Causative Drug Research Articles

Assessment of Causality in Hospitalized Children With Aminoglycoside-Related Nephrotoxicity

To evaluate the incidence of aminoglycoside-related nephrotoxicity and ascertain drug causality and its risk factors. This prospective study was conducted from January, 2019 to January, 2021, and recruited 110 consecutively admitted children aged 1 month to 12 years, receiving aminoglycosides for ≥4 days. Drug causality was assessed using Liverpool adverse drug reaction causality assessment tool. 42 (38.2%) children developed acute kidney injury (AKI), with 71 (64.5%) having composite nephrotoxicity (AKI and/or tubular-dysfunction). Only 17 (15.5%) had AKI definitively attributable to aminoglycosides. Hypotension [OR 0.016 (95% CI 0.01-0.71), P=0.03], PRISM-III score 20-29% [OR 55.48 (95% CI 3.66-840.53), P=0.004] and post-surgery patients [OR 3.2 (95% CI 1.01-10.1), P=0.047] were independent predictors of AKI. Only a small proportion of children receiving aminoglycosides had AKI definitively attributable to the drug.

Relationship between tracheal intubation and the drugs used by patients with drug overdose due to self-harm

BackgroundTracheal intubation may be performed in patients with drug overdose due to self-harm; however, the details of the causative drug are unknown. The purpose of this study was to clarify the relationship between drugs or its blood levels of patients with drug overdose and the need for tracheal intubation based on the actual measurement results.MethodsFrom October 2018 to March 2020, 132 patients with drug overdose due to self-harm who were transported to the emergency department (ED) were studied. Patient drugs were measured using gas chromatography–mass spectrometry (GC-MS) and were analyzed on the basis of the GC/MS Forensic Toxicological Database. Logistic analysis was performed by combining patient information and GC-MS information.ResultsThe Glasgow Coma Scale (GCS) and Japan Coma Scale (JCS) efficiently predicted tracheal intubation in patients with drug overdose during transport triage; GCS (cut-off value: 12, area under the curve (AUC): 0.81, 95% confidence interval (CI): 0.71–0.88, sensitivity: 0.85, specificity: 0.71, P < 0.05) and JCS (cut-off value: 3, AUC: 0.74, 95% CI: 0.60–0.84, sensitivity: 0.60, specificity: 0.84, P < 0.05). The drugs detected in all patients with drug overdose in order were benzodiazepine receptor agonists (BZs; 43.9%), anticonvulsants (38.6%), antipsychotics (25.0%), and antidepressants (9.8%). In univariate logistic analysis, antipsychotics (odds ratio (OR) 2.46, 95% CI 1.19–5.20, P < 0.05), anticonvulsants (OR 2.71, 95% CI 1.26–5.98, P < 0.05), and anticonvulsants above alert blood levels (OR 27.8, 95% CI 2.92–264.1, P < 0.05) were significantly associated with tracheal intubation in patients with drug overdose, but not BZs and antidepressants. Also, in multivariate logistic analysis, antipsychotics (OR 2.27, 95% CI 1.07–4.83, P < 0.05), anticonvulsants (OR 2.50, 95% CI 1.14–5.64, P < 0.05) and in multivariate logistic analysis of blood levels, anticonvulsants above the alert blood levels (OR 24.9, 95% CI 2.56–241.6, P < 0.05) were significantly associated with tracheal intubation in patients with drug overdose respectively.ConclusionsLogistic analysis revealed that the use of anticonvulsants and antipsychotics were significantly associated with an increased OR in the tracheal intubation of patients with drug overdose due to self-harm.

A clinical profile of adverse drug reaction in HIV patients on highly active antiretroviral therapy

Background: The expansion of antiretroviral therapy has increased the life expectancy of patients living with HIV (PLHIV). However, the Highly Active Antiretroviral Therapy (HAART) has a wide range of toxicity ranging from low grade intolerance to life threatening adverse drug reactions (ADR). Mild toxicity does not require any change in therapy. Moderate to severe toxicity may require substitution with an alternate class of drug while life threatening side effects need discontinuation of HAART till the condition of patient is stabilized and toxicity is resolved. Aim and Objective: To estimating the frequency of occurrence of ADRs in PLHIV on HAART. To estimate the clinical profile and severity of ADRs. Materials and Methods: The data of the patient who were registered at Centre of Excellence, Bowring and Lady Curzon Hospital, Bangalore Medical Collage & Research Institution, Bangalore, from May 2015 to April 2017, were retrospectively reviewed. Demographic data, routine blood investigations, ADRs and CD4 count at that time were noted. Results: In our study conducted from May 2015 to April 2017, 1834 PLHIV were included. Out of these patients, 1554 PLHIV were on HAART. 601 patients showed ADRs secondary to HAART. The age distribution was between 18 to 75 years and the mean age was 43.19+9.18. M: F:: 62:38. 409 patients had hypertriglyceridemia, 472 patients had hypercholesterolemia, 84 had hyperbilirubinemia, 48 developed anemia, 17 patients developed hepatotoxicity, 25 developed drug induced skin rash. Significant association was found between the above reactions and the causative drug. Other reactions like hyperglycemia, night mares, Steven Johnson syndrome (SJS) observed in the study did not show statistical significance. Conclusion: The commonly observed adverse drug reactions of HAART were hypertriglyceridemia, hypercholesterolemia, hyperbilirubinemia, anemia, hepatotoxicity and skin rashes. However hyperglycemia, SJS, night mares were rarely seen.

Perindopril Arginine, Indapamide, and Amlodipine Fixed Dose Combination Induced Gingival Overgrowth: Two Cases with Specific Clinical Presentation

Drug induced gingival overgrowth (DIGO) is a frequent adverse effect of systemic medications. Amlodipine, although accepted as a safe antihypertensive drug due to its longer duration of action with lower dose and fewer adverse reactions compared to other antihypertensive agents, is among the causative drugs. As the aetiology of hypertension is multifactorial, a fixed dose combination containing amlodipine and other antihypertensive agents is currently preferred by physicians as a new treatment approach. The aim of this article is to report two cases of perindopril arginine, indapamide, and amlodipine fixed dose combination induced gingival overgrowth with an emphasis on the specific clinical presentation. Intraoral examination revealed poor oral hygiene, excessive dental plaque accumulation, and erythematous, oedematous, lobulated, enlarged marginal and interdental gingivae prone to bleeding. It was noteworthy that a red band appearance was present on the enlarged labial marginal gingivae in the patients. One month after the drug substitution, proper oral hygiene education and plaque control, and non-surgical periodontal treatment, a marked regression in DIGO and accompanying inflammatory symptoms were observed. Medical and dental practitioners should be aware that antihypertensive drugs used alone or in combination with other agents have the potential to cause gingival overgrowth.

Traditional Japanese Kampo medicines contribute to successful withdrawal from the causative drug in medication-overuse headache

Traditional Japanese Kampo medicines contribute to successful withdrawal from the causative drug in medication-overuse headache

Drug-induced interstitial pneumonia during perioperative chemotherapy for breast cancer

Drug-induced interstitial pneumonia (DIP) that occurs during chemotherapy for breast cancer is a rare but a serious adverse event. Treatments of DIP requires interruption of breast cancer treatment, which may affect the patient's prognosis. However, there are few reports which discuss DIP during breast cancer treatments. Purpose of this report is to make clear how DIP occurred and influenced breast cancer treatment in our hospital.A total of 74 patients who started perioperative chemotherapy in Tokushima Municipal Hospital for breast cancer from January 2019 to December 2020 were evaluated for DIP. Patients' and tumors' characteristics, and regimens which caused DIP were investigated. The clinical courses of the DIP patients were also followed up.Twelve of the 74 patients developed DIP. All 12 patients had histories of cyclophosphamide administration;however, the causative drug could not be determined. Ten of the 12 patients were treated with steroids, and all the patients recovered ultimately from the interstitial pneumonia. While chemotherapy was administered in six patients after mild DIP, no relapse of pneumonia was observed.DIP during perioperative chemotherapy for breast cancer was resolved with appropriate treatment. Patients were able to resume breast cancer treatment with minimal interruption. J. Med. Invest. 69 : 107-111, February, 2022.

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: 11-year Demographic Clinical and Prognostic Characteristics.

Background:Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute, life-threatening, severe drug reactions. Randomized studies on these diseases are difficult to perform.Aims and Objectives:The purpose of this study was to summarize the demographic and clinical characteristics of patients with SJS and TEN in a tertiary hospital in Turkey.Materials and Methods:We evaluated the records of 33 patients with SJS and TEN who were followed in our clinic or examined between January 2008 and June 2019, retrospectively. Age, sex, time of admission to hospital, causative drug, presence of concomitant disease, skin findings, mucosal involvement, the severity-of-illness score for TEN, the medication used, antibiotic use, transfer to intensive care, development of complications, and death or discharge status were noted.Results:Of the 33 patients, 11 (33.3%) had SJS, 3 (9.1%) had SJS/TEN overlap, and 19 (57.6%) had TEN. The majority (60.6%) of the patients were female. Nineteen (57.6%) patients had one, and 13 (39.4%) had more than one suspected drug exposure in their history. The most commonly suspected drugs were antibiotics. Twelve (36.4%) patients had intensive care unit hospitalization. Ten (30.3%) patients died.Conclusion:The demographic data of our study were consistent with the literature. Similar to the literature, antibiotics were the most common reaction-causing drugs. However, antiepileptic drugs, which were more frequently reported in other studies, were identified as suspicious in only one patient. We believe that our study will contribute to the determination of characteristics of this rare disease with real-life data.

One-step and highly sensitive quantification of fusion genes with isothermal amplification initiated by a fusion-site anchored stem-loop primer.

As causative oncogenes and drug targets, fusion genes play critical roles in tumorigenesis, development, and treatment and thus are regarded as tumor-specific molecular biomarkers. Specific identification and sensitive quantification of fusion genes are of great significance in cancer diagnosis, classification, and prognosis as well as minimal residual disease (MRD) monitoring. Herein, we proposed a specific and sensitive method for the quantitative detection of fusion transcripts by designing stem-loop primers to directly track fusion junctions of fusion genes and subsequently initiate reverse transcript loop-mediated isothermal amplification (LAMP). Benefitting from the specific and direct mechanism of stem-loop primers and the high amplification efficiency of LAMP, the proposed method can sensitively measure fusion gene transcripts with a detection limit of 100 aM (1 zmol) and achieve a wide linear dynamic range spanning at least six orders of magnitude (100 aM-100 pM). Significantly, the whole fusion transcript assay can be accomplished in one step under isothermal conditions, greatly simplifying the operation and detection processes. Meanwhile, the one-step analysis method in one tube may effectively eliminate false-positive results from product cross-contamination during multiple experimental operations and cover-opening measurements. We have demonstrated that the proposed method is practical and accurate for the quantitation of fusion transcripts in biological samples. Owing to the outstanding features of high sensitivity, excellent specificity, and simple operation, the new strategy may provide a robust and attractive platform for the quantification of fusion genes.

Clinical characteristics of drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: A single-center study.

BackgroundStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe adverse cutaneous reactions, most commonly triggered by medications, characterized by extensive necrosis and detachment of the epidermis.ObjectiveWe investigated the differences in clinical characteristics of drug-induced SJS/TEN depending on the type of drug in a single center.MethodsThe relevance of sex, age, culprit drugs, clinical features, courses, treatment options, and follow-up results were retrospectively evaluated in patients diagnosed with drug-induced SJS/TEN at Pusan National University Hospital between 2008 and 2019.ResultsNinety-two patients with a mean age of 58.7 ± 20.2 years (range, 10–93 years) were included in the study. Those aged 60–80 years accounted for the largest number of patients (42.4%). Patients with drug-induced SJS/TEN comprised 40 women (43.5%) and 52 men (56.5%). We categorized drug-induced SJS/TEN cases by culprit drugs into 6 groups: antibiotics, allopurinol, antiepileptic (AED), nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and other drugs. The rate of NSAID-induced disease significantly increased from SJS to TEN (p = 0.016). Among the patients in the NSAID group, the proportion of TEN (40%) was higher than that in the other groups (p = 0.021). The mean body surface area was significantly lower in the AED group than in the non-AED groups (7.1 ± 9.8 vs. 23.1 ± 27.3, p = 0.020) and higher in the NSAID group than in the non-NSAID groups (47.5 ± 39.5 vs. 15.7 ± 20.0, p = 0.010).ConclusionThis study showed that the clinical characteristics of each causative drug group may be different in drug-induced SJS/TEN. Our findings may help clinicians better understand drug-induced SJS/TEN.

Patterns of Antiepileptic Drug Reactions in Children: A Multicenter Study.

ObjectivesAntiepileptic drugs are among the most common triggers of cutaneous adverse reactions. About 5–17% of epileptic patients develop idiosyncratic skin reactions at some point during their treatment course, most of which occur within the first two months of drug initiation. This study aimed to investigate the pattern of cutaneous drug reactions associated with anticonvulsant use among the pediatric population in Iran to identify high-risk individuals.Materials & Methods In this retrospective descriptive study, medical records of children aged two months to 14 years, who were diagnosed with drug reactions due to anticonvulsant drugs between April 2007 and March 2018, were reviewed, and relevant information were extracted. This multicenter study was conducted in several provinces of Iran.ResultsA total of 186 cases with a final diagnosis of the antiepileptic drug-induced eruption were evaluated. The median age of participants was 36 months (range: 2-168), and 56% were male. In approximately 70% of the children, the phenobarbital was the culprit. The median time interval between initiation of the causative drug and development of rash and fever was 10 and 7 days, respectively. The most common rash type was maculopapular rashes (69%). Overall, 33% of the patients only received antihistamines after discontinuation of the causative drug.Conclusion Similar to previously published studies in Iran, phenobarbital was the main cause of cutaneous drug reactions to antiepileptic drugs, indicating the necessity of paying more attention when prescribing phenobarbital for Iranian pediatrics.

Management of Psychiatric Disorders in Patients with Cardiovascular Diseases.

Management of Psychiatric Disorders in Patients with Cardiovascular Diseases.

Possibility of Multiple Drug-Drug Interactions in Patients Treated with Statins: Analysis of Data from the Japanese Adverse Drug Event Report (JADER) Database and Verification by Animal Experiments.

Adverse drug events due to drug-drug interactions can be prevented by avoiding concomitant use of causative drugs; therefore, it is important to understand drug combinations that cause drug-drug interactions. Although many attempts to identify drug-drug interactions from real-world databases such as spontaneous reporting systems have been performed, little is known about drug-drug interactions caused by three or more drugs in polypharmacy, i.e., multiple drug-drug interactions. Therefore, we attempted to detect multiple drug-drug interactions using decision tree analysis using the Japanese Adverse Drug Event Report (JADER) database, a Japanese spontaneous reporting system. First, we used decision tree analysis to detect drug combinations that increase the risk of rhabdomyolysis in cases registered in the JADER database that used six statins. Next, the risk of three or more drug combinations that significantly increased the risk of rhabdomyolysis was validated with in vivo experiments in rats. The analysis identified a multiple drug-drug interaction signal only for pitavastatin. The reporting rate of rhabdomyolysis for pitavastatin in the JADER database was 0.09, and it increased to 0.16 in combination with allopurinol. Furthermore, the rate was even higher (0.40) in combination with valsartan. Additionally, necrosis of leg muscles was observed in some rats simultaneously treated with these three drugs, and their creatine kinase and myoglobin levels were elevated. The combination of pitavastatin, allopurinol, and valsartan should be treated with caution as a multiple drug-drug interaction. Since multiple drug-drug interactions were detected with decision tree analysis and the increased risk was verified in animal experiments, decision tree analysis is considered to be an effective method for detecting multiple drug-drug interactions.

HiSAT: A Novel Method for the Rapid Diagnosis of Allergy.

To identify causative substances for allergies to drugs or foods, the lymphocyte transformation test (LTT) is currently widely used as in vitro test, but its accuracy is not satisfactory. We have developed a novel method designated high-sensitivity allergy test (HiSAT) for determining allergy expression by measuring cell kinetics, using the chemotactic cells from non-allergic volunteers against a gradient field of cytokines released from immune cells when allergy develops. HiSAT requires a very small sample of 5 µL or less, and is applicable to three types of tests, depending on the situation in clinical practice: (i) diagnosis of the allergic expression, (ii) identification of the causative drug, and, in principle, (iii) pre-inspection.

Drug-induced liver injury: A primer for cardiologists

Although drug-induced liver injury (DILI) is an uncommon diagnosis, it is an important cause of morbidity and mortality in hepatology practice. A timely diagnosis of DILI is important to stop causative drugs and keeping a high index of suspicion is important. There is no gold standard single test to diagnosed DILI, causality scores help in establishing a diagnosis. DILI presenting as acute liver failure is associated with poor prognosis in natural course. The association of nonalcoholic fatty liver disease with cardiac disease makes it more important to think of DILI in a patient with liver dysfunction. We discuss various aspects of DILI in cardiology context in the current review.

Analysis of Adverse Drug Reactions to First-Line Anti-Tuberculosis Drugs Using the Korea Adverse Event Reporting System

BackgroundAdverse drug reactions (ADRs) to first-line anti-tuberculosis (TB) drugs are common; however, there have been few reports of nationwide epidemiologic studies on ADRs to anti-TB drugs in Korea. This study aimed to investigate the clinical characteristics of various ADRs to first-line anti-TB drugs using a nationwide database of ADRs.MethodsWe used the Korea Adverse Event Reporting System (KAERS) database (2009–2018). The study subjects were selected using the Korean Standard Classification of Diseases codes for pulmonary and extrapulmonary TB and electronic data interchange codes for isoniazid (INH), rifampicin (RIF), ethambutol (ETB), and pyrazinamide (PZA). The causality assessment of “possible,” “probable,” or “certain” by World Health Organization-Uppsala Monitoring Center System causality category was selected.ResultsA total of 1,562,024 ADRs were reported in the KIDS-KAERS database from 2009 to 2018, where ADRs to first-line anti-TB drugs were 17,843 cases (1.14%). The most common causative drugs were RIF (28.7%), INH (24.0%), ETB (23.4%), and PZA (23.9%) in that order. 48.5% of cases were reported in the older patients (≥ 60 years). According to organ system, gastro-intestinal system disorder was most common (32.0%), followed by skin and appendage (25.9%), liver and biliary system (14.2%). Nausea was the most common ADR (14.6%), followed by hepatic enzyme elevation (14.2%), rash (11.7%), pruritus (9.1%), vomiting (8.9%), and urticaria (4.2%). Most ADRs appeared within 1 month, but ADRs such as neuropathy, paresthesia, hematologic abnormalities, renal function abnormalities and liver enzyme abnormality were also often reported after 2 months.ConclusionOur data are clinically informative for recognizing and coping with ADRs of anti-TB drugs.

Knowledge, Attitude and Perception of Pharmacovigilance Awareness among Interns at a Tertiary Care Teaching Hospital, Andhra Pradesh, India

Introduction: Pharmacovigilance plays an important role in the healthcare sector, in terms of health and economic burden. Studies on interns are limited and it is an aspect that requires further study. Aim: To evaluate the knowledge, attitude and perception of MBBS interns at a teaching hospital in southern India. Also to study the reasons for under-reporting of Adverse Drug Reactions (ADR). Materials and Methods: This questionnaire-based, crosssectional study was conducted among the 112 MBBS interns at Konaseema Institute of Medical sciences and Research Foundation, Amalapuram, Andhra Pradesh, India, in December 2013. The interns were asked to complete 25 predesigned questionnaire based on the Knowledge, Attitude and Perception (KAP). The answered questionnaires were statistically analysed by using Microsoft Excel worksheet. Results: Out of total 112 MBBS interns, only 94 completed the questionnaire within the stipulated time. There were 41 males and 53 females, with a mean age of 25±2 years. The response rate was 83.9%. A 48 (51.1%) interns had come across Adverse Drug Reactions (ADR) cases during their practice, however, among them only 24 (50%) reported them. Difficulty to identify the causative drug was the major cause for under-reporting as per 23 (24.4%) interns. Majority (60.6%) were of the opinion that pharmacovigilance only covers drug-related side-effects, not other types of side-effects. Conclusion: Interns are the upcoming doctors, hence increased attention must be paid to their lack of pharmacovigilance knowledge in order to improve the clinical management and rational use of drugs.

Agreement between a regional pharmacovigilance centre and an adjudication committee regarding adverse drug reactions on a cohort of hospitalised children

The EREMI project was set up to collect data on adverse drug reactions (ADRs) occurring due to off-label and/or unlicensed drugs prescribed to hospitalised children in France. These events were evaluated by a regional pharmacovigilance centre (RPC) and an adjudication committee (AC). The aim of this study was to assess the agreement between these two different entities on their evaluation of ADRs. The RPC first validated the ADRs and assessed their causality using the Naranjo scale. The AC assessed then ADRs using all available information, including the RPC evaluation. The agreement on severity and nature of ADRs, role of treatment (suspect or concomitant) and drug causality was calculated using Cohen's nonparametric kappa coefficient (k). Three hundred and eighty-six events were reported in 219 children. The RPC excluded 65 events and validated 321 ADRs. Agreement was very good on nature of ADRs (k=0.85) and role of treatment (k=0.81), moderate on severity of ADRs (k=0.60) and very poor on drug causality (k=0.05). Agreement between the RPC and the AC was not constant throughout this evaluation. They troubled to agree on severe ADRs and on drug causality.

Antituberculosis Drug-induced Linear IgA Dermatosis

Introduction: Linear IgA dermatosis is a rare autoimmune vesiculobullous disease characterized by homogeneous linear IgA deposits in basement membrane of epidermis, and it can be idiopathic or drug-induced. The pathogenesis of drug-induced linear IgA dermatosis is not fully known yet, but it is associated with specific T cells. The clinical manifestations of the disease include vesiculobullous eruption, erythematous plaques, or string of pearls. Most cases still need additional therapy to avoid the expansion of the disease. Case Presentation: In this study, we present a 17-year-old male patient with erythema plaques, vesicles, and bullae with erosion in facial, oral, neck, trunk, genital, and extremities, pruritus, and burning sensation. The patient was undergoing pulmonary tuberculosis (TB) treatment for one week. Physical examination was done, and total BSA 10% and negative Asboe-Hansen sign were seen. The treatment consisted of delaying administration of TB drugs, desoximetasone cream 0.25%, cetirizine 10 mg, and aspiration of bullae. Conclusions: Drug-induced linear IgA dermatosis can occur at any age due to the administration of rifampicin and other antibiotics, angiotensin-I converting enzyme (ACE) inhibitors, or nonsteroidal anti-inflammatory drugs (NSAIDs). The drug can stimulate specific T cells that release Th2 cytokines to produce IgA antibodies against the basement membrane of epidermis. Drugs may cause an autoimmune response by cross-reaction with the target epitope, altering the conformation of epitopes, or exposing previously sequestered antigens to the immune system. The causative drug was stopped, and methyl prednisolone 0.5 - 1 mg/kg/day was given as initial therapy. In this study, we reported a rare case of a 17-year-old male with anti-TB drug-induced linear IgA dermatosis. Diagnosis was done based on clinical manifestation, histopathology, and immunofluorescence. The causative drug was stopped, the patient was given topical and systemic steroid therapy and drug desensitization. Remission was noted after six weeks of therapy, and oral steroid was slowly tapered and stopped on day 42. After stopping oral steroids, no lesions were reported. A 6-month follow-up revealed no signs of recurrence.

Findings by an International Collaboration on SJS/TEN With Severe Ocular Complications.

Stevens-Johnson Syndrome (SJS) is an acute inflammatory vesiculobullous reaction of the skin and mucosa, e.g., the ocular surface, oral cavity, and genitals. In patients with extensive skin detachment and a poor prognosis, the condition is called toxic epidermal necrolysis (TEN). Not all, but some patients with SJS/TEN manifest severe ocular lesions. Approximately 50% of SJS/TEN patients diagnosed by dermatologists and in burn units suffer from severe ocular complications (SOC) such as severe conjunctivitis with pseudomembrane and ocular surface epithelial defects in the acute stage. In the chronic stage, this results in sequelae such as severe dry eye and visual disturbance. Before 2005, our group of Japanese scientists started focusing on ophthalmic SJS/TEN with SOC. We found that cold medicines were the main causative drugs of SJS/TEN with SOC and that in Japanese patients, HLA-A*02:06 and HLA-B*44:03 were significantly associated with cold medicine-related SJS/TEN with SOC (CM-SJS/TEN with SOC). We expanded our studies and joined scientists from Korea, Brazil, India, Taiwan, Thailand, and the United Kingdom in an international collaboration to detect the genetic predisposition for SJS/TEN with SOC. This collaboration suggested that in Japanese patients, cold medicines, including NSAIDs, were the main causative drugs, and that HLA-A*02:06 was implicated in Japanese and Korean patients and HLA-B*44:03 in Japanese-, Indian-, and European ancestry Brazilian patients. Our joint findings reveal that there are ethnic differences in the HLA types associated with SJS/TEN with SOC.

Pathogenesis of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis With Severe Ocular Complications.

Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) is an acute inflammatory vesiculobullous reaction of the mucosa of the ocular surface, oral cavity, and genitals, and of the skin. Severe ocular complications (SOC) are observed in about half of SJS/TEN patients diagnosed by dermatologists and in burn units. Ophthalmologists treat SOC, and they tend to encounter the patients not only in the acute stage, but also in the chronic stage. Our investigation of the pathogenesis of SJS/TEN with SOC led us to suspect that abnormal innate mucosal immunity contributes to the ocular surface inflammation seen in SJS/TEN with SOC. We confirmed that cold medicines such as NSAIDs and multi-ingredient cold medications are the main causative drugs for SJS/TEN with SOC. Single nucleotide polymorphism (SNP) association analysis of cold medicine-related SJS/TEN with SOC showed that the Toll-like receptor 3 (TLR3)-, the prostaglandin-E receptor 3 (PTGER3)-, and the IKZF1 gene were significantly associated with SNPs and that these genes could regulate mucocutaneous inflammation including that of the ocular surface. We also examined the tear cytokines of SJS/TEN with SOC in the chronic stage and found that IL-8, IL-6, IFN-γ, RANTES, eotaxin, and MIP-1β were significantly upregulated in SJS/TEN with SOC in the chronic stage. Only IP-10 was significantly downregulated in SJS/TEN with SOC in the chronic stage. This mini-review summarizes the pathological mechanisms that we identified as underlying the development of SJS/TEN with SOC.