Severe Cutaneous Adverse Reactions to Drugs

Faith L. Chia; Khai Pang Leong


Curr Opin Allergy Clin Immunol. 2007;7(4):304-309. 

In This Article


The pathogenesis of SJS/TEN is not fully understood, but there have been many advances that will contribute to formulating a pathophysiological model for SJS and TEN.

Genetic susceptibility plays a role in the pathogenesis of TEN/SJS. A recent study[9] in a Han Chinese population showed that HLA-B*1502 is strongly associated with carbamazepine-induced SJS. While all patients with SJS from carbamazepine had the HLA-B*1502 allele, this was observed in only 3% of the tolerant patients. Furthermore, in contrast to SJS/TEN, HLA-B*1502 was not observed in patients with other forms of carbamazepine-induced reactions such as hypersensitivity syndrome or maculopapular eruptions.[10] Importantly, these findings have not been replicated in Caucasian patients,[11] although a European study from the RegiSCAR group found that of 12 patients with carbamazepine-induced SJS/TEN, all four who were positive for the HLA-B*1502 allele had Asian ancestry.[12] In another study in Han Chinese, HLA-B*5801 allele was an important genetic risk factor for allopurinol-induced SJS and TEN.[13] HLA*A0206 was associated with SJS with ocular complications in Japanese patients, though the authors did not list the causative drugs, which are likely to be multiple.[14]

The association between specific HLA subtypes and drug reactions is patently different in different populations and more studies must be performed to understand this phenomenon. The knowledge of the HLA association with drug allergy will be useful in primary and secondary prevention. For example, a physician may order HLA typing to estimate the patient's risk of reaction before initiating treatment with a drug commonly associated with allergy. For a patient who is developing a maculopapular rash after drug treatment, genetic testing may predict if the reaction is likely to progress to SJS or TEN. Pharmacoeconomic studies must be carried out before routine genotyping for a particular HLA allele prior to prescription of drugs can be recommended. It had been shown that pretesting for HLA-B*5701 reduced the incidence of abacavir hypersensitivity syndrome in HIV patients.[15*]

The T lymphocyte is accepted as the key mediator in most delayed drug reactions.[16*,17] Over the course of the drug reaction, the T cells' expression of cutaneous lymphocyte-associated antigen (CLA) rises and falls in parallel with disease severity, facilitating lymphocytic traffic to the skin. There is also a corresponding increase in the E-selectin expression (the ligand of CLA) on cutaneous endothelial cells. The elevated level of CLA tends to persist in the dermal lymphocytes compared with those in the peripheral blood. Tumour necrosis factor (TNF)-α and IFNγ were also strongly expressed by peripheral blood mononuclear cells early in the course of the reaction.[18] In another report, most of the lymphocytes derived from blister fluid of patients with TEN were found to be T cell receptor αβ-positive, CD3-positive and CD8-positive. These cells are activated and most express CD56 as well. They displayed in-vitro cytotoxic activity via the perforin/granzyme-mediated pathway in response to the appropriate drug.[19]

The overriding pathological finding in SJS and TEN is dermal cell apoptosis, which can be triggered by at least four pathways: Fas and Fas ligand, TNF-α, TNF-α-related apoptosis-inducing ligand (TRAIL) and granzyme B. Increased serum soluble Fas ligand concentration was demonstrated in patients with TEN and SJS patients compared to patients with drug-induced erythema multiforme and to healthy controls.[20] The peripheral blood mononuclear cells (PBMCs) secreted Fas ligand when stimulated by the appropriate drugs.[20] Furthermore, levels of perforin, granzyme B and Fas ligand have been shown to correspond to disease severity in delayed reactions to drugs.[21]

Lesional skin from patients with SJS and TEN overexpress TNF-α, IFNγ, IL-2, IL-5, IL-13, CCR-3, CXCR3, and CXCR4.[22**] Because both the Th1 and Th2 cytokines are expressed, the authors concluded that there was no skewing of the lymphocytic phenotype. Cutaneous T cell-attracting chemokine (CTACK)-CCR10 mRNA levels were found to be raised in lesional skin of patients with SJS/TEN, returning to baseline after resolution of the disease.[23]

The role of the dendritic cell has been assessed in patients with extant maculopapular rashes induced by amoxycillin. The drug-induced changes in the dendritic cells isolated from these patients include increases in cell proliferation and HLA-DR, CD80 and CD86 expression.[24]


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