Dapsone hypersensitivity syndrome (DHS) was first reported by Lowe and Smith[1] in 1949 in Nigeria and was termed “dapsone syndrome” by Allday and Barnes[2] in 1951. DHS is a drug-induced hypersensitivity syndrome (DIHS) caused by dapsone 4′4’-diaminodiphenylsulfone (DDS). DHS is characterized by fever, rash, lymphadenopathy, and hepatitis, which usually develop after patients receive DDS for 5 to 6 weeks. Epidemiological studies have estimated DHS prevalence and fatality rates of 1.4% and 9.9%, respectively.[3] Until recently, the “wait and see” approach was used for patients with suspected DHS. Herein, we review recent developments in DHS research, focusing on its etiology, pathogenesis, diagnosis, and prevention, to make DDS a safer medication for most of the population through the prospective exclusion of susceptible patients before DDS administration.
Specific HLA alleles have been known to be major determinants of drug-induced immune responses and tissue injury since 2002.[4] No genetic risk factor for DHS was identified until 2013. HLA-B∗13:01 has been found to be a strong risk factor for DHS, according to a genome-wide association study (odds ratio, 20.53; P = 6.84 × 10−25)[5] and major histocompatibility complex (MHC) I region typing (odds ratio, 69.6; P = 1.96 × 10−11)[6] in the Chinese population. The same HLA association has been verified in Taiwan (China),[7] Japan,[8] Thailand,[9] Malaysia,[10] India,[11] Korea,[12] and Indonesia.[13] In addition, the HLA-B∗13:01 allele is significantly associated with DDS-induced Stevens–Johnson syndrome and toxic epidermal necrolysis.[9] Moreover, HLA-B∗13:01 is strongly associated with trichloroethylene-induced hypersensitivity dermatitis in China[14] and co-trimoxazole-induced severe cutaneous adverse reactions in Asians.[15]
The frequency of HLA-B∗13:01 varies substantially, from 0% to 28.3%,[16] among populations. In the Chinese population, the HLA-B∗13:01 allele frequency can range from 2% to 20% across provinces.[5] However, DHS has also been reported in populations of European descent[17] and in patients from Nigeria,[1,2] in whom the expression of HLA-B∗13:01 is rare. In addition, the positive predictive value of HLA-B∗13:01 for DHS is 7.8%.[5] Therefore, additional genetic variants located within or outside HLA loci might be involved in DHS. In 2017, five significantly associated amino acid polymorphisms in HLA-DRB1 (positions: 133, 142, −17, 11, and 13) in HLA-DRB1∗15:01 and HLA-DRB1∗16:02 were identified to be associated with DHS in the Chinese population.[18] Combining HLA-B∗13:01 allele with amino acid variant Leu133 of DRB1 slightly increases the positive predictive value to 9.2%. In addition to HLA associations, the CYP2C9∗3 variant (A1075C) has been found in eight patients with DHS.[7] This finding is important, because CYP enzymes metabolize DDS to a hydroxylamine metabolite that undergoes auto-oxidation and forms nitroso dapsone.[19] However, non-MHC SNPs were not significantly associated with DHS in our recent two-stage GWAS of patients with DHS in the Chinese population (unpublished data).
The display of drug antigens by MHC proteins, patient genotype, and patient phenotype are critical factors in the development of drug hypersensitivity.[20] Thus, DDS and its metabolite, the HLA allele, and T-lymphocytes may play important roles in the pathogenesis of DHS. To date, one study has focused on the nature of the chemical interaction between DDS and HLA-B∗13:01. Three-dimensional structural analyses have indicated that three amino acids (I94I95R97) of HLA-B∗13:01 differing from those in HLA-B∗13:02 (T94W95T97) are all located in the peptide antigen-binding site. The amino acid at position 95 endows HLA-B∗13:01 with a deeper sub-pocket around the F-pocket. Molecular docking calculations have indicated that this unique pocket of HLA-B∗13:01 binds DDS more tightly than does HLA-B∗13:02. Therefore, HLA-B∗13:01 might potentially serve as an important predictor of DHS.[21]
The association of DHS with HLA-B∗13:01 supports an underlying T-cell mediated process. In support of this possibility, the parent drug and nitroso metabolite have been found to interact with HLA class I and class II molecules expressed on dendritic cells, and to stimulate naïve CD4+ and CD8+ T-cells from healthy donors after the removal of Tregs from peripheral blood mononuclear cells (PBMCs).[19] Chen et al[7] have reported granulysin up-regulation in patients with DIHS caused by dapsone, and that dapsone-specific cytotoxic T-lymphocytes are activated after co-culture of the parent drug and HLA-B∗13:01 expressing cells. Zhao et al[22] have performed a detailed analysis of the phenotype and function of DDS and nitroso dapsone-specific T-cells from DHS patients with HLA-B∗13:01. Dapsone- and nitroso dapsone-responsive CD4+/CD8+ T-cell clones were isolated from the peripheral blood, and drug exposure was associated with the secretion of IFN-γ, and cytolytic molecules such as perforin, granzyme B, and Fas L. CD4+ clones express the homing receptors CXCR3 and CCR4, whereas the chemokine receptors displayed on CD8+ clones are restricted to CCR6, 9, and 10. CCR4 and CCR10 are thought to have important roles in the migration of T-cells into the skin.[23] CD4+ and CD8+ T cells are activated by the parent drug via direct HLA binding,[22,24] whereas nitroso dapsone covalently binds protein, and antigen presenting cell processing is required for MHC binding and the generation of T-cell stimulatory peptides[22] [Figure 1]. HLA-B∗13:01 restricted CD8+ DDS-responsive clones express a variety of TCR sequences, whereas the dominant clonotype from nitroso dapsone-responsive CD8+ T cell clones was shared amongst patients.[25] Recently, Jiang et al[24] have showed that TRAV12-3/TRBV28 clonotype with shared CDR3 region could specifically recognize HLA-B∗13:01-DDS complex to trigger inflammatory cytokines.
;)
Figure 1: Mechanism of DHS. Dapsone (left) could interact directly with HLA-B∗13:01 resulting in activation of T cell, whereas nitroso dapsone (right) binds covalently to endogenous peptide then subjected to antigen processing and presented by HLA-B∗13:01 to T cell. DHS: Dapsone hypersensitivity syndrome.
The criteria used for diagnosis of DHS remain based on the study by Richardus and Smith.[26] However, in clinical practice, diagnosis is difficult due to patients taking multiple drugs, atypical symptoms, and so on. Furthermore, to decrease mortality, timely and adequate management should occur as soon as the diagnosis is made.[27] Drug-specific cytokine-releasing cells with enzyme-linked immunospot (ELISpot) assays can be measured during the acute stage of reaction. IFN-γ, IL-5, and granzyme B have been reported to have higher levels in PBMCs from patients with DHS after in vitro stimulation with DDS. ELISpot detection of these three related cytokines has a sensitivity of 87.5% and thus may be an attractive method for diagnosis of DHS.[28] A validated approach to diagnostic testing would enable clinicians to accurately diagnose DHS.
Genetic testing has been used to minimize the incidence of severe cutaneous adverse events.[29] One study has evaluated the clinical use of prospective HLA-B∗13:01 screening to decrease the incidence of DHS.[30] A total of 1512 individuals underwent HLA-B∗13:01 genotyping before receiving dapsone. Among the 1251 HLA-B∗13:01 non-carriers, 1239 patients received dapsone, and no DHS was reported. Therefore, screening for HLA-B∗13:01 before DDS administration can identify patients at high risk of developing DHS in the Chinese population. As described above, the frequency of HLA-B∗13:01 varies across different ethnic populations. Nonetheless, HLA-B∗13:01 screening is a useful tool for population assessment for DDS therapy and the prevention of DHS.
Clinical and functional studies have suggested an important role of HLA-B∗13:01 in the pathogenesis of DHS. Prospective HLA-B∗13:01 screening applied alongside effective diagnostic testing in patients who develop adverse events can significantly decrease the incidence of DHS in the Chinese population and enable better management of the small number of patients who develop DHS. Further research is needed to identify other genetic or environmental factors contributing to DHS, and to determine how they influence disease susceptibility and severity. Finally, further investigations using PBMC and tissue samples from populations outside China or Asia are needed to explore how DHS develops.
Funding
This work was supported by grants from the Academic promotion program of Shandong First Medical University (Nos. 2019LJ002, 2019RC007, 2020RC001), the Youth technology Innovation Support Project of Shandong Colleges and Universities (No. 2019KJL003), the National Natural Science Foundation of China (Nos. 81811530342, 81972946, 81903224, 82103734), the Shandong Provincial Foreign Expert Project (No. WST2019004), and the China Scholarship Council (No. 201806220227).
Conflicts of interest
None.
References
1. Lowe J, Smith M. The chemotherapy of leprosy in Nigeria; with an appendix on glandular fever and exfoliative dermatitis precipitated by sulfones. Int J Lepr 1949;17:181–195.
2. Allday EJ, Barnes J. Toxic effects of diaminodiphenylsulphone in treatment of leprosy. Lancet 1951;2:205–206. doi: 10.1016/s0140-6736(51)91443-2.
3. Lorenz M, Wozel G, Schmitt J. Hypersensitivity reactions to dapsone: a systematic review. Acta Derm Venereol 2012;92:194–199. doi: 10.2340/00015555-1268.
4. Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, et al. Association between presence of HLA-B∗5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 2002;359:727–732. doi: 10.1016/s0140-6736(02)07873-x.
5. Zhang FR, Liu H, Irwanto A, Fu XA, Li Y, Yu GQ, et al. HLA-B∗13:01 and the dapsone hypersensitivity syndrome. N Engl J Med 2013;369:1620–1628. doi: 10.1056/NEJMoa1213096.
6. Wang H, Yan L, Zhang G, Chen X, Yang J, Li M, et al. Association between HLA-B∗1301 and dapsone-induced hypersensitivity reactions among leprosy patients in China. J Invest Dermatol 2013;133:2642–2644. doi: 10.1038/jid.2013.192.
7. Chen WT, Wang CW, Lu CW, Chen CB, Lee HE, Hung SI, et al. The function of HLA-B∗13:01 involved in the pathomechanism of dapsone-induced severe cutaneous adverse reactions. J Invest Dermatol 2018;138:1546–1554. doi: 10.1016/j.jid.2018.02.004.
8. Kinehara Y, Kijima T, Inoue K, Hirata H, Takeuchi Y, Fukushima K, et al. Dapsone hypersensitivity syndrome-related lung injury without eosinophilia in the bronchoalveolar lavage fluid. Intern Med 2015;54:827–831. doi: 10.2169/internalmedicine.54.3406.
9. Tempark T, Satapornpong P, Rerknimitr P, Nakkam N, Saksit N, Wattanakrai P, et al. Dapsone-induced severe cutaneous adverse drug reactions are strongly linked with HLA-B∗13: 01 allele in the Thai population. Pharmacogenet Genomics 2017;27:429–437. doi: 10.1097/FPC.0000000000000306.
10. Ramalingam R, Too CL, Tang MM. Dapsone hypersensitivity syndrome and dapsone-induced liver injury in four Malaysian indigenous individuals with leprosy. Malays J Dermatol 2018;40:73–79.
11. Chiramel MJ, George R, Daniel D, Sam Arul Das R, Mani V, Antonisamy B, et al. Case-control study measuring the association between HLA-B∗13:01 and dapsone hypersensitivity syndrome in Indian patients. Lepr Rev 2019;90:371–377. doi: 10.47276/lr.90.4.371.
12. Park HJ, Park JW, Kim SH, Choi SY, Kim HK, Jung CG, et al. The HLA-B∗13:01 and the dapsone hypersensitivity syndrome in Korean and Asian populations: Genotype- and meta-analyses. Expert Opin Drug Saf 2020;19:1349–1356. doi: 10.1080/14740338.2020.1796965.
13. Krismawati H, Irwanto A, Pongtiku A, Irwan ID, Maladan Y, Sitanggang YA, et al. Validation study of HLA-B∗13:01 as a biomarker of dapsone hypersensitivity syndrome in leprosy patients in Indonesia. PLoS Negl Trop Dis 2020;14:e0008746. doi: 10.1371/journal.pntd.0008746.
14. Li H, Dai Y, Huang H, Li L, Leng S, Cheng J, et al. HLA-B∗1301 as a biomarker for genetic susceptibility to hypersensitivity dermatitis induced by trichloroethylene among workers in China. Environ Health Perspect 2007;115:1553–1556. doi: 10.1289/ehp.10325.
15. Wang CW, Tassaneeyakul W, Chen CB, Chen WT, Teng YC, Huang CY, et al. Whole genome sequencing identifies genetic variants associated with co-trimoxazole hypersensitivity in Asians. J Allergy Clin Immunol 2021;147:1402–1412. doi: 10.1016/j.jaci.2020.08.003.
16. Gonzalez-Galarza FF, Christmas S, Middleton D, Jones AR. Allele frequency net: a database and online repository for immune gene frequencies in worldwide populations. Nucleic Acids Res 2011;39:D913–D919. doi: 10.1093/nar/gkq1128.
17. Schulkes KJ, Tervaert JW, Rijken F, Haas LE. Dapsone hypersensitivity syndrome not related to G6PD deficiency. BMJ Case Rep 2015;2015:bcr2015212742. doi: 10.1136/bcr-2015-212742.
18. Yue Z, Sun Y, Wang C, Yu W, Cao J, Bao F, et al. Amino acid variants of HLA-DRB1 confer susceptibility to dapsone hypersensitivity syndrome in addition to HLA-B∗13:01. J Invest Dermatol 2018;138:1101–1106. doi: 10.1016/j.jid.2017.11.027.
19. Alzahrani A, Ogese M, Meng X, Waddington JC, Tailor A, Farrell J, et al. Dapsone and nitroso dapsone activation of naive T-cells from healthy donors. Chem Res Toxicol 2017;30:2174–2186. doi: 10.1021/acs.chemrestox.7b00263.
20. Ogese MO, Ahmed S, Alferivic A, Betts CJ, Dickinson A, Faulkner L, et al. New approaches to investigate drug-induced hypersensitivity. Chem Res Toxicol 2017;30:239–259. doi: 10.1021/acs.chemrestox.6b00333.
21. Watanabe H, Watanabe Y, Tashiro Y, Mushiroda T, Ozeki T, Hashizume H, et al. A docking model of dapsone bound to HLA-B∗13:01 explains the risk of dapsone hypersensitivity syndrome. J Dermatol Sci 2017;88:320–329. doi: 10.1016/j.jdermsci.2017.08.007.
22. Zhao Q, Alhilali K, Alzahrani A, Almutairi M, Amjad J, Liu H, et al. Dapsone- and nitroso dapsone-specific activation of T cells from hypersensitive patients expressing the risk allele HLA-B∗13:01. Allergy 2019;74:1533–1548. doi: 10.1111/all.13769.
23. Xia M, Hu S, Fu Y, Jin W, Yi Q, Matsui Y, et al. CCR10 regulates balanced maintenance and function of resident regulatory and effector T cells to promote immune homeostasis in the skin. J Allergy Clin Immunol 2014;134:634–644. e10. doi: 10.1016/j.jaci.2014.03.010.
24. Jiang H, Wang CW, Wang Z, Dai Y, Zhu Y, Lee YS, et al. Functional and structural characteristics of HLA-B∗13:01-mediated specific T cells reaction in dapsone-induced drug hypersensitivity. J Biomed Sci 2022;29:58. doi: 10.1186/s12929-022-00845-8.
25. Zhao Q, Almutairi M, Tailor A, Lister A, Harper N, Line J, et al. HLA Class-II-restricted CD8
+ T cells contribute to the promiscuous immune response in dapsone-hypersensitive patients. J Invest Dermatol 2021;141:2412–2425. e2. doi: 10.1016/j.jid.2021.03.014.
26. Richardus JH, Smith TC. Increased incidence in leprosy of hypersensitivity reactions to dapsone after introduction of multidrug therapy. Lepr Rev 1989;60:267–273. doi: 10.5935/0305-7518.19890033.
27. Tian W, Shen J, Zhou M, Yan L, Zhang G. Dapsone hypersensitivity syndrome among leprosy patients in China. Lepr Rev 2012;83:370–377. doi: 10.47276/lr.83.4.370.
28. You J, Sun L, Zhao Q, Zhang H, Huai P, Yu G, et al. Dynamic cytokine profiles combined with enzyme-linked immunospot assay are useful for immunologically confirming the dapsone hypersensitivity syndrome. J Am Acad Dermatol 2021;84:814–816. doi: 10.1016/j.jaad.2020.06.032.
29. Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, et al. HLA-B∗5701 screening for hypersensitivity to abacavir. N Engl J Med 2008;358:568–579. doi: 10.1056/NEJMoa0706135.
30. Liu H, Wang Z, Bao F, Wang C, Sun L, Zhang H, et al. Evaluation of prospective HLA-B∗13:01 screening to prevent dapsone hypersensitivity syndrome in patients with leprosy. JAMA Dermatol 2019;155:666–672. doi: 10.1001/jamadermatol.2018.5360.
