Association between HLA-B*1301 and Dapsone-Induced Hypersensitivity Reactions among Leprosy Patients in China
2013; Elsevier BV; Volume: 133; Issue: 11 Linguagem: Inglês
10.1038/jid.2013.192
ISSN1523-1747
AutoresHongsheng Wang, Liangbin Yan, Guocheng Zhang, Xiang‐Sheng Chen, Jun Yang, Ming Li, Jianping Shen, Meiwen Yu, Ran Huo, Baoxi Wang,
Tópico(s)Autoimmune Bullous Skin Diseases
Resumoarea under the curve cytochrome P450 2C9 dapsone-induced hypersensitivity reaction human leukocyte antigen major histocompatibility complex N-acetyltransferase2 TO THE EDITOR Dapsone (4,40-diaminodiphenylsulfone) has been widely used in the treatment of leprosy since its discovery in the 1940s, and some of its reported side effects include methemoglobinemia, hemolysis, agranulocytosis, and dapsone-induced hypersensitivity reactions (DIHRs) (Zhu and Stiller, 2001Zhu Y.I. Stiller M.J. Dapsone and sulfones in dermatology: overview and update.J Am Acad Dermatol. 2001; 45: 420-434Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar). DIHR is a life-threatening drug reaction, which has been reported in ∼2% of leprosy patients on dapsone therapy; thus, with 12.5% mortality, DIHR is one of the major causes of mortality in leprosy patients (Pandey et al., 2007Pandey B. Shrestha K. Lewis J. et al.Mortality due to dapsone hypersensitivity syndrome complicating multi-drug therapy for leprosy in Nepal.Trop Doct. 2007; 37: 162-163Crossref PubMed Scopus (18) Google Scholar; Shen et al., 2011Shen J. Liu M. Zhou M. Li W. Causes of death among active leprosy patients in China.Int J Dermatol. 2011; 50: 57-60Crossref PubMed Scopus (13) Google Scholar). DIHR is clinically manifested through fever, rash, lymphadenopathy, and hepatitis, and is categorized under the drug-induced hypersensitivity or drug rash with eosinophilia and systemic symptoms syndromes (Sener et al., 2006Sener O. Doganci L. Safali M. et al.Severe dapsone hypersensitivity syndrome.J Investig Allergol Clin Immunol. 2006; 16: 268-270PubMed Google Scholar; Kardaun et al., 2007Kardaun S.H. Sidoroff A. Valeyrie-Allanore L. et al.Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?.Br J Dermatol. 2007; 156: 609-611Crossref PubMed Scopus (733) Google Scholar; Kumari et al., 2011Kumari R. Timshina D.K. Thappa D.M. Drug hypersensitivity syndrome.Indian J Dermatol Venereol Leprol. 2011; 77: 7-15Crossref PubMed Scopus (43) Google Scholar). Unlike other drug reactions, DIHR usually presents with low hemoglobin and a higher risk of liver involvement, including cholestatic or hepatocellular disease, or both (Richardus and Smith, 1989Richardus J.H. Smith T.C. Increased incidence in leprosy of hypersensitivity reactions to dapsone after introduction of multidrug therapy.Lepr Rev. 1989; 60: 267-273Crossref PubMed Scopus (53) Google Scholar; Zhu and Stiller, 2001Zhu Y.I. Stiller M.J. Dapsone and sulfones in dermatology: overview and update.J Am Acad Dermatol. 2001; 45: 420-434Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar). Although the exact mechanism of DIHR remains unclear, numerous reports have described the associations between human leukocyte antigens (HLA, especially MHCI) and drug eruptions in patients with various diseases (Mallal et al., 2002Mallal S. Nolan D. Witt 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: 727-732Abstract Full Text Full Text PDF PubMed Scopus (1222) Google Scholar; Chung et al., 2004Chung W.H. Hung S.I. Hong H.S. et al.Medical genetics; a marker for Stevens-Johnson syndrome.Nature. 2004; 428: 486Crossref PubMed Scopus (1362) Google Scholar; Pavlos et al., 2012Pavlos R. Mallal S. Phillips E. HLA and pharmacogenetics of drug hypersensitivity.Pharmacogenomics. 2012; 13: 1285-1306Crossref PubMed Scopus (153) Google Scholar). Some HLA profiles are useful tools in diagnosing and preventing life-threatening adverse drug reactions (Chung et al., 2004Chung W.H. Hung S.I. Hong H.S. et al.Medical genetics; a marker for Stevens-Johnson syndrome.Nature. 2004; 428: 486Crossref PubMed Scopus (1362) Google Scholar; Mallal et al., 2008Mallal S. Phillips E. Carosi G. et al.HLA-B*5701 screening for hypersensitivity to abacavir.N Engl J Med. 2008; 358: 568-579Crossref PubMed Scopus (1486) Google Scholar). Dapsone is metabolized through acetylation and N-hydroxylation. Genetic polymorphism of human NAT2 determining slow acetylator status is a predisposing factor for allergic diseases and drug adverse reactions (Zielinska et al., 1998Zielinska E. Niewiarowski W. Bodalski J. The arylamine N-acetyltransferase (NAT2) polymorphism and the risk of adverse reactions to co-trimoxazole in children.Eur J Clin Pharmacol. 1998; 54: 779-785Crossref PubMed Scopus (28) Google Scholar; Gawronska-Szklarz et al., 1999Gawronska-Szklarz B. Luszawska-Kutrzeba T. Czaja-Bulsa G. et al.Relationship between acetylation polymorphism and risk of atopic diseases.Clin Pharmacol Ther. 1999; 65: 562-569Crossref PubMed Scopus (44) Google Scholar). Cytochrome P450 2C9 (CYP2C9) has also been shown to be the initial step in the formation of toxic intermediate metabolites of sulfonamides, which are analogs of dapsone, that can induce hemolytic anemia and skin rash (Winter et al., 2000Winter H.R. Wang Y. Unadkat J.D. CYP2C8/9 mediate dapsone N-hydroxylation at clinical concentrations of dapsone.Drug Metab Dispos. 2000; 28: 865-868PubMed Google Scholar; Wolkenstein et al., 2005Wolkenstein P. Loriot M.A. Flahault A. et al.Association analysis of drug metabolizing enzyme gene polymorphisms in AIDS patients with cutaneous reactions to sulfonamides.J Invest Dermatol. 2005; 125: 1080-1082Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). We performed a case–control study from June 2009 to June 2012 in Southern China and screened 1058 cases of leprosy patients. Among them, 21 cases (1.98%) met the enrollment criteria for DIHR according to Richardus and Smith, 1989Richardus J.H. Smith T.C. Increased incidence in leprosy of hypersensitivity reactions to dapsone after introduction of multidrug therapy.Lepr Rev. 1989; 60: 267-273Crossref PubMed Scopus (53) Google Scholar criteria; 105 dapsone-tolerant control cases were also studied, defined as leprosy patients with more than 8 weeks of exposure to dapsone but without any episode of drug eruption and reaction. In addition, 100 non-leprosy control individuals were recruited from local community blood donors. The socio-demographic characteristics of the DIHR patients, dapsone-tolerant patients, and healthy controls are summarized in Table 1 (Supplementary Table S1 online). No significant difference was observed in terms of age, sex, and ethnicity among the three groups (age: P=0.713, sex: P=1.000, ethnicity: P=1.000). Patients presented with clinical signs of DIHR at a median of 28±8.5 days after starting dapsone. The most common documented clinical signs of DIHR were fever (100%) and rash (100%). Of the 21 cases, 15 (71.4%) and 6 (28.6%) cases presented with maculopapular eruptions and vesiculopapules, respectively. Lymphadenopathy was noted in 16 (76.2%) cases. The abnormal laboratory profiles involved elevated levels of serum liver enzymes and hypoalbuminemia in all cases, as well as low hemoglobin, leukocytosis, and eosinophilia in 18 (85.7%), 18 (85.7%), and 10 cases (47.6%), respectively. Cessation of dapsone therapy was recommended by local doctors upon suspecting DIHR; the patients were then treated with systemic corticosteroids at average doses of 0.5 to 1mgkg−1 of prednisolone, and their skin eruptions subsided on an average of 21.6±8.7 days.Table 1Demographic data for the cases and controlsVariableLeprosy patients with DIHR (n=21)DDS-tolerant leprosy patients (n=105)Healthy controls1Healthy controls: healthy non-leprosy controls not exposed to dapsone. (n=100)Age (years mean±SD)38.2±11.740.3±11.839.5±10.7Male (no. (%))11 (52.4%)55 (52.4%)53 (53.0%)Female (no. (%))10 (47.6%)50 (47.6%)47 (47%)DDS-exposure duration (weeks) 8-Han Chinese12 (57.1%)55 (52.4%)52 (52.0%)Non-Han Chinese9 (42.9%)50 (47.6%)48 (48.0%) Miao group4 (19.0%)22 (21.0%)20 (20.0%) Tu group2 (9.5%)12 (11.4%)12 (12.0%) Zhuang group2 (9.5%)12 (11.4%)12 (12.0) Buyi group1 (4.8%)4 (3.8%)4 (4.0%)Abbreviations: DDS, diamino diphenyl sulphone (dapsone); DIHR, dapsone-induced hypersensitivity reaction.1 Healthy controls: healthy non-leprosy controls not exposed to dapsone. Open table in a new tab Download .doc (.08 MB) Help with doc files Supplementary Table S1 Abbreviations: DDS, diamino diphenyl sulphone (dapsone); DIHR, dapsone-induced hypersensitivity reaction. Major histocompatibility complex (MHC) I region typing and gene polymorphisms of related metabolism enzymes were detected in 122 leprosy patients exposed to dapsone and 96 healthy controls (Supplementary Materials and Methods online). HLA-B*1301 and HLA-Cw*0304 were present in significantly higher frequencies in DIHR patients than in either dapsone-tolerant patients or healthy controls (Table 2; Supplementary Table S2 online). Particularly, HLA–B*1301 was found in 90% of DIHR patients and was present in only 6.9% of dapsone-tolerant patients, with a sensitivity and specificity of 90 and 93.1%, respectively (AUC: 0.92). If either HLA-B*1301 or HLA B*1313 was present, the sensitivity and specificity were 100 and 92.2%, respectively (AUC: 0.961). The most common of these three-locus MHC I-combined haplotypes in DIHR patients was HLA-A*1101-B*1301-Cw*0304 (68.4%); however, it was present in only 1% of dapsone-tolerant patients. Among DIHR and dapsone-tolerant patients, the presence of HLA-B*1301 and HLA-C*0304 alleles had a positive predictive value for DIHR (76%), and the absence of this combination of alleles had a negative predictive value of 99.0%, whereas the presence of the HLA-B*1301 haplotype alone was associated with positive (72.0%) and negative (97.9%) predictive values for DIHR. No significant association was observed among any of the genotypes or phenotypes of CYP2C9 (including the single-nucleotide polymorphisms of its promoter) and NAT2 with occurrence of DIHR. Download .pdf (.1 MB) Help with pdf files Supplementary InformationTable 2Frequency of HLA alleles in cases and controlsHLA alleleLeprosy patients with DIHR (n=20)DDS-tolerant leprosy patients (n=102)Healthy controls1Healthy controls: healthy non-leprosy controls not exposed to dapsone. n=96)OR (95% CI)pcB*130118 (90%)7(6.9%)11(11.5%)122.1 (23. 5–636.2)2Cases/dapsone-tolerant controls.69.6 (14.2–341.0)3Cases/healthy controls.6.038 × 10−12 2Cases/dapsone-tolerant controls.1.961 × 10−11 3Cases/healthy controls.B*13132 (10%)1 (1.0%)0 (0%)C*030419 (95%)22 (21.6%)24 (25%)B*1301, C*030417 (85%)6 (5.9%)2Cases/dapsone-tolerant controls.4 (4.2%)90.667 (20.7–397. 8)2Cases/dapsone-tolerant controls.4.280 × 10−11 2Cases/dapsone-tolerant controls.B*1301 or B*131320 (100%)8 (7.9%)2Cases/dapsone-tolerant controls.11 (11.5%)3Cases/healthy controls.470.0 (25.9–8521.3)2Cases/dapsone-tolerant controls.154.6 (18.8–1267.4)3Cases/healthy controls.8.320 × 10−15 2Cases/dapsone-tolerant controls.4.040 × 10−13 3Cases/healthy controls.A*11:01, B*13:01, C*03:0413 (68.4%, n=19)3 (3.0%, n=101)4Failure in genotyping for HLA A in 1 leprosy patient with DIHR and 1 DDS-tolerant leprosy patient.70. 8 (15.8–317.8)2Cases/dapsone-tolerant controls.216.7 (24.1–1944.6)5Cases/dapsone-tolerant controls (analysis of the haplotype of linkage disequilibrium for HLA-A*1101-B*1301-Cw*0304).1.668 × 10−8 2Cases/dapsone-tolerant controls.4.644 × 10−10 5Cases/dapsone-tolerant controls (analysis of the haplotype of linkage disequilibrium for HLA-A*1101-B*1301-Cw*0304).Abbreviations: CI, confidence interval; DDS, diamino diphenyl sulphone (dapsone); DIHR, dapsone-induced hypersensitivity reaction; HLA, human leukocyte antigen; OR, odds ratio.1 Healthy controls: healthy non-leprosy controls not exposed to dapsone.2 Cases/dapsone-tolerant controls.3 Cases/healthy controls.4 Failure in genotyping for HLA A in 1 leprosy patient with DIHR and 1 DDS-tolerant leprosy patient.5 Cases/dapsone-tolerant controls (analysis of the haplotype of linkage disequilibrium for HLA-A*1101-B*1301-Cw*0304). Open table in a new tab Download .doc (.61 MB) Help with doc files Supplementary Table S2 Abbreviations: CI, confidence interval; DDS, diamino diphenyl sulphone (dapsone); DIHR, dapsone-induced hypersensitivity reaction; HLA, human leukocyte antigen; OR, odds ratio. The current study proposes that the presence of the HLA-B*1301 haplotype is strongly associated with DIHR development, supporting an important and immediately applicable clinical role for HLA typing in this setting. However, several limitations are present. First, although the study was carried out in several geographical areas in China, further studies among patients with different ethnic backgrounds are needed. Second, the sample size may not be large enough for the subgroup analysis to show potential associations between HLA alleles and subgroups of DIHR, even though current data showed statistical significance and a strong association between HLA-B*1301 and DIHR. Third, given the difficulty of sample collection, non-leprosy patients with DIHR and other dapsone-related side effects were not investigated in this study; confirmation as to whether the findings in leprosy patients can be used for non-leprosy patients with DIHR is still required. In summary, HLA-B*1301 can be a useful biomarker in predicting DIHR before administering dapsone to leprosy patients in the Chinese population. DIHR mechanism appears to be immunologically related to HLA, but not to dapsone metabolism. Further studies are needed to investigate the molecular mechanisms of HLA subtypes and DIHR in leprosy patients. A large-scale prospective study is also necessary to verify the value of HLA-B*1301 as a predictive biomarker for DIHR. Nevertheless, our results provide plausible basis for predicting DIHR in dapsone-exposed leprosy cases, and have implications for further scientific research and control of DIHR in leprosy. The study was approved by the Medical Ethics Committee of the Chinese Academy of Medical Sciences Institute of Dermatology in Nanjing [KYZR2009-016], and written, informed consent was obtained from all participants. This study was supported by grants from the National Natural Science Foundation of China (No. 30972651) and the Research Special Fund for Public Welfare Industry of Health of China (No. 201002016), as well as by funding from the Key Clinical Program of the Ministry of Health of China (No. 2010-2012-125). Support for the HLA analyses was provided by Liming Wu and Ruixiao Ma. DISCLAIMER The sponsor of the study had no role in the study design, data collection, data analysis, data interpretation, or manuscript preparation. HW and LY had full access to data collected for the study, and BW and HW had final responsibility and decision for publication submission. Supplementary material is linked to the online version of the paper at http://www.nature.com/jid
Referência(s)