Severe cutaneous adverse reaction

What is a severe cutaneous adverse reaction?

A severe cutaneous adverse reaction, or SCAR, refers to several distinct conditions.

• Acute generalised exanthematous pustulosis (AGEP)
• Drug-induced hypersensitivity syndrome (DIHS), also known as drug reaction with eosinophilia and systemic symptoms (DRESS)
• Stevens–Johnson syndrome / toxic epidermal necrolysis (SJS/TEN)

Common features can be seen creating diagnostic difficulty. There are also cases where diagnostic criteria overlap.

A multinational registry called the RegiSCAR Project has been formed to further examine severe cutaneous adverse reactions.

Severe cutaneous adverse reaction: overlap AGEP and SJS/TEN*

Painful widespread erosions 

Flaccid blisters 

Positive Nikolsky sign 

*Hydroxychloroquine resulted in widespread painful erosions, mucositis, flaccid vesicles, pustules. Biopsy was consistent with AGEP.

Who gets SCARs?

• AGEP has an incidence of approximately 1–5 cases per million population per year, and mainly affects adults.
• The population incidence of DIHS/DRESS is unknown. Amongst patients taking anticonvulsants, the incidence of DIHS/DRESS ranges from 1–5 cases per 10,000 per year. DIHS/DRESS also mainly affects adults.
• SJS/TEN is seen in all age groups, with an incidence of 1–2 cases per million population per year.

What causes SCARs?

While the pathophysiology of SCARs is not yet fully understood, the activation of drug-specific T lymphocytes has been implicated. Specific human leukocyte antigen alleles have been identified that are associated with an increased risk of forms of severe cutaneous adverse reaction.

• In AGEP, 90% of cases are thought to be drug-related, but infections have also been implicated in AGEP.
• In DIHS/DRESS, a causative drug can be identified in approximately 80% of cases.
• With the SJS/TEN spectrum, a drug can be identified in approximately 85% of cases. In some of the remaining 15% of cases, often children, the trigger for SJS/TEN is believed to be infection; in particular, with Mycoplasma pneumoniae. (However, some authors argue reactions to mycoplasma should be separately classified.)

What are the clinical features of SCAR?

AGEP features non-follicular sterile pustules.

• These non-follicular sterile pustules are often prominent in the major flexures (neck, arm pits, under the breasts, and groin).
• They typically form on a base of red swollen skin.
• AGEP is associated with fever of > 38 C and neutrophilia.
• AGEP typically has a short latency of 2–5 days between exposure and onset, and settles over 1–2 weeks.

DIHS/DRESS features rash, solid organ involvement (most commonly, the liver), fever, lymphadenopathy and facial oedema.

• The patient may describe a prodromal phase of feeling generally unwell prior to the onset of the rash.
• DIHS/DRESS typically presents with erythematous papules and plaques, or a morbilliform eruption.
• The most common haematological finding is eosinophilia.
• DIHS/DRESS has a latency period of 2–6 weeks between drug exposure and the onset of illness.
• The course of DIHS/DRESS is typically prolonged; from a few weeks to a few months.

SJS/TEN often presents with a few days of prodromal illness with fever (> 39 C), malaise, cough, a blocked or runny nose, sore throat and sore eyes.

• The rash then appears and extends over 5–7 days. It usually starts on the face, chest, and the proximal limbs, and then spreads widely.
• The rash is painful and itchy.
• Atypical target lesions or purpuric macules may occur. Then flat, flaccid blisters form. Atypical target lesions on palms and soles are common.
• Mucosal involvement is seen in more than 90% of cases and is erosive and haemorrhagic.
• SJS/TEN typically has a latency period of 7–10 days, but this can range from 5 to 28 days between drug exposure and the onset of symptoms.

How is SCAR diagnosed?

The SCAR conditions are diagnosed from the patient history and a careful clinical examination; diagnosis can be aided by investigations such as blood tests and skin biopsy.

What is the treatment for SCARs?

SCARs will usually require hospital admission.

• It is crucial to identify and stop the causative drug (if any) and to provide supportive care.
• DIHS/DRESS is also treated with systemic corticosteroids.
• AGEP and SJS/TEN do not as yet have a definitive treatment.

What is the outcome for SCARs?

• AGEP has an excellent prognosis with the expectation of full recovery.
• A majority of patients with DIHS/DRESS will make a full recovery. However, there can be serious after-effects associated with solid organ involvement, including an increased risk of a number of autoimmune conditions.
• SJS/TEN causes significant morbidity and mortality. The SCORTEN (SCORe of Toxic Epidermal Necrosis) illness severity score can be used to predict mortality. Long-term negative after-effects, such as visual impairment, are often seen in survivors.

Overlap between SJS/TEN, DIHS/DRESS and AGEP

SJS/TEN, DIHS/DRESS and AGEP can share features, and there are also case reports of overlap where the full diagnostic criteria for more than one form of SCAR have been met.

In a study of 117 patients with DIHS/DRESS using the RegiSCAR database, 30% had pustules, 16% blistering, and 56% had mild mucosal involvement.

• Blisters seen in DIHS/DRESS are usually tense and due to cutaneous oedema.
• Mucous membrane involvement is rare in AGEP. Mucous membrane involvement in DIHS/DRESS is usually mild, unlike the haemorrhagic crusts seen in SJS/TEN.
• Up to 18% of AGEP cases have been described as having systemic involvement.
• Solid organ involvement may also occur in SJS/TEN.

A skin biopsy can help to distinguish between the SCARs.

• AGEP is characterised by marked dermal and epidermal spongiosis and intraepidermal neutrophilic spongiotic pustules.
• DIHS/DRESS can have wide variety of findings, including spongiosis, a superficial perivascular lymphocytic infiltrate, an eosinophilic infiltrate, or a lichenoid infiltrate; necrotic keratinocytes are also seen in some cases.
• SJS/TEN can see individual keratinocyte apoptosis through to confluent epidermal necrosis with subepidermal vesicle and bullae formation.