Fatal Myocarditis in Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS) Without Mortality-Related Risk Factors: A Case Report and Literature Review.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe drug reaction characterized by skin rash, organ involvement, lymph node swelling, eosinophilia, and atypical lymphocytosis, with myocarditis being a rare but potentially fatal complication. It has been reported that in patients with cardiac involvement due to DRESS, older age and shorter periods between offending drug exposure and symptom onset are associated with mortality. We report a case of fatal DRESS-associated myocarditis in a young woman, occurring one month after drug exposure, despite intensive immunosuppressive therapy. This case report highlights the risk of mortality from DRESS-associated myocarditis even in patients lacking known risk factors.

Tuning CAR T-cell therapies for efficacy and reduced toxicity.

Chimeric antigen receptor (CAR) T-cell therapies are a standard of care for certain relapsed or refractory B-cell cancers. However, many patients do not respond to CAR T-cell therapy or relapse later, short- and long-term toxicities are common, and current CAR T-cell therapies have limited efficacy for solid cancers. The gene engineering inherent in CAR T-cell manufacture offers an unprecedented opportunity to control cellular characteristics and design products that may overcome these limitations. This review summarises available methods to "tune" CAR T-cells for optimal efficacy and safety. The components of a typical CAR, and the modifications that can influence CAR T-cell function are discussed. Methods of engineering passive, inducible or autonomous control mechanisms into CAR T-cells, allowing selective limitation or enhancement of CAR T-cell activity are reviewed. The impact of manufacturing processes on CAR T-cell function are considered, including methods of limiting CAR T-cell terminal differentiation and exhaustion, and the use of specific T-cell subsets as the CAR T starting material. We discuss the use of multicistronic transgenes and multiplexed gene editing. Finally, we highlight the need for innovative clinical trial designs if we are to make the most of the opportunities offered by CAR T-cell therapies.

Clues of HLAs, metabolic SNPs, and epigenetic factors in T cell-mediated drug hypersensitivity reactions.

Drug hypersensitivities are common reactions due to immunologic responses. They are of utmost importance because they may generate severe and fatal outcomes. Some drugs may cause Adverse Drug Reactions (ADRs), such as drug hypersensitivity reactions (DHRs), which can occur due to the interaction of intact drugs or their metabolites with Human Leukocyte Antigens (HLAs) and T cell receptors (TCRs). This type develops over a period of 24-72 h after exposure and is classified as type IV of DHRs. Acute generalized exanthematic pustulosis (AGEP), Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) are types of Severe Cutaneous Adverse Reactions (SCARs). In this review, we aim to discuss the types of ADRs, the mechanisms involved in their development, and the role of immunogenetic factors, such as HLAs in type IV DHRs, single-nucleotide polymorphisms (SNPs), and some epigenetic modifications, e.g., DNA/histone methylation in a variety of genes and their promoters which may predispose subjects to DHRs. In conclusion, development of promising novel in vitro or in vivo diagnostic and prognostic markers is essential for identifying susceptible subjects or providing treatment protocols to work up patients with drug allergies as personalized medicine.

Drug Reaction With Eosinophilia and Systemic Symptoms Syndrome Preceding Toxic Epidermal Necrolysis Secondary to Sildenafil: A Case Report.

Drug reactions with eosinophilia and systemic symptoms (DRESS) syndrome and Stevens-Johnson syndrome-toxic epidermal necrolysis (SJS-TEN) are reactive entities of aberrant cytotoxic immunologic reactions to exogenous medications. While they are conventionally seen as distinct, separate conditions, we present a case of a rare evolution of DRESS syndrome into SJS-TEN in the setting of simultaneous amoxicillin-clavulanate initiation and long-term sildenafil use in a 66-year-old South Asian female with a known history of prior DRESS syndrome and pulmonary arterial hypertension. We discuss the conditions leading to her unique clinical presentation and provide considerations for future clinical encounters.

Comparison over Time of Adverse Drug Reactions in Diabetes Patients Treated with Sodium-Glucose Cotransporter 2 Inhibitors.

BACKGROUNDS: The prescription of sodium-glucose cotransporter-2 (SGLT2) inhibitors have been increasing due to their additional benefits, including weight loss, cardioprotection and renoprotection. Accordingly, there are concerns about the potential rise in severe adverse drug reactions (ADRs), such as urinary tract infections, diabetic ketoacidosis, volume depletion, and hypoglycemia. The Society has announced recommendations on the proper use of SGLT2 inhibitors. We aimed to elucidate the recent occurrence of severe ADRs which need discontinuation of SGLT2 inhibitors or hospitalization. METHODS: In this retrospective cohort study, we identified 391 diabetic patients who were prescribed SGLT2 inhibitors upon admission to our hospital between April 2017 and March 2023. Of these, 68 patients who discontinued SGLT2 inhibitors for reasons other than ADRs were excluded. Patients were classified into the 2017 group and the 2020 group based on the treatment period of SGLT2 inhibitors, and the occurrence of ADRs and patient backgrounds were compared between the two groups. RESULTS: A total of 323 eligible patients were identified. Discontinuations of SGLT2 inhibitors decreased in the 2020 group (p < 0.05). However, discontinuations due to frailty increased (p < 0.05). Hospitalization due to ADRs, specifically those due to urinary tract infections, diabetic ketoacidosis, or volume depletion, did not specifically decrease (p = 0.273). CONCLUSIONS: This study indicated that there has been some improvement in the awareness of the proper use of SGLT2 inhibitors and there is still a need to continue enlightenment activities.

Analysis of eplerenone in the FDA adverse event reporting system (FAERS) database: a focus on overall patient population and gender-specific subgroups.

Introduction: Eplerenone is approved for the treatment of hypertension as well as symptomatic heart failure with reduced ejection fraction (HFrEF) following an acute myocardial infarction. However, the adverse events (AEs) have not been systematically analyzed. The aim of this study was to identify adverse drug reactions (ADRs) related to eplerenone using the FDA Adverse Event Reporting System (FAERS) database. By identifying previously unreported AEs, the study could potentially contribute to updating the drug's label. Methods: In order to find significant AEs, four algorithms, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN) and Empirical Bayesian Geometric Mean (EBGM), were used to analyze the signal strength of the ADRs connected to eplerenone that were gathered from the FAERS database over the previous 20 years. Results: From 2004Q1 to 2023Q4, a total of 20, 629, 811 reported cases were gathered from the FAERS database for this study. After processing the data and filtering, 1,874 case reports were analyzed. Of these cases, 1,070 AEs were identified, 128 of which were eplerenone-related ADRs. We investigated the occurrence of ADRs induced by eplerenone in 27 organ systems. Our study showed that the AEs listed in the medication's package insert correspond with those listed in the literature, including hyperkalemia and increased creatinine. Additionally, the prescription label for eplerenone does not include all system organ class (SOC) terms, like Vascular disorders, hepatobiliary Disorders, etc. Discussion: The study used multiple algorithms to quantify the signal strength and then identified any previously unrecognized ADRs, further studies are needed to confirm the association of ADRs with eplerenone. The findings of this study may provide important insights into the safety profile of eplerenone, ensure that healthcare providers have up-to-date information about their potential risks and help guide them in the correct use of the drug.

A pharmacovigilance study assessing risk of angioedema with angiotensin receptor blockers using the US FDA adverse event reporting system.

BACKGROUND: Angiotensin receptor blockers (ARBs) are widely used for treating hypertension and heart failure. Angioedema has been reported as a controversial adverse effect of ARBs and the evidence on individual ARB risks is limited. This study aimed to assess signals of angioedema with different ARBs using the US FDA Adverse Event Reporting System (AERS) database. RESEARCH DESIGN AND METHODS: Reports of angioedema from 2004-2024 in AERS with an ARB as the primary suspect were extracted using Medical Dictionary for Regulatory Activities queries. Disproportionality analyses including reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network and multi-item gamma Poisson shrinker were conducted to identify safety signals for individual ARBs. RESULTS: A total of 3,683 unique reports met the selection criteria. Irbesartan and losartan generated signals in all statistical measures, followed by telmisartan and candesartan in some measures. Valsartan had the highest report count. Most reports reported hospitalization, prolonged hospitalization or life-threatening outcomes consequent to angioedema. CONCLUSION: This pharmacovigilance study using AERS highlights potential higher risks of angioedema with losartan and irbesartan compared to other ARBs, warranting validation through prospective epidemiological studies to characterize individual ARB safety profiles.

Evaluation of the Effectiveness of the Adverse Drug Reaction Alert Card System in Preventing the Recurrence of Adverse Drug Reactions.

Introduction Adverse drug reactions (ADRs) are among the leading causes of morbidity and mortality. It causes a significant prolongation of hospital stays, leading to an increased economic and infrastructural burden on the healthcare system. Thus, primary prevention will help in preventing recurrent ADRs. People are often unable to state whether they have suffered an ADR from a medicine or not. The patients also find it difficult to recall the offending drug. They seldom seem to carry any information that would warn others of their reactions. Thus, there was a need to introduce the ADR Alert Card. A pilot study was first conducted in 2018 to assess the feasibility of this card. All patients suffering from an ADR were thus provided an alert card. Following its implementation, there was a general acceptability regarding the potential of this card in ADR recurrence prevention among healthcare professionals (HCPs). Therefore, there is a need to assess the effectiveness of this card for ADR recurrence prevention. Objective This study aims to estimate the percentage of people who have shown the ADR Alert Card to their HCPs and benefited from it. Methods This was a prospective observational study, which was conducted at Dr. D. Y. Patil Medical College, Pune, from November 2022 to May 2024 and received approval from the Institutional Ethics Committee (IEC) before its initiation. All the patients who faced an ADR were given an ADR Alert Card by their HCP. All the patients to whom their HCP had given the card were part of this study. Any patient who suffered an ADR due to overdosage of medication was excluded from the study. After screening for inclusion and exclusion criteria, the data were analyzed using MS Excel (Microsoft Corporation, Redmond, Washington). A questionnaire was validated by professors in pharmacology, medicine, and community medicine. The patients were contacted through telephone conversations and provided with this questionnaire. They were asked questions regarding the ease of carrying the card, the benefit it provided them, whether they had shown it to their HCP, whether it helped them in an emergency, and their willingness to link it digitally. Their responses were recorded in Google Forms, and pie charts were generated. Results All 110 patients (100%) agreed that the ADR Alert Card was beneficial. Most (99, 90%) patients had shown the card to their HCP at their subsequent visit. The card helped 107 (97%) patients to describe their medical history easily. All the patients (110, 100%) agreed that carrying the card was easy, and most patients (95, 86%) agreed to recommend using the card to others. Additionally, most patients (79, 72%) were willing to link their card to their National Health ID. However, a small proportion of patients (28, ~25%) were skeptical whether they would link the card to the National Health ID or not. The card had helped 28 (25%) patients in an emergency. Approximately 11 (10%) patients had reported an ADR to the regulatory authority. Conclusion The patients welcomed this new concept to be inculcated in their daily lives as an effective means to enhance their healthcare. This study evaluates the number of patients who actually benefitted from using this card. It encourages patients to participate actively in their own healthcare. In an emergency situation, it proves to be a source of important health information. This study could lay the foundation for further research to prevent recurrent ADRs.

Allopurinol: Clinical Considerations in the Development and Treatment of Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, and Other Associated Drug Reactions.

Allopurinol lowers urate production through the inhibition of xanthine oxidase. It is oxidatively hydroxylated to oxypurinol and is the most prescribed medication for gout treatment. Although it has a beneficial effect in the treatment of this common disease, like many medications, it is also known for having numerous adverse effects. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), diseases that exist on a spectrum, are two of the most dangerous adverse effects associated with allopurinol use. These immune-mediated disease processes involve almost every organ system. They are essential to recognize as early as possible, as they could potentially be deadly, requiring cessation of the medication with initial signs of rash or other early manifestations of SJS/TEN. One major consideration in the increased risk of allopurinol-mediated or modulated SJS/TEN is the need to have a lower dose in the setting of renal disease. The purpose of this review is not only to examine the involvement of allopurinol in SJS/TEN but also to provide detailed information about the drug, allopurinol, and general features and characteristics of SJS/TEN and other associated drug reactions.

Characteristics of isoniazid-induced psychosis: a systematic review of case reports and case series.

PURPOSE: Isoniazid, a first-line antitubercular drug, is associated with nervous system adverse drug reactions such as seizures, peripheral neuropathy, and psychosis. This systematic review of case reports and case series aimed to characterize the demographic, social, and clinical factors associated with isoniazid-induced psychosis in patients with active tuberculosis (TB) and those who received isoniazid for latent TB infection (LTBI). METHODS: We comprehensively searched the Embase, PubMed, and Scopus databases to identify relevant studies published between the date of inception of the database and June 2024. RESULTS: A total of 28 studies, including 21 case reports and 7 case series involved 37 patients who developed isoniazid-induced psychosis. A higher frequency of isoniazid-induced psychosis was observed during the first 2 months of treatment, with a relatively early onset observed among patients aged 18 years or less. Delusions and/or hallucinations are the common symptoms of isoniazid-induced psychosis. Psychomotor disturbances, disorganized speech or formal thought disorder, disorganized or abnormal behaviour, and neuropsychiatric symptoms (sleep disturbances, hostility or aggression, confusion, affective symptoms, anxiety symptoms, and cognitive difficulties) were the other symptoms observed in the included studies. More than 80% of cases rechallenged with isoniazid resulted in the recurrence of psychotic symptoms. CONCLUSION: Patients with TB and LTBI should be assessed for psychotic and neuropsychiatric symptoms during isoniazid therapy, mainly in the first 2 months. Further research is required to understand the impact of underlying risk factors, such as genetic predisposition and isoniazid pharmacokinetics, as well as the clinical utility and dosage recommendations of pyridoxine for managing isoniazid-induced psychosis.

A Dermatological Dilemma: The Importance of Recognizing Dermatologic Manifestations of Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS) in Skin of Color Patients.

Many dermatologic conditions that are seen in medical literature are typically on lighter skin tones making it easier to identify. This can pose a difficult problem in the care of skin of color patients. The purpose of this paper is to highlight the importance of dermatologic manifestations in skin of color patients and the disparities that exist in the medical field. Here, we present the case of a 51-year-old African American male who was hospitalized on a prolonged course of antibiotics found to have drug reaction with eosinophilia and systemic symptoms (DRESS). Although the initial diagnosis was not made at symptom onset due to the atypical presentation in darker skin tones, the patient improved when the diagnosis was eventually made with cessation of the offending agent and steroid therapy. There is a vital need for continued awareness of the disparities that exist within medical literature and the medical field in regard to skin of color patients.

Lamotrigine Emerging as a Driver of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: An 8-Year Retrospective Study.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent severe manifestations of a potentially life-threatening spectrum defined by a desquamating rash of the skin and mucous membranes. This study was prompted by the observed increase in the off-label use of lamotrigine as a causal agent in SJS/TEN in our regional burn center. METHODS: A retrospective cohort of 48 patients presenting to the Connecticut Burn Center from 2015-2022 with suspicion for SJS/TEN were reviewed for age, sex, causative drug, presenting symptoms, hospital course, biopsy confirmation, length of stay, comorbidities, and 30-day mortality. Descriptive statistical analysis was conducted to identify trends in causative agent, clinical presentation, and mortality. RESULTS: Thirty patients in our cohort received a final diagnosis of SJS/TEN. While antibiotics remain the most frequent cause of SJS/TEN across the study period (33.3 %, n = 10), the incidence of cases attributable to lamotrigine increased from 1 case between 2015 and 2018 (6.7 %) to 6 cases between 2019 and 2022 (40 %). In 2020 alone, 50 % of all cases were attributable to lamotrigine (n = 4). Of the patients where lamotrigine was implicated, 71.4 % (n = 5) were prescribed lamotrigine for off-label use in the treatment of non-bipolar mood disorders. The average lamotrigine-associated SJS/TEN patient was younger (p < 0.001), had fewer comorbidities, and was more likely to be female than the general SJS/TEN population. CONCLUSION: Off-label use of lamotrigine is emerging as a major driver of SJS/TEN with notable changes in patient demographics. Further research is necessary to understand how changing trends in the patient population will impact clinical course and optimal management.

Drug related adverse event assessment in neonates in clinical trials and clinical care.

INTRODUCTION: Assessment of drug-related adverse events is essential to fully understand the benefit-risk balance of any drug exposure, weighing efficacy versus safety. This is needed for both drug labeling and clinical decision-making. Assessment is based on seriousness, severity and causality, be it more difficult to apply in neonates. Adverse event detection or prevention in the neonatal clinical setting is also more complicated because of polypharmacy, and off-label or unlicensed pharmacotherapy. AREAS COVERED: Tools became available to assess severity and causality of adverse events in neonates recruited in clinical trials. The first version of the Neonatal Adverse Event severity score (NAESS) reduced the inter-observer variability. Causality tools like the Naranjo score were also tailored to neonates. These tools are also instrumental to support proactive pharmacovigilance in clinical care, while multidisciplinary care teams and computerized pharmacovigilance using advanced data analysis, like machine learning are emerging approaches to develop effective decision strategies. EXPERT OPINION: All stakeholders involved in development of medicines or its clinical use should be aware of the limitations of the currently available assessment tools. Extension and optimization of these tools, advanced data analysis approaches, and capturing the variability in time-dependent physiology are warranted to improve pharmacovigilance in neonates.

Systematic analysis of the adverse effects of commonly used clinical tetracycline drugs based on the FAERS database.

BACKGROUND: Tetracyclines are a class of antibacterial drugs commonly used in clinical practice, but there is no systematic analysis of the adverse effects (AEs) of these drugs. We performed such pharmacovigilance analyses using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database to explore tetracycline-related AEs. RESEARCH DESIGN AND METHODS: We used the pharmacovigilance analysis tool Open Vigil 2.1 to access FAERS data and obtained AE reports from January 2004 to June 2023, including doxycycline, minocycline, tigecycline, omadacycline, sarecycline, and eravacycline as the top suspect drugs. The signal value of the AE of the analyzed drug was calculated by the reporting odds ratio (ROR). RESULTS: A total of 15,020 cases were identified by analyzing drugs. In terms of adverse signals, doxycycline caused gastrointestinal mucosal necrosis (ROR = 1699.652); minocycline was reported to cause bone hyperpigmentation (ROR = 30976.223); tigecycline is responsible for blood fibrinogen decreased (ROR = 1714.078). CONCLUSIONS: AE reports of tetracycline drugs varied significantly. We found some AEs not mentioned in the instruction, such as the ototoxicity of tetracyclines. Doxycycline was associated with psychiatric side effects; minocycline presented in thyroid and skin tissue-associated tumors; abnormal signals were detected with eravacycline in the blood system.

Case report: two cases of rhabdomyolysis following esketamine treatment.

Major depressive disorder is a mental disorder affecting millions of people worldwide. A considerable proportion of patients demonstrate a lack of response to conventional treatment. With the recent introduction of esketamine, a new treatment option has been approved for treatment-resistant depression. Although the medication is efficacious in a substantial portion of cases, rare, but possibly serious, adverse effects may occur. This case series shows two cases of rhabdomyolysis, a destruction of muscle tissue with elevated creatine kinase levels, after administration of esketamine. The first case presented is about a 33 year old male patient who suffered from a severe episode of a depressive disorder. He got nasal esketamine as an emergency treatment. While there was an initial improvement regarding the depressive symptoms, the patient developed muscle pain and fatigue after the administration of the fourth dose, with creatine kinase (CK) levels above 22,000 U/L, indicating rhabdomyolysis. Following the discontinuation of esketamine and the implementation of supportive care, the CK levels returned to normal and the depressive symptoms abated. The second case is about a 22-year-old male patient who also suffered from a severe depressive episode and got eketamine as an emergency treatment. Following the tenth dose, the patient exhibited muscle weakness and elevated CK levels (8,032 U/L), which persisted even after dose reduction. Esketamine administration was stopped, and the following monitoring demonstrated a slow return to normal levels of CK and liver enzymes. In both cases, there was no known medical history and both patients developed rhabdomyolysis after administration of esketamine. The temporal connection suggests a possible causal relationship. We found no literature on esketamine-induced rhabdomyolysis following the administration of nasal esketamine. However, these two cases emphasize the need of monitoring for laboratory changes like elevated CK-levels in patients receiving esketamine, especially considering its growing use in treatment-resistant depression.

Seriousness and outcomes of reported adverse drug reactions in old and new antiseizure medications: a pharmacovigilance study using EudraVigilance database.

Introduction: Epilepsy is a widespread disease requiring long-term drug treatment. The aim of this study was to collect information on reported suspected adverse drug reactions (sADRs) of antiseizure medications (ASMs) and study their seriousness and outcomes in various system organ classifications (SOCs). We intended to compare old and new ASMs' ADRs. Methods: Using EudraVigilance (EV) database, we extracted line listings of reported sADRs with different ASMs over the period from January 2012 to December 2021. The list of ASMs was compiled according to the Anatomical therapeutic chemical classification system. The Medical Dictionary for Regulatory Activities version 24.0 was used for determining the SOCs of individual reported preferred terms (PTs) sADRs. In addition, we calculated the Reporting Odds Ratio (ROR), 95% confidence interval (95% CI), p-value (statistically significant if p< 0.05) and chi-square statistics. Results: A total of 276,694 reports were contained in the exported line listings which included 1,051,142 individual sADRs reported as PTs such as seizure (3.49%), drug ineffective (2.46%), somnolence (1.32%), dizziness (1.29%) and represented four SOCs: nervous system disorders (19.26%), general disorders and administration site conditions (14.39%), psychiatric disorders (11.29%) and injury, poisoning and procedural complications (9.79). Among patients, the age group between 18 and 64 years had the highest percentage (52.40%), followed by those aged over 64 years (18.75%). Of all the reported PTs, 882,706 (83.98%) had reported seriousness. Old ASMs had a significant positive association with "caused/prolonged hospitalisation", "congenital anomaly", "disabling", "life threatening" and "results in death", while new ASMS with 'other medically important condition'. There were 386 (0.04%) PTs related to Sudden Unexpected Death in Epilepsy (SUDEP). Conclusion: In our study, we examined 10 years' reported sADRs of ASMs in the EV international database. The majority of PTs were serious. Old ASMs were generally more commonly associated with undesired outcomes and seriousness. Considering their expected seriousness and outcomes, the safety profile of the different ASMs, can play a cardinal role in the selection of ASMs.