We have explained some terms we have used in a glossary. Please see Table 1.
|Allele||One of two or more alternative forms of a gene at corresponding sites (loci) on homologous chromosomes|
|Hardy-Weinberg equilibrium||This states that allele and genotype frequencies in a population will remain constant from generation to generation in the absence of other evolutionary influences|
|HLA||Human leukocyte antigen: a group of protein molecules located on bone marrow and other cells that can provoke an immune response|
|Hypersensitivity||A state of altered reactivity in which the body reacts with an exaggerated immune response to a foreign substance, such as a drug|
|Polymorphic||A variation in the DNA that is too common to be due merely to new mutation. A polymorphism must have a frequency of at least 1% in a population|
|Maculopapular rash||A rash with both macules (flat and coloured like a freckle) and papules (a small raised spot)|
Description of the condition
Some drugs may cause skin rashes that vary in their severity and incidence. Skin reactions caused by drugs, often termed 'drug-induced skin injury' (DISI), are common (carbamazepine-induced skin rash has a 10% incidence rate (Marson 2007)); they present with a range of clinical manifestations ranging from a mild maculopapular skin rash to life-threatening skin rashes such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) (Pirmohamed 2004; Roujeau 1987). The most severe forms are very rare, but these may result in up to 30% mortality. Less severe forms of hypersensitivity reactions are troublesome and may prevent people from taking medications that are otherwise effective.
The mechanisms involved in the pathogenesis of these drug-induced reactions are still poorly understood; however, immunogenetic and non-immune factors have been implicated. Recent evidence suggests that drug-specific T-cells can be identified in individuals who previously experienced adverse drug reactions (ADRs) to the culprit drug (Illing 2012).
Description of the intervention
Figure 1 represents a diagram of decision-making informed by genetic testing.
To date, the strongest association with drug-induced skin injury has been reported with genetic variants in the human leukocyte antigens (HLA) (Amstutz 2013; Chung 2004; Hetherington 2002; Hung 2005; Mallal 2002; McCormack 2011; Ozkaya-Bayazit 2001). Human leukocyte antigens are cell surface proteins involved in presenting antigens to the immune system. They are encoded by most polymorphic genes in the human genome. However, different genetic markers are associated with hypersensitivity in different populations, and the effect size varies in different ethnicities. Also, there is evidence that some common factors could predispose to DISI irrespective of the underlying drug aetiology. In addition, it is possible that different severity phenotypes can share the same predisposing factor.
Table 2 shows reported associations between hypersensitivity reactions, which include skin injury and genetic variants in HLA genes.
|Drugs associated with skin injury||Class of drug||HLA allele||Population||Reference|
|Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)|
|Allopurinol||Antiuric acid||B*5801||Han Chinese||Hung 2005|
|Carbamazepine||Antiepileptic||B*1502||Han Chinese||Cheung 2013; Chung 2004; Chong 2013; Hung 2006; Man 2007|
|-||-||-||Thai||Kulkantrakorn 2012; Locharernkul 2008; Tassaneeyakul 2010; Tangamornsuksan 2013|
|-||-||A*3101||White||Amstutz 2013; McCormack 2011;|
|Phenytoin||Antiepileptic||B*1502||Han Chinese||Hung 2010; Man 2007|
|Oxicam||Non-steroidal anti-inflammatory drug (NSAID)||A2, B12||White||Roujeau 1987|
|Sulphamethoxazole||Antibiotic||A29, B12, DR7||White||Roujeau 1986|
|Hypersensitivity syndrome (DIHS or DRESS)|
|Abacavir||Antiretroviral||B*5701||White||Hetherington 2002; Hughes 2004; Mallal 2002; Mallal 2008; Martin 2004|
|-||-||-||African Americans||Hughes 2004a; Saag 2008|
|Aminopenicillins||Antibiotic||A2, Drw52||White||Romano 1998|
|Nevirapine||Antiretroviral||DRB1*01||White - Australian||Martin 2005|
|-||-||DRB1*01||White - French||Vitezica 2008|
|-||-||Cw8, B14||White - Italian||Littera 2006|
|-||-||C*0404||Black African||Carr 2013|
|Aspirin||NSAIDS||DRB1*1302, DQB1*0609||-||Kim 2005; Palikhe 2008|
|Iodine contrast media||-||DR||White - Spanish||Torres 2008|
|Paraphenylenediamine||Hair dye||DP||White - German||Sieben 2002|
|Gold sodium thiomalate||Treatment of rheumatoid arthritis||DR5||White - Spanish||Rodriguez-Pérez 1994|
|Lamotrigine||Antiepileptic||B*5801, A*6801||White||Kazeem 2009|
|Trichloroethylene||Industrial solvent, dry cleaning||B*1301||Japanese||Li 2007; Watanabe 2010|
|Fixed drug eruptions|
|Co-trimoxazole||Antibiotic||A30, B13, Cw6||White - Turkish||Ozkaya-Bayazit 2001|
How the intervention might work
Two recent clinical trials suggested that pretreatment genetic testing could reduce the possibility of severe hypersensitivity induced with an anti-AIDS drug, abacavir (Mallal 2008), and an antiepileptic drug, carbamazepine (Chen 2011).
Patients who have a clinical requirement for a particular drug treatment can be stratified on the basis of a genetic test. Those who test positive for the risk marker are not prescribed the culprit drug, while those who test negative are safe to take the medicine of interest. In this way, it may be possible to reduce the incidence of severe drug skin reactions in the genotyped group compared to the randomly assigned group of patients who are not offered genetic testing, but for whom decision on drug choice is based on traditional clinical and biochemical parameters.
Why it is important to do this review
Adverse drug reactions affecting the skin are common; they can have high morbidity and mortality and are a burden for healthcare systems around the world. If we were able to predict them on the basis of a simple genetic test, it should be possible to prevent these reactions with one of the following approaches:
by prescribing alternative therapy if available;
by informing patients and healthcare providers; or
by informing drug developers in order to improve drug design and future drug development.
We aim to assess current research evidence to determine whether prospective pharmacogenetic screening is effective in reducing drug-associated skin reactions.