Necrolysis Spectrum from Basic Theory to Practice Essentials


Classification


Type of lesions


Distribution


%BSA


EMM


Typical target


Acral



SJS


Spots atypical target


Widespread


<10


SJS–TEN overlap


Spots atypical target


Widespread


10–30%


TEN with spots


Spots atypical target


Widespread


≥30%


TEN without spots


Diffuse erythema, no spots or target


Widespread


≥30%



Adopted from Jean-Claude Roujeau [1]


SCAR Severe Cutaneous Adverse Reactions study, BSA body surface area




43.2 Epidemiology


The incidence is 2–7 cases per million people per year [3]. It is well known that this rare drug reaction affects women at a slightly higher rate than men. SJS/TEN can occur at any age group, but it appears to affect adults more than children [4]. Mortality rates of SJS, SJS-TEN, and TEN were 5–10%, 30%, and 50%, respectively [5, 6].


Certain risk factors make patients at higher risk of this disorder such as being a slow acetylator, immunocompromised hosts, concurrent use of radiotherapy and anticonvulsants, specific human leukocyte antigen (HLA) alleles, and ethnicity. Racial disparities in SJS/TEN incidence was reported by a large population-based study, which found that SJS/TEN is more strongly associated with people of nonwhite ethnicities, particularly Asians and Blacks [7]. Asian patients have twofold higher risk when compared to Caucasian patients [8]. Thus, FDA recently recommended genotyping of Asians for the allele HLA-B∗15:02 prior to the administration of carbamazepine (Table 43.2).


Table 43.2

HLA association in different population


































































































































Associated drug


HLA allele


Specific eruption


Ethnicity


Aromatic convulsant


B∗15:02


SJS/TEN


Han Chinese, Indian, Malaysian, Vietnamese, Singaporean, Hong Kongese


Carbamazepine


A∗31:01


DRESS/SJS/TEN


Northern European, Japanese, Korean

 

B∗15:11


SJS/TEN


Han Chinese, Japanese, Korean

 

B∗59:01


SJS/TEN


Japanese

 

B∗38:01


SJS/TEN


Spanish

 

B∗15:02


SJS/TEN


Han Chinese, Thai

 

B∗51:01


SJS/TEN


Han Chinese, Japanese, Malaysian


Oxcarbazepine


A∗33:03, B∗38:02, B∗51:01, B∗56:02, B∗58:01, C∗14:02


SJS/TEN


Thai


Phenytoin


B∗15:13


DRESS/SJS/TEN


Malaysian

 

CYP2C9∗3


DRESS/SJS/TEN


Han Chinese, Japanese, Malaysian

 

CYP2C9∗3


SJS/TEN


Thai

 

B∗15:02


SJS/TEN


Han Chinese

 

B∗38; B∗58:01, A∗68:01, Cw∗07:18


SJS/TEN


European


Phenobarbital


B∗38:01


SJS/TEN


Spanish


Lamotrigine


A∗31:01


SJS/TEN


Korean

 

A∗24:02


DRESS/SJS/TEN


Spanish


Allopurinol


B∗58:01


DRESS/SJS/TEN


Han Chinese, Thai, Japanese, Korean, European


Nevirapine


C∗04:01


DRESS/SJS/TEN


Malawian


Cotrimoxazole


B∗15:02, C∗06:02, C∗08:01


SJS/TEN


Thai


Sulfamethoxazole


B∗38:02


SJS/TEN


European


Sulfonamide


A∗29, B∗12, DR∗7


TEN


European


Oxicam NSAIDs


B∗73:01


SJS/TEN


European


Methazolamide


B∗59:01, CW∗01:02


SJS/TEN


Korean, Japanese



Adopted with modification from Chun-Bing Chen et al. [9]


Use of medication is the most common cause of EN. Other rare causes reported in literature include infection and vaccination, and collagen vascular diseases have been found to account for a small number of cases [1013]. This is most likely due to confusion regarding diagnostic consideration among SJS, EM, and Mycoplasma pneumoniae-induced rash and mucositis (MIRM).


Hundreds of medications have been reported as being associated with EN. Commonly implicated medications are allopurinol, aromatic anticonvulsants, antimicrobial sulfonamides, lamotrigine, nevirapine, and oxicam nonsteroidal anti-inflammatory drugs (Table 43.3). Other low-risk medication includes sertraline, acetic acid nonsteroidal anti-inflammatory drugs, macrolides, quinolones, cephalosporins, and aminopenicillins [14]. Newer drugs such as nivolumab and ipilimumab have likewise been reported to cause SJS/TEN [15, 16].


Table 43.3

High-risk drug causing epidermal necrolysis









Allopurinol


Aromatic anticonvulsants: carbamazepine, phenobarbital, phenytoin


Antibacterial sulfonamides: sulfamethoxazole, sulfasalazine


Lamotrigine


Nevirapine


Oxicam nonsteroidal anti-inflammatory drugs


43.3 Pathogenesis


Several theories have been proposed for the pathogenesis of epidermolytic necrolysis, but molecular sequencing and cellular events are not fully understood. In susceptible individuals, upon exposure to a certain drug or one of its metabolite, a series of reactions occur that lead to keratinocytes apoptosis and subsequent epidermal necrosis and detachment [9].


43.3.1 Antigen Presentation


Drugs are considered as foreign body material that are too small on their own to be immunogenic. But when they bind to hapten-carrier complex, they are presented to HLA molecules, and then are recognized by T-cell receptors (TCR). This recognition results in the induction of drug-specific immune response by CD8+ cytotoxic T cell (CTL).


43.3.2 Fas-FasL Interaction


Fas ligands (FasL) are transmembrane protein molecules expressed on target cells that belong to tumor necrosis factor (TNF) family. Upon their interaction, Fas-associated death domain proteins (FAAD) is recruited and bind to Fas-FasL complex. Subsequently, FAAD recruits procaspase 8, turning it into caspase 8 and triggering it into caspase cascade which result in DNA degranulation. However, the molecular events leading to the upregulation of surface keratinocyte FasL during TEN remain unknown [17].


43.3.3 Perforin/Granzyme B


Other research suggests that perforin and granzyme B play more important role in keratinocytes apoptosis in EN than does Fas–FasL interaction. Granzyme B is a serine protease released by cytoplasmic granules that induce apoptosis. Upon activation, CTL and natural killer cells (NK) produce perforin, which in turn delineates the entry of granzyme B into the target cells [1820].


43.3.4 Granulysin


Granulysin is a cytolytic protein produced mainly by CTL, NK cells, and NK T cells. This molecule participates in programmed cellular death by creating holes in cellular membrane and thereby cellular destruction. In 2008, Chung et al. provided evidence that granulysin is the key mediator for disseminated keratinocyte apoptosis in SJS/TEN. This study found that the granulysin level in blister fluids of SJS/TEN patient was much higher than other cytotoxic proteins, such as Fas-FasL, perforin, and granzyme B [21].


43.3.5 Delayed-Type Drug Hypersensitivity


Specific T lymphocytes or NK cells are activated upon antigen recognition. Soon afterwards, various cytokines/chemokines are released to attack keratinocytes or promote trafficking, proliferation, regulation, or activation of T cells and other leukocytes.


43.3.6 Other Cytokines and Chemokines Are Involved in EN Pathogenesis Such as TNF-α, IFN-γ and IL-15 & IL-36


TNF-α is a major proinflammatory cytokine and is produced by macrophages, T lymphocytes, NK cells, neutrophils, mast cells and eosinophils. This molecule is highly expressed in plasma and blister fluids of SJS/TEN and appear to be a significant inducer of keratinocyte apoptosis [22].


IFN-γ is a significant cytokine for innate and adaptive immunity that is mainly produced by CD4+ T-helper cells, CD8+ CTL, and NK cells. IFN-γ was found to be elevated in skin tissue, blister, and plasma of SJS/TEN patients. In 2013, Viard-Leveugle et al. suggested a link between two path mechanism modalities of EN, delayed-type drug hypersensitivity and target cellular death. This study demonstrated that activated T cells secrete high amount of TNF-α and IFN-γ which lead to an increased expression and activity of inducible nitric oxide synthetase (iNOS). The resulting increase in nitric oxide significantly upregulates keratinocyte FasL expression and eventually keratinocyte apoptosis.


IL-15 and IL-36 participate in the immune reaction of EN by regulating trafficking, proliferation, and activation of T lymphocytes. Moreover, IL-15 has also been shown to enhance the cytotoxicity of cultured NK cells and blister cells from TEN [5]. Thereby IL-15 has been found to be associated with disease severity and mortality of SJS/TEN.


43.4 Clinical Presentation


EN presentation starts typically within 4–28 days of exposure to medication, with a prodrome of malaise, fatigue, anorexia, cough, and fever. Three days later, skin lesions appear on the trunk or face and progress to the extremities; with painful ill-defined erythematous coalescing macules and patches and central purpura (Fig. 43.1). These lesions could be confused with the targetoid lesions of erythema multiforme. A clinical clue that could differentiate between these two entities is that in SJS the rash is macular and flat in nature, while in EM it is more popular and raised which is also associated with more classic target lesions.

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Nov 4, 2020 | Posted by in Aesthetic plastic surgery | Comments Off on Necrolysis Spectrum from Basic Theory to Practice Essentials
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