stevens-johnson syndrome part 1

8/19/2019 Stevens-Johnson Syndrome PART 1

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24/2/2559 Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis

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Official reprint from UpToDatewww.uptodate.com ©2016 UpToDate

AuthorsMilton H Nirken, MDWhitney A High, MDJean-Claude Roujeau, MD

Section EditorsN Franklin Adkinson, Jr, MDMoise L Levy, MD

Deputy Editor Rosamaria Corona, MD, DSc

Stevens-Johnson syndrome and toxic epidermal necroly sis: Pathogenesis, clinical manifestations, and diagnosis

All topics are updated as new evidence becomes avail able and our peer review process is complete.Literature review current through: Jan 2016. | This topic last updated: Aug 20 , 2015.

INTRODUCTION AND TERMINOLOGY — Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe mucocutaneous reactions, most commonlytriggered by medicati ons, characterized by extensive necrosis and detachment of the epidermis. According to a widely accepted classification, SJS and TEN are consideredvariants of a disease continuum and are distinguished chiefly by severity, b as ed upon the percentage of body surface involved with blisters and erosions ( table 1 ) [1,2 ]:

We will use the term "SJS/TEN" to refer collectively to SJS, TEN, and SJS/TEN overlap syndrome.

The pathogenesis, clinical manifestations, and diagnosis of SJS/TEN are discussed in this topic. Treatment, prognosis, and long-term complications are discussed separately.Oth er drug eruptions are reviewed elsewhere.

EPIDEMIOLOGY — Estimates of incidence for Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS/TEN overlap range from two to seven cases per million people per year [ 3-7]. SJS is more common, outnumbering TEN by as much as three cases to one [ 8]. The incidence of SJS/TEN is approximately 100-fold higher amongHIV-infected individuals than in the general population [ 9]. SJS/TEN can occur in patients of any age. It is more common in women than in men, with a male to female ratio of 0.6[10].

The overall mortality rate among patients with SJS/TE N is a pproximately 30 percent, ranging from approximately 10 percent for SJS to more than 30 percent for TEN. Mortalitycontinues to increase up to one year after disease onset.

In a survival analysis of a large cohor t of SJS/T EN patients, the overall mortality rate was 23 percent at six weeks, 28 percent at three months, and 34 percent at one year [ 10].Wh en distinguish ing patients by severity, the mortality rates at six weeks were 12 percent for SJS, 29 percent for SJS/TEN overlap, and 46 percent for TEN and increased at oneyea r to 24 perc ent for SJS, 43 per cent for SJS/T EN overlap, an d 49 percent fo r TEN. Older age (>70 years) and presence of severe comorbidities, but not disease severity, wereassociated with mortality beyond three months of disease onset. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-termsequelae" .)

ETIOLOGY

Drugs — Medications are the leading trigger of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in both adults and children. The risk of SJS/TEN seems to belimited to the first eight weeks of treatment. Drugs used for a longer time are unlikely to be the cause of SJS/TEN. Approximately 20 to 25 percent of cases and probably an evenhigher proportion of pediatric cases cannot be clearly attributed to a drug [ 11 ].

In a large multinational case-control study including 379 cases of SJS/TEN and 1505 controls, the following agents or groups of agents were most commonly implicated ( table 2 )[12,13 ]:

In children, the medications most often associated with SJS/TEN are sulfonamide antimicrobials, phenobarbital , carbamazepine , and lamotrigine . An association withacetaminophen /paracetamol has also been reported [ 14,15 ].

Infection — Mycoplasma pneumoniae and cytomegalovirus infections are the next most common trigger of SJS/TEN, particularly in children [ 16-19 ]. A review of case series andsingle-case reports suggests that M. pneumoniae -associated cases may be characterized more often by moderate to severe involvement of two or more mucosal sites and sparseor even absent skin involvement [ 20]. Between September and November 2013, an outbreak of eight pediatric cases of M. pneumoniae -associated SJS/TEN was reported inColorado, likely related to high levels of M. pneumoniae infection in the region [ 21]. At least seven more cases of SJS occurred in the same area in the first months of 2014 [ 22]. Allchildren had severe oropharyngeal mucositis, seven also had conjunctival involvement, and five genital mucosal involvement. Mild skin involvement was present in all cases.However, it is uncertain whether M. pneumoniae -associated mucositis with minimal or no skin involvement represents an atypical SJS variant or is a distinct entity [ 23,24 ].

Other — Rare causes of SJS/TEN include vaccinations, systemic diseases, contrast medium, external chemical exposure, herbal medicines, and foods [ 2,25,26 ]. Cases of SJS/TEN have been reported after bone marrow transplantation. Radiotherapy in addition to treatment with antiepileptic drugs (eg, phenytoin , phenobarbital , carbamazepine ) or amifostine can trigger SJS/TEN, with lesions localized predominantly at sites of radiation treatment [ 27 ].

PREDISPOSING FACTORS — Risk factors for Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) include HIV infection, genetic factors, underlying immunologicdiseases, and possibly physical factors.

HIV infection — Patients with HIV infection have been reported to have 100-fold higher risk of SJS/TEN than the general population [ 9]. The reasons for this susceptibility are notfully understood, although exposure to multiple medications, polymorphisms of genes involved in drug metabolism, immune dysregulation, and the presence of concomitantinfections may contribute [ 28-32 ].

Genetic factors — Genetic factors associated with an increased risk of SJS/TEN include the following:

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SJS is the less severe condition, in which skin detachment is 30 percent of the body surface area ( picture 2A-D ). Mucous membranes are involved in the majority of cases.●

S JS/TEN overlap describes patients with skin detachment of 10 to 30 percent of body surface area.●

(See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, pro gnosis, and long-term sequelae" .)●(See "Drug reaction with eosinophilia and systemic symptoms (DRESS)" .)●(See "Acute generalized exanthematous pustulosis (AGEP)" .)●(See "Exanthematous (morbilliform) drug eruption" .)●(Se e "Fixed drug eruption" .)●(Se e "Lichenoi d drug eruption (drug-induced lichen planus)" .)●(Se e "Acneiform eruption secon dary to epidermal growth factor receptor (EGFR) inhibitors" .)●

Allopurinol● Aromatic anticonvulsants● Antibacterial sulfonamides●Lamotrigine●Nevirapine●Oxicam NSAIDs●

Certain HLA-types (table 3 ) – Patients with HLA-B*15:02 phenotype are at increased risk for SJS/TEN due to carbamazepine and other aromatic anticonvulsants (eg,phenytoin , phenobarbital ). The prevalence of this allele is significant, approximately 7 to 10 percent, in patients of Asian and South Asian ancestry.

●

Genome-wide studies have also found an association between the HLA-A*31:01 allele and carbamazepine -induced severe cutaneous drug reactions, including SJS/TEN, inJapanese and in persons of European descent [ 33,34 ]. However, a subsequent multinational study and meta-analysis found that HLA-A*31:01 is strongly associated withcarbamazepine-induced drug reaction with eosinophilia and systemic symptoms (DRESS) in European and Asian patients, but shows only a weaker association withSJS/TEN [ 35].

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Genetic screening — The US Food and Drug Administration has suggested screening patients of Asian and South Asian ancestry for HLA-B*15:02 if use of carbamazepine isunder consideration [ 43-46 ]. One consensus panel has recommended screening all carbamazepine-naïve patients for the HLA-A*31:01 allele prior to starting treatment, regardless of race or ethnicity, since the allele is prevalent in most ethnic groups [ 47].

The clinical utility of testing for HLA-B*58:0 1 allele prior to treatment with allopurinol has not been demonstrated in any population [ 48]. However, the Clinical Pharmacogenetics

Implementation Consortium (CPIC) recommends that allopurinol should not be prescribed to patients who are known carriers of HLA-B*58:01 [49]. (See "Antiseizure drugs:Mechanism of action, pharmacology, and adverse effects", section on 'Carbamazepine' and "Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects", sectionon 'Role of HLA testing' and "Prevention of recurrent gout: Pharmacologic urate-lowering therapy and treatment of tophi", section on 'Allopurinol' .)

Other factors

PATHOGENESIS — The pathologic mechanisms that induce skin damage in Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are incompletely understood. Early

studies of the immunophenotype of lymphocytes detected in the blister fluid of SJS/TEN lesions suggested a cell-mediated cytotoxic reaction against keratinocytes leading tomassive apoptosis [ 59]. Subsequent studies demonstrated that cytotoxic T-cells are drug-specific and directed against the native form of the drug rather than against a reactivemetabolite [ 60-62 ].

Drugs can stimulate the immune system by directly binding to the major histocompatibility complex (MHC) I and the T-cell receptor. This results in the clonal expansion of apopulation of drug-specific cytotoxic T-cells that kill keratinocytes directly and indirectly through the recruitment of other cells that release soluble death mediators, includinggranulysin [ 63]. (See "Drug allergy: Pathogenesis", section on 'Interaction of drugs with the immune system' .)

Mediators of keratinocyte apoptosis — Drug-specific C D8 cytotoxic T cells, along with natural killer (NK) cells are thought to be the major inducers of keratinocyte apoptosis[60,61 ]. Various cytotoxic proteins and cytokines such as soluble Fas ligand, perforin/granzyme, tumor necrosis factor (TNF)-alpha, and TNF-related apoptosis inducing ligand(TRAIL) have been proposed as mediators for the extensive keratinocyte apoptosis in SJS/TEN. However, it is now accepted that granulysin, a cytolytic protein found in cytotoxic Tcells and natural killer (NK) cells plays a key role in the pathogenesis of SJS/TEN [ 64].

Granulysin — Granulysin is a cytolytic protein produced and secreted by cytotoxic T lymphocytes, natural killer (NK) cells, and NK/T cells. The gene expression profiling of cells from five patients with SJS or TEN identified granulysin as the most highly expressed cytotoxic molecule [ 65]. Both fluid and cells from SJS/TEN patient blisters demonstratedcytotoxicity when incubated with keratinocytes, but the effect was reduced by depletion of granulysin. Control fluid or cells from patients with burns did not show such activity. Thelevels of granulysin in blister fluid correlated with the severity of disease. In addition, injection of granulysin from patient blisters into mouse skin caused dose-dependent blisteringand necrosis.

The mechanism through which cytotoxic T lymphocytes and natural killer cells are stimulated to release granulysin is unknown. The results of one study suggest that the interactionbetween the CD94/NKG2C receptor on cytotoxic T lymphocytes and HLA-E, an MHC class Ib molecule, expressed by keratinocytes in patients with SJS or TEN, may promotedegranulation [ 66].

Other factors — Soluble Fas-ligand, perforin, TNF-alpha, TNF-related apoptosis-inducing ligand (TRAIL), and granzyme B, which are involved in distinct non-apoptotic cell deathpathways, are also found in high concentrations in the peripheral mononuclear cells and blister fluid of SJS/TEN patients [ 67-69 ]. However, elevations in these mediators are notspecific to SJS/TEN.

HISTOPATHOLOGY — The hallmark of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is the keratinocyte necrosis, ranging from partial to full-thicknessnecrosis of epidermis. In early lesions, apoptotic keratinocytes are scattered in the basal layer of the epidermis, but in established lesions full-thickness epidermal necrosis andsubepidermal bullae may be seen [ 8]. A scant perivascular lymphohistiocytic inflammatory infiltrate containing a variable amount of eosinophils is present in the superficial dermis(picture 3 ).

CLINICAL PRESENTATION

Prodrome — Fever, often exceeding 39°C (102.2°F), and influenza-like symptoms precede by one to three days the development of mucocutaneous lesions [ 70]. Photophobia andconjunctival itching or burning, and pain on swallowing may be early symptoms of mucosal involvement. Malaise, myalgia, and arthralgia are present in most patients.

In some patients, an exanthematous eruption can be the heralding sign of SJS/TEN. Signs and symptoms that should alert the clinician to the possibility of Stevens-Johnsonsyndrome/toxic epidermal necrolysis (SJS/TEN) include fever >38°C (100.4°F), mucositis, skin tenderness, and blistering ( table 4 ) [70,71 ]. (See "Exanthematous (morbilliform) drugeruption", section on 'Early signs of severe reaction' .)

Cutaneous lesions — The skin lesions typically begin with ill-defined, coalescing erythematous macules with purpuric centers, although many cases of SJS/TEN may present withdiffuse erythema ( picture 1A, 2A, 2C-D ) [72,73 ]. The skin is often tender to the touch and skin pain can be prominent and out of proportion to the cutaneous findings.

Lesions start on the face and thorax before spreading to other areas and are symmetrically distributed [ 74]. The scalp is typically spared, and palms and soles are rarely involved[75,76 ]. Atypical target lesions with darker centers may be present. As the disease progresses, vesicles and bullae form and within days the skin begins to slough.

Nikolsky sign (ie, the ability to extend the area of superficial sloughing by applying gentle lateral pressure on the surface of the skin at an apparently uninvolved site) may bepositive. The Asboe-Hansen sign or "bulla spread sign" (a lateral extension of bullae with pressure) may also be present. The ultimate appearance of the skin has been likened tothat of extensive thermal injury [ 77]. (See "Approach to the patient with cutaneous blisters", section on 'Nikolsky sign' .)

Mucosal lesions — Mucosal involvement occurs in approximately 90 percent of cases of SJS/TEN and can precede or follow the skin eruption [ 78]. Painful crusts and erosionsmay occur on any mucosal surface [ 70,79 ].

Oral — The oral mucosa and the vermilion border are almost invariably involved, with painful hemorrhagic erosions covered with a grayish-white membrane ( picture 1C-D ).Stomatitis and mucositis lead to impaired oral intake with consequent malnutrition and dehydration.

Ocular — Ocular involvement is reported in approximately 80 percent of patients. The most common change in the eyes is a severe conjunctivitis with a purulent discharge(picture 1E ), but bullae may develop. Corneal ulceration is frequent, and anterior uveitis or panophthalmitis may occur. Pain and photophobia are accompanying symptoms. The eyechanges often regress completely, but scarring with the development of synechiae between the eyelids and conjunctiva may be late sequelae [ 80,81 ]. (See "Stevens-Johnsonsyndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae", section on 'Long-term sequelae' .)

Urogenital — Urethritis develops in up to two-thirds of patients, and may lead to urinary retention. Genital erosions are frequent. In women, vulvovaginal involvement maypresent with erosive and ulcerative vaginitis, vulvar bullae, and vaginal synechiae, and may lead to long-term anatomic sequelae. These include labial and vaginal adhesions andstenosis, obstructed urinary stream and urinary retention, recurrent cystitis, or hematocolpos [ 82-86 ]. Vulvovaginal adenosis (presence of metaplastic cervical or endometrial

A systematic review and meta-analysis found a significant association between HLA-B*58:01 and allopurinol -induced SJS/TEN in both Asian and non-Asian populations [ 36].

Genetic polymorphisms – Polymorphisms in the CYP2C19 gene, coding for a cytochrome P450 isoform, may confer an increased risk of SJS/TEN following theadministration of phenobarbital , phenytoin , or carbamazepine [37]. Other CYP2C variants, including CYP2C9*3 , known to be associated with reduced phenytoin clearance,may be associated with an increased risk of severe cutaneous adverse reactions to phenytoin, including SJS/TEN and DRESS [ 38]. Other polymorphisms potentiallyassociated with SJS/TEN include those in the IL-4 receptor gene [ 39,40 ], prostaglandin E receptor 3 gene [ 41], and a group of genes located in the 6p21 region ( BAT1 , HCP5 ,MICC , and PSORS1C1 ), which are in linkage disequilibrium with HLA-B*58:01 [42]. However, larger studies are needed to assess the role of genetic polymorphism in thepathogenesis of SJS/TEN.

●

Malignancy may increase the risk of SJS/TEN, although data are conflicting as to whether malignancy truly increases the risk, or is simply associated with increased exposureto causative medications [ 50,51 ].

●

High doses and rapid introduction of medications [ 13,52 ].●

Patients with systemic lupus erythematosus (SLE) appear to be at an increased risk of SJS/TEN [ 53]. In a retrospective review of 1366 patients with SJS/TEN, theprevalence of SLE was 1.2 percent, whereas the estimated prevalence in the general population is approximately 0.02 to 0.05 percent [ 54]. However, in lupus patients thedifferentiation between SJS/TEN and an extreme phenotype of acute cutaneous lupus ("TEN-like" lupus erythematosus) may be difficult and requires accurateclinicopathologic correlation [ 54,55 ].

●

Physical stimuli, such as ultraviolet light or radiation therapy, may be co-factors in some cases [ 56-58 ].●

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glandular epithelium in the vulva or vagina) also has been reported in women with SJS/TEN [ 87-89 ].

Other — Pharyngeal mucosa is affected in nearly all patients; tracheal, bronchial, and esophageal membranes are less frequently involved [ 90,91 ]. Intestinal involvement is rare[92].

Laboratory abnormalities — Hematologic abnormalities, particularly anemia and lymphopenia, are common in SJS/TEN [ 74]. Eosinophilia is unusual; neutropenia is present inabout one-third of patients, and is correlated with a poor prognosis [ 74,93 ]. However, the administration of systemic corticosteroids can cause demarginalization and mobilization of neutrophils into the circulation, and this may obscure neutropenia.

Hypoalbuminemia, electrolyte imbalance, and increased blood urea nitrogen and glucose may be noted in severe cases, due to massive transdermal fluid loss and hypercatabolicstate. Serum urea nitrogen >10 mmol/L and glucose >14 mmol/L are considered markers of disease severity [ 94]. Mild elevations in serum aminotransferase levels (two to threetimes the normal value) are present in about one-half of patients with TEN, while overt hepatitis occurs in approximately 10 percent [ 79].

CLINICAL COURSE — The acute phase of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) lasts 8 to 12 days and is characterized by persistent fever, severemucous membrane involvement, and epidermal sloughing that may be generalized and result in large, raw, painful areas of denuded skin. Reepithelialization may begin after severaldays, and typically requires two to four weeks [ 95]. Skin that remained attached during the acute process may peel gradually and nails may be shed.

COMPLICATIONS

Acute phase — In severe cases with extensive skin detachment, acute complications may include massive loss of fluids through the denuded skin, electrolyte imbalance,hypovolemic shock with renal failure, bacteremia, insulin resistance, hypercatabolic state, and multiple organ dysfunction syndrome. Abdominal compartment syndrome secondaryto excessive replacement fluid therapy has been reported in a few patients [ 96]. (See "Abdominal compartment syndrome" .)

Patients with Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are at high risk of bacterial infection. Sepsis and septic shock, most often caused by S. aureus andP. aeruginosa, are the main cause of death in these patients. In a study of 179 patients with SJS/TEN, bacteremia was detected in 48 (27 percent) [ 97]. The main pathogensimplicated were S. aureus , P. aeruginosa , and Enterobacteriaceae organisms. The risk of bacteremia was higher in patients older than 40 years, in those with skin detachment onmore than 30 percent of BSA, and in those with greater than 10,000 white blood cell count. (See "Sepsis and the systemic inflammatory response syndrome: Definitions,epidemiology, and prognosis" .)

Pulmonary complications (eg, pneumonia, interstitial pneumonitis) are frequent. Presenting symptoms include cough and elevated respiratory rate. Strict clinical surveillance isnecessary for these patients, due to the risk of progression to acute respiratory distress syndrome. Acute respiratory failure requiring mechanical ventilation has been reported inapproximately 25 percent of patients with SJS/TEN [ 90]. (See "Acute respiratory distress syndrome: Clinical features and diagnosis in adults" .)

Gastrointestinal complications may result from epithelial necrosis of the esophagus, small bowel, or colon. Diarrhea, melena, small bowel ulcerations, colonic perforation, and smallbowel intussusception have been reported in a few patients [ 98-101 ].

Long-term sequelae — Long-term sequelae of SJS/TEN are discussed separately. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, andlong-term sequelae", section on 'Long-term sequelae' .)

PATIENT EVALUATION AND DIAGNOSIS

Clinical findings and history — There are no universally accepted diagnostic criteria for Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), and histologic findingsare neither specific nor diagnostic. Despite these limitations, the diagnosis of SJS or TEN would be appropriate in a patient with the following clinical features [ 102 ] (see 'Clinicalpresentation' above):

Assessment of drug causality — For patients suspected to have SJS/TEN, the identification of the causative drug is essential because early withdrawal of the offending agentmay improve the prognosis [ 104 ]. In addition, the identification of the culprit drug is of paramount importance to prevent reexposure in patients recovering from SJS/TEN.

The assessment of drug causality is based upon detailed history and clinical judgement. Information about the drugs that are most frequently associated with SJS/TEN is helpful(table 2 ). An algorithm of drug causality for epidermal necrolysis (ALDEN) has been developed as a tool for rapid assessment of drug causality in patients presenting with SJS/TEN,particularly in those exposed to multiple medications [ 11 ]. Each potentially offending drug is assigned a score from -11 to 10 based upon six parameters ( table 5 ):

The score is categorized as very probable (≥6), probable (4 to 5), possible (2 to 3), unlikely (0 to 1), and very unlikely (≤0).

Assessment of severity — The severity and prognosis of SJS/TEN depends upon the amount of skin detachment or "detachable" skin (ie, skin with positive Nikolsky sign). Basedupon the percentage of the body surface area (BSA) involved, patients can be classified into three severity groups [ 1]:

The correct evaluation of the extent of lesions may be difficult in areas with spotty lesions. It is useful to remember that in both children and adults the surface of the patient’s hand,including palm and fingers, corresponds to approximately one percent of the total body surface area. (See "Classification of burns", section on 'Percent body surface areaestimates' .)

The prognosis of individual patients can be rapidly evaluated in the early stages of disease by applying a prognostic scoring system called SCORTEN, based upon seven clinicaland laboratory variables ( table 6 ) [94]. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae", section on 'SCORTENscore' .)

Skin biopsy — A skin biopsy for routine histopathologic examination and possibly direct immunofluorescence is useful in confirming the diagnosis and excluding other conditions

that may mimic SJS/TEN. An appropriate sample may be obtained by performing a large (>4 mm) punch biopsy or a deep shave biopsy ("saucerization").

In the early stages of disease, apoptotic keratinocytes are scattered in the basal layer of the epidermis and there is a perivascular mononuclear inflammatory infiltrate in the papillarydermis composed primarily of T-lymphocytes [ 8]. This infiltrate is not diagnostic, and may be seen in a wide variety of conditions, including a simple drug-induced exanthem. As thelesions progress, frank subepidermal bullae develop, with full thickness epidermal necrosis ( picture 3 ). Direct immunofluorescence is always negative.

Cultures — Because of the high risk of bacterial superinfection and sepsis, appropriate cultures should be performed from blood, wounds, and mucosal lesions. In children, PCRand/or serologies for Mycoplasma pneumoniae infection should also be obtained in the early stage of disease and three weeks later. (See "Mycoplasma pneumoniae infection inchildren", section on 'Diagnosis' .)

A suggestive history of drug exposure or illness. Drug exposure commonly precedes the onset of symptoms by one to four weeks (average 14 days), but reexposure mayresult in onset of symptoms in as little as 48 hours [ 103 ].

●

A prodrome of acute-onset febrile illness and malaise●

Erythematous macules, targetoid lesions, or diffuse erythema progressing to vesicles and bullae ( picture 1A )●

Positive Nikolsky sign and/or "bulla spread sign"●

Oral, ocular, and/or genital mucositis with painful mucosal erosions ( picture 1C, 1E )●

Necrosis and sloughing of the epidermis of varying degree ( picture 2C )●

Time delay from initial drug intake to onset of reaction●Probability of drug presence in the body on the index day●

A previous history of exposure to the same drug, w ith or without reaction●Presence of the drug beyond the progression phase of the disease●Drug notoriety as a cause of SJS/TEN based upon previous studies●Presence or absence of other etiologic causes●

SJS – skin detachment of 30 percent of BSA ( picture 2A-D )●SJS/TEN overlap – skin detachment of 10 to 30 percent of BSA●

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Investigational tests — Candidate serum markers of SJS/TEN, including soluble Fas ligand, soluble CD40 ligand, granulysin, and high-mobility group box 1 protein (HMGB1, anonhistone nuclear protein released by necrotic and apoptotic cells) have been evaluated in a few small studies [ 67,105-107 ]. However, further studies are necessary to determinewhether these markers may be helpful in the early diagnosis of SJS/TEN. (See 'Pathogenesis' above.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) includes:

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces arewritten in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed.These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient educationarticles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

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REFERENCES

1. Bastuji-Garin S, Rzany B, Stern RS, et al. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol1993; 129:92.

2. Roujeau JC. Stevens-Johnson syndrome and toxic epidermal necrolysis are severity variants of the same disease which differs from erythema multiforme. J Dermatol 1997;24:726.

3. Rzany B, Mockenhaupt M, Baur S, et al. Epidemiology of erythema exsudativum multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis in Germany(1990-1992): structure and results of a population-based registry. J Clin Epidemiol 1996; 49:769.

4. Strom BL, Carson JL, Halpern AC, et al. Using a claims database to investigate drug-induced Stevens-Johnson syndrome. Stat Med 1991; 10:565.

5. Chan HL, Stern RS, Arndt KA, et al. The incidence of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. A population-based study withparticular reference to reactions caused by drugs among outpatients. Arch Dermatol 1990; 126:43.

6. Roujeau JC, Guillaume JC, Fabre JP, et al. Toxic epidermal necrolysis (Lyell syndrome). Incidence and drug etiology in France, 1981-1985. Arch Dermatol 1990; 126:37.

7. Schöpf E, Stühmer A, Rzany B, et al. Toxic epidermal necrolysis and Stevens-Johnson syndrome. An epidemiologic study from West Germany. Arch Dermatol 1991;

127:839.8. Rzany B, Hering O, Mockenhaupt M, et al. Histopathological and epidemiological characteristics of patients with erythema exudativum multiforme major, Stevens-Johnson

syndrome and toxic epidermal necrolysis. Br J Dermatol 1996; 135:6.

9. Mittmann N, Knowles SR, Koo M, et al. Incidence of toxic epidermal necrolysis and Stevens-Johnson Syndrome in an HIV cohort: an observational, retrospective case seriesstudy. Am J Clin Dermatol 2012; 13:49.

10. Sekula P, Dunant A, Mockenhaupt M, et al. Comprehensive survival analysis of a cohort of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. J InvestDermatol 2013; 133:1197.

11. Sassolas B, Haddad C, Mockenhaupt M, et al. ALDEN, an algorithm for assessment of drug causality in Stevens-Johnson Syndrome and toxic epidermal necrolysis:

Erythema multiforme – Erythema multiforme usually presents with typical target lesions, or raised atypical targetoid lesions that are predominantly located on the extremities(picture 4 ). Bullae and epidermal detachment are usually limited and involve less than 10 percent of the body surface area. Erythema multiforme is in most cases associatedwith infection with herpes simplex virus ( table 1 ). (See "Pathogenesis, clinical features, and diagnosis of erythema multiforme" .)

●

Erythroderma and erythematous drug eruptions – The generalized and symmetric maculopapular erythema of a drug eruption can mimic early SJS/TEN. However,exanthematous drug eruptions lack mucosal involvement and the prominent skin pain of TEN. Histology shows only a mild interface dermatitis with a perivascular inflammatory infiltrate of lymphocytes, neutrophils, and eosinophils. (See "Erythroderma in adults" and "Exanthematous (morbilliform) drug eruption" .)

●

Acute generalized exanthematous pustulosis – Severe cases of acute generalized exanthematous pustulosis (AGEP) may be difficult to differentiate from SJS/TEN ( picture5). AGEP typically develops within a few days of exposure to the offending drug, most often a beta lactam antibiotic, and resolves without treatment in one to two weeks after drug discontinuation. The histologic hallmark of AGEP is a spongiform subcorneal and/or intraepidermal pustule ( picture 5 ). (See "Acute generalized exanthematous pustulosis(AGEP)" .)

●

Phototoxic eruptions – Severe phototoxic eruptions may be confused with SJS/TEN. Important clues to the correct diagnosis include recent sun exposure, known phototoxicproperties of certain medications, and location of the lesions on sun-exposed areas. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis,and treatment" .)

●

Staphylococcal scalded skin syndrome – Staphylococcal scalded skin syndrome (SSSS) is caused by epidermolytic toxins produced by certain strains of Staphylococciand is usually seen in neonates and young children. SSSS presents with generalized erythema rapidly followed by the development of flaccid blisters and desquamation(picture 6 ). The mucous membranes are not involved. Histology reveals sloughing of only the upper layers of the epidermis, in contrast with the subepidermal split with fullthickness epidermal necrosis observed in SJS/TEN. (See "Vesiculobullous and pustular lesions in the newborn", section on 'Staphylococcal scalded skin syndrome' .)

●

Paraneoplastic pemphigus – Paraneoplastic pemphigus is a rare disorder that can represent the initial presentation of a malignancy or occur in a patient with a knownneoplastic process, such as non-Hodgkin lymphoma in adults or Castleman's disease in children. Patients may develop severe mucocutaneous disease with ocular and oralblisters and skin lesions ( picture 7A-C ). (See "Paraneoplastic pemphigus" .)

●

Linear IgA bullous dermatosis – Linear IgA bullous dermatosis (LABD) is a rare autoimmune blistering disease that may mimic toxic epidermal necrolysis ( picture 8 ).

Histology reveals a subepidermal blister with an underlying neutrophil-predominant dermal infiltrate. Direct immunofluorescence shows linear deposits of IgA along thebasement membrane. (See "Linear IgA bullous dermatosis" .)

●

th th

th th

Basics topic (see "Patient information: Stevens-Johnson syndrome (The Basics)" )●

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe mucocutaneous reactions, most commonly triggered by medications, characterized byextensive necrosis and detachment of the epidermis. Cases with less than 10 percent epidermal involvement are classified as SJS; those with 30 percent or more involvementare classified as TEN; cases with 10 to 30 percent involvement are considered overlap SJS/TEN. However, we use the term "SJS/TEN" to refer collectively to SJS, TEN,and SJS/TEN overlap syndrome. (See 'Introduction and terminology' above.)

●

Medications are the leading trigger of SJS/TEN in both adults and children. Allopurinol , aromatic anticonvulsants, antibacterial sulfonamides, and "oxicam" NSAIDS are mostcommonly implicated ( table 2 ). Mycoplasma pneumoniae and cytomegalovirus infection are the next most common trigger of SJS/TEN, particularly in children. (See 'Etiology'above.)

●

Risk factors for SJS/TEN include HIV infection, genetic factors, concomitant viral infections, underlying autoimmune diseases, and possibly physical factors. (See'Predisposing factors' above.)

●

SJS/TEN begins with a prodrome of fever and influenza-like symptoms one to three days before the development of mucocutaneous and skin lesions. The cutaneous eruptiontypically starts with ill-defined, coalescing erythematous macules with atypical target lesions ( picture 1A, 2A, 2C-D ). As the disease progresses, vesicles and bullae form andwithin days the skin begins to slough. Mucosal involvement occurs in approximately 90 percent of cases of SJS/TEN and can precede or follow the skin eruption. (See'Clinical presentation' above.)

●

In severe cases with extensive skin detachment, acute complications may include massive loss of fluids and electrolyte imbalance, hypovolemic shock with renal failure,bacteremia, insulin resistance, hypercatabolic state, and multiple organ dysfunction syndrome. (See 'Complications' above.)

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The diagnosis of SJS/TEN is based upon clinical and histologic findings in a patient with a history of antecedent drug exposure or illness. Histologic findings on skin biopsyare supportive, but not independently diagnostic. (See 'Patient evaluation and diagnosis' above.)

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