H Y Lee1,2, M X Shen3, Y L Lim4, Y K Tay2,5, M M F Chan2,6, S M Pang1,2, Z W Xiao3, S B Ang2,7, E C Ren8,9. 1. Department of Dermatology, Singapore General Hospital, Singapore, Singapore. 2. Duke-NUS Graduate Medical School, Singapore, Singapore. 3. Singapore Immunology Network, A*STAR, 8A Biomedical Grove, Immunos #03-06, Singapore, 138648, Singapore. 4. National Skin Center, Singapore, Singapore. 5. Dermatology Department, Changi General Hospital, Singapore, Singapore. 6. Department of Pathology, Singapore General Hospital, Singapore, Singapore. 7. Menopause Unit and Family Medicine Service, KK Women's and Children's Hospital, Singapore, Singapore. 8. Singapore Immunology Network, A*STAR, 8A Biomedical Grove, Immunos #03-06, Singapore, 138648, Singapore. ren_ee_chee@immunol.a-star.edu.sg. 9. Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. ren_ee_chee@immunol.a-star.edu.sg.
Abstract
UNLABELLED: 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.
UNLABELLED: 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 osteoporoticpatients 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:Osteoporoticpatients 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 osteoporoticpatients who may be prescribed strontium ranelate.
Authors: J Y Reginster; E Seeman; M C De Vernejoul; S Adami; J Compston; C Phenekos; J P Devogelaer; M Diaz Curiel; A Sawicki; S Goemaere; O H Sorensen; D Felsenberg; P J Meunier Journal: J Clin Endocrinol Metab Date: 2005-02-22 Impact factor: 5.958
Authors: Ann K Daly; Peter T Donaldson; Pallav Bhatnagar; Yufeng Shen; Itsik Pe'er; Aris Floratos; Mark J Daly; David B Goldstein; Sally John; Matthew R Nelson; Julia Graham; B Kevin Park; John F Dillon; William Bernal; Heather J Cordell; Munir Pirmohamed; Guruprasad P Aithal; Christopher P Day Journal: Nat Genet Date: 2009-05-31 Impact factor: 38.330
Authors: Jean-Yves Reginster; Dieter Felsenberg; Steven Boonen; Adolfo Diez-Perez; Rene Rizzoli; Maria-Luisa Brandi; Tim D Spector; Kim Brixen; Stefan Goemaere; Catherine Cormier; Adam Balogh; Pierre D Delmas; Pierre J Meunier Journal: Arthritis Rheum Date: 2008-06
Authors: Rebecca Pavlos; Katie D White; Celestine Wanjalla; Simon A Mallal; Elizabeth J Phillips Journal: Immunol Allergy Clin North Am Date: 2017-11 Impact factor: 3.479