Severe cutaneous adverse reactions (SCARs) include three entities, namely, Drug Reaction, Eosinophilia and Systemic Sclerosis (DRESS), Stevens-Johnson syndrome and/or toxic epidermal necrolysis (SJS/TEN) and acute generalized exanthematous pustulosis (AGEP). It has posed a challenge to the community of dermatologists and internists. Thus a rapid addressal is required. 

Beyond conventional pharmacovigilance exercise

A diagnostic dilemma remains considering two commonly used criteria, i.e., RegiSCAR (The European Registry of Severe Cutaneous Adverse Reactions to Drugs and Collection of Biological Samples) and Japanese consensus diagnostic criteria for Drug-Induced Hypersensitivity Syndrome/DRESS. The two criteria have very different bases, as RegiSCAR criteria try to quantify the probability of causality assessment; the Japanese criteria try to group the cases of SCAR as atypical and typical. 

In some published reports of DRESS, the classification system for causality assessment is more generic and uses World Health Organization- Uppsala Monitoring Centre (WHO-UMC) criteria. 

Thus a common causality assessment criterion is needed, to enable better categorization of the three components of SCAR.

Using pharmacogenetic tools to identify genetic predisposition to SCARs

SCAR is unpredictable. However, pharmacogenetic evaluations can reduce the degree of unpredictability in some of the adverse drug reactions (ADR). 

SCAR variations in humans are assessed mostly in leukocyte antigens (HLA) genes, with HLA-B*58:01 known to be associated with allopurinol induced SCAR (SJS/TEN and DRESS). Many allelic variants of HLA-A genes are known to be related with carbamazepine induced SJS/TEN and DRESS with recommendations suggesting for HLA-A*15:02 evaluation before initiation of carbamazepine in populations where the variant is common. 

Thus evaluation in diverse ethnicities will help to understand the inherent risk for SCAR and identify persons at a higher predisposition to SCAR. 

Mechanistic studies for identifying targets for intervention

Various pathophysiology explains the findings of the three conditions listed in SCAR. Involvement of specific subpopulations of T cells like Cytotoxic T lymphocytes (CTLs), regulatory T cells (Treg), and T-helper type 1 (Th1), Th2, Th17, in delayed hypersensitivity causes SCAR. However, the ultimate phenotypic outcome involves multiple interactions between a variety of cell lineages, their products, soluble mediators, environmental, and genetic factors. 

Histopathological dendritic cell infiltration, spongiform superficial epidermal pustules, oedema of the papillary dermis, and perivascular infiltrates of lymphocytes can be found.

Anticonvulsants, like carbamazepine, causes the majority of cases of SJS/TEN. In vitro evidence has shown carbamazepine to produce reactive metabolites by CYP isoforms in the skin which can bind to protein and mediate an inflammatory response. Also, the capacity of making a structural alteration of the protein binding pocket of HLA B *15:2 is different for the carbamazepine and it’s epoxide metabolite (carbamazepine-10,11-epoxide) (EPX), proposing a critical pathway of immunogenic adverse reactions including SCAR. 

Furthermore, the use of complementary and alternative medicines (CAM) needs to be paid special attention to, as these medicines contain arsenic or steroid/steroid-like substances which can lead to severe allergic reactions including SCAR. 

Issues around therapeutic agents

Arresting the involved agents is the mainstay of therapy, but it may be difficult if the patient is on multiple therapeutic agents and/or complementary and alternative medicines. Steroids are the mainstay of treatment, but a tendency to subsequent infections remains a major concern. 

Intravenous immune globulin (IVIG) treatment coupled with pulse methylprednisolone or high dose corticosteroids has shown efficacy in reducing mortality from SJS and TEN. Validation of prognostic markers like HLA-B*57:01 for guiding therapy may be advantageous. 

In conclusion, the number of cases of SCAR should not exceed 13.6% of the total ADR cases at any given time, in any given center. 

Source- Shafiq N, Bhattacharjee S, Malhotra S. Severe Cutaneous Adverse Reaction (SCAR): Clinical pharmacologists viewpoint. Indian Dermatol Online J 2022;13:10-2