People can develop severe sensitivities to medications that might look like drug allergies. Allergic reactions usually include symptoms such as hives, mild rashes, itching, and swelling that could lead to anaphylaxis. These reactions occur when antibodies are elevated in response to inactive ingredients in pills or sometimes to active chemicals. Allergies typically have an immediate onset – i.e. within minutes to an hour after exposure to the allergen. Stopping the treatment can resolve these allergic reactions. While some adverse drug reactions are caused by genetic factors, it is still difficult to pinpoint exact DNA mutations causing extreme drug hypersensitivity reactions (DHR) for many individuals.

Genetic deficiencies leading to drug toxicity

G6PD deficiency causes Hemolytic Anemia, which may be triggered by specific medications or foods. Yellowing of the skin and eyes, in some cases, is linked to UGT1A1 deficiency. These and similar enzymes metabolize different substances in foods and medications.

However, there are more severe skin and mucosa drug reactions that can be life-threatening and are linked to the immune system and medication levels in the blood.

Medications posing a higher risk of extreme medication hypersensitivities

Antibiotics and anticonvulsants are more commonly reported to cause severe skin toxicities:

• vancomycin and sulfa antibiotics,
• allopurinol
• carbamazepine, lamotrigine and similar anticonvulsants

Types of severe skin toxic conditions

Medication hypersensitivity is a group of syndromes that includes drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome (DIHS), Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), and Mast cell activation syndrome (MCAS). These conditions differ in the timing and severity of their clinical manifestations.

MCAS is a form of pseudo-allergic drug reaction that can develop very fast after medication exposure. MCAS might arise as a hypersensitivity to:

• Morphine and other opioids (but not fentanyl) and other drugs used in general anesthesia.
• Radiocontrast dyes used for imaging.
• Drugs for traumatic brain injury: icatibant, leuprolide, octreotide, sermorelin, cetrorelix.
• Antibiotics: ciprofloxacin, moxifloxacin, levofloxacin and other fluoroquinolone and vancomycin

Both TEN and SJS can appear within a few hours to about two weeks after starting a new treatment. SJS is a less severe form of the condition and is characterized by red patches that gradually spread from the head and torso to the extremities, as well as blistering and swelling of the lips and mucous membranes. TEN is a more severe form of SJS, and it is characterized by similar symptoms that are much more pronounced and widespread.

DRESS / DHR, can occur a few weeks after starting a new treatment. Symptoms may include skin rashes, fever, increased white blood cell count, allergic antibodies, and abnormal liver or kidney function. Patients may not experience any adverse reactions during the first two weeks of treatment, but a change in antibiotics or additional medication can trigger a sudden onset of DRESS. The risk of DRESS is higher with higher doses of vancomycin and certain other medications, which can lead to toxic drug levels in the body. Unfortunately, the medication hypersensitivity persists for life in these conditions, which develop many years after initial symptoms disappear and are attributed to several genetic factors.

Genetics of medication hypersensitivity conditions

Human leukocyte antigen (HLA) genes help the immune system to distinguish between the molecules of your body and foreign elements. While some genetic factors have been identified for medication hypersensitivities, the clinical utility of pharmacogenetic HLA testing to prevent these conditions is still limited.

Drug labels often suggest screening patients for HLA-A or HLA-B subtypes to check for severe medication hypersensitivity risk. The HLA-A subtype called the HLA-A*32:01 allele, is most commonly associated with DRESS. Other subtypes including but not limited to are HLA-B*57:01, B*58:01, B*15:02, B*31:01, B*13:01, C*04:01 associated with increased risk of SJS/TEN and DRESS. The challenge is that some of these genetic risk factors are more common in specific ethnic populations. However, many more HLA-A and HLA-B subtypes can increase the risk of severe skin drug reactions. Therefore, a negative test result does not guarantee the safe use of anticonvulsants and high-risk antibiotics. It’s important to note that only some people with the risk alleles develop drug-induced toxicities.

Additional genes affecting risk of drug toxicity

For antiepileptic medications and allopurinol, additional genetic variations play a critical role. Phenytoin and valproate are metabolized by the CYP2C9 enzyme. Inherently reduced function of CYP2C9 increases drug blood concentrations, leading to an increased risk of adverse drug effects, including medication hypersensitivity. To reduce the risk of drug toxicity, dose reductions are required. Variations in the ABCG2 gene have been associated with allopurinol’s metabolism and effectiveness. Dose adjustments based on ABCG2 can help to titrate the allopurinol dose.

Skin sensitivity testing

Skin patches with small drug doses can assess a person’s sensitivity and risk of severe reactions to many of these medications. Skin patch testing for allopurinol and antiepileptics prior to treatment initiation can help to reduce the risk of SJS/TEN. However, such prospective screening cannot assess the risk of DRESS. Still, skin patch tests are helpful for diagnosis confirmation in people who experience medication hypersensitivity to assess which antibiotics and antiepileptics could be used safely.

Summary

• Severe medication hypersensitivity can be life-threatening and should be carefully investigated to identify the specific medication and other drugs that could cause similar reactions.
• For people with high-risk HLA alleles, choosing different medications or starting treatment with a lower dose can help prevent serious skin reactions.
• Negative HLA test results indicate an average, but not absent, risk of medication-induced hypersensitivity.
• Skin patch testing can provide a more accurate assessment of SJS/TEN risk but cannot predict the risk of DRESS. Skin patch tests can confirm which medications can trigger MCAS.
• Once developed, broad medication hypersensitivity persists for life, requiring careful assessment of all medications. If you have medication hypersensitivity, always consult with an expert pharmacist before starting a new medication.

Selected references

Phillips EJ et al., Drug hypersensitivity: Pharmacogenetics and clinical syndromes J Allergy Clin Immunol. 2011 Mar; 127(3 Suppl): S60–S66.

Manson LEN EJ et al.,  Genotyping for HLA risk alleles versus patch tests to diagnose anti-seizure medication induced cutaneous adverse drug reactions.  Front Pharmacol. 2022 Nov 21;13:1061419.