Association of HLA Alleles with Anti-Epileptic (Carbamazepine and Phenytoin) in Inducing Steven Johnson Syndrome or Toxic Epidermal Necrolysis: A Narrative Review

Fever, Rash, and Systemic Symptoms: Understanding the Role of Virus and HLA in Severe Cutaneous Drug Allergy

8. Drug allergy

Drug-induced toxic epidermal necrolysis: A rare case report - JOOO- Print ISSN No: - 2395-6186 Online ISSN No:- 2395-6194 Article DOI No:- 10.18231/j.jooo.2019.008, Journal of Oral Medicine, Oral Surgery, Oral Pathology and Oral Radiology-J Oral Med Oral Surg Oral Pathol Oral Radiol

Background:Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions (SCARs). There is scant literature on the characteristics and causes of these conditions among the Nigerian population. Here, we describe the epidemiology, associated morbidity and mortality, and culpable drugs in SJS and TEN cases using the National Pharmacovigilance (NPC) database in Nigeria.Methods:A retrospective review of the NPC database was done to analyze SJS and TEN cases reported over a period of 14 years. Annual reports, age and sex of patients, type of reporter, suspects and concomitant drugs, time to onset (TTO) of the reactions, and outcome of SJS and TEN were evaluated.Results:The NPC received a total of 24,015 adverse drug reaction (ADR) reports. SJS and TEN accounted for 284 (0.1%) of the total reports, of which 254 (89.4%) were SJS and the remainder were TEN. Females (n = 184, 64.8%) and individuals aged 19–40 years (n = 181, 63.7%) were the most affected by SJS and TEN. Antiretrovirals, followed by antibiotics, were the most common drug classes reported to cause SJS and TEN, with nevirapine (n = 174, 40.7%) and co-trimoxazole (n = 143, 33.5%) being the most widely implicated drugs. Among patients with reported outcomes, 73 (28.7%) SJS and 3 (10.0%) TEN cases recovered without sequelae, at the time of reporting. Severity of the SCAR was reported for only 171 (69.0%) cases, of which 12 (4.7%) and 8 (26.7%) resulted in death (Grade 5) among SJS and TEN cases, respectively.Conclusions:Antiretroviral and antibiotics were the commonly reported offending group of drugs for SJS and TEN cases. Nevirapine and co-trimoxazole were the commonly reported suspect drugs. SJS and TEN were reported most frequently in females and in patients aged 19–40 years, indicating that drug surveillance and counseling in these groups of patients may be beneficial.

Toxic epidermal necrolysis (TEN) and Stevens Johnson Syndrome (SJS) are severe adverse cutaneous drug reactions that predominantly involve the skin and mucous membranes. Both are rare, with TEN and SJS affecting approximately 1or 2/1,000,000 annually, and are considered medical emergencies as they are potentially fatal. They are characterized by mucocutaneous tenderness and typically hemorrhagic erosions, erythema and more or less severe epidermal detachment presenting as blisters and areas of denuded skin. Currently, TEN and SJS are considered to be two ends of a spectrum of severe epidermolytic adverse cutaneous drug reactions, differing only by their extent of skin detachment. Drugs are assumed or identified as the main cause of SJS/TEN in most cases, but Mycoplasma pneumoniae and Herpes simplex virus infections are well documented causes alongside rare cases in which the aetiology remains unknown. Several drugs are at "high" risk of inducing TEN/SJS including: Allopurinol, Trimethoprim-sulfamethoxazole and other sulfonamide-antibiotics, aminopenicillins, cephalosporins, quinolones, carbamazepine, phenytoin, phenobarbital and NSAID's of the oxicam-type. Genetic susceptibility to SJS and TEN is likely as exemplified by the strong association observed in Han Chinese between a genetic marker, the human leukocyte antigen HLA-B*1502, and SJS induced by carbamazepine. Diagnosis relies mainly on clinical signs together with the histological analysis of a skin biopsy showing typical full-thickness epidermal necrolysis due to extensive keratinocyte apoptosis. Differential diagnosis includes linear IgA dermatosis and paraneoplastic pemphigus, pemphigus vulgaris and bullous pemphigoid, acute generalized exanthematous pustulosis (AGEP), disseminated fixed bullous drug eruption and staphyloccocal scalded skin syndrome (SSSS). Due to the high risk of mortality, management of patients with SJS/TEN requires rapid diagnosis, evaluation of the prognosis using SCORTEN, identification and interruption of the culprit drug, specialized supportive care ideally in an intensive care unit, and consideration of immunomodulating agents such as high-dose intravenous immunoglobulin therapy. SJS and TEN are severe and life-threatening. The average reported mortality rate of SJS is 1-5%, and of TEN is 25-35%; it can be even higher in elderly patients and those with a large surface area of epidermal detachment. More than 50% of patients surviving TEN suffer from long-term sequelae of the disease.

Adverse cutaneous drug reactions (ACDRs) are caused by a wide variety of agents. The aim was to study the incidence and clinico-demographic profile of ACDRs to identify any potential risk factors and compare the results with other studies. A cross-sectional observational study was conducted over a period of one year from October 2012 to October 2013 in the outpatient department (OPD) of a tertiary care teaching hospital of the Kashmir valley in India and various ACDRs were recorded. The incidence of ACDRs was 0.16%. The mean age of patients was 39.36 ± 16.77 years. The male: female ratio was 0.97:1. The most frequently reported cutaneous reactions were with antimicrobials (57.33%) followed by NSAIDs (21.33%) and antiepileptic drugs (17.33%). Less common groups involved were steroids, antipsychotics and bisphosphonates (1.33% each). Fixed drug eruptions (FDEs) were the commonest (45.33%) followed by maculopapular (17.33%), photoallergic (8%), erythema multiforme (6.66%), Stevens-Johnson syndrome (5.33%) and lichenoid eruptions (4%). Less common patterns were urticaria, Drug Reaction with Eosinophilia and systemic symptoms (DRESS syndrome) and acneform eruptions (2.66% each) followed by angioedema, acute generalized exanthematous pustulosis (AGEP), exfoliative dermatitis and toxic epidermal necrolysis (1.33% each). Physicians should have adequate knowledge of adverse drug reactions, especially of newer drugs which are increasing every year in order to minimize such events.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare immune-mediated severe cutaneous adverse reactions with incidence rate of 0.05 to 2 persons per million populations per year. Drugs are the most commonly implicated in 95% of cases. To audit the causative drugs, clinical outcome, and cost of management in SJS, TEN, and SJS-TEN overlap. Tertiary care hospitals-based multicentric retrospective study (case series). Indoor case papers of SJS, TEN, and SJS-TEN overlap admitted between January 2006 and December 2009 in four tertiary care hospitals of Gujarat were scrutinized. Data were collected for demographic information, causative drugs, investigations, treatment given, duration of hospital stay, time interval between onset of symptoms and drug intake, clinical outcome, and complications. Data were analyzed to find out proportion of individual drugs responsible, major complications, and clinical outcome in SJS, TEN, and SJS-TEN overlap. Total cost of management was calculated by using cost of drugs, investigations, and consumables used during entire hospital stay. One-way Analysis of Variance followed by Tukey-Kramer multiple comparison test was used for comparison of incubation period, duration of hospital stay, and cost of management. Antimicrobials (50%), nonsteroidal anti-inflammatory drugs (22.41%), and antiseizure drugs (18.96%) were the most commonly associated groups. Nevirapine (28.12%) was the most common drug. Antiseizure drugs were more often associated with serious form of adverse reaction (TEN: 81.8%) than other drugs. Duration of hospital stay (20.6 vs 9.7 days) and cost of management (7,910/- vs 2,460/-) were significantly higher in TEN than SJS (P=0.020 and P<0.001, respectively). Time duration between drug intake and onset of symptoms (17.7 vs 27.5 days) was nonsignificantly lower in TEN as compared with SJS. Secondary infection (28.12%) was the most common complication noted. Mortality rate was 15.6% among all cases; 9% in SJS and 26.7% in TEN. Antimicrobial drugs are the most commonly implicated drugs and cost of managing these adverse drug reactions is higher than other serious ADRs.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) associated with the use of nonsteroidal antiinflammatory drugs (NSAIDs) are described. A search of the English- language medical literature was conducted to identify studies and cases of SJS and TEN associated with NSAIDs and cyclooxygenase-2-selective NSAIDs available in the United States. Several epidemiologic studies, case reports, and case series involving SJS and TEN associated with NSAIDs were identified. Of the available NSAIDs, oxicam derivatives appeared to have the greatest association with SJS and TEN. The relative risks reported with other NSAIDs are much lower. The risk with cyclooxygenase-2-selective NSAIDs and meloxicam is less clear, since all were introduced after the completion of the epidemiologic studies. SJS or TEN from NSAIDs and cyclooxygenase-2-selective NSAIDs appears to affect the same patient population as other medications that cause SJS or TEN. The risk of SJS or TEN caused by NSAIDs is extremely low (less than 2 per 1 million users per week for oxicam derivatives, less than 1 per 1 million users per week for other NSAIDs, and 6 cases per 1 million person-years for celecoxib). Aspirin is not typically associated with SJS or TEN. Of the other salicylates, SJS or TEN has only been reported with diflunisal. The risk of SJS or TEN in patients receiving NSAIDs is extremely low; older patients, women, and patients within the first month of treatment initiation appear to have the greatest risk. Health care providers and patients should be aware of the signs and symptoms of SJS and TEN.

Patient: Female, 75-year-oldFinal Diagnosis: Toxic epidermal necrolysisSymptoms: Exanthema • rash • shivers • weaknessMedication: —Clinical Procedure: Analgesia • ciclosporine • corticosteroids • topical and systemic treatmentSpecialty: Critical Care Medicine • DermatologyObjective:Rare diseaseBackground:Allopurinol is the first-line therapy for the treatment of symptomatic hyperuricemia (gout). In clinical practice, there is a tendency to overmedicate asymptomatic patients who have elevated serum urate. Because of this practice, serious and life-threatening reactions such as Stevens-Johnson syndrome (SJS) or the more dramatic toxic epidermal necrolysis (TEN), both frequently caused by uricostatics, may occur. To increase awareness of these complications, we present a case with fulminant TEN caused by allopurinol.Case Report:A 75-year-old woman noticed a mildly itching skin rash accompanied by fever, shivering, and weakness approximately 3 weeks after taking newly prescribed allopurinol. The initial clinical examination revealed a generalized maculopapular exanthema. An adverse drug reaction was recognized, and allopurinol was discontinued. Ambulatory supportive therapy using prednisolone and cetirizine was started but failed. The patient developed a progressive exanthema with painful widespread blistering, skin peeling, and mucosal and conjunctival lesions. After recurrent presentations to the Emergency Department, the patient was transferred to our Intensive Care Unit (ICU). The clinical picture confirmed the suspected diagnosis of TEN. Massive fluid replacement, predniso-lone, and cyclosporine were used as anti-inflammatory therapy. Polyhexanide and octenidine were applied for local treatment. All treatment measures were guided daily by a multidisciplinary team. After 7 days in the ICU, the patient was transferred to the Dermatology Department and was discharged from the hospital 42 days later.Conclusions:With the prescription of allopurinol, there should be awareness of potentially life-threatening complications such as SJS or TEN. Patients with SJS or TEN should be immediately transferred to an ICU with dermatological expertise and multidisciplinary therapy.

The study sought to identify the magnitude and characteristic of severe cutaneous adverse reactions (SCAR's) like Steven-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN). A prospective study was conducted by the Department of Pharmacology in association with Department of Dermatology in SMHS hospital. The study was carried out from June 2013-June 2015 on hospitalized cases of cutaneous adverse drug reaction reporting in hospital. The SCAR's were reported in a structured questionnaire based on adverse drug reaction (ADR) reporting form provided by the Central Drug Standard Control Organization (CDSCO) Ministry of Health and Family welfare, Government of India. The SCAR's were analysed for their characteristics, causality, severity and prognosis. Causality assessment was done by using a validated ADR probability scale of Naranjo as well as WHO Uppsala Monitoring Center (WHO-UMC) system for standardized case causality assessment. The management protocol were analysed for their clinical outcome through a proper follow up period. A total of 52 hospitalized cases of cutaneous adverse drug reactions were reported during the study period. We identified a total of 15 cases (28%) of SCAR's involving 9(17%) of SJS and 6 (12%) of TEN. SJS was seen in 2(22%) males and 7(78%) females. TEN was seen in all females (100%) and in no male. Drugs implicated in causing these life threatening reactions were identified as anticonvulsant agents like carbamazepine (CBZ), phenytoin (PHT) and Lamotrigine (LTG), oxicam NSAID, Sulfasalazine and levofloxacin. Despite higher reported mortality rates in SJS and TEN all patients survived with 2 patients surviving TEN suffered from long term opthalmological sequelae of the disease. Present study suggest that drug induced cutaneous eruptions are common ranging from common nuisance rashes to rare life threatening diseases like SJS and TEN, SJS/TEN typically occur 1-3 weeks after initiation of therapy. Aromatic AED's, LTG, oxicam NSAID's, sulfasalazine and levofloxacin have a tremendous potential to trigger SCARS's. To ensure safe use of pharmaceutical agents and better treatment outcomes post marketing voluntary reporting of severe rare and unusual reactions remains inevitable.

Stevens-Johnson Syndrome After Immunization With Smallpox, Anthrax, and Tetanus Vaccines

Spontaneous reporting systems (SRS) have been established to monitor drug safety problems after marketing, especially rare, but serious adverse drug reactions (ADRs). Among these are the skin disorders erythema multiforme (EM), Stevens- Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The purpose of this study has been to evaluate the data on these serious skin disorders available in a SRS. All reports concerning these diseases submitted to the Danish Committee on ADRs during the period 1968 to 1991 were reviewed according to predefined criteria. Information was often scarce,and the diagnosis of the reporter had to be accepted at face value in 28% of cases. Two hundred cases of EM, 74 of SJS and 29 of TEN were identified. More than 60% of cases were hospitalized. The diseases had fatal outcome in six patients with TEN, three with SJS and a single patient suffering from EM. One hundred and twenty-eight different drugs were reported as causal agents. Major drug groups involved were antibiotics (sulphonamides and penicillins), non-steroidal anti-inflammatory drugs, anti-epileptics and analgesics. Incidence estimates based on spontaneous reports were compared to the incidence according to the literature and data from a nationwide hospital discharge diagnosis register. The reporting fraction for EM and SJS is estimated to 10-30%, and for TEN to 25-50%, but the validity of reports is in some cases difficult to assess owing to lack of detail.

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe adverse drug reaction with potentially life-threatening skin disease. The widely accepted consensus regarding therapy does not exist at present and epidemiological data of Taiwan in recent years is limited. Objective: To evaluate the efficacy of systemic steroid therapy in treatment of SJS and TEN and also analysis the associated epidemiology data. Methods: This study was performed by retrospectively chart review of patients admitted with SJS or TEN in a tertial referral medical center in southern Taiwan between 2002 and 2007. Clinical data including mortality, morbidity, the category of offending drugs and the systemic steroid treatment effects were analyzed. Results: Total 52 patients were included; 10 were classified as TEN and 42 as SJS. Overall mortality is 3.8% and infectious morbidity is 23%. In aspect of causative agents, anticonvulsants (especially carbamazepine) were the most common drugs followed by Non-Steroid Anti-inflammatory Drugs, allopurinol and antibiotics in our series. Early systemic steroid administration may shorten the hospitalization duration than supportive care (p＜0.012) in our study. Conclusion: In our study, early administration of systemic steroids maybe benefits in the forms of inflammation prevention and disease progression. Short-term use to preclude infection morbidity, as well as a tapering dose as soon as possible, is suggested.

Adverse cutaneous drug reactions associated with antiepileptic drugs (AEDs) are a serious problem in the clinical setting. New-generation AEDs have been reported to be better tolerated than old-generation forms; however, information about the risks of adverse cutaneous drug reactions to new-generation AEDs is limited. The purpose of this study was to clarify the association of AEDs with adverse cutaneous drug reactions using a spontaneous reporting database. We performed a retrospective pharmacovigilance disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency between April 2004 and January 2017 were analyzed. Based on reports of all adverse events, we obtained 4805 reports of adverse cutaneous drug reactions associated with AEDs, and calculated the reporting odds ratio (ROR) and 95% confidence interval (CI) for drug rash, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Individual AEDs had variable signals for drug rash, SJS, and TEN. The strongest signals were detected for drug rash caused by lamotrigine (ROR 9.18, 95% CI 8.65-9.74), SJS caused by zonisamide (ROR 9.85, 95% CI 8.23-11.78), and TEN caused by phenobarbital (ROR 14.08, 95% CI 11.28-17.57). There are clear differences in the risk of cutaneous reactions among AEDs, and further studies are needed to confirm these findings.

Cutaneous emission is a regular type of unfavorable medication response. Stevens-Johnson syndrome (SJS) is one such example of a serious cutaneous emission. The condition presents with extreme purulent conjunctivitis, serious stomatitis with broad mucosal putrefaction, and purpuric macules. The etiology is connected to the utilization of medications as opposed to other factors.1 The normal guilty parties are antimicrobials, such as sulfonamide, followed by nonsteroidal anti-inflammatory drugs (NSAIDs), anticonvulsant medications, and tranquilizers used to treat gout. Here, we report an instance of SJS instigated as a result of an overdose of amoxicillin.2 A 63-year-old male patient presented to the medical clinic with grievances of rashes everywhere throughout the body and sores around the lips since 3 days. The patient had a history of medication ingestion for fever and after ingestion of the medication, injuries appeared on his lips within 12 hours and the seriousness of the response was noted within 24 hours. On examination, vesicular sores over the tongue, buccal mucosa, and lips were noted and the fundamental examination generally revealed no other critical discoveries. On detailed enquiry, the patient gave a background marked by ingestion of amoxicillin 500 mg, after which he experienced swelling over the lips and rashes over the body. The patient's history revealed that he was not hypersensitive to any sort of medications and neither was his family. His research center esteem demonstrated huge increment in differentially (polymorphs: 72%; eosinophil: 12%). Considering his history, clinical examination, and research facility discoveries, the patient was diagnosed as having amoxicillin-induced SJS. We used Naranjo's Adverse Drug Reaction Probability Scale and the World Health Organization (WHO) Causality Scale to determine whether SJS could have been caused by amoxicillin as an adverse drug reaction (ADR). The Naranjo score for the suspected ADR was 7 and thus SJS was a likely ADR presumably brought about by the amoxicillin (Table 1). The total rating of the suspected ADR with the WHO Causality Scale indicated that SJS was a likely ADR brought about by the amoxicillin it is mentioned in Table 2. The patient was treated with parenteral antimicrobial (Inj. cefotaxime 1 g, bd), antibiotic (T. Chloramphenicol maleate 4 mg, bd), treatment of injuries (Oint. triamcinolone acetonide buccal glue 0.1%), and steroids beginning from the third day (T. prednisolone 5 mg, od). An alarm card for the suspected ADR was given to the patient by the Drug Information Center, Government Headquarters' Hospital, Erode, India, for future awareness. In 1922, Stevens and Johnson depicted two male patients of 7 and 8 years of age who experienced unprecedented summed up ejection with fever and inflamed buccal mucosa.2 SJS can be separated from other skin conditions according to three clinical criteria: (1) individual skin injuries, (2) appropriation of sores, and (3) degree of epidermal separation. The trademark discoveries in SJS are broad erythematous or purpuric macules that structure level atypical target injuries as the sickness advances to cause full-thickness epithelial necrosis.3 In the oral cavity, SJS causes across-the-board ulcerative sores. A prodrome happens in around 30% of cases and may start within 1 to 3 weeks of beginning another medication and endures 1 to about 14 days before the beginning of mucocutaneous appearances, giving influenza-like indications, sore throat, migraine, arthralgia, myalgia, fever, bullous and different rashes, pneumonia, nephritis, or myocarditis.4 Balanitis, urethritis, and vulvar ulcers may also occur. Our patient did not report any prodrome, yet skin, mouth, and genital ulcerations were present. Medication-induced SJS is portrayed by mucosal disintegrations in addition to far-reaching circulation of atypical targets or purpuric macules and epithelial separation, including under 10% body surface area on the storage compartment, face and extremities.1 SJS must be clinically separated from viral stomatitis, pemphigus, erythema multiforme (EM), toxic epidermal necrolysis, and the subepithelial resistant rankling issue, such as pemphigoid. There are no particular demonstrative tests for SJS.5 Our case indicated ulceration of the oral cavity, eye redness, ulceration of genital locale alongside various recuperated injuries on the chest, midriff, and appendages, which indicated ordinary appearance of “target sores.” The sores were across the board when contrasted with EM, which is confined. Amoxicillin and clavulanic corrosive mix treatment was recognized as the causative specialist in light of the fleeting connection between the organization of the mix and the start of the ejections. There have likewise been a few different past reports connecting amoxicillin and clavulanic corrosive to SJS. As per Naranjo's Adverse Drug Reaction Probability Scale, amoxicillin-induced SJS was conceivable in our patient (a score of 7). The initial phase in the administration was a quick withdrawal of the culpable operator followed by strong consideration. A past report reveals that a prompt withdrawal of the medication may reduce the mortality risk.5 Adjuvant medicines, for example, corticosteroids, may be utilized in extreme instances of SJS.6 In developing nations like India, where unavoidable illnesses are generally predominant, anti-infection agents ought to be utilized with caution to avoid ADR. Overuse of medications such as NSAIDs, anti-infection agents, and anti-seizure drugs can result in SJS and dangerous epidermal necrolysis, which is a perilous condition. Medical practitioners should be aware of the risks and advise their patients accordingly. Amoxicillin-induced SJS can be treated with anti-infection agents, such as cefotaxime and chloramphenicol maleate, and with corticosteroids. A hazard evaluation is required for avoiding harm to extra tissue. The authors wish to thank the dean and the teaching and non-teaching faculty of Government Hospital, Erode for their valuable support for this study. There are no conflicts of interest. We declare that this work was done by the authors named in this article. E. Karthikeyan, M.E., and S. Srinivasan conceived and designed the study. S.S. carried out the laboratory work. K.K., S. Sivaneswari, and E. Kalpana analyzed the data and wrote the manuscript. All authors have read and approved the final manuscript.