Personalized Medicine for HLA-associated Drug-hypersensitivity Reactions

Mandvi Bharadwaj; Patricia Illing; Lyudmila Kostenko

Disclosures

Personalized Medicine. 2010;7(5):495-516. 

In This Article

HLA-class-II-associated Drug Hypersensitivities

NSAID Hypersensitivities associated with HLA Class II Alleles

Aspirin, or acetylsalicylic acid, is one of the most widely used NSAIDs in medical practice. Aspirin performs its anti-inflammatory function by irreversibly inactivating cyclooxygenase enzymes, thus inhibiting production of proinflammatory prostaglandins, as well as thromboxanes, lipids produced by platelets to induce blood clotting. Aspirin causes two phenotypically distinct hypersensitivity reactions; aspirin-induced urticaria, associated with the HLA-DRB1*1302–DQB1*0609 haplotype,[62] and aspirin-intolerant asthma (AIA), associated with HLA-DPB1*0301.[63,64] It has been theorized that these diseases may partially be the result of increased leukotriene synthesis due to arachidonic acid, the natural substrate of cyclooxygenase, following the lipooxygenase pathway and generating increased amounts of these inflammatory mediators involved in inflammation and asthma.[65]

Urticaria is a skin reaction characterized by red wheals with dermal and epidermal edema accompanied by inflammatory infiltrate, including lymphocytes, eosinophils and neutrophils. An increased number of mast cells has been implicated in disease etiology in both affected and unaffected skin of sufferers compared with normal controls.[66,67] Both acute (reaction duration 6 weeks or less) and chronic (reaction duration greater than 6 weeks) aspirin-induced urticaria show a similar strength of association with the HLA-DRB1*1302–DQB1*0609 haplotype in the Korean population with 10% of aspirin-induced urticaria patients possessing this haplotype versus 2% of AIA sufferers and 3.2% of healthy controls.[62] The infiltration of lymphocytes in urticarial lesions and the upregulation of MHC class II by both resident and infiltrating cells open the possibility of a mechanistic role for the disease associated HLA alleles in this hypersensitivity.[68]

By contrast, AIA occurs in 10–20% of adult asthmatics, although prevalence is higher in women. Early symptoms such as persistent rhinitis appear at an average age of 30 years old proceeded by the development of asthma, nasal polyposis and aspirin sensitivity over the next 1–5 years. Challenge with aspirin causes violent, potentially fatal, asthmatic attacks.[69,70] AIA has been associated with HLA-DPB1*0301 in both a Polish and a Korean population study with odds ratios of 4.4 and 8.3, respectively. The presence of this association in two very different populations gives credence to this antigen as a risk factor rather than a polymorphism in LD.

Although these associations are relatively weak compared with other HLA allele associated hypersensitivities, their presence in multiple populations does make them appealing for help in phenotyping these reactions, though they would not significantly reduce ADR incidence as predictive markers. Furthermore associations with alleles of non-HLA genes such as TNF-α, TGF-β1 and IL-10 promoters make it clear that several factors are involved in the etiology of these reactions, and may potentially be better predictive markers, or help form a panel of markers that could be used as a basis of aspirin denial.[71–74]

Aspirin is not the only NSAID responsible for ADR. Another study looking at cutaneous and anaphylactoid reactions to NSAIDs in general found that HLA-DR11 was present in 58.8% of those experiencing anaphylactoid reactions and 27.7% of those experiencing cutaneous reactions but only 15.9% of tolerant individuals and 6.3% of individuals with IgE mediated anaphylactoid reactions to unrelated stimuli. The main NSAIDs involved in anaphylactoid reactions were dipyrone and propyphenazone; however aspirin, paracetamol and a panel of other drugs, that were not NSAIDs were also seen to cause these reactions. Aspirin was more commonly the culprit drug in cutaneous reactions.[75]

The existence of this association with several drugs of a similar mechanism may indicate that the conditions generated by these drugs rather than the drugs themselves are the stimulus for any immune phenomena.

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