[Skip to Content]
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
[Skip to Content Landing]
Figure.
Enrollment and Outcomes
Enrollment and Outcomes

None of the patients recruited were given dapsone until they were informed of their HLA-B*13:01 status. Eight-week follow-up for all of the participants was performed, including 6 weekly telephone interviews and 2 more clinical visits. MB indicates multibacillary; MDT, multidrug therapy; and PB, paucibacillary.

Table 1.  
Baseline Characteristics of the Participants
Baseline Characteristics of the Participants
Table 2.  
Adverse Events During the 8-Week Follow-up
Adverse Events During the 8-Week Follow-up
1.
Chan  HL, Stern  RS, Arndt  KA,  et al.  The incidence of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis: a population-based study with particular reference to reactions caused by drugs among outpatients.  Arch Dermatol. 1990;126(1):43-47. doi:10.1001/archderm.1990.01670250049006PubMedGoogle ScholarCrossref
2.
Mallal  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(9308):727-732. doi:10.1016/S0140-6736(02)07873-XPubMedGoogle ScholarCrossref
3.
Martin  AM, Nolan  D, James  I,  et al.  Predisposition to nevirapine hypersensitivity associated with HLA-DRB1*0101 and abrogated by low CD4 T-cell counts.  AIDS. 2005;19(1):97-99. doi:10.1097/00002030-200501030-00014PubMedGoogle ScholarCrossref
4.
Littera  R, Carcassi  C, Masala  A,  et al.  HLA-dependent hypersensitivity to nevirapine in Sardinian HIV patients.  AIDS. 2006;20(12):1621-1626. doi:10.1097/01.aids.0000238408.82947.09PubMedGoogle ScholarCrossref
5.
Hung  SI, Chung  WH, Liou  LB,  et al.  HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol.  Proc Natl Acad Sci U S A. 2005;102(11):4134-4139. doi:10.1073/pnas.0409500102PubMedGoogle ScholarCrossref
6.
McCormack  M, Alfirevic  A, Bourgeois  S,  et al.  HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans.  N Engl J Med. 2011;364(12):1134-1143. doi:10.1056/NEJMoa1013297PubMedGoogle ScholarCrossref
7.
Zhang  FR, Liu  H, Irwanto  A,  et al.  HLA-B*13:01 and the dapsone hypersensitivity syndrome.  N Engl J Med. 2013;369(17):1620-1628. doi:10.1056/NEJMoa1213096PubMedGoogle ScholarCrossref
8.
Chung  WH, Chang  WC, Lee  YS,  et al; Taiwan Severe Cutaneous Adverse Reaction Consortium; Japan Pharmacogenomics Data Science Consortium.  Genetic variants associated with phenytoin-related severe cutaneous adverse reactions.  JAMA. 2014;312(5):525-534. doi:10.1001/jama.2014.7859PubMedGoogle ScholarCrossref
9.
Chung  WH, Hung  SI, Hong  HS,  et al.  Medical genetics: a marker for Stevens-Johnson syndrome.  Nature. 2004;428(6982):486. doi:10.1038/428486aPubMedGoogle ScholarCrossref
10.
Chen  P, Lin  JJ, Lu  CS,  et al; Taiwan SJS Consortium.  Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan.  N Engl J Med. 2011;364(12):1126-1133. doi:10.1056/NEJMoa1009717PubMedGoogle ScholarCrossref
11.
Mallal  S, Phillips  E, Carosi  G,  et al; PREDICT-1 Study Team.  HLA-B*5701 screening for hypersensitivity to abacavir.  N Engl J Med. 2008;358(6):568-579. doi:10.1056/NEJMoa0706135PubMedGoogle ScholarCrossref
12.
Ko  TM, Tsai  CY, Chen  SY,  et al; Taiwan Allopurinol-SCAR Consortium.  Use of HLA-B*58:01 genotyping to prevent allopurinol induced severe cutaneous adverse reactions in Taiwan: national prospective cohort study.  BMJ. 2015;351:h4848. doi:10.1136/bmj.h4848PubMedGoogle ScholarCrossref
13.
Mushiroda  T, Takahashi  Y, Onuma  T,  et al; GENCAT Study Group.  Association of HLA-A*31:01 screening with the incidence of carbamazepine-induced cutaneous adverse reactions in a Japanese population.  JAMA Neurol. 2018;75(7):842-849. doi:10.1001/jamaneurol.2018.0278PubMedGoogle ScholarCrossref
14.
Allday  EJ, Barnes  J.  Toxic effects of diaminodiphenylsulphone in treatment of leprosy.  Lancet. 1951;2(6675):205-206. doi:10.1016/S0140-6736(51)91443-2PubMedGoogle ScholarCrossref
15.
Zhu  YI, Stiller  MJ.  Dapsone and sulfones in dermatology: overview and update.  J Am Acad Dermatol. 2001;45(3):420-434. doi:10.1067/mjd.2001.114733PubMedGoogle ScholarCrossref
16.
Rao  PN, Lakshmi  TS.  Increase in the incidence of dapsone hypersensitivity syndrome—an appraisal.  Lepr Rev. 2001;72(1):57-62.PubMedGoogle Scholar
17.
Leslie  KS, Gaffney  K, Ross  CN, Ridley  S, Barker  TH, Garioch  JJ.  A near fatal case of the dapsone hypersensitivity syndrome in a patient with urticarial vasculitis.  Clin Exp Dermatol. 2003;28(5):496-498. doi:10.1046/j.1365-2230.2003.01336.xPubMedGoogle ScholarCrossref
18.
Lorenz  M, Wozel  G, Schmitt  J.  Hypersensitivity reactions to dapsone: a systematic review.  Acta Derm Venereol. 2012;92(2):194-199. doi:10.2340/00015555-1268PubMedGoogle ScholarCrossref
19.
Tian  W, Shen  J, Zhou  M, Yan  L, Zhang  G.  Dapsone hypersensitivity syndrome among leprosy patients in China.  Lepr Rev. 2012;83(4):370-377.PubMedGoogle Scholar
20.
Wang  H, Yan  L, Zhang  G,  et al.  Association between HLA-B*1301 and dapsone-induced hypersensitivity reactions among leprosy patients in China.  J Invest Dermatol. 2013;133(11):2642-2644. doi:10.1038/jid.2013.192PubMedGoogle ScholarCrossref
21.
Chen  WT, Wang  CW, Lu  CW,  et al; Taiwan Severe Cutaneous Adverse Reaction Consortium.  The function of HLA-B*13:01 involved in the pathomechanism of dapsone-induced severe cutaneous adverse reactions.  J Invest Dermatol. 2018;138(7):1546-1554. doi:10.1016/j.jid.2018.02.004PubMedGoogle ScholarCrossref
22.
Tempark  T, Satapornpong  P, Rerknimitr  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(12):429-437. doi:10.1097/FPC.0000000000000306PubMedGoogle ScholarCrossref
23.
Watanabe  H, Watanabe  Y, Tashiro  Y,  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(3):320-329. doi:10.1016/j.jdermsci.2017.08.007PubMedGoogle ScholarCrossref
24.
 Chemotherapy of leprosy for control programmes.  World Health Organ Tech Rep Ser. 1982;675:1-33.PubMedGoogle Scholar
25.
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(database issue):D913-D919. doi:10.1093/nar/gkq1128PubMedGoogle ScholarCrossref
26.
Shi  L, Xu  SB, Ohashi  J,  et al.  HLA-A, HLA-B, and HLA-DRB1 alleles and haplotypes in Naxi and Han populations in southwestern China (Yunnan province).  Tissue Antigens. 2006;67(1):38-44. doi:10.1111/j.1399-0039.2005.00526.xPubMedGoogle ScholarCrossref
27.
Yang  G, Deng  YJ, Hu  SN,  et al.  HLA-A, -B, and -DRB1 polymorphism defined by sequence-based typing of the Han population in Northern China.  Tissue Antigens. 2006;67(2):146-152. doi:10.1111/j.1399-0039.2006.00529.xPubMedGoogle ScholarCrossref
28.
Richardus  JH, Smith  TC.  Increased incidence in leprosy of hypersensitivity reactions to dapsone after introduction of multidrug therapy.  Lepr Rev. 1989;60(4):267-273.PubMedGoogle Scholar
29.
Ji  B, Perani  EG, Petinon  C, Grosset  JH.  Bactericidal activities of single or multiple doses of various combinations of new antileprosy drugs and/or rifampin against M. leprae in mice.  Int J Lepr Other Mycobact Dis. 1992;60(4):556-561.PubMedGoogle Scholar
30.
Sapkota  BR, Shrestha  K, Pandey  B, Walker  SL.  A retrospective study of the effect of modified multi-drug therapy in Nepali leprosy patients following the development of adverse effects due to dapsone.  Lepr Rev. 2008;79(4):425-428.PubMedGoogle Scholar
31.
Pandey  B, Shrestha  K, Lewis  J, Hawksworth  RA, Walker  SL.  Mortality due to dapsone hypersensitivity syndrome complicating multi-drug therapy for leprosy in Nepal.  Trop Doct. 2007;37(3):162-163. doi:10.1258/004947507781524700PubMedGoogle ScholarCrossref
32.
 Global leprosy update, 2016: accelerating reduction of disease burden.  Wkly Epidemiol Rec. 2017;92(35):501-519.PubMedGoogle Scholar
33.
Wozel  G, Blasum  C.  Dapsone in dermatology and beyond.  Arch Dermatol Res. 2014;306(2):103-124. doi:10.1007/s00403-013-1409-7PubMedGoogle ScholarCrossref
Views 1,869
Citations 0
Original Investigation
March 27, 2019

Evaluation of Prospective HLA-B*13:01 Screening to Prevent Dapsone Hypersensitivity Syndrome in Patients With Leprosy

Author Affiliations
  • 1Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Science, Jinan, Shandong, China
  • 2Shandong Provincial Hospital for Skin Diseases, Shandong University, Jinan, Shandong, Chinakrismawati
  • 3Shandong Provincial Key Lab for Dermatovenereology, Jinan, Shandong, China
  • 4Shandong Provincial Medical Center for Dermatovenereology, Jinan, Shandong, China
  • 5Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research of Singapore
  • 6Papua Biomedical Research Center, National Institute for Health Research, Indonesian Ministry of Health, Jl Kesehatan 10, Dok II, Jayapura, Papua, Indonesia
  • 7Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu
JAMA Dermatol. 2019;155(6):666-672. doi:10.1001/jamadermatol.2018.5360
Key Points

Question  Can prospective HLA-B*13:01 screening reduce the incidence of dapsone hypersensitivity syndrome by identifying patients with HLA-B*13:01–positive leprosy who should not receive dapsone treatment?

Findings  In this cohort study of 1539 Chinese patients with newly diagnosed leprosy, dapsone hypersensitivity syndrome did not develop in any of those in the HLA-B*13:01–negative group who were receiving dapsone. This finding was significantly lower than the 13 dapsone hypersensitivity syndrome cases that would be expected to occur according to the historical rate of incidence (1.0% per year).

Meaning  Prospective HLA-B*13:01 screening may significantly reduce the incidence of dapsone hypersensitivity syndrome in the Chinese population.

Abstract

Importance  Dapsone hypersensitivity syndrome (DHS) is the most serious adverse reaction associated with dapsone administration and one of the major causes of death in patients with leprosy, whose standard treatment includes multidrug therapy (MDT) with dapsone, rifampicin, and clofazimine. Although the HLA-B*13:01 polymorphism has been identified as the genetic determinant of DHS in the Chinese population, no studies to date have been done to evaluate whether prospective HLA-B*13:01 screening could prevent DHS by identifying patients who should not receive dapsone.

Objective  To evaluate the clinical use of prospective HLA-B*13:01 screening for reduction of the incidence of DHS by excluding dapsone from the treatment for patients with HLA-B*13:01–positive leprosy.

Design, Setting, and Participants  A prospective cohort study was conducted from February 15, 2015, to April 30, 2018, in 21 provinces throughout China. A total of 1539 patients with newly diagnosed leprosy were enrolled who had not received dapsone previously. After excluding patients who had a history of allergy to sulfones or glucose-6-phosphate dehydrogenase deficiency, 1512 individuals underwent HLA-B*13:01 genotyping. All of the patients were followed up weekly for the first 8 weeks after treatment to monitor for adverse events.

Exposures  Patients who were HLA-B*13:01 carriers were instructed to eliminate dapsone from their treatment regimens, and noncarrier patients received standard MDT.

Main Outcomes and Measures  The primary outcome was the incidence of DHS. The historical incidence rate of DHS (1.0%) was used as a control.

Results  Among 1512 patients (1026 [67.9%] men, 486 [32.1%] women; mean [SD] age, 43.1 [16.2] years), 261 (17.3%) were identified as carriers of the HLA-B*13:01 allele. A total of 714 adverse events in 384 patients were observed during the follow-up period. Dapsone hypersensitivity syndrome did not develop in any of the 1251 patients who were HLA-B*13:01–negative who received dapsone, while approximately 13 patients would be expected to experience DHS, based on the historical incidence rate of 1.0% per year (P = 2.05 × 10−5). No significant correlation was found between other adverse events, including dermatologic or other events, and HLA-B*13:01 status.

Conclusions and Relevance  Prospective HLA-B*13:01 screening and subsequent elimination of dapsone from MDT for patients with HLA-B*13:01–positive leprosy may significantly reduce the incidence of DHS in the Chinese population.

Introduction

Severe cutaneous adverse reactions (SCARs) are rare, life-threatening, with a mortality rate of 10% to 40%.1 In addition to compromising patients, they place a major burden on the health care system. Although SCARs were previously considered to be unpredictable, genome-wide association studies and candidate gene analyses have identified human leukocyte antigen (HLA) polymorphisms as a major risk factor of SCARs,2-9 thereby facilitating the use of genetic testing in clinical practice to minimize the incidence of SCARs. To date, genetic testing of HLA alleles has been adopted in routine clinical practice in some populations, such as HLA-B*15:02 for carbamazepine-induced Stevens-Johnson syndrome or toxic epidermal necrolysis (SJS/TEN),10HLA-B*57:01 for abacavir-induced hypersensitivity syndrome or adverse drug reaction with eosinophilia and systemic symptoms,11HLA-B*58:01 for allopurinol-induced DRESS and SJS/TEN,12 and HLA-B*31:01 testing to prevent carbamazepine-induced cutaneous adverse drug reactions.13 Prospective screening of these HLA alleles has significantly reduced the incidence of these drug-induced SCARs,10-13 which encouraged further efforts toward the discovery of genetic risk factors and their clinical screenings to prevent other SCARs.

Dapsone (4,4′-diaminodiphenylsulfone) is a sulfone drug with antibiotic and anti-inflammatory activities to treat infectious conditions, such as leprosy and Pneumocystis jirovecii pneumonia in patients with HIV infection as well as many other dermatologic inflammatory diseases, including dermatitis herpetiformis, IgA dermatoses, and others. One of the most serious and distinct adverse events associated with dapsone is termed dapsone hypersensitivity syndrome (DHS),14 which is recognized as a hypersensitivity syndrome or adverse drug reaction or with eosinophilia and systemic symptoms and characterized by a variety of symptoms encompassing various organs, with the skin and liver being most commonly involved. Dapsone hypersensitivity syndrome occurs in 0.5% to 3.6% of patients typically 4 to 6 weeks after initiating treatment with dapsone.15-17 The incidence of this potentially fatal hypersensitivity reaction may have increased with the global introduction of MDT for leprosy.16 According to a systematic review published in 2012, the prevalence of DHS was estimated to be 1.4%, with an associated mortality rate of 9.9% worldwide.18 Among the Chinese population, the incidence and mortality rates of DHS were 1.0% and 11.1%, respectively.19

In 2013, a study7 discovered HLA-B*13:01 as a genetic determinant of DHS in the Chinese population through genome-wide association studies, and Wang et al20 reported the same association of HLA-B*13:01 with DHS in Chinese population by carrying out a candidate gene analysis. This association was recently confirmed in Taiwan and Thailand.21,22 In addition, dapsone was found to bind specifically to the antigen-recognition site of the HLA-B*13:01 allele, which may alter the presentation of peptides that usually associate with this allele.23 Recently, a functional analysis revealed that cytotoxic T cells could be activated in an HLA-B*13:01-dependent manner in the development of DHS.21 Collectively, these studies indicated that HLA-B*13:01 was causally involved in the immunopathogenesis of DHS, with screening for that allele possibly providing a method to reduce the incidence of DHS.

According to a previous study,7 the incidence of DHS was significantly higher among the participants carrying HLA-B*13:01 allele than the noncarriers (odds ratio, 20.53; 95% CI, 11.55-36.48; P = 6.84 × 10−25) after dapsone treatment. Correspondingly, as a risk estimator of DHS, HLA-B*13:01 testing would be expected to have a sensitivity of 85.5% and a specificity of 85.7%. Based on the incidence of 1.0%,18,19 the positive predictive value of this allele is 5.7%, and the negative predictive value is 99.8%. Theoretically, 1 patient could be prevented from experiencing DHS for every 117 individuals tested. Therefore, prospective HLA-B*13:01 screening to reduce the incidence of DHS in routine clinical practice seems warranted and will benefit patients receiving dapsone treatment. Herein, we report a prospective study to evaluate the utility of prospective testing of the HLA-B*13:01 allele before initiation of dapsone therapy in reducing the incidence of DHS in a Chinese population.

Methods
Study Design

All participating physicians (dermatologists and those treating leprosy) were instructed in relevant study procedures during contact sessions or through illustrated guides or videos. A flowchart of the study design is presented in eFigure 1 in the Supplement. This study was approved by the institutional review board of the Shandong Provincial Institute of Dermatology and Venereology, and written informed consent was obtained from all the participants; there was no financial compensation.

Patients with newly diagnosed leprosy were recruited from 21 provincial leprosy control centers throughout China from February 15, 2015, to April 30, 2018. At the first clinical visit for recruitment, patients with a history of dapsone treatment, allergy to sulfones, or glucose-6-phosphate dehydrogenase deficiency were excluded. In addition to clinical evaluation, 2 mL of peripheral whole blood was collected for HLA-B*13:01 genotyping. After recruitment, patients were provided with either rifampicin if they had paucibacillary (PB) leprosy or a 2-drug regimen (rifampicin and clofazimine) if they had multibacillary (MB) leprosy, while waiting for the results of genotyping analysis. The genotyping results were available to the physicians within 5 to 7 working days.

At the second clinical visit after genotyping results were obtained, the risk of DHS was fully explained to the patients carrying the HLA-B*13:01 polymorphism, and these patients were not provided with dapsone. Noncarriers continued with the standard MDT regimen (for MB leprosy: dapsone, rifampicin, and clofazimine; for PB leprosy: dapsone and rifampicin) as recommended by the World Health Organization.24 Because the onset of DHS occurs within 4 to 6 weeks after the initiation of dapsone treatment, we implemented a follow-up period of 8 weeks after the second clinical visit. All patients were monitored for adverse reactions by telephone interview at 1, 2, 3, 5, 6, and 7 weeks and through clinical visits at 4 and 8 weeks. The medical information was collected at each clinical visit and telephone interview.

Patients were asked to return to the clinic immediately for dermatologic evaluation if early symptoms of DHS developed (sudden fever, new eruption, or any other adverse development). In these patients, further clinical visits and immunologic tests (epicutaneous patch test and lymphocyte transformation test) were performed as required.

HLA-B*13:01 Genotyping

Genomic DNA was isolated from 2 mL of peripheral blood (QuickGene DNA whole blood kit; Wako Chemicals). HLA-B*13:01 genotyping was performed using a sequence-specific oligonucleotide probe method at the Shandong Provincial Dermato-Venereology Key Laboratory. This method had been fully developed and validated in our group’s previous study.7 In addition, the DNAs of the patients whose sequence-specific oligonucleotide probe method results were positive were subjected to further next-generation sequencing–based HLA typing (NGSgo; GenDx). The results of the sequence-specific oligonucleotide probe method and next-generation sequencing analyses were consistent for every sample.

Immunologic Tests for DHS

We established immunologic tests for DHS diagnosis, including an epicutaneous patch test and lymphocyte transformation test (eFigure 2 and eTable 1 in the Supplement). These tests were performed on patients presenting with potential DHS.

Incidence of DHS Among Patients With Leprosy

The incidence of DHS among patients with leprosy in China was reported to be 1.0%.19 We adopted this percentage as a baseline value to determine whether prospective HLA-B*13:01 screening and subsequent exclusion of dapsone treatment in patients with an HLA-B*13:01 polymorphism reduced the incidence of DHS in patients with leprosy.

Statistical Analysis

The prevalence of the HLA-B*13:01 allele was found to be 13.17% in the Chinese population.7 Thus, 1415 participants would provide a statistical power of 98.5% to detect a reduction in the incidence of DHS from 1.0% to 0.17% at a statistical significance level of 5%. The Fisher exact test was used to compare the rate of DHS in the prospective screening population with the historical incidence rate. A value of P < .05, determined with unpaired, 2-tailed testing, was considered to be statistically significant. R, version 3.03 (R Foundation), was used in statistical analysis.

Results
Patients

Between February 15, 2015, and April 30, 2018, a total of 1539 patients with newly diagnosed leprosy from 21 provinces throughout China were recruited into this study. After 27 were excluded owing to protocol violation, 1512 individuals underwent HLA-B*13:01 genotyping and the 8-week follow-up (eFigure 1 in the Supplement). All demographic and clinical characteristics of these 1512 participants are provided in Table 1. This study cohort consisted of 1026 men (67.9%) and 486 women (32.1%), with a mean (SD) age of 43.1 (16.2) years. All participants self-reported to be of Chinese descent, with 1435 (94.9%) recruited from Southern China. The population consisted of Chinese Han (60.6%), Miao (9.3%), Yi (8.7%), Chuang (6.0%), and other (15.3%) ethnicities. A total of 1085 patients (71.8%) were classified as having MB leprosy, with 427 (28.2%) having PB leprosy.

Of the 1512 patients, 261 (17.3%) were found to carry the HLA-B*13:01 allele, and as a result, dapsone was removed from their MDT regimen. Three of 261 (1.1%) patients were lost to follow-up and 1 did not take any drugs for leprosy because of other health issues. A total of 223 (14.7%) patients took rifampicin and clofazimine, and 34 (2.2%) took rifampicin, clofazimine and ofloxacin. Among the 1251 patients who were HLA-B*13:01 negative, 7 were lost to follow-up and 5 did not take any drugs for leprosy owing to other health issues. Of 1239 patients receiving dapsone, 881 (71.1%) received MDT for MB and 358 (28.9%) received MDT for PB. All patients apart from those lost to follow-up and who did not use any additional medication, were monitored closely for adverse events for 8 weeks following initiation of treatment. The Figure shows the enrollment and outcomes in this study.

We listed the allele frequencies and prevalence of HLA-B*13:01 in northern and southern China in eTable 2 in the Supplement. The frequency of this allele in northern China was 3.6% and in southern China was 9.1%; these percentages are consistent with previous reports of 2% to 5% in northern China and 5% to 20% in southern China.25-27

Adverse Events

A total of 714 of 1496 (47.7%) adverse events in 384 patients were observed during the 8-week observation period: 108 (7.1%) in the HLA-B*13:01–positive group and 606 (40.1%) in the HLA-B*13:01–negative group. A total of 167 (43.5%) patients had more than 1 adverse effect. None of the participants received a diagnosis of DHS (Table 2).

In general, mild cutaneous events (rash, itching, and blisters) and systemic involvement (gastrointestinal symptoms, anemia, hepatic abnormalities, and lymphadenopathy) were observed in the HLA-B*13:01–positive and HLA-B*13:01–negative groups. Only 1 patient who was HLA-B*13:01–positive developed a severe cutaneous event (urticaria), which was thought to be induced by rifampicin. Another patient who was HLA-B*13:01–positive with severe gastrointestinal symptoms terminated leprosy treatment. None of the patients had a combination of rash, fever, hepatic abnormalities, and lymphadenopathy and met the diagnosis criteria proposed by Richardus and Smith.28

A total of 19 leprosy reactions occurred. Of these, 3 developed in the HLA-B*13:01–negative group and were initially suspected to be DHS, but these diagnoses were eventually excluded by immunologic tests and the patients resumed taking dapsone, under close supervision, without recurrence of symptoms. Other adverse events included flu-like symptoms, fatigue, dizziness, headaches, and fainting. These events occurred in both HLA-B*13:01 carriers and noncarriers.

Anemia was observed in the HLA-B*13:01–negative population and was recognized as a common pharmacologic adverse effect of dapsone that was related to the dosage of the drug. No significant difference in other adverse events occurred between the 2 groups.

Primary Outcome

No incident of DHS occurred in participants who were using dapsone. This finding differed significantly from the historical incidence of 1.0% per year (P = 2.05 × 10−5).

Discussion
Principal Findings

To our knowledge, this study is the first to provide evidence suggesting that prospective HLA-B*13:01 screening, coupled with withholding dapsone from MDT treatment for the HLA-B*13:01 carriers, could significantly reduce the incidence of DHS among the Chinese population (P = 2.05 × 10−5). Based on the historical rate of DHS incidence in Chinese population (1.0%), we anticipated to observe approximately 13 DHS cases in the 1239 participants who were receiving dapsone, although no DHS occurred in the present study. At the time of writing, all the participants in the present study have been followed up for more than 3 months, and no occurrence of DHS has been reported. Therefore, prospective HLA-B*13:01 screening is of considerable value in preventing the occurrence of DHS and associated mortality in patients with leprosy who are receiving MDT.

In the present study, dapsone was eliminated from the MDT regimen in 258 individuals who were HLA-B*13:01–positive. Of these, 203 (78.7%) were patients with MB leprosy whose treatments were adjusted by excluding dapsone, and 54 (20.9%) patients with PB leprosy who received clofazimine alone or clofazimine in conjunction with ofloxacin. However, given the World Health Organization’s recommendation that standard MDT is required for effective treatment of leprosy, there is a concern whether the revision of MDT will increase the risk of treatment failure. Among the 3 drugs included in MDT, dapsone was the first compound used to treat leprosy,15 but rifampicin has a greater effect against Microbacterium leprae by killing 99.5% of live bacteria with a single dose.29 The role of dapsone, together with clofazimine, is to reduce the emergence of rifampicin-resistant bacteria.

A retrospective study was carried out in 67 Nepalese patients with leprosy who discontinued dapsone because of severe adverse effects, and the efficacy of a combination of rifampicin and clofazimine for treating leprosy was found to be satisfactory.30 After the completion of the follow-up protocol of the present study, 219 of 257 patients with a modified MDT regimen were followed up to 6 months (1 visit per month) by local physicians who treat leprosy; the mean bacteria index declined in most of those patients. It therefore seems reasonable to conclude that the risk of treatment failure in patients with HLA-B*13:01–positive leprosy as a consequence of excluding dapsone from MDT is minimal, and the risk of severe adverse effects in individuals who are HLA-B*13:01–positive exposed to dapsone outweighs the risk of less-effective treatment. However, given that relapses in leprosy are not usually seen until many years after the completion of treatment, longer-term follow-up is required to reach a more definite conclusion. In addition to the benefit and the risk of HLA-B*13:01 screening to patients, other factors, such as cost-effectiveness analysis, need to be taken into consideration for the further implementation of this test in routine practice.

Preemptive HLA-B*13:01 screening to reduce the incidence of DHS has clinical use in other populations. Dapsone hypersensitivity syndrome has been reported in Indian (1.6%),16 Thai (3.6%),28 and Nepalese (2%)31 populations. The frequency of the HLA-B*13:01 polymorphism varies across different ethnic populations. Although rare in white and African populations, the HLA-B*13:01 allele has a higher frequency in Asian populations, ranging from 0.9% to 21.1% in Chinese, 0% to 12% in Indian, 2.1% to 4.1% in Thai, and 1.3% to 1.5% in Indonesian patients (eTable 3 in the Supplement). The variable frequency of the HLA-B*13:01 allele across different Asian populations shows a correlation with the distribution of DHS (eTable 3 in the Supplement). In addition, the association between HLA-B*13:01 and DHS has been observed in Thai, Japanese (1 case), Burmese (1 case), and Indonesian populations (oral communication, Hana Krismawati, MD, November 27, 2017). The assessment of these reports indicated that an association between DHS and HLA-B*13:01 likely exists across different ethnic groups (eTable 3 in the Supplement). Therefore, HLA-B*13:01 testing should be considered for any other Asian populations before initiation of MDT for leprosy. Given that 161 263 new leprosy cases of 214 783 new cases globally were from Asia in 2016,32 with an incidence of 1.0% and mortality of 11.1%, 1613 DHS cases and 179 deaths could potentially be prevented per year. Preemptive HLA-B*13:01 screening may bring significant clinical benefit to Asian populations. Owing to the relative lack of occurrence of HLA-B*13:01 in white and African populations, genotypic screening for this allele in these groups is of lesser clinical value.

Limitations

This study has limitations. First, because DHS has significant morbidity and appreciable mortality in patients with leprosy who receive MDT, we carried out a nonrandomized, prospective analysis owing to ethnic considerations by comparing the incidence of DHS with the historical data. The same study design has been used to evaluate the clinical utility of HLA-B*15:02 testing to reduce the incidence of carbamazepine-induced SJS/TEN10; HLA-B*58:01 testing to lower the incidence of allopurinol-induced DRESS and SJS/TEN12; and HLA-B*31:01 testing to reduce the incidence of carbamazepine-induced cutaneous adverse drug reactions.13 According to data from the Leprosy Management Information System in China maintained by the National Center for Sexually Transmitted Diseases and Leprosy Control, the incidence of DHS was 3.03% in China (eTable 4 in the Supplement). However, because the diagnosis of DHS was based on the criteria proposed by Richardus and Smith,28 the Leprosy Management Information System in China may have overestimated the incidence of DHS. A retrospective survey of DHS was performed in the Chinese population by using more stringent diagnostic criteria: (1) meeting the criteria proposed by Richardus and Smith in 198928 and (2) excluding patients whose symptoms could be attributed to other drugs or leprosy reactions.19 The incidence rate of DHS was found to be 1.0%, which was thought to be underestimated in this retrospective study because of the stringent diagnostic criteria without a sensitive tool to diagnose the very early stage of DHS. To be conservative, we used data from the retrospective study as the historical control in the present study and found that the incidence of DHS was significantly reduced with the use of preemptive HLA-B*13:01 genetic screening (for incidence of 1.0%, P = 2.05 × 10−5 and for incidence of 3.03%, P = 1.73 × 10−14).

Second, this study was performed by enrolling only patients with leprosy, although dapsone is still widely used in a variety of other dermatologic (eg, dermatitis herpetiformis and linear IgA dermatosis) and nondermatologic (eg, rheumatoid arthritis, eosinophilic fasciitis, and HIV prophylaxis) diseases, either as the first-choice treatment or in combination with additional drugs.33 The enrollment limited to patients with leprosy owes to the fact that dapsone has been used as a part of MDT blister packs during the past 10 years in mainland China. Among patients with conditions other than leprosy that are treated with dapsone, the incidence of DHS was reported to be 1.66%.33 Recent studies demonstrated that the HLA-B*13:01 allele was associated with DHS among patients without leprosy in Thai and Taiwanese populations.21,22 Therefore, although not directly evaluated in the present study, prospective HLA-B*13:01 testing before the administration of dapsone may also have clinical utility in other diseases.

Conclusions

The results of the present study suggest that prospective HLA-B*13:01 screening could significantly reduce the incidence of DHS in the Chinese population. The screening may also benefit other populations, but further investigation is required.

Back to top
Article Information

Accepted for Publication: November 26, 2018.

Open Access: This article is published under the JN-OA license and is free to read on the day of publication.

Corresponding Author: Furen Zhang, PhD, Shandong Provincial Hospital for Skin Diseases, 27397 Jingshi Lu, Jinan 250022, Shandong Province, China (zhangfuren@hotmail.com).

Published Online: March 27, 2019. doi:10.1001/jamadermatol.2018.5360

The Dapsone Hypersensitivity Syndrome Prevention Working Group Authors: Li Xiong, MD; Jun Yang, BS; Jinlan Li, MD; Wei Ke, BS; Ming Li, BS; Yong Ning, MD; Junhao Xiong, MD; Ming Li, BS; Mingzhou Xiong, MD; Bin Yang, PhD; Qizhi Duan, BS; Hong Wang, BS; Wei Li, BS; Yanfei Kuang, PhD; Junhua Li, BS; Lamei Wang, BS; Qiuyang Cao, BS; Peng Xiao, BS; Bangzhong Xiao, BS; Lianhua Zhang, BS; Zhaoxing Lin, BS; Yaofei Wang, BS; Yunliang Shen, MD; Liying Yan, BS; Wenbin Wu, BS; Hu Zheng, BS; Xianfa Zhan, MD; Wanghua Li, BS; Xiujian Shang, BS; Yujun Xu, BS; Qiao Liu, MD.

Affiliations of The Dapsone Hypersensitivity Syndrome Prevention Working Group Authors: Yunnan Provincial Center for Disease Control and Prevention, Kunming, Yunnan (L. Xiong, J. Yang); Guizhou Provincial Center for Disease Control and Prevention, Guiyang, Guizhou (J. Li, Ke, M. Li); Sichuan Provincial Institute of Dermatology, Chengdu, Sichuan (Ning, J. Xiong); Guangdong Provincial Institute of Dermatology, Guangzhou, Guangdong (M. Li, M. Xiong, B. Yang); Guangxi Provincial Institute of Dermatology, Nanning, Guangxi (Duan, H. Wang, W. Li); Hunan Provincial Center for Disease Control and Prevention, Changsha, Hunan (Kuang, J. Li); Jiangxi Provincial Institute of Parasitic Diseases, Nanchang, Jiangxi (L. Wang, Cao); Chongqing Center for Disease Control and Prevention, Chongqing (P. Xiao, B. Xiao); Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu (Zhang); Shanxi Provincial Institute for Endemic Disease Control, Xi'an, Shanxi (Lin, Y. Wang); Zhejiang Provincial Institute of Dermatology, Huzhou, Zhejiang (Shen, Yan); Fujian Center for Disease Control and Prevention, Fuzhou, Fujian (Wu); Anhui Provincial Institute of Dermatology, Hefei, Anhui (Zheng); Hubei Provincial Center for Disease Control and Prevention, Wuhan, Hubei (Zhan, W. Li); Xinjiang Center for Disease Control and Prevention, Urumchi, Xinjiang (Shang); Hainan Provincial Center for Skin Disease and STI Control, Haikou, Hainan (Xu, Liu).

Author Contributions: Dr F. R. Zhang had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: H. Liu, Jianjun Liu, F. Zhang.

Acquisition, analysis, or interpretation of data: H. Liu, Z. Wang, Bao, C. Wang, L. Sun, L. Xiong, J. Yang, H. Zhang, G. Yu, Mi, Jianke Li, L. Li, Q. Zhao, Yue, W. Zhao, W. Yu, J. Cao, F. Xiong, Yaru Wang, Chai, Cheng, Y. Zhang, F. Fu, Lang, X. Wang, Ke, Ming Li, Ning, J. Xiong, Ming Li, M. Xiong, B. Yang, Duan, H. Wang, Wei Li, Kuang, Irwanto, Krismawati, Junhua Li, L. Wang, Q. Cao, P. Xiao, B. Xiao, L. Zhang, Lin, Yaofei Wang, Y. Shen, Liying Yan, Wu, Zheng, Zhan, Wanghua Li, Shang, Xu, Q. Liu, Y. Sun, X. Fu You, Jian Liu, Pan, Chu, D. Liu, Chen, J. Shen, Liangbin Yan, G. Zhang, Jianjun Liu.

Drafting of the manuscript: H. Liu, Z. Wang, F. Zhang.

Critical revision of the manuscript for important intellectual content: H. Liu, Z. Wang, Bao, C. Wang, L. Sun, L. Xiong, J. Yang, H. Zhang, G. Yu, Mi, Jianke Li, L. Li, Q. Zhao, Yue, W. Zhao, W. Yu, J. Cao, F. Xiong, Yaru Wang, Chai, Cheng, Y. Zhang, F. Fu, Lang, X. Wang, Ke, Ming Li, Ning, J. Xiong, Ming Li, M. Xiong, B. Yang, Duan, H. Wang, Wei Li, Kuang, Irwanto, Krismawati, Junhua Li, L. Wang, Q. Cao, P. Xiao, B. Xiao, L. Zhang, Lin, Yaofei Wang, Y. Shen, Liying Yan, Wu, Zheng, Zhan, Wanghua Li, Shang, Xu, Q. Liu, X. Fu, Y. Sun, You, Jian Liu, Pan, Chu, D. Liu, Chen, J. Shen, Liangbin Yan, G. Zhang, Jianjun Liu, F. Zhang.

Statistical analysis: Z. Wang, Irwanto, Zheng, Y. Sun.

Obtained funding: F. Zhang.

Administrative, technical, or material support: H. Liu, Bao, C. Wang, L. Sun, L. Xiong, J. Yang, H. Zhang, G. Yu, Mi, Jianke Li, L. Li, Q. Zhao, Yue, W. Zhao, W. Yu, J. Cao, F. Xiong, Yaru Wang, Chai, Cheng, Y. Zhang, F. Fu, Lang, X. Wang, Ke, Ming Li, Ning, J. Xiong, Ming Li, M. Xiong, B. Yang, Duan, H. Wang, Wei Li, Kuang, Irwanto, Krismawati, Junhua Li, L. Wang, Q. Cao, P. Xiao, B. Xiao, L. Zhang, Lin, Yaofei Wang, Y. Shen, Liying Yan, Wu, Zheng, Zhan, Wanghua Li, Shang, Xu, Q. Liu, X. Fu, You, Jian Liu, Pan, Chu, D. Liu, Chen, J. Shen, Liangbin Yan, G. Zhang.

Supervision: H. Liu, Jianjun Liu, F. Zhan funded by grants from the National Key Research and Development Program of China (2016YFE0201500), the National Natural Science Foundation of China (81620108025, 81601387, 81602746, 31601040, 81822038, 81472868), the Key research and development program of Shandong Province (2016ZDJS07A06), the Natural Science Foundation of Shandong Province (JQ201616, ZR2016HB47), the National Clinical Key Project of Dermatology and Venereology, the Shandong Provincial Advanced Taishan Scholar Construction Project, and the Innovation Project of Shandong Academy of Medical Science.

Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
Chan  HL, Stern  RS, Arndt  KA,  et al.  The incidence of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis: a population-based study with particular reference to reactions caused by drugs among outpatients.  Arch Dermatol. 1990;126(1):43-47. doi:10.1001/archderm.1990.01670250049006PubMedGoogle ScholarCrossref
2.
Mallal  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(9308):727-732. doi:10.1016/S0140-6736(02)07873-XPubMedGoogle ScholarCrossref
3.
Martin  AM, Nolan  D, James  I,  et al.  Predisposition to nevirapine hypersensitivity associated with HLA-DRB1*0101 and abrogated by low CD4 T-cell counts.  AIDS. 2005;19(1):97-99. doi:10.1097/00002030-200501030-00014PubMedGoogle ScholarCrossref
4.
Littera  R, Carcassi  C, Masala  A,  et al.  HLA-dependent hypersensitivity to nevirapine in Sardinian HIV patients.  AIDS. 2006;20(12):1621-1626. doi:10.1097/01.aids.0000238408.82947.09PubMedGoogle ScholarCrossref
5.
Hung  SI, Chung  WH, Liou  LB,  et al.  HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol.  Proc Natl Acad Sci U S A. 2005;102(11):4134-4139. doi:10.1073/pnas.0409500102PubMedGoogle ScholarCrossref
6.
McCormack  M, Alfirevic  A, Bourgeois  S,  et al.  HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans.  N Engl J Med. 2011;364(12):1134-1143. doi:10.1056/NEJMoa1013297PubMedGoogle ScholarCrossref
7.
Zhang  FR, Liu  H, Irwanto  A,  et al.  HLA-B*13:01 and the dapsone hypersensitivity syndrome.  N Engl J Med. 2013;369(17):1620-1628. doi:10.1056/NEJMoa1213096PubMedGoogle ScholarCrossref
8.
Chung  WH, Chang  WC, Lee  YS,  et al; Taiwan Severe Cutaneous Adverse Reaction Consortium; Japan Pharmacogenomics Data Science Consortium.  Genetic variants associated with phenytoin-related severe cutaneous adverse reactions.  JAMA. 2014;312(5):525-534. doi:10.1001/jama.2014.7859PubMedGoogle ScholarCrossref
9.
Chung  WH, Hung  SI, Hong  HS,  et al.  Medical genetics: a marker for Stevens-Johnson syndrome.  Nature. 2004;428(6982):486. doi:10.1038/428486aPubMedGoogle ScholarCrossref
10.
Chen  P, Lin  JJ, Lu  CS,  et al; Taiwan SJS Consortium.  Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan.  N Engl J Med. 2011;364(12):1126-1133. doi:10.1056/NEJMoa1009717PubMedGoogle ScholarCrossref
11.
Mallal  S, Phillips  E, Carosi  G,  et al; PREDICT-1 Study Team.  HLA-B*5701 screening for hypersensitivity to abacavir.  N Engl J Med. 2008;358(6):568-579. doi:10.1056/NEJMoa0706135PubMedGoogle ScholarCrossref
12.
Ko  TM, Tsai  CY, Chen  SY,  et al; Taiwan Allopurinol-SCAR Consortium.  Use of HLA-B*58:01 genotyping to prevent allopurinol induced severe cutaneous adverse reactions in Taiwan: national prospective cohort study.  BMJ. 2015;351:h4848. doi:10.1136/bmj.h4848PubMedGoogle ScholarCrossref
13.
Mushiroda  T, Takahashi  Y, Onuma  T,  et al; GENCAT Study Group.  Association of HLA-A*31:01 screening with the incidence of carbamazepine-induced cutaneous adverse reactions in a Japanese population.  JAMA Neurol. 2018;75(7):842-849. doi:10.1001/jamaneurol.2018.0278PubMedGoogle ScholarCrossref
14.
Allday  EJ, Barnes  J.  Toxic effects of diaminodiphenylsulphone in treatment of leprosy.  Lancet. 1951;2(6675):205-206. doi:10.1016/S0140-6736(51)91443-2PubMedGoogle ScholarCrossref
15.
Zhu  YI, Stiller  MJ.  Dapsone and sulfones in dermatology: overview and update.  J Am Acad Dermatol. 2001;45(3):420-434. doi:10.1067/mjd.2001.114733PubMedGoogle ScholarCrossref
16.
Rao  PN, Lakshmi  TS.  Increase in the incidence of dapsone hypersensitivity syndrome—an appraisal.  Lepr Rev. 2001;72(1):57-62.PubMedGoogle Scholar
17.
Leslie  KS, Gaffney  K, Ross  CN, Ridley  S, Barker  TH, Garioch  JJ.  A near fatal case of the dapsone hypersensitivity syndrome in a patient with urticarial vasculitis.  Clin Exp Dermatol. 2003;28(5):496-498. doi:10.1046/j.1365-2230.2003.01336.xPubMedGoogle ScholarCrossref
18.
Lorenz  M, Wozel  G, Schmitt  J.  Hypersensitivity reactions to dapsone: a systematic review.  Acta Derm Venereol. 2012;92(2):194-199. doi:10.2340/00015555-1268PubMedGoogle ScholarCrossref
19.
Tian  W, Shen  J, Zhou  M, Yan  L, Zhang  G.  Dapsone hypersensitivity syndrome among leprosy patients in China.  Lepr Rev. 2012;83(4):370-377.PubMedGoogle Scholar
20.
Wang  H, Yan  L, Zhang  G,  et al.  Association between HLA-B*1301 and dapsone-induced hypersensitivity reactions among leprosy patients in China.  J Invest Dermatol. 2013;133(11):2642-2644. doi:10.1038/jid.2013.192PubMedGoogle ScholarCrossref
21.
Chen  WT, Wang  CW, Lu  CW,  et al; Taiwan Severe Cutaneous Adverse Reaction Consortium.  The function of HLA-B*13:01 involved in the pathomechanism of dapsone-induced severe cutaneous adverse reactions.  J Invest Dermatol. 2018;138(7):1546-1554. doi:10.1016/j.jid.2018.02.004PubMedGoogle ScholarCrossref
22.
Tempark  T, Satapornpong  P, Rerknimitr  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(12):429-437. doi:10.1097/FPC.0000000000000306PubMedGoogle ScholarCrossref
23.
Watanabe  H, Watanabe  Y, Tashiro  Y,  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(3):320-329. doi:10.1016/j.jdermsci.2017.08.007PubMedGoogle ScholarCrossref
24.
 Chemotherapy of leprosy for control programmes.  World Health Organ Tech Rep Ser. 1982;675:1-33.PubMedGoogle Scholar
25.
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(database issue):D913-D919. doi:10.1093/nar/gkq1128PubMedGoogle ScholarCrossref
26.
Shi  L, Xu  SB, Ohashi  J,  et al.  HLA-A, HLA-B, and HLA-DRB1 alleles and haplotypes in Naxi and Han populations in southwestern China (Yunnan province).  Tissue Antigens. 2006;67(1):38-44. doi:10.1111/j.1399-0039.2005.00526.xPubMedGoogle ScholarCrossref
27.
Yang  G, Deng  YJ, Hu  SN,  et al.  HLA-A, -B, and -DRB1 polymorphism defined by sequence-based typing of the Han population in Northern China.  Tissue Antigens. 2006;67(2):146-152. doi:10.1111/j.1399-0039.2006.00529.xPubMedGoogle ScholarCrossref
28.
Richardus  JH, Smith  TC.  Increased incidence in leprosy of hypersensitivity reactions to dapsone after introduction of multidrug therapy.  Lepr Rev. 1989;60(4):267-273.PubMedGoogle Scholar
29.
Ji  B, Perani  EG, Petinon  C, Grosset  JH.  Bactericidal activities of single or multiple doses of various combinations of new antileprosy drugs and/or rifampin against M. leprae in mice.  Int J Lepr Other Mycobact Dis. 1992;60(4):556-561.PubMedGoogle Scholar
30.
Sapkota  BR, Shrestha  K, Pandey  B, Walker  SL.  A retrospective study of the effect of modified multi-drug therapy in Nepali leprosy patients following the development of adverse effects due to dapsone.  Lepr Rev. 2008;79(4):425-428.PubMedGoogle Scholar
31.
Pandey  B, Shrestha  K, Lewis  J, Hawksworth  RA, Walker  SL.  Mortality due to dapsone hypersensitivity syndrome complicating multi-drug therapy for leprosy in Nepal.  Trop Doct. 2007;37(3):162-163. doi:10.1258/004947507781524700PubMedGoogle ScholarCrossref
32.
 Global leprosy update, 2016: accelerating reduction of disease burden.  Wkly Epidemiol Rec. 2017;92(35):501-519.PubMedGoogle Scholar
33.
Wozel  G, Blasum  C.  Dapsone in dermatology and beyond.  Arch Dermatol Res. 2014;306(2):103-124. doi:10.1007/s00403-013-1409-7PubMedGoogle ScholarCrossref
×