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ESSENTIALS OF DIAGNOSIS

  • Most classic rheumatic diseases are complex traits. Multiple genetic variants contribute small risks to the development of the disease.

General Considerations

Substantial advances in the ability to characterize an individual’s genetic profile deeply, either through single nucleotide polymorphism (SNP) genotyping or next-generation sequencing, have led to the rapid identification of genetic variants associated with rheumatologic diseases. However, most classic autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus (SLE), are known to be genetically complex; that is, multiple genetic variants, each imparting very modest risk, contribute to the development of disease. Therefore, at this point, genetic tests are generally not used to diagnose “classic” autoimmune diseases. However, in this section, we will discuss well-recognized genetic associations, as well as specific instances in which genetic testing may be utilized to inform diagnosis or treatment decisions.

Genetic Testing to Guide Medication Selection

A. Allopurinol

Allopurinol is a xanthine oxidase inhibitor used to lower uric acid levels in the management of gout. Allopurinol causes serious cutaneous adverse reactions (SCARS) in approximately 2% of individuals. These reactions range from mild skin rashes to severe manifestations, including drug rash with eosinophilia and systemic symptoms (DRESS) or the Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). The severe reactions can be accompanied by fever, hepatitis, and other internal organ manifestations such as interstitial nephritis. These reactions are usually due to a type IV hypersensitivity reaction and occur because of a pharmacologic interaction between oxypurinol, the principal metabolite of allopurinol, and the human leukocyte antigen (HLA) receptor. The ability of oxypurinol to bind to HLA molecules varies enormously, and thus an individual’s risk for SCARS depends on his or her immunogenetic profile. Severe drug hypersensitivity reactions can occur in individuals with specific HLA alleles, such as HLA-B*58:01. Binding of drug alters the conformation of this HLA molecule, which leads to stimulation of T cells by HLA-drug complexes. This off-target activity of the drug is highly dependent on the drug concentration. Decreased renal function and increased plasma levels of oxypurinol correlate with the poor prognosis of allopurinol-induced SCARS.

The HLA-B*58:01 allele, which increases the risk of SCARS significantly, is found more frequently in individuals of Han Chinese (20%), Korean, and Thai descent. HLA-B*58:01 is rare, however, among Japanese. Among non-Asian patients with allopurinol hypersensitivity reactions, many do not have HLA-B*58:01 allele, so other relevant allele or haplotype associations may yet be identified. While the negative predictive value of HLA-B*58:01 for allopurinol-induced SCARs has been reported to be nearly 100%, its positive predictive value is only on the order of 2%. A cost-effectiveness study in Taiwan calculated that 461 patients needed to be tested for HLA-B*58:01 to prevent 1 case of SCAR, based on a prevalence of the genetic marker in the population of 18% and an estimated incidence of allopurinol-related SCAR (2.2/1000 persons) in ...

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