RAMB - Agosto 2016

tevens

-J

ohnson

syndrome

and

toxic

epidermal

necrolysis

review

ssoc

ras

2016; 62(5):468-473

469

skin detachment between 10 and 30% of the body sur-

face; and TEN, cases greater than 30%.

4,8

pidemiology

Statistics in Brazil are scarce in relation to its prevalence.

The literature suggests that SJS and TEN occur in approxi-

mately 2 to 3 people per million/year in Europe and the USA.

The incidence of SJS specific ranges from 1.2 to 6 per mil-

lion/year, with fatality in 5% of cases, while TEN affects 0.4

to 1.2 per million/year withmortality of 30% of patients.

2,7-9

They can affect patients of all ages and races. TEN is

more common in women, while SJS occurs more in the

male population. Incidence increases with age and in cer-

tain risk groups

predisposing factors include: the exis-

tence of multiple comorbidities, polymedicated individ-

uals, genetic susceptibility factors, immunosuppression

(in HIV-positive patients, the risk is 1,000 times greater

than in the general population), and concomitant use of

radiotherapy and anticonvulsants.

1,2,4

athophysiology

The pathophysiological mechanism is not fully under-

stood. It is believed to be a delayed hypersensitivity reac-

tion mediated by Th1 cells.

Some individuals have a genetic predisposition to de-

velop such disorders: the so-called slow acetylators, defi-

cient in enzymes involved in the destruction of toxic drug

metabolites, such as glutathione transferase. Recently, ge-

netic association of some HLA major histocompatibility

complex alleles with the occurrence of serious drug reac-

tions has been described.

Histopathological hallmark of these diseases is wide-

spread epidermal necrosis due to death by apoptosis of

keratinocytes. CD8 cells act as mediators in this process.

There are two pathways leading to apoptosis: the bind-

ing of Fas (CD95), a membrane receptor present in kera-

tinocytes, with its FasL ligand (CD95L), and the release

of the perforin and granzyme B pathways.

1,2,4

tiology

It is believed that drugs are the main cause of SJS (50 to

80% of cases) and TEN (around 80%), although these dis-

eases can also be triggered by infections and malignan-

cies.

The most common drugs are sulfonamides and pen-

icillins (26%) and the most often associated infectious

agent is herpes simplex virus (19.7%).

While drugs and cancer are more associated with adult

patients, infections are the leading cause in children: it is

estimated that half of patients diagnosed with SJS had a

recent upper respiratory tract infection.

There are over 100 medications of various classes as-

sociated with the occurrence of SJS and TEN. In a recent

international multicenter case-control study that includ-

ed countries in Europe and Israel, the EuroSCAR (Euro-

pean Severe Cutaneous Adverse Reactions) trial, allopu-

rinol was the most common cause of SJS and TEN,

particularly when prescribed at doses equal to or higher

than 200 mg per day. The following drugs were listed as

the main ones related to the occurrence of SJS and TEN,

based on RegisSCAR/EuroSCAR files.

1,10

•

High risk: allopurinol, carbamazepine, cotrimoxazole

and other sulphonamides, sulfasalazine, lamotrigine,

nevirapine, oxicam-derivative nonsteroidal anti-inflam-

matory drugs (e.g., meloxicam), phenobarbital, pheny-

toin;

•

Moderate risk: cephalosporins, macrolides, quinolo-

nes, tetracyclines, acetic acid-derivative nonsteroidal

anti-inflammatory drugs (e.g., diclofenac);

•

Low risk: beta-blockers, angiotensin-converting enzy-

me inhibitors, calcium channel inhibitors, thiazide

diuretics, sulfonylurea antidiabetics, insulin, propio-

nic acid-derivative nonsteroidal anti-inflammatory

drugs (e.g., ibuprofen).

Analgesics include: paracetamol

and acetylsalicylic acid.

It is important to note that in 2014, the Food and Drug

Administration (FDA) required the manufacturers of ac-

etaminophen (paracetamol) to include SJS risk warnings

in the package insert. Dipyrone, by contrast, is not in the

list of agents involved in the etiology of SJS; the possible

association with SJS seems to stem from the concomi-

tant use in infectious diseases whose etiological agents

could be the real cause of the disease.

La Grenade et al., in a study of cases of SJS and TEN

between 1969 and 2004, concluded that there is a signif-

icant risk of developing both drug reactions with sulfon-

amide derivative selective COX-2 inhibitors, particularly

valdecoxib. With lower risk, but statistically significant,

other COX-2 inhibitors such as celecoxib and rofecoxib,

also correlated to these adverse reactions.

The reported viral diseases include herpes simplex vi-

rus (HSV), HIV, coxsackievirus, influenza, hepatitis, lym-

phogranuloma venereum, and smallpox. Bacterial agents

include group A beta-hemolytic streptococcus, the bacilli

of diphtheria, brucellosis, typhoid fever and tularemia, my-

cobacteria and mycoplasma. Fungal causes include para-

coccidioidomycosis, dermatophytosis and histoplasmosis.

Protozoan parasites malaria and trichomonas were also re-

lated. In children, enteroviruses and Epstein-Barr virus are