctivitis, cough and insomnia. Pruritus is typically associated with drug causes in adults.

8 Viral exanthemes

9 Clinical characteristics Type of primary lesion (e.g. urticaria, erythematous papule, pustule, purpuric papule, vesicle or bulla) Distribution and number of lesions Mucous membrane involvement, facial edema Associated signs and symptoms: fever, pruritus, lymph node enlargement, visceral involvement

10 Chronological factors Document all drugs to which the patient has been exposed and the dates of administration Date of eruption Time interval between drug introduction (or reintroduction) and skin eruption Response to removal of the suspected agent Consider excipients (e.g. soybean oil)

11 Benign drug eruption The latency from drug initiation to onset of rash ranges from 5 to 21 days, but typically occurs at 7 10 days. A drug induced exanthem may be accompanied by pruritus. The clinical features are variable; lesions may be scarlatiniform, rubelliform or morbilliform, or may consist of a profuse eruption of small pink papules showing no close resemblance to any infective exanthem. There is a broad spectrum of phenotypes encountered in cutaneous adverse reactions and many can mimic other inflammatory rashes. Rarely, drug hypersensitivity dermatoses can be life threatening and involve internal organs; however, most eruptions are mild, affect the skin only and are self limiting on drug withdrawal. These disorders can be considered as the benign cutaneous adverse reactions

12 Alerting Clinical features Clinical features that can alert the clinician to the possibility of a more severe drug-induced eruption include edema of the face or a marked peripheral blood hypereosinophilia (suggestive of DRESS [DIHS]) mucous membrane lesions or painful or dusky skin, which may announce TEN or SJS

13 Drug reactions including Severe drug reaction acute generalized exanthematous pustulosis (AGEP), Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) Are severe cutaneous adverse reactions to drugs acknowledged to be dominantly T cell mediated

14 Immunologically Mediated Drug Reactions IgE-dependent drug reactions (formerly type I, Gell Coombs classification): urticaria, angioedema and anaphylaxis. Cytotoxic drug-induced reactions (antibody against a fixed antigen; formerly type II): petechiae secondary to drug-induced thrombocytopenia. Immune complex-dependent drug reactions (formerly type III): vasculitis, serum sickness and certain types of urticaria. Possible delayed-type, cell-mediated drug reactions (formerly type IV; sometimes not well defined) exanthematous, fixed and lichenoid drug eruptions, as well as Stevens Johnson syndrome (SJS) and TEN.

15 Forms of type 4 hypersensitivity reaction: mechanisms and clinical correlations Adapted from Pichler, 2007 Rook textbook of dermatology, 9th edition, 2016

16 Drug reaction Immunologically Mediated Drug Reactions Non-immunologic Mechanisms Overdose Pharmacological effects Cumulative toxicity Delayed toxicity Drug-drug interctaction Alteration in metabolism Exacerbation of disease Idiosyncratic with Possible Immunologic Mediation

17 Idiosyncratic with Possible Immunologic Mediation Idiosyncratic drug eruptions represent reactions that are unpredictable and cannot be explained on the basis of the pharmacologic properties of the drug. Reactive metabolites of drugs can bind covalently to proteins, and the altered protein, considered as foreign, then induces an immune response. However, the way in which a drug is metabolized into a reactive species (or fails to be metabolized) differs in nature and amount depending upon the patient s specific metabolic pathways. These variations are genetically influenced

18 Idiosyncratic with Possible Immunologic Mediation Examples would be the increased incidences of the procainamideinduced systemic lupus syndrome and sulfonamide-induced TEN in slow acetylators as opposed to rapid acetylators. In addition, certain HLA alleles increase the risk of adverse drug reactions, e.g. the association of HLA-B*5701 with hypersensitivity reactions to abacavir and HLA B*1502 with SJS/TEN in Han Chinese. The pathophysiology of drug-induced skin reactions such as exanthematous drug eruptions, DRESS (DIHS), acute generalized exanthematous pustulosis (AGEP) and TEN, as well as the increased susceptibility of HIV-infected patients, may be partially explained by an interplay between immune mechanisms and genetic predisposition.

19 HLA and drug reactions The association of drug induced adverse reactions with particular HLA alleles is increasingly well recognized

20 Erythema Multiform vs SJS-TEN It has now become clear that Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are variants within a continuous spectrum of adverse drug reactions, Whereas erythema multiforme (EM) is a distinct disorder with different clinical signs and precipitating factors, e.g. herpes simplex virus (HSV) infections. Therefore, EM will be discussed separately from SJS and TEN.

21 The characteristic elementary skin lesion of EM is the typical target lesion. The latter measures <3 cm in diameter, has a regular round shape and a well-defined border, and it consists of at least three distinct zones, The vast majority of lesions appearing within 24 hours Erythema Multiform- Target lesions favor acrofacial sites, but the palms, neck, face and trunk are common locations as well. Involvement of the legs is seen less frequently. EM lesions may also appear within areas of sunburn

22 Erythema Multiform- Minor and Major Erythema multiforme minor: typical and/or occasionally atypical papular target lesions with little or no mucosal involvement and no systemic symptoms Erythema multiforme major: typical and/or occasionally atypical papular target lesions with severe mucosal involvement and systemic features A preceding HSV infection is the most common precipitating factor; occasionally, there are other preceding infections or, rarely, drug exposure Diagnosis of erythema multiforme requires clinicopathologic correlation and is not based solely on histologic findings Erythema multiforme does not carry the risk of progressing to toxic epidermal necrolysis

23

24 Erythema multiform-infection

25 Erythema multiform drugs and others

26 Erythema Multiform- SJS-TEN Differentiation of SJS from erythema multiforme major (EMM) is difficult: In both EMM and SJS, there is mucous membrane involvement and cutaneous blistering with epidermal detachment of less than 10% body surface area (BSA). However, in EMM the lesions consist of typical targets or raised atypical targets, predominantly localized on the limbs and extremities; in SJS, the lesions are atypical targets with predilection for the torso.

27 SJS-Lyell (TEN) Lyell? Rare! 1,89 case for 1 million

28 Etiology : drugs! Risque Excès de risque b relatif Sulfamides antibactériens 172 4,5 Triméthoprime-sulfaméthoxazole 160 4,3 Aminopénicilline 6,7 0,2 Quinolones 10 0,3 Céphalosporines 14 0,4 Tétracyclines 8,1 0,2 Phénobarbital a 45 1,2 Carbamazépine a 90 2,5 Phénytoïne a 53 1,5 Acide valproïque a 25 0,7 AINS oxicams a 72 2,0 Allopurinol a 52 1,5 Chlormézanone a 62 1,7 Corticoïdes a 54 1,5 [a] MÉDICAMENT PRIS PENDANT UNE DURÉE INFÉRIEURE OU ÉGALE À 2 MOIS. [b] NOMBRE DE CAS DE LYELL ATTRIBUABLES À UN MÉDICAMENT PAR MILLION D'UTILISATEURS EN 1 SEMAINE.

29 Physiopathogeny The keratinocyte, major target and actor - The target is the keratinocyte, and more specifically the multistratified epithelium, keratinized or not. Oral cavity, larynx, conjoncitiva, but also trachea and bronchial tree The Continundrun of toxic epidermal necrolysis. G Pierard, P Paquet, S Jennes, C Franchimont The noval biomedical, 2015-Nova Sciences publishers, Inc -White K, Chung WH, et al, J Allergy Clin Immunol, 2015

30 Physiopathogeny Exfoliation is due to extensive death of keratinocytes via apoptosis; Appears to be a MHC-I restricted specific drug sensitivity resulting in clonal expansion of CD8 cytotoxic Lymphocytes The latter is mediated via the cytotoxic secretory proteins perforin granzyme and granulysin, and interaction of the death receptor ligand pair Fas FasL Fas Ligand is likely to be particularly important, and TNF contributes via the TNF receptor

31 Clinical diagnosis? Mucosal involvment Nikolski Sign Atypical targets Purpuric macules Palmoplantar lesions Confluent erythema

32 Nikolsky sign In SJS/TEN, lesional necrolytic epidermis readily peels back to reveal the dermis

33 There are multiple discrete red macules each has a darker centre and a slightly paler outer ring Atypical targets

34 The dusky, purpuric lesions on this patient's skin are coalescing and blistering. Purpuric macules

35 Palmo plantar lesions Palmoplantar involvement. Multiple circular lesions are present on(a) the palms and (b) the soles. Blistering is occurring at both sites, but prominently on the feet.

36 Confluent erythema. Individual lesions may coalesce to form large areas of erythema, Confluent Erytema

37 Mucosal involvment Eye eyelid oedema, conjunctivitis and keratitis Urogenital symptoms During the acute phase, urogenital pain is prominent and urinary dysfunction (dysuria or retention) is common.

38 Mucosal involvment Lips oral cavity oropharynx,

39 Clinical manifestations Brutal opening with Non specific symptoms: Pseudo-grippal syndrom which can appear before cutaneous symptoms Mucosal symptoms that appears first (90%) : Erosions/ulcérations which appears 1 to 3 days before cutaneous manifestations for 1/3 of the patients Cutaneous manifestation : confluent macular rash in the presternal region and the face appearing in 2 to 5 days with vesiculae and flat bullae ( sign of the wet laudry) wet Nikolsky sign The association of cutaneous rash and mucosal symptoms should induce an urgent histological confirmation! Harr T and French L, Orphanet, J of Rare Diseases, 2010, S: 39

40 Diagnostic procedure Classical histology? Histology with immediate cryosection? Classical histology, with cryosection and direct immunofluresence?

41 Diagnostic procedure Classical histology? Biopsy with immediate cryosection? Classical histology, with cryosection and direct immunofluorescence

42 Diagnostic procedure Histology with immediate cryosection : skin biopsy sample sent on physiological serum that will be immediately preceded on the cryo section Classical histology : a good sample and be able to identify the infiltrate Direct immunofluresce : to complete the differential diagnosis

43 Differential diagnosis SJS and TEN should also be distinguished from dermatoses such as Staphylococcal scalded skin syndrome, Generalized fixed drug eruption, drug-induced Linear IgA bullous dermatosis, Toxic erythema of chemotherapy, and acute generalized exanthematous pustulosis, As their management and prognosis are also quite different.

44 SJS SJS-TEN- TEN

45 Prise en charge: Arbre décisionnel d après Mo Ellis MW et al. Mil Med 2002;167:701-4

46 Historique!! Beningn rash versus severe Approche clinique-diagnostique Antecedents? Début de la localisation du rash, Type de rash? Aspect circiné? Pustules, fragilité cutanée? Atteinte muqueuse,..? Origine infectieuse? virale? les identifier via l anamnese, vérifier la présence de vésicules,..herpes? Mycoplasme? Médicaments? Même occasionnels, infections précédemment? Signes généraux? Fièvre, arthralgies, état général Biologie : lymphocytose, éosinophilie, atteinte hépatique,..