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Increased risk of strontium ranelate-related SJS/TEN is associated with HLA

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Abstract

Summary

Severe adverse drug reactions (ADR) of Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) in some patients receiving strontium ranelate have been reported, but the risk factors are unclear. We show that HLA-A*33:03 and B*58:01 are significantly associated with patients who developed SJS/TEN; and provide the first evidence that genetic risk factors are involved in strontium ranelate-associated SJS/TEN.

Introduction

In this study, HLA as a genetic risk factor was assessed among osteoporotic patients prescribed with strontium ranelate that developed severe cutaneous adverse drug reactions (SCARs) compared with those who were tolerant.

Methods

Genomic DNA isolated from peripheral blood mononuclear cells (PBMCs) of patients was HLA typed using sequencing-based typing method to determine their HLA profiles.

Results

Osteoporotic patients who are currently on strontium ranelate were enrolled in the study (n = 76). Tolerant controls were defined as patients who received strontium ranelate for a minimum of 3 months (range 3 months to 8 years) with no reports of any cutaneous reactions as these reactions usually occur within the first 12 weeks after starting treatment. Retrospective cases of SJS/TEN were also identified (n = 5). The majority of the accrued samples were of Han Chinese descent: controls (n = 72) and cases (n = 4). All cases and controls were genotyped at four HLA genes, namely HLA-A, HLA-B, HLA-C, and HLA-DRB1. In comparing the samples of Han Chinese descent (72 controls and 4 cases), we found significant associations with HLA-A*33:03 (p = 0.002) and HLA-B*58:01 (p = 0.023). There was no significant association with any HLA-C or HLA-DRB1 alleles.

Conclusions

This study reveals that the occurrence of SJS/TEN in Han Chinese patients receiving strontium ranelate is HLA associated. This has important clinical implications for understanding the underlying mechanisms for this ADR as well as evaluating the potential role of genetic pre-screening for osteoporotic patients who may be prescribed strontium ranelate.

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Acknowledgments

We are indebted to the SJS-TEN patients and control groups, and other members of the health care teams in Singapore General Hospital, KK Women’s and Children’s Hospital, National Skin Center, and Changi General Hospital for their support and contribution to this work. This study is supported by the Singapore Immunology Network core grant F0006 in collaboration with Servier Laboratories.

Author information

Authors and Affiliations

  1. Department of Dermatology, Singapore General Hospital, Singapore, Singapore

    H. Y. Lee & S. M. Pang

  2. Duke-NUS Graduate Medical School, Singapore, Singapore

    H. Y. Lee, Y. K. Tay, M. M. F. Chan, S. M. Pang & S. B. Ang

  3. Singapore Immunology Network, A*STAR, 8A Biomedical Grove, Immunos #03-06, Singapore, 138648, Singapore

    M. X. Shen, Z. W. Xiao & E. C. Ren

  4. National Skin Center, Singapore, Singapore

    Y. L. Lim

  5. Dermatology Department, Changi General Hospital, Singapore, Singapore

    Y. K. Tay

  6. Department of Pathology, Singapore General Hospital, Singapore, Singapore

    M. M. F. Chan

  7. Menopause Unit and Family Medicine Service, KK Women’s and Children’s Hospital, Singapore, Singapore

    S. B. Ang

  8. Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    E. C. Ren

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  1. H. Y. Lee
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Corresponding author

Correspondence to E. C. Ren.

Ethics declarations

Peripheral blood samples drawn for genomic DNA isolation was collected with informed consent. The study was approved by the SingHealth Institutional Review Board CIRB Ref 2013/600/3.

Conflicts of interest

None

Additional information

H.Y. Lee and M.X. Shen contributed equally to this work.

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Lee, H., Shen, M., Lim, Y. et al. Increased risk of strontium ranelate-related SJS/TEN is associated with HLA. Osteoporos Int 27, 2577–2583 (2016). https://doi.org/10.1007/s00198-016-3568-9

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  • DOI: https://doi.org/10.1007/s00198-016-3568-9

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