Harr and French Orphanet Journal of Rare Diseases 2010, 5:39


REVIEW Open Access

Toxic epidermal necrolysis and Stevens-Johnson
Thomas Harr*, Lars E French

Toxic epidermal necrolysis (TEN) and Stevens Johnson Syndrome (SJS) are severe adverse cutaneous drug reactions
that predominantly involve the skin and mucous membranes. Both are rare, with TEN and SJS affecting approxi-
mately 1or 2/1,000,000 annually, and are considered medical emergencies as they are potentially fatal. They are
characterized by mucocutaneous tenderness and typically hemorrhagic erosions, erythema and more or less severe
epidermal detachment presenting as blisters and areas of denuded skin. Currently, TEN and SJS are considered to
be two ends of a spectrum of severe epidermolytic adverse cutaneous drug reactions, differing only by their extent
of skin detachment. Drugs are assumed or identified as the main cause of SJS/TEN in most cases, but Mycoplasma
pneumoniae and Herpes simplex virus infections are well documented causes alongside rare cases in which the
aetiology remains unknown. Several drugs are at “high” risk of inducing TEN/SJS including: Allopurinol, Trimetho-
prim-sulfamethoxazole and other sulfonamide-antibiotics, aminopenicillins, cephalosporins, quinolones, carbamaze-
pine, phenytoin, phenobarbital and NSAID’s of the oxicam-type. Genetic susceptibility to SJS and TEN is likely as
exemplified by the strong association observed in Han Chinese between a genetic marker, the human leukocyte
antigen HLA-B*1502, and SJS induced by carbamazepine. Diagnosis relies mainly on clinical signs together with the
histological analysis of a skin biopsy showing typical full-thickness epidermal necrolysis due to extensive keratino-
cyte apoptosis. Differential diagnosis includes linear IgA dermatosis and paraneoplastic pemphigus, pemphigus vul-
garis and bullous pemphigoid, acute generalized exanthematous pustulosis (AGEP), disseminated fixed bullous drug
eruption and staphyloccocal scalded skin syndrome (SSSS). Due to the high risk of mortality, management of
patients with SJS/TEN requires rapid diagnosis, evaluation of the prognosis using SCORTEN, identification and inter-
ruption of the culprit drug, specialized supportive care ideally in an intensive care unit, and consideration of immu-
nomodulating agents such as high-dose intravenous immunoglobulin therapy. SJS and TEN are severe and life-
threatening. The average reported mortality rate of SJS is 1-5%, and of TEN is 25-35%; it can be even higher in
elderly patients and those with a large surface area of epidermal detachment. More than 50% of patients surviving
TEN suffer from long-term sequelae of the disease.

Background, disease name and synonyms ‘EM majus’ should not be used to describe SJS as they
Stevens-Johnson syndrome (SJS) was first described in are distinct disorders [1-4].
1922, as an acute mucocutaneous syndrome in two In 1956, Alan Lyell described four patients with an
young boys. The condition was characterized by severe eruption resembling scalding of the skin which he called
purulent conjunctivitis, severe stomatitis with extensive toxic epidermal necrolysis or TEN [4]. It was only as
mucosal necrosis, and purpuric macules. It became more patients with TEN were reported in the years fol-
known as SJS and was recognized as a severe mucocuta- lowing Lyell’s original publication, that it became clear
neous disease with a prolonged course and potentially that TEN was drug induced, and that certain drugs such
lethal outcome that is in most cases drug-induced, and as sulfonamides, pyrazolones, barbiturates, and antiepi-
should be distinguished from erythema multiforme (EM) leptics were the most frequent triggers of TEN. Increas-
majus. Recent clinical studies have shown that the term ingly to date, SJS and TEN are considered to be two
ends of a spectrum of severe epidermolytic adverse cuta-
neous drug reactions, differing only by their extent of
* Correspondence: thomas.harr@usz.ch
Department of Dermatology, University Hospital Zurich, Switzerland skin detachment.

© 2010 Harr and French; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.

entropion ment (erythema and erosions) of the buccal. Bas- TEN in a patient with severe aplastic anaemia after allo. and due other cases a cause could not be determined due to lack to its rarity in adults.89 cases of TEN per million inhabi. and ocular include symptoms such as fever. and. erosions) or tion of Herpes simplex under treatment with azithromy. Certain infectious diseases may cations [24]. Single case factor. severe dry of cutaneous involvement are the presternal region of the eyes (46% of cases). to 1. or concomitant radiotherapy more detailed skin examination should be performed by [11. Histological examination including direct immu- were reported in patients with AIDS compared to 0. Figure 1) [1]. blisters.9 cases of TEN per million inhabitants per year based cicatrizing lesions.12]. crusts. detachment. The severity of acute ocu- USA [6]. and have a tendency to approximately 1000-fold higher than in the general rapid coalescence (Table 1). to a lower extend staphyloccocal of data of drug intake or details [10]. which is already detached (e. large areas of epidermal detach- background of patients (HLA. Further. fornix foreshortening. The occurrence of in the evaluation of the extent of skin involvement. the coexistence of cancer. more. for example. erythematous zones (Nikolsky sign). as it can niae infections are widely documented to cause SJS and also be positive in. Herpes simplex virus was recognized in several The extent of skin involvement is a major prognostic cases of SJS. patients with TEN develop late ocular complications cede cutaneous manifestations by a few days. on all cases reported to the FDA AERS database in the and corneal ulceration [22. stinging eyes and dis. conjunctivitis. The above mentioned skin population. Regional differences in drug prescription. trichiasis (16%). erythema. but is not specific for TEN or SJS. nail dystrophies (37. with formation or corneal erosion. but also the palms and soles. According to a study of Yip et al. lagophthalmos (2%). 15 cases of SJS/TEN biopsy.5%). in severe cases. Ocular involvement at the SJS and TEN are rare diseases in absolute numbers with onset of disease is frequent. distichiasis (14%). and can range from acute an incidence of 1. It should be emphasized that only necrotic skin. 50% of comfort upon swallowing. ment develop. In another study only ten out of tant in order to rule out differential diagnoses such as 50 cases of SJS/TEN in HIV patients could be clearly autoimmune blistering diseases.5%). whereas in the tion. especially in children [16]. visual loss (5%). The morphology of early skin lesions have an impact on the incidence of TEN. autoimmune bullous TEN without initial exposure to drugs [13-15]. Early sites including. (14%). ankyloblepharon (2%).com/content/5/1/39 Epidemiology tracts are also affected [20. detachable skin (Nikolsky positive) should be included cine as potential causes of SJS [18]. tuji-Garin et al. and ocular tants per year reported for Western Germany and Berlin discharge. genital and/ (5%). and or ocular mucosa occurs in more than 90% of patients. However there are still cases of SJS/ (Table 1.and hypopigmentation of Stevens Johnson Syndrome (SJS) can be unspecific and the skin (62. Acute Phase According to the study of Magina et al [25] following Initial symptoms of toxic epidermal necrolysis (TEN) and symptoms are found: hyper.ojrd. can have an impact on the incidence of SJS exerting tangential mechanical pressure on several and TEN. to conjunctival membrane or pseduomembrane in 1996 [5]. TEN without any obvious identifiable cause. corneal ulceration (2%) [24]. other infections have occasionally is positive if mechanical pressure induces epidermal been reported as the sole cause. In a study of ger signs and warrant the initiation of rapid diagnostic HIV positive patients of the greater Paris area in the confirmation with immediate cryosections of a skin late eighties and early nineties. these symptoms pre. eyelid edema. symblepharon.04 nofluorescence analysis of the skin biopsy is also impor- expected cases [9]. The Nikolsky sign To a lesser extent. scalded skin syndrome. proposed classifying patients into three geneic haematopoietic stem cell transplantation has also groups according to the degree of skin detachment been reported [19]. reports describe Lupus erythematodes [17] or reactiva. acute generalized exanthematic pustulosis. with approximately 1 case per thousand per signs associated with mucosal involvement are clear dan- year in the HIV-positive population ([8]. symblepharon trunk and the face. Lower incidence rates were reported by Chan lar manifestation is not however predictive of late compli- et al in Singapore [7].21].g. Long-term complications . Typically. Involve. metabolizing enzymes). which may or clearly the case for HIV where the annual incidence is may not be slightly infiltrated. La Grenade et al report similar results.Harr and French Orphanet Journal of Rare Diseases 2010. bullous fixed drug erup- attributed to the use of medications. by order of decreasing frequency. skin diseases. Mycoplasma pneumo. Late phase and sequelae Clinical Features Sequelae are common features of late phase TEN. In the absence of epidermal detachment.23]. and this is includes erythematous and livid macules. complications. 5:39 Page 2 of 11 http://www. the genetic In a second phase. Hypertrophic scars are only and in some cases the respiratory and gastrointestinal seen in very few patients [26].

A genetic correla- Genetic factors associated with drug hypersensitivity are a tion could not however be shown in Japanese or complex issue that has been studied in different Europeans [33-35]. and and strong association between HLA. lamotrigine. This leads to the conclusion that this genetic constellation (HLA-B*1502) is not a population independent marker for SJS/TEN in carbamazepine exposed individuals. allopurinol) and another three high risk drugs (sulfamethoxazole. Subsequently. Arch Derm [34].Harr and French Orphanet Journal of Rare Diseases 2010. or NSAID’s of oxicam-type induced SJS/TEN nor a sufficient explana- tion for the cause of the disease in Europeans [35. 1993) of cases). in a large European study (RegiSCAR). lamotrigine. 5:39 Page 3 of 11 http://www. Another study confirmed the susceptibility of indivi- ing exocrine pancreatic impairment [29]. phageal mucosa. Indeed. to a lesser extent (lower odds ratio). This RegiSCAR study revealed that HLA-B*1502 is neither a marker for carbamazepine. and ten (adapted after 1) Clinical entity SJS SJS-TEN overlap TEN Primary lesions Dusky red lesions Dusky red lesions Poorly delineated erythematous plaques Flat atypical targets Flat atypical targets Epidermal detachment Dusky red lesions Flat atypical targets Distribution Isolated lesions Isolated lesions Isolated lesions (rare) Confluence (+) on face and Confluence (++) on face and Confluence (+++) on face.com/content/5/1/39 Table 1 clinical features that distinguish sjs. in patients of European origin [36]. 100% of Han Chinese patients with a severe adverse drug reaction to allopurinol were HLA-B*5801 positive [37]. trunk. et al. resembling Sjögren-like syndrome [28]. Severe cutaneous reactions in HLA-B*1502 subjects were not only associated with the drug carbamazepine. Indeed. A smaller Indian based study however showed Etiology and pathogenesis only a weak correlation between HLA-B*1502 and carba- Genetic susceptibility mazepine induced severe drug allergy. association with an odds ratio of 2504 led to further stu- tivitis or both. a strong association between SJS/ Figure 1 Pictural representation of SJS. with phenytoin and lamotrigine [31]. A unique present mucosal involvement in the acute phase. dies in a similar ethnical group of Hong Kong Han Chi- Additionally. HLA-B genotyping was performed in patients with severe cutaneous adverse reactions caused by the two previously mentioned drugs (carbamazepine. SJS and carbamazepine [30]. and to a lesser extent lung and genital who showed a strong association in Han Chinese between mucosa [27]. drug hypersensitivity the mucosal sequelae involve mainly the oral and oeso. . [31].9 Bolognia and Bastuji-Garin S. and also. and trunk trunk elsewhere Mucosal involvement Yes Yes Yes Systemic symptoms Usually Always Always Detachment (%body surface <10 10-30 >30 area) of mucosal involvement occur in 73% of patients who populations and a variety of ethnic backgrounds. NSAID’s of oxicam-type). This high of nine patients had either xerostomia or keratoconjunc. Thai patients [32]. SJS-TEN overlap and TEN showing the surface of epidermal detachment (Adapted TEN and HLA-B*5801 was found in Japanese patients from Fig 21. sjs-ten overlap.36].ojrd. duals with HLA-B*1502 to carbamazepine in a Thai popu- lation [32]. A second strong association between HLA genotype and SJS/TEN has been reported for allopurinol. another group reported a patient with nese with severe adverse reactions to antiepileptic drugs Sjögren-like pluriglandular exocrine insufficiency includ. to a lesser extent (55% 129: 92. and ethnic background was discovered by Chung et al. but also. sulfamethoxazole. In a small post SJS/TEN study seven out the HLA-B*1502.

allopurinol is the most the above ex-vivo demonstration of the lytic ability of common cause of SJS/TEN in Europe and Israel [52].41]. The find- tosis has however lead to the search for cytotoxic pro. How a culprit drug in a given patient who will that triggers keratinocyte apoptosis is supported by develop SJS/TEN regulates the function of these key research performed using an ex-vivo experimental set players is the subject of ongoing research. express common cutaneous leukocyte antigen (CLA) Gene expression analysis of blister fluid cells. lysis of blister fluid from patients with SJS/TEN has also were able to demonstrate that blister T cells from recently identified secretory granulysin (a cationic cyto- patients exert drug specific cytototoxic activity against lytic protein secreted by CTL’s. it is still not SJS/TEN when used over a short period of time: trime- fully understood what causes the up-regulation of FasL/ troprim-sulfamethoxazole and other sulfonamide- . and based on our knowledge to date. and levels of sFasL are consistently elevated when spread epidermal detachment observed in SJS/TEN. as a key molecule responsible for the induction of kera- cytes [42].immune with membarne bound FasL that can account for the reaction that causes SJS/TEN. ging an individual with the same drug can result in The role of soluble FasL (sFasL) in SJS/TEN remains rapid recurrence of SJS/TEN [38. recombinant granulysin mimicks features of with SJS/TEN and the overwhelming keratinocyte apop. FasL and granulysin as molecules responsible for the In conclusion.39].com/content/5/1/39 Pathomechanism of SJS/TEN Fas on keratinocytes. has been questioned by some as TEN. Drug exposure and a resulting hypersensitivity reaction tinocyte membrane FasL. the functional relevance of up-regulated kera.to date only incompletely understood . Roujeau et al. SJS/TEN when injected intradermally in mice. and most immune cells (including CTLs) in the skin of patients importantly. that however. nocytes as target cells. Italy and in vitro. These CD8+ T cells observed activity. keratinocyte FasL in TEN was limited in its effect on and mostly in patients receiving daily doses of at least lymphoid target cells and not demonstrated with kerati. 200 mg. and ana- and are negative for CD45RA and CD28. and the subse. serum granulysin levels being normal in upon cell-cell contact. The high levels of granulysin mRNA. of sFasL can be found in the serum of patients with SJS/ lowed by necrosis is the pathogenic basis of the wide. one study showed that sera of SJS/ the initiation phase. the strongest evidence the latter. The pathogenesis of SJS/TEN is not fully understood including T cells found in blister fluid at the onset of but is believed to be immune-mediated. SJS/TEN support the currently prevalent concept. Blister fluid cells express mediated cytotoxicity was mediated by granzyme B. lends further support an important role of suggests a key contribution of the cytotoxic molecules granulysin in SJS/TEN [51]. To date. CD8 T-cells as well as the cytolytic molecules FasL and The role of the membrane form of the death ligand granulysin are key players in the pathogenesis of SJS/ FasL and its cognate death receptor Fas in the signalling TEN.Harr and French Orphanet Journal of Rare Diseases 2010. cells of patients stimulated by the causative drug patibility (MHC) class-I restricted drug presentation excreted high levels of sFasL [50]. blister fluid contains mainly cytotoxic CD8+T sis and furthermore that peripheral blood monuclear lymphocytes [40.44]. reported interferon gamma.ojrd. very poorly cytolytic. Drugs However. histopathological and immunological findings in Soluble FasL as opoposed to membrane-bound FasL is. and this sensitivity can be further enhanced by Portugal between 1989 and 1993. The histopathology controversial. The analysis is performed preceding skin detachment [48]. Germany. and how the immune system. Nevertheless. 5:39 Page 4 of 11 http://www. It appears clear now that increased levels of SJS/TEN lesions show that keratinocyte apoptosis fol. Nassif et al. In absolute case numbers. It is well known that primary In a case control study of patients hospitalized for SJS/ keratinocytes are sensitive to the cytolytic effect of FasL TEN in selected hospitals in France. the protein is found in discrepancy between the paucity of the infiltration of increased concentrations in blister fluid. and furthermore demonstrated that this cell. as re-challen. up with TEN lesional skin biopsy cryostat section over- lays with Fas-expressing lymphoid target cells [44]. and thus its ability to induce is the cause of the very large majority of cases of SJS/ keratinocyte cell death. Indeed. noted that sera can contain small membrane vesicles quent . in the early phase of TEN were able to induce abundant keratinocyte apopto- disease. disease may regulate this. ing that elevated serum granulysin levels apparently dis- teins and/or cytokines that may “amplify” the extent of criminate between serious and non-blistering adverse keratinocyte apoptosis that CTLs alone could induce drug reactions. and it is therefore unli- SJS and TEN are specific drug hypersensitivity reactions kely to be a cause of keratinocyte apoptosis in TEN in which cytotoxic T lymphocytes (CTL) play a role in [49]. However. TEN. NK cells and NKT cells) both autologous B-lymphocyte cell lines and keratino. clinical. tinocyte death in TEN [43]. a cytokine known to be present in that the following drugs are at increased risk of inducing the skin during TEN [45-47]. disseminated keratinocyte apoptosis in SJS/TEN [43. suggesting that a major histocom. but it should be leads to clonal expansion of CD8+ CTLs.

com/content/5/1/39 antibiotics. more than 100 million inhabitants in which special including ocular. This simultaneously with skin signs in almost all cases. and sertraline. and Major differential diagnosis of SJS/TEN are autoimmune that the risk of developing SJS/TEN per 10 000 new blistering diseases. (SSSS). lamotrigine. that the in a multinational case-control study in Europe covering Nikolsky sign is not specific for SJS/TEN. An often addressed be determined so as to define the appropriate medical issue is the induction of TEN or SJS after vaccination. but the incidence is currently very developing SJS/TEN is highest when the drug has been low with 0.ojrd. aminopenicillins. sulfafurazole). Patients . Interestingly the long term use of glucocorticosteroids for a variety of Management and Therapy diseases does not change the incidence of the occur. In order to evaluate vaccine adverse event reporting system concludes that prognosis in patients with SJS/TEN. Furthermore. Mucosal. ment of blisters. phenobar. (paracetamol) [57]. carbamazepine. However the should be additionally performed and no immunoglobu- incidence of SJS/TEN under treatment with valproic lin and/or complement deposition in the epidermis and/ acid is confounded by the concomitant use of other or the epidermal-dermal zone should be detected. the validated despite the plausibility of a relationship between vaccination SCORTEN disease severity scoring system can be used and SJS/TEN.5). The incidence for val. were able to show that almost all cases of SJS/TEN developed Differential diagnosis within 63 days of starting use of antiepileptic drugs. weeks or more of administration [5. as well ting. SSSS was one of the most important differential studies in different populations indicate that the risk of diagnoses in the past.4 cases per 10 000 users [54]. tous pustulosis (AGEP). drugs. involvement develops shortly before or attention was given to newly marketed drugs [53].55]. on which a positive these drugs have a high relative risk compared to other Nikolsky sign can be induced by mechanical pressure on drugs. disseminated fixed bullous drug proic acid was low compared to other antiepileptic eruption and staphyloccocal scalded skin syndrome drugs with 0. The setting for further management. and subsequently declines within 8 per year [54]. Case reports exist for hydroxchloroquine [58]. but it Management in the acute stage involves sequentially appears that glucocorticoids lengthen the interval evaluating the severity and prognosis of disease.Harr and French Orphanet Journal of Rare Diseases 2010. distinguish SJS. However. lamotrigine (2. In order to rule out autoimmune phenytoin. tenoxicam). and NSAID’s of the oxicam. phenobarbital. 5:39 Page 5 of 11 http://www. SJS-TEN and TEN the surface area of as drugs with a significantly increased risk of inducing the detachment is the main discriminating factor (Figure SJS/TEN. valproic acid. sulfadiazine. Treatment in acute stage rence of SJS/TEN for the incriminated drugs. the actual risk remained low with 5 cases or less the skin. allopurinol and corticoster. the severity and prognosis of the disease should naproxene [59] and clobazam [60]. sulfonamides (sulfasalazine. Among drugs usually taken for cinations outweighs the potential risk of SJS/TEN [61]. longer periods of time (carbamazepine. phenytoin. however. non-steroidal antinflammatory Diagnosis and diagnostic methods drugs of the oxicam-type. A similar population was of epidermal detachment characterized by the develop- studied between 1997 and 2001 by Mockenhaupt et al. acute generalized exanthema- bital (8. and eventual “specific” drug therapy as described in as a possibly increased susceptibility to acetaminophen detail below. prompt between the beginning of the intake of the drug and identification and withdrawal of the culprit drug(s).13 cases per one million inhabitants recently initiated. ing wide spread necrotic epidermis involving all layers sulfadoxine. A recent survey of TEN in chil. Rapid evaluation of severity and prognosis Photo-induced TEN or SJS are only reported in very rare As soon as the diagnosis of SJS or TEN has been estab- cases. blistering diseases. It should be noted. Older drugs identified as having a high risk of 1). during the first 2 months of treatment with a sharp Typical clinical signs initially include areas of erythema- drop of incidence thereafter [8]. phe- nobarbital. rapidly initiating supportive care in an appropriate set- dren identified similar drugs to those in adults. followed within minutes to hours by the onset per million users per week. including linear IgA dermatosis and users was significantly increased for carbamazepine paraneoplastic pemphigus but also pemphigus vulgaris (1. allopurinol.1) and phenytoine (8. such as lamotrigine [5]. The diagnosis relies on the one hand on clinical symp- oids). the highest risk of induction of SJS/TEN occurs toms and on the other hand on histological features. Mockenhaupt et al.4 cases per 10 000 users). lished. quinolones to the large amount of vaccinations and the benefits of vac- and chlormezanone. confirms the diagnosis. direct immune fluorescence staining type (meloxicam. although tous and livid macules on the skin. and bullous pemphigoid. Histological work up of immediate cryosections or inducing SJS/TEN were sulfamethoxazol/trimethoprim conventional formalin-fixed sections of the skin reveal- (SMX/TMP).3).09 and 0. the very small number of reports compared (see section devoted to prognosis and Table 2). cephalosporins. piroxicam. onset of SJS/TEN [56]. To study identified nevirapine.

Harr and French Orphanet Journal of Rare Diseases 2010. various dose regi- USA [65].2 Malignancy Yes = 1. earlier the causative drug is withdrawn. Unfortunately. other appropriate sources such as the Litt’s drug erup.8 Initial surface of epidermal detachment >10% Yes = 1. Appropriate early and aggressive replace- Prompt withdrawal of causative drugs should be a prior. Drug Therapy The chronology of administration of a culprit drug.was significantly methasone) may be of benefit [68]. In the absence of strong evidence of SJS/TEN is a life threatening condition and therefore efficacy. a medication with known anti-TNFa A single center retrospective study on the outcome of activity that is immunomodulatory and anti-angiogenetic patients after admission to a burn center identified sep. sis at the time of admission as the most important nega. have shown that the quently occur. Wounds should be treated conservatively. No = 0 with a SCORTEN score of 3 or above should be mana. followed by age. important on an individual basis. but lose significance in . higher in patients who were transferred to a burn unit a recent retrospective case-control study conducted by within 7 days after disease-onset compared with patients Schneck et al. 80 mL per hour with 0.8% vs 51. although no benefit has been proven in Supportive Care controlled trials. ment therapy is required in case of hyponatraemia. dressing which likely favors re-epithelialization.4% (p < 0. the early 1990’s. No = 0 >5 90 Serum glucose >14 mmol/l Yes = 1. in France and Germany concluded that admitted after 7 days (29. .com/content/5/1/39 Table 2 SCORTEN severity-of-illness score SCORTEN Parameter Individual score SCORTEN (sum of individual scores) Predicted mortality (%) Age > 40 years Yes = 1. sequence of the discovery of the anti-Fas potential of A critical element of supportive care is the manage. randomised.High-dose intravenous immunoglobulins. Garcia-Doval et al.Systemic steroids were the standard treatment until tion reference manual [63]. No = 0 2 12. showed that survival rate .Thalidomide. the better the without skin debridement which is often performed in prognosis. pooled human intravenous immunoglobulins (IVIG) in ment of fluid and electrolyte requirements. a specific therapy for SJS/TEN that has shown time between first administration and development of efficacy in controlled clinical trials unfortunately does SJS/TEN. No = 0 0-1 3. ity when blisters or erosions appear in the course of a hypokalaemia or hypophosphataemia which quite fre- drug eruption. No = 0 4 58.05)). .1 Tachycardia (>120/min) Yes = 1. 5:39 Page 6 of 11 http://www. is between 1 and 4 weeks in the majority of not exist. and to a lesser controlled study higher mortality was observed in the extent the percentage of total body surface area thalidomide-treated group suggesting that thalidomide is involved. No = 0 3 35. in a double-blind. and consider the chronology of administration of the drug topical sulfa containing medications should be avoided. IVIG have been tested for the treatment of . or To date. Intravenous vitro [44]. their use has become increasingly disputed. Several treatment modalities given in addition cases. No = 0 Bicarbonate >20 mmol/l Yes = 1. and that patients exposed to causative drugs burn units.inde. A multicenter study conducted in the ment of short versus long duration. fluid should be given to maintain urine output of 50 - ged in an intensive care unit if possible. placebo- tive prognostic factor. On the other hand. This corticosteroids did not show a significant effect on mor- positive association of early referral and survival has tality in comparison with supportive care only [69]. 199 admitted patients. and due to the confusion resulting from the supportive care is an essential part of the therapeutic numerous steroid treatment regimens reported (treat- approach [64]. The reported ability or likelihood of a drug be the to supportive care are reported in the literature and cause of SJS/TEN can be found in Pubmed/Medline or these are discussed below. has been evaluated for the treatment of TEN [70.3 Serum urea >10 mmol/l Yes = 1. As a con- presence of other factors [67].ojrd. as blistered skin acts as a natural biological with long half-lives have an increased risk of dying [62].71]. and including 15 regional burn centers with mens). been confirmed in other studies [27. Co-morbidities and the use of steroids may be detrimental in TEN.5% NaCl supplemented with 20 Prompt withdrawal of culprit drug(s) mEq of KCl.66]. A recent retrospective monocenter study suggests that a pendent of the severity of disease (APACHE-score and short course “pulse” of high dose corticosteroids (dexa- TBSA = Total body surface area) . Non- In order to identify the culprit drug(s) it is important to adhesive wound dressings are used where required. and the reported ability of the drug to induce SJS/TEN.

Given the favourable side-effect geting the proinflammatory cytokine TNFa has been .89]. as well as the exclusion of 2 stu. All except one study [72]. Valeyrie-Allanore L conducted an open. followed by CsA showed a stop in disease progression tality and total IVIG dose after controlling for age and within 72 h [87]. and 26 completed the treatment with CsA increase in IVIG dose. heterogeneous diagnostic definitions and phase II trial to determine the safety and possible bene- methods of each study.TNF antagonists. and fewer patients with which the dose of IVIG administered was reported for multi-organ failure and death were observed [86]. IgA deficiency. fit of ciclosporin [90]. is an [44. Other single case reports also reported affected body surface area [83]. analyzed the published literature between 1992 Patients treated with CsA had significantly shorter time and 2006.8 2 — 3.3) Predicted mortality 33 — — 35 — 38 * — 35.7-2.(%) 44 39 45 49 58 “65” — — “44” 19 49 — Total dose IVIG (g/kg) 4 3 3 2 2-5 2. have performed a study as a case be of greater benefit than doses of 2 g/Kg or less.1).74-82]. with each 1 g/Kg 7 TEN). confirm the treatment of toxic epidermal necrolysis. and their effect reported in different non.9 (0. each patient. given known excellent tolerability and a low toxic potential of the absence of other validated specific therapeutic IVIG when used with appropriate precaution in patients alternatives. Twenty-nine patients were dies owing to lack of individual IVIG dosing data. 12 SJS-TEN overlap and tic regression results showed that. although each study has its potential has also been applied in a few children with SJS/TEN.Ciclosporin (CsA). thrombo-embolic risk) [73].3 2 1.8 36 24 28. 5:39 Page 7 of 11 http://www. biases and the 12 studies are not directly comparable. To date. selected all studies performed in adults in to complete re-epithelialisation. which was statistically significant. and performed a initially with high-doses of intravenous dexamethasone multivariate logistic regression analysis to evaluate mor. with potential risk factors (renal insufficiency. a calcineurin-inhibitor. and notably the mortality was zero percent useful for the treatment of TEN. A new therapeutic approach tar- kg total dose of IVIG. profile of IVIG and the data existing to date. Analysis of studies published (Table 3). et al. numerous case reports and authors’ opinion early administration of high-dose 12 non-controlled clinical studies containing 10 or more immunoglobulin (3 g/kg total dose given over 3-4 days) patients have analyzed the therapeutic effect of IVIG in should be considered alongside supportive care for the TEN (Table 3). tion bias. The prognostic score predicted 2.69. ciclosporin may be lower doses.Harr and French Orphanet Journal of Rare Diseases 2010. 9 and two non-controlled studies suggest a possible bene- of the 12 studies suggest that there may be a benefit of fit [84. CsA.com/content/5/1/39 Table 3 Summary of studies concerning IVIG for TEN Trent Viard Prins Campione Al-Mutairi Shortt Tan Stella Rajaratnam Bachot Brown Schneck 2003 1998 2003 2003 2004 2004 2005 2007 2010 2003 2004 2008 (80) (44) (73) (76) (74) (78) (79) (82) (81) (72) (75) (69) Study design Retro Prosp Retro Prosp Prosp Retro Retro Retro Retro Prosp Retro Retro N/ N/ N/ N/ N/ N/ N/ Cont N/ N/ N/ Cont Cont Cont Cont Cont Cont Cont Cont Cont Cont Cont Patients 24 10 48 10 12 16 12 23 14 34 24 75 Detachm.85]. included in the trial (10 SJS. over a month. Arevalo et al. there was a 4.75 Patients treated with high doses of IVIG had a signifi. To series with two treatment arms: CsA alone versus cyclo- determine if a dose response relationship exists. cardiac The concomitant administration of corticosteroids or insufficiency. Although this study has a positive effect of the use of CsA in TEN [88. Recently.ojrd. high-dose IVIG on the mortality associated with TEN . deaths and none occurred (p = 0. suggesting that.72.6 1. IVIG Taken together. logis. limitations stated by the authors and including publica.6 25 (SCORTEN/APACHE*) in % Actual mortality in % 4 0 12 10 0 25 8 26 21 32 41. in the controlled studies.7 34 TEN. Trent phosphamide in combination with corticosteroids. in the subset of 30 patients treated with more than 3 g/ . cantly lower mortality compared with those treated with although not statistically significant. efficient drug in transplantation and autoimmune dis- suggests that total IVIG doses of more than 2 g/kg may eases. immunosuppressive agents remains controversial.2-fold increase in administered orally (3 mg/kg/d for 10 days) and tapered TEN patient survival. excluded cases appearing as duplicates in A small case series with three TEN patients treated separate publications where possible.

Visual age reported mortality rate of SJS is 1-5%. [64]. genital. which compared their case tine diagnostic option at the moment.com/content/5/1/39 proposed by Hunger et al. several drugs are possible candidates and allergological quent death of the patient. Induction of SJS/TEN ted. pulmon. Novel in vitro methods to help ment of sequelae should be interdisciplinary. but the power of et al. Yip et al. in conjunction with high-dose on ex vivo/in vitro tests. although two case reports allow a conclusion as to the potential of this approach describe intradermal testing without triggering of a sec- to be drawn due to the small number of patients trea. serum glucose. In order to standardize the evaluation of risk and plications have an inflammatory background and have prognosis in patients with SJS/TEN.105]. it can be even higher in elderly patients and who receive specific ophtalmological treatment during those with a large surface area of epidermal detachment the first week of disease [23]. larger studies are needed to clarify these prelimin. hypersensitivity [109]. Unfor- ary results with a special attention to potential side tunately the sensitivity of the LTT is still very low in effects. A small single retrospective study body surface area of epidermal detachment.ojrd. Special identify culprit drug in SJS/TEN are still needed [110]. tachycardia.101] and three cases with an overlap of acute generalized may require laryngectomy. exanthematous pustulosis and TEN and treatment response to infliximab [92]. Treatment of sequelae Another recently reported approach looks for up-regu- Due to the often combined involvement of the skin. but not a rou- using PE by Furubacke et al.103]. been documented following local eye or combined treatments. not allow re-challenge and intradermal testing with the . gastrointestinal. different scoring to be treated occasionally with ophthalmic steroids and/ systems have been proposed. serum urea. CPP has been studied in patients had a relevant positive patch test [106]. attention should be given to the prevention of ocular complications. 5:39 Page 8 of 11 http://www. dry- (infliximab 5 mg/kg) and reported that disease progres. with patch testing in SJS/TEN. patients allergic to beta-lactam antibiotics [107]. Yun plications in frequency and severity. initial neal transplantation. enstein et al. phocyte stimulation in vitro as a sign of drug ary. have evaluation of disease severity [112]. and of TEN outcome is reported to be significantly better in patients is 25-35%. has shown that low sensitivity is a problem showed no difference in terms of mortality [96]. for example. SJS/TEN even if performed within one week after onset of the disease [108]. . lowing parameters: age. PE has also culprit drugs due to the feared risk of re-inducing a sec- been tried in SJS/TEN. Early referral to an ophthalmologist is Prognosis mandatory for assessment of the extent of eye involve. Hypopharyngeal stenosis combined sion stopped within 24 hours followed by a complete with dysphagia and oesophageal strictures are long-term re-epithelialisation within 5 days [91]. SJS and TEN are severe and life-threatening.Plasmapheresis/plasma exchange (PE). however. a small single retrospective study Patch-testing is an investigational option. Allergological testing ble TNFa Receptor Etanercept 25 mg on days 4 and 8 A detailed drug history is very important when striving after onset of TEN in a single case resulted in cessation to identify the culprit drug in SJS/TEN. with IVIG showed no significant effect on ocular com. small case series. In some cases of epidermal detachment within 24 hours but subse. The benefit of local antibiotic (LDH) may be an additional useful parameter in the treatment (ointments) is not clear. and bicarbonate (Table 2) [111]. Although a beneficial test (LTT). or alone [98]. They treated one patient with reported that the use of local antibiotic treatment leads a single dose of the chimeric anti-TNFa antibody to more late complications. testing can be of help in identifying the most likely can- rently insufficient to draw a conclusion on the didate. reported recently that lactate dehydrogenase the study was weak [99]. the follow up and treat. report complications which are difficult to treat [100. Meiss et al. the frequent confounding factors including different has. The SCORTEN is now the or extensive lubrication of the eye [26] in order to pre. ond episode of TEN [102. The aver- ment and prompt treatment with topical steroids. ness of the eyes [24]. but the current data does not ond episode of SJS/TEN. eyes lation of CD69 on T-lymphocytes two days after lym- and mucous membranes (oral. Furthermore.Cyclophosphamide (CPP).. the severity of SJS and TEN does therapeutic potential of TNF antagonists in TEN. and other potential biases treatment [104. most widely used scoring system and evaluates the fol- vent progression leading ultimately to the need for cor. as well as urinary). either in combination with other treat. that measures the proliferation of T cells to effect of CPP is suggested by the authors of these small a drug in vitro has shown a sensitivity of 60-70% for trials.Harr and French Orphanet Journal of Rare Diseases 2010. The published data is cur. Administration of the solu. as only two of 22 tested . The lymphocyte transformation corticosteroids [97]. [93-95]. In principle. including. Some of the ocular com. Data from Wolk- series with two published case series serving as controls. malignancy. Currently the focus of allergological testing lies more ments such as CsA [86].

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