Idiosyncratic Drug-Induced Liver Injury Associated With and Without Drug Reaction With Eosinophilia and Systemic Symptoms.

INTRODUCTION: Immunoallergic drug-induced liver injury (DILI) presenting with features of drug reaction with eosinophilia and systemic symptoms (DRESS) is a distinct phenotype. We describe the clinical characteristics, hepatitis pattern, severity, complications, and implicated medications in DILI patients with and without DRESS. METHODS: Using established criteria, we analyzed DILI registry patients with and without DRESS from 1998 to 2021. RESULTS: DILI associated with DRESS (DwD) comprised 179 among 943 cases (19%) of DILI. Compared with the cohort without DRESS, patients with DwD are more often women and have shorter latency, lesser degrees of injury ( P < 0.01), and lower mortality (7.8%) than those without DRESS (16%). Antiepileptic drugs (36%), sulfonamides (19%), antituberculosis drugs (14%), antibiotics (10%), and antiretroviral drugs (8%) account for 87% of the cases of DwD. DISCUSSION: A limited number of drugs cause DwD, representing a fifth of patients with DILI. DwD is characterized by lesser degrees of liver injury and mortality likely because of earlier presentation.

Leflunomide-induced liver injury: Differences in characteristics and outcomes in Indian and US registries.

BACKGROUND: Leflunomide, a disease-modifying anti-rheumatic drug, has been associated with elevations of serum aminotransferases. Herein, we describe the clinical, laboratory features and outcomes of 17 patients with leflunomide/teriflunomide hepatotoxicity from two large drug-induced liver injury (DILI) registries. METHODS: Consecutive, adjudicated cases of leflunomide (n = 16)-or teriflunomide (n = 1)-related DILI from a single centre in Bangalore, India and the multicentre US Drug-Induced Liver Injury Network (DILIN) were reviewed. RESULTS: Nine (0.8%) of the 1070 Indian patients and 8 (0.5%) of the 1400 DILIN patients fulfilled the criteria for DILI because of leflunomide- or teriflunomide. 89% of the Indian cases were women and all were associated with severe cutaneous adverse reaction (SCAR) and a median drug latency of 49 days, whereas 37.5% of the DILIN cases were female, none exhibited SCAR and the median drug latency was 166 days. Hepatocellular injury (70%) was more common in women than men (92% vs. 20%) and was associated with younger mean age (41 vs. 59 years), higher peak INR (2.3 vs. 1.2) and higher mortality (58% vs. 0%). Mortality was observed in six patients from India (2 of the three with myocarditis) and one received liver transplantation from the USA. CONCLUSION: Leflunomide-induced liver injury is predominantly hepatocellular. Leflunomide hepatotoxicity is more likely accompanied by SCAR, a short latency and a higher mortality in the Indian cohort, with a predominance of females, compared to US DILIN patients. The differences in skin involvement, immunoallergic features and outcomes among subjects from India vs. the USA suggest that genetic or environmental factors are important in the pathogenesis of liver injury.

Drug-induced liver injury with skin reactions: Drugs and host risk factors, clinical phenotypes and prognosis.

While dermatologic manifestations of adverse drug reactions are frequent, drug-induced liver injury is rare. Numerous drugs are implicated in either Drug-Induced Liver Injury or Drug-Induced Skin Injury. However, concomitant Drug-Induced Liver Injury and Drug-Induced Skin Injury are uncommon, not well characterized and appear to be caused by a limited number of drugs. These are often associated with immuno-allergic or hypersensitivity features such as fever, skin rash, blisters or peeling of skin, eosinophilia, lymphadenopathy and mucositis. Liver injury can range from asymptomatic elevation of liver biochemical tests to severe hepatitis and acute liver failure needing liver transplantation. Severe cutaneous adverse reaction, particularly drug reaction with eosinophilia and systemic symptoms is commonly associated with internal organ involvement, the liver being the most frequently involved in approximately 90% of the cases. In Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis, abnormalities in liver biochemistry tests are common but severe liver disease is rare. There is a strong association of Human Leukocyte Antigen genotype with both drug reaction with eosinophilia and systemic symptoms and Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis. It is likely that the delayed immune-mediated reaction triggering skin reaction is also responsible for hepatitis. Drug-specific lymphocytes are found in the organs involved and also in circulating blood, which along with the cytokines and chemokines play a role in pathogenesis. Anti-epileptic drugs, allopurinol, sulfonamides, antibiotics and nevirapine are the top five causes of concomitant liver and skin injury. This review will focus on drug and host factors causing concomitant Drug-Induced Skin Injury and Drug-Induced Liver Injury and discuss the characteristics of liver involvement in patients with severe cutaneous adverse reaction.

Drug-induced liver injury associated with Stevens-Johnson syndrome/toxic epidermal necrolysis: Patient characteristics, causes, and outcome in 36 cases.

UNLABELLED: The liver and skin are the organs most commonly involved in serious adverse drug reactions. Rarely a drug reaction can affect both organs concurrently. The association of drug-induced liver injury (DILI) and Stevens-Johnson syndrome (SJS) or toxic epidermal necrosis (TEN) is even rarer and not well studied. We describe our experience of DILI occurring in association with SJS/TEN including the etiologic agents, clinical and biochemical characteristics, and outcome. We identified patients who developed DILI in association with SJS/TEN from a registry of DILI patients from a single center. Causality assessment for DILI and SJS/TEN was carried out with the Roussel Uclaf Causality Assessment Method and the Algorithm for Drug Causality for Epidermal Necrolysis, respectively. Among 748 consecutive patients with DILI from 1997 to March 2015, 36 (4.8%) had associated features of SJS/TEN. The mean age was 32 years (females 19). Children and patients with human immunodeficiency virus constituted 25% (n = 9) and 22% (n = 8), respectively. Only a small number of "high-risk" drugs such as antiepileptic agents, sulfonamides, and antiretroviral drugs accounted for the majority of cases. Overall mortality was 36% (n = 13), which rose to 45.5% in the presence of jaundice. Mortality was less in children 11% (n = 1) and human immunodeficiency virus patients 12.5% (n = 1). CONCLUSIONS: DILI associated with SJS/TEN is rare and associated with a high death rate, particularly in those with jaundice; however, children and human immunodeficiency virus-infected individuals have a favorable outcome; a small group of drugs contributed to a disproportionate number of cases, and causality with Roussel Uclaf Causality Assessment Method and the Algorithm for Drug Causality for Epidermal Necrolysis was highly probable or probable in all cases.