The risk of anti‐osteoporotic agent‐induced severe cutaneous adverse drug reactions and their association with HLA

BACKGROUND There is increasing use of anti-osteoporotic agents (AOA) worldwide for prevention or management of patients with osteoporosis. However, there have been reports of severe cutaneous adverse reactions (SCAR) induced by AOA. A recent study showed weak association between HLA and strontium ranelate (SR)-SCAR. OBJECTIVE To characterize patients with AOA-SCAR, and investigate the HLA association as well as utility of in vitro diagnostic methods. METHODS We enrolled 16 cases with AOA-cutaneous adverse drug reactions (cADR), including SCAR (n=10: 8 with Stevens-Johnson syndrome [SJS] and 2 with drug rash with eosinophilia and systemic symptoms [DRESS]) and maculopapular exanthema (MPE) (n=6) from Taiwan and Hong Kong. We analyzed the clinical characteristics, outcomes, HLA alleles and in vitro testing of AOA-SCAR as well as tolerability to alternative drugs. We further performed literature review and meta-analysis on the HLA association of AOA-SCAR. RESULTS Our data showed strontium ranelate is the most common causality of AOA-SCAR in Asian papulations. There was no cross hypersensitivity of SR-SCAR with other AOA. HLA genotyping showed that SR-SJS was most significantly associated with HLA-A*33:03 (Pc=5.17x10-3 , OR: 25.97, 95% CI:3.08-219.33). Meta-analysis showed that HLA-A*33:03 was associated with SR-SJS (P=5.01x10-5 ; sensitivity: 85.7%) in Asians. The sensitivity of lymphocyte activation test (LAT) for identifying the culprit drug of SR-SJS was 83.3%. CONCLUSIONS Strontium ranelate is identified as the most notorious AOA associated with SCAR. The HLA-A*33:03 genetic allele and LAT testing may add benefits to the diagnosis of SR-SCAR in patients whose reaction developed while taking multiple drugs.