Thompson & Thompson Genetics in Medicine, 8th Edition

Case 1. Abacavir-Induced Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (Genetically Determined Immunological Adverse Drug Reaction)

Autosomal Dominant

Principles

• Pharmacogenetic test that has been widely adopted as standard of care

• Significant positive and negative predictive values

• Ethnic differences in the frequency of the predisposing allele

Major Phenotypic Features

• Widespread red/purple patches on the skin and mucosal membranes (eye, mouth, genitalia) 10 to 14 days after beginning antiretroviral treatment with abacavir.

• Skin sloughing of greater than 30% of body surface area is referred to as toxic epidermal necrolysis; a similar rash but with sloughing of less than 10% of body surface area is referred to as Stevens-Johnson syndrome.

History and Physical Findings

P.R., a 37-year-old German man, was admitted to the hospital in 2001 with shortness of breath and confusion and found to have both Pneumocystis carinii pneumonia and Toxoplasma gondii encephalitis, opportunistic infections that occur commonly in the setting of newly diagnosed human immunodeficiency virus (HIV)-1 acquired immunodeficiency syndrome (AIDS). His CD4 cell count was 2/mm3 and HIV-1 viral load was 120,000 copies/mL. Treatment with trimethoprim-sulfamethoxazole was started, and he was started on antiretroviral therapy (ART) that included the nucleoside analogue reverse transcriptase inhibitor abacavir. His encephalitis and pneumonia cleared, and he was discharged from the hospital on oral antiparasitic treatment.

Two weeks after beginning ART, P.R. presented with a nonfebrile, generalized macular rash involving his palms and mouth. His blood pressure was 130/60 mm Hg, temperature was 37.1° C, pulse was 88 beats/min, he was breathing 15 breaths/min, and oxygen saturation was 96% on room air. He had a disseminated cutaneous eruption of discrete dark red macules on 90% of the body surface area, a detachment of 5% of the epidermis, genital ulcerations, erosive stomatitis, and conjunctival lesions with hyperemia but without keratitis or corneal erosions. The application of minor pressure to the skin resulting in sloughing of the skin (Nikolsky sign).

Skin biopsy was compatible with Stevens-Johnson syndrome. Because of previous reports of cutaneous hypersensitivity reactions with abacavir treatment, the drug was stopped, and he was transferred to a burn unit, monitored for further skin sloughing, and treated with supportive care. The epidermis began to heal over the next week, and the skin lesions resolved completely within 3 weeks. His ART was changed to a combination of protease inhibitors and different nucleoside analogue reverse transcriptase inhibitors without recurrence of the skin reaction. His viral load decreased to undetectable, and the CD4 count returned to normal.

One year later, when the increased susceptibility to SJS with abacavir therapy was shown to depend on human leukocyte antigen (HLA) genotype, he had HLA typing and was found to carry the SJS-abacavir susceptibility allele HLA-B*5701.

Background

Adverse drug reactions are defined as harmful reactions caused by normal use of a drug at correct doses. The majority (75% to 80%) of all adverse drug reactions are caused by predictable, nonimmunological effects, some of which are due to genetically determined pharmacokinetic or pharmacodynamic differences between individuals. The remaining 20% to 25% of adverse drug events are caused by largely unpredictable effects that may or may not be immune-mediated. Immune-mediated reactions account for 5% to 10% of all drug reactions and represent true drug hypersensitivity, with immunoglobulin E–mediated drug allergies with hives or laryngeal swelling, falling into this category. A different kind of skin reaction, a generalized maculopapular rash, is also common with certain medications, including sulfa drug antibiotics.

One particularly dangerous adverse drug reaction is T-cell mediated damage to skin and mucous membranes, referred to as Stevens-Johnson syndrome (SJS), and its more serious extreme manifestation, toxic epidermal necrolysis (TEN) (Fig. C-1). Both SJS and TEN are characterized by malaise and fever, followed by rapid appearance of red/purple patches on the skin, which progress to sloughing of the skin, similar to what is seen with a thermal burn. Mucosal membranes (eye, mouth, genitalia) are frequently affected. In SJS, skin sloughing involves less than 10% of body surface area, whereas TEN involves sloughing of greater than 30% of the body surface area.

image

FIGURE C-1 A, Numerous coalescing dusky lesions with flaccid bullae and multiple sites of epidermal detachment involving 10% to 30% of skin surface. This extent of epidermal detachment is in the “zone of overlap” between Stevens-Johnson syndrome and toxic epidermal necrolysis. B,Stevens-Johnson syndrome, showing involvement of lips and mucous membranes of the mouth. See Sources & Acknowledgments.

Histological features in the skin in drug-induced SJS/TEN patients include epidermal necrosis, in some cases extending through the full thickness of the epidermis as seen with thermal burn, individual keratinocyte apoptosis, subepidermal bullae, and dense dermal infiltrates with lymphocytes, as well as a substantial number of eosinophils or neutrophils.

The mortality rate in SJS/TEN ranges from 10% to 30%. Although SJS and TEN represent only a small fraction of all immune-mediated drug reactions, they are particularly severe and can be life threatening.

Pathogenesis

SJS/TEN is mediated by cytotoxic T cells. Molecular immunological studies have elucidated why T-cell–mediated hypersensitivity occurs in individuals with the HLA-B*5701 allele treated with abacavir. In HLA-B*5701–expressing cells cultured in the presence of abacavir, up to 25% of the peptides present in the antigen-presenting groove of their class I cell-surface antigen-presenting molecules are novel self-peptides that are not seen in the absence of abacavir. Abacavir appears to interact specifically with segments of the HLA-B*5701 peptide-binding groove, altering its binding properties. This alteration allows HLA-B*5701 to present novel peptides that happen to have a much higher cross-reactivity to self, including skin antigens. Drugs precipitate over 50% of SJS cases and up to 95% of TEN cases.

Management

Discontinuation of the offending drug and transfer to a burn unit for supportive care are the mainstays of treatment. Other therapies such as systemic corticosteroids and intravenous immunoglobulin have been suggested but have not to date been proven to be either beneficial or harmful.

Prevention

The 50% positive predictive value for SJS or TEN in HLA-B*5701–positive individuals treated with abacavir and the nearly 100% negative predictive value for SJS or TEN in individuals treated with abacavir who lack HLA-B*5701 led the Infectious Diseases Society of America and other international health services to require, as a standard of care, that only individuals who lack the HLA-B*5701 allele be given abacavir therapy. The varying frequency of the allele in different populations, however, and the availability of other nucleoside analogue reverse transcriptase inhibitors that lack the potential to cause SJS/TEN have led to a lively debate as to whether it is cost-effective to carry out HLA-B typing before starting abacavir treatment in everybody, or whether testing should be considered only in individuals from ethnic backgrounds with the highest frequencies of the HLA-B*5701 allele. Nonetheless, the combination of a 50% positive predictive value, a very high negative predictive value, and the life-threatening nature of SJS/TEN make screening a reasonable choice in all patients for whom abacavir treatment is being considered, regardless of ethnic background.

Inheritance Risk

As with all HLA alleles (see Chapter 8), inheritance is autosomal codominant. Studies of large cohorts of patients treated with abacavir have demonstrated that approximately 50% of patients carrying an HLA-B*5701 allele will develop SJS or TEN, whereas none of the patients without this antigen will develop these conditions.

The frequency of the HLA-B*5701 allele (and therefore the risk for abacavir-induced SJS and TEN) differs greatly among various ethnic groups (see Table).

Population

Frequency of the HLA-B*5701 Allele (%)

White

8-10

African American

2.5

Chinese

0-2

South Indian

5-20

Thai

4-10

Similar associations between SJS or TEN and other HLA alleles have been seen with the antiepileptic drug carbamazepine (HLA-B*1502), the uric acid–lowering drug allopurinol (HLA-B*5801) used for gout, and other commonly used medications.

Questions for Small Group Discussion

1. Suggest a mechanism by which SJS/TEN might arise in individuals with different HLA-B alleles when exposed to different drugs.

2. Why might there be different frequencies of various HLA-B alleles in different ethnic groups?

References

Downey A, Jackson C, Harun N, et al. Toxic epidermal necrolysis: review of pathogenesis and management. J Am Acad Dermatol. 2012;66:995–1003.

Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008;358:568–579.

Martin MA, Kroetz DL. Abacavir pharmacogenetics—from initial reports to standard of care. Pharmacotherapy. 2013;33:765–775.

Mockenhaupt M, Viboud C, Dunant A, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs: the EuroSCAR-study. J Invest Dermatol. 2008;128:35–44.