Unique motif shared by HLA-B*59:01 and HLA-B*55:02 is associated with methazolamide-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese.

BACKGROUND: Methazolamide (MTZ) has been occasionally linked to the lethal Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which are associated with HLA-B*59:01. However, some MTZ-induced SJS/TEN (MTZ-SJS/TEN) cases are negative for HLA-B*59:01, implying that other genetic factors besides HLA-B*59:01 are contributing to MTZ-SJS/TEN. OBJECTIVES: To comprehensively identify HLA and non-HLA genetic susceptibility to MTZ-SJS/TEN in Han Chinese. METHODS: Eighteen patients with MTZ-SJS/TEN, 806 subjects of the population control and 74 MTZ-tolerant individuals were enrolled in this study. Both exome-wide and HLA-based association studies were conducted. Molecular docking analysis was employed to simulate the interactions between MTZ and risk HLA proteins. RESULTS: We found a strong signal in the major histocompatibility complex region on chromosome 6 with 22 SNPs reaching exome-wide significance. Compared with MTZ-tolerant controls, a significant association of HLA-B*59:01 with MTZ-SJS/TEN was validated [odds ratio (OR) = 146.00, 95% confidence interval (CI): 16.12-1321.98; P = 6.19 × 10-10 ]. Moreover, 66.7% of MTZ-SJS/TEN patients negative for HLA-B*59:01 were carriers of HLA-B*55:02, whilst 2.7% of the tolerant individuals were observed with HLA-B*55:02 (OR = 71.00, 95% CI: 7.84-643.10; P = 1.43 × 10-4 ). Within HLA-B protein, the E45-L116 motif could completely explain the association of HLA-B*59:01 and HLA-B*55:02 with MTZ-SJS/TEN (OR = 119.33, 95% CI: 29.19-1227.96; P = 4.36 × 10-13 ). Molecular docking analysis indicated that MTZ binds more stably to the pocket of HLA-B*59:01 and HLA-B*55:02 than to that of non-risk alleles of HLA-B*40:01 and HLA-C*01:02. CONCLUSIONS: This study confirmed the association of HLA-B*59:01 with MTZ-SJS/TEN and identified HLA-B*55:02 as a novel risk allele in Han Chinese with the largest sample size to date. Notably, the rs41562914(A)-rs12697944(A) haplotype, encoding E45-L116, is capable of serving as a powerful genetic predictor for MTZ-SJS/TEN with a sensitivity of 89% and specificity of 96%.

Methazolamide in high-altitude illnesses.

As a carbonic anhydrase inhibitor and a methylated lipophilic analogue of acetazolamide, Methazolamide has higher lipid solubility, less plasma protein binding and renal excretion, and fewer side effects, compared to acetazolamide. Methazolamide can increase systemic metabolic acidosis and sequentially improve ventilation and oxygenation level. The increased oxygenation level leads to reduced reactive oxygen species (ROS) production, relived cerebral edema, mitigated hypoxic pulmonary vasoconstriction, abrogated hypoxic fatigue, and decreased excessive erythrocytosis. In addition to the effect as a carbonic anhydrase inhibitor, methazolamide directly activates the transcription factor anti-oxidative nuclear factor-related factor 2 (Nrf2) and inhibits interleukin-1ß (IL-1ß) release. These pharmacological functions of methazolamide are beneficial for the prevention and treatment of high-altitude illnesses. Besides, methazolamide causes less fatigue side effects than acetazolamide does. It is also worth noting that several studies suggested that a lower dose of methazolamide has similar prophylaxis and treatment efficacy in acute mountain sickness (AMS) to a higher dose of acetazolamide. Given methazolamide's advantages over acetazolamide, methazolamide may thus represent an alternative for acetazolamide when taken for high-altitude illnesses prophylaxis and treatment. However, more in-depth clinical trials are needed to fully evaluate this efficacy of methazolamide.

Comprehensive assessment of T cell receptor ß repertoire in Stevens-Johnson syndrome/toxic epidermal necrolysis patients using high-throughput sequencing.

Stevens-Johnson syndrome (SJS) /toxic epidermal necrolysis (TEN) are life-threatening severe cutaneous adverse drug reactions characterized by widespread epidermal necrosis. Recent studies have indicated that SJS/TEN is a specific immune reaction regulated by T cells. Certain drug serves as foreign antigens that are presented by major histocompatibility complex (MHC) and recognized by T cell receptors (TCRs), inducing adaptive immune responses. However, few studies have performed detailed characterization of TCR repertoire in SJS/TEN, and it remains unclear whether the particular types of TCRs expanded clonally are drug-specific, which would provide a potential underlying mechanism of SJS/TEN. In this study, using high-throughput sequencing, we comprehensively assessed the diversity, composition and molecular characteristics of the TCRß repertoires in 17 SJS/TEN patients associated with three different causative drugs including methazolamide (MZ), carbamazepine (CBZ) and allopurinol (ALP). Systematic analysis of the TCRß sequences revealed that SJS/TEN patients had more highly expanded clones and less TCR repertoire diversity, and the TCR repertoire diversity of these patients showed certain associations with the clinical severity of disease. Similar predominant clonotypes, shared-usage TRBV/TRBJ subtypes and combinations thereof were observed among different subjects with the same causative agent. Our observations provide enhanced understanding of the role of T lymphocytes in the pathogenesis of SJS/TEN and enumerate potential therapeutic targets.

Association between HLA-B*5901 and methazolamide-induced Stevens-Johnson syndrome/toxic epidermal necrolysis: a systematic review and meta-analysis.

Methazolamide-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are life-threatening adverse drug reactions. Based on previous studies, HLA genotypes may play an important role in methazolamide-induced SJS/TEN. Therefore, to identify the associations between HLA genotypes and methazolamide-induced cutaneous adverse drug reactions (cADRs) (i.e., SJS/TEN and hypersensitivity syndrome), a systematic review and meta-analysis were performed. Two studies (one study in Korean and another in Han Chinese) met the inclusion criteria. The studies included 13 patients with methazolamide-induced SJS/TEN, 30 methazolamide-tolerant, and 768 population controls. Associations between HLA-B*5901, HLA-B*5901-Cw*0102 haplotype, and methazolamide-induced SJS/TEN were identified in methazolamide-tolerant and population controls. Overall ORs were 305.0 (95% CI = 11.3-8, 259.4) in methazolamide-tolerant and 715.3 (95% CI = 83.1-6,158.5) in population control. In addition, statistically significant associations between the HLA-Cw*0102 and methazolamide-induced SJS/TEN were found in methazolamide-tolerant (OR = 12.1; 95% CI = 1.3-111.7) and population control (OR = 17.5; 95% CI = 3.2-96.6). Since HLA-B*5901 and HLA-B*5901-Cw*0102 haplotype are associated with methazolamide-induced SJS/TEN, genetic screening prior to methazolamide therapy in Asian populations is warranted.

HLA-B*59:01: a marker for Stevens-Johnson syndrome/toxic epidermal necrolysis caused by methazolamide in Han Chinese.

Methazolamide is an intraocular pressure-lowering drug that is used in the treatment of glaucoma and other ophthalmologic abnormalities. The use of methazolamide has been shown to cause Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in patients of Asian ancestry. Methazolamide-induced SJS/TEN is associated with the presence of HLA-B59 serotype/HLA-B*59:01 in Korean and Japanese populations. To better understand the genetic risk factors for these adverse reactions in the Han Chinese population, we characterized the HLA class I genotypes of eight Chinese patients with methazolamide-induced SJS/TEN from 2008 to 2014. The frequency of HLA-B*59:01 was 87.5% (7/8) in the case patients, which was significantly different from 0% (0/30) in the methazolamide-tolerant patients (odds ratio (OR)=305.0; P=6.3 × 10(-7)) and 0.35% (1/283) in healthy subjects from the human major histocompatibility complex database (OR=1974.0; P=2.0 × 10(-12)). HLA-C*01:02, which is closely linked to HLA-B*59:01, had a weaker but notable association with methazolamide-induced SJS/TEN compared with the tolerant controls (OR=12.1; P=0.016) and general population (OR=15.5; P=2.0 × 10(-3)). The distribution of the HLA-B*59:01-C*01:02 haplotype was also significantly different in cases and controls. This study demonstrated a strong association between HLA-B*59:01 and methazolamide-induced SJS/TEN in the Han Chinese population for the first time. Pretherapy screening for HLA-B*59:01 would be useful to reduce the risk of methazolamide-induced SJS/TEN.

Research on Susceptible Genes and Immunological Pathogenesis of Cutaneous Adverse Drug Reactions in Chinese Hans.

Cutaneous adverse drug reactions (cADRs) include mild maculopapular exanthems (MPE), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP). We used HLA high-resolution genotyping and genome wide association analysis (GWAS) to identify the genetic markers for cADRs induced by common culprit drugs in Han Chinese population. To further understand the immunopathogenesis of cADRs, and with the goal of developing treatment strategies, we compared the expression of cytoxic cytokines between the patients with cADRs and normal controls. Our data suggested that the carbamazepine induced SJS/TEN, allopurinol induced CADRs, methazolamide induced SJS/TEN and SASP induced DRESS were respectively strongly associated with HLA-B*15:02, HLA-B*58:01, HLA-B*59:01 and HLA-B*13:01. In addition, increased expression of cytotoxic cytokines in sera and tissues of cADRs patients were found, compared with healthy controls. Our findings may shed light on prediction and prevention of cADRs, provide clues to pathogenesis, and guide treatment strategies of these reactions.

Toxic epidermal necrolysis induced by methazolamide in a Chinese-Korean man carrying HLA-B*59:01.

BACKGROUND: Methazolamide is used to lower intraocular pressure in patients with glaucoma. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) associated with methazolamide treatment have been diagnosed in Korean, Japanese, and Japanese-American patients. According to recent research, the human leukocyte antigen (HLA) allele HLA-B*59:01 is strongly linked to SJS/TEN associated with methazolamide treatment. OBJECTIVE: A patient of Chinese-Korean ethnicity was diagnosed with TEN associated with methazolamide treatment. The purpose of this study was to examine the potential genetic basis of this disease. METHODS: A polymerase chain reaction sequence-specific primer (PCR-SSP) typing system was used to genotype this patient's peripheral blood DNA for HLA-B*59. RESULTS: The genotype HLA-B*59:01 was detected in the patient. CONCLUSIONS: This study demonstrates the genotype of HLA-B*59:01 in a patient with TEN associated with methazolamide treatment and thus supports the possible correlation between genetic background and methazolamide-associated SJS/TEN.

Efficacy and safety of oral methazolamide in patients with type 2 diabetes: a 24-week, placebo-controlled, double-blind study.

OBJECTIVE: To evaluate the safety and efficacy of methazolamide as a potential therapy for type 2 diabetes. RESEARCH DESIGN AND METHODS: This double-blind, placebo-controlled study randomized 76 patients to oral methazolamide (40 mg b.i.d.) or placebo for 24 weeks. The primary efficacy end point for methazolamide treatment was a placebo-corrected reduction in HbA1c from baseline after 24 weeks (ΔHbA1c). RESULTS: Mean ± SD baseline HbA1c was 7.1 ± 0.7% (54 ± 5 mmol/mol; n = 37) and 7.4 ± 0.6% (57 ± 5 mmol/mol; n = 39) in the methazolamide and placebo groups, respectively. Methazolamide treatment was associated with a ΔHbA1c of -0.39% (95% CI -0.82, 0.04; P < 0.05) (-4.3 mmol/mol [-9.0, 0.4]), an increase in the proportion of patients achieving HbA1c ≤6.5% (48 mmol/mol) from 8 to 33%, a rapid reduction in alanine aminotransferase (∼10 units/L), and weight loss (2%) in metformin-cotreated patients. CONCLUSIONS: Methazolamide is the archetype for a new intervention in type 2 diabetes with clinical benefits beyond glucose control.

Bilateral transient myopia, angle-closure glaucoma, and choroidal detachment induced by methazolamide.

PURPOSE: We report the case of a patient with acute bilateral transient myopia, secondary angle-closure glaucoma, and choroidal detachment associated with oral administration of methazolamide. CASE: A 51-year-old man developed bilateral transient myopia and secondary angle-closure glaucoma with choroidal detachment after oral administration of methazolamide. Both eyes presented a shallow anterior chamber and elevated intraocular pressure. Ultrasound biomicroscopy revealed annular ciliochoroidal effusion and diffuse thickening of the ciliary body. Angiography showed many scattered islands of hypofluorescence in both eyes. OBSERVATIONS: Methazolamide was stopped and prednisolone given orally. Eight days after treatment initiation, clinical symptoms and signs had resolved. The abnormal findings on ultrasound biomicroscopy and angiography disappeared by 2 months. CONCLUSIONS: Methazolamide can induce bilateral transient myopia, angle-closure glaucoma, and choroidal detachment. Prompt identification of the causative medications and subsequent discontinuation can induce rapid resolution of angle closure.

HLA-B*5901 is strongly associated with methazolamide-induced Stevens-Johnson syndrome/toxic epidermal necrolysis.

AIMS: The carbonic anhydrase inhibitor methazolamide infrequently causes Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). An association between these diseases and the HLA-B59 serotype has been suggested in case reports. This study examined the disease-associated B*59 allele and investigated the association of these diseases with other HLA class I alleles. METHODS: We performed high-resolution HLA-A, -B and -C genotyping in five patients with methazolamide-induced SJS/TEN using a PCR-sequencing-based typing method and analyzed the association between HLA-class I alleles and occurrence of methazolamide-induced SJS/TEN. RESULTS: B*5901 and Cw*0102 alleles were observed in all patients and A*2402 was observed in four patients. The B*5901 allele showed the strongest association with methazolamide-induced SJS/TEN (p < 0.001; odds ratio: 249.8; 95% CI: 13.4-4813.5), followed by Cw*0102 (p = 0.004; odds ratio: 22.1; 95% CI: 1.2-414.3), when compared with the general population as a control. The frequency of the patients carrying B*5901, Cw*0102 and A*2402 simultaneously was significantly higher than that in the general population (p < 0.001; odds ratio: 110.1; 95% CI: 11.7-1038.6). CONCLUSION: A strong association was observed between HLA-B*5901 and methazolamide-induced SJS/TEN in Korean patients. HLA-B*5901 may be a useful screening marker for predicting methazolamide-induced SJS/TEN in patients of Korean and Japanese ancestry.

Stevens-Johnson syndrome induced by methazolamide treatment.

Four cases of Stevens-Johnson syndrome considered to be induced by methazolamide were reported. In all of the cases, the first signs of Stevens-Johnson syndrome (i.e., swelling of the skin and mucous membranes or slight fever) appeared about 2 weeks after the patient started taking methazolamide (75 or 100 mg/d). After the appearance of erythema, the skin and mucous membrane lesions progressed rapidly and spread over the entire body, even after the patient ended methazolamide treatment and started treatment with prednisolone. During prednisolone treatment, the skin and mucous lesions became bullous, ruptured spontaneously, and dried with crust or erosion. HLA typing was positive for HLA-B59 in 3 of 4 cases. Methazolamide should be prescribed with caution in patients of Japanese or Korean descent.