Increased serum anti-CYP2E1 IgG autoantibody levels may be involved in the pathogenesis of occupational trichloroethylene hypersensitivity syndrome: a case-control study.

Occupational exposure to trichloroethylene (TCE) causes a systemic skin disorder with hepatitis known as TCE hypersensitivity syndrome (TCE-HS). Human Leukocyte Antigen (HLA)-B*13:01 is its susceptibility factor; however, the immunological pathogenesis of TCE-HS remains unknown. We herein examined the hypothesis that autoantibodies to CYP2E1 are primarily involved in TCE-HS. A case-control study of 80 TCE-HS patients, 186 TCE-tolerant controls (TCE-TC), and 71 TCE-nonexposed controls (TCE-nonEC) was conducted to measure their serum anti-CYP2E1 antibody (IgG) levels. The effects of TCE exposure indices, such as 8-h time-weighted-average (TWA) airborne concentrations, urinary metabolite concentrations, and TCE usage duration; sex; smoking and drinking habits; and alanine aminotransferase (ALT) levels on the antibody levels were also analyzed in the two control groups. There were significant differences in anti-CYP2E1 antibody levels among the three groups: TCE-TC > TCE-HS patients > TCE-nonEC. Antibody levels were not different between HLA-B*13:01 carriers and noncarriers in TCE-HS patients and TCE-TC. The serum CYP2E1 measurement suggested increased immunocomplex levels only in patients with TCE-HS. Multiple regression analysis for the two control groups showed that the antibody levels were significantly higher by the TCE exposure. Women had higher antibody levels than men; however, smoking, drinking, and ALT levels did not affect the anti-CYP2E1 antibody levels. Anti-CYP2E1 antibodies were elevated at concentrations lower than the TWA concentration of 2.5 ppm for TCE exposure. Since HLA-B*13:01 polymorphism was not involved in the autoantibody levels, the possible mechanism underlying the pathogenesis of TCE-HS is that TCE exposure induces anti-CYP2E1 autoantibody production, and HLA-B*13:01 is involved in the development of TCE-HS.

Síndrome DRESS secundária ao uso de alopurinol: um relato de caso / DRESS syndrome secondary to the use of allopurinol: a case report

A Síndrome de DRESS (do inglês, Drug Rash with Eosinophilia and Systemic Symptoms) é uma patologia rara que consiste em uma severa reação medicamentosa mediada por células T. O presente relato de caso retrata uma paciente do sexo feminino, 59 anos, que apresentou icterícia, febre não termometrada, acolia, colúria, mialgia, placas hipercrômicas e lesões pruriginosas. Referiu uso recente de alopurinol, paracetamol e nimesulida, apresentando melhora importante e espontânea após a suspensão das medicações. A extensão do tempo de exposição ao medicamento agressor ocasiona um maior período de internação e risco de mortalidade. Além disso, os dados restritos sobre a Síndrome de DRESS impõe desafios ao seu diagnóstico. Sendo assim, este estudo busca destacar a importância do diagnóstico clínico precoce, a suspensão do medicamento agressor e a instituição da terapêutica adequada para um prognóstico favorável

The Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) Syndrome is a rare pathology that consists of a severe drug reaction mediated by T cells. The present case report depicts a female patient, 59 years old, who presented jaundice, non thermometered fever, acholia, choluria, myalgia, hyperchromic plaques and pruritic lesions. She mentioned recent use of allopurinol, paracetamol and nimesulide, showing significant and spontaneous improvement after discontinuation of medications. The extension of time of exposure to the offending drug causes a longer period of hospitalization and risk of mortality. In addition, the restricted data on DRESS Syndrome poses challenges to its diagnosis. Therefore, this study seeks to highlight the importance of early clinical diagnosis, suspension of the offending drug and the institution of appropriate therapy for a favorable prognosis

Drug reaction with eosinophilia and systemic symptoms syndrome secondary to acetazolamide associated with markedly elevated procalcitonin.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is an important cause of multi-organ dysfunction and can mimic other disorders including sepsis. We describe a patient presenting with septic shock and accompanying high procalcitonin. Although initially treated empirically with antibiotics, the emergence of eosinophilia during the admission lead to a revised diagnosis of DRESS syndrome, presumed secondary to acetazolamide. This case highlights the importance of regular clinical assessment and re-evaluation is key in identifying emerging features such as eosinophilia, rash and organ dysfunction, which can secure the diagnosis. Furthermore, the case also highlights that acetazolamide may be a rare cause of DRESS syndrome.

Granulysin-Based Lymphocyte Activation Test for Evaluating Drug Causality in Antiepileptics-Induced Severe Cutaneous Adverse Reactions.

Aromatic antiepileptic drugs (AEDs) are common causes of cutaneous adverse drug reactions, which range from morbilliform drug eruption to life-threatening severe cutaneous adverse reactions, including drug reaction with eosinophilia and systemic symptoms, Stevens‒Johnson syndrome, and toxic epidermal necrolysis. Different in vitro methods for identifying the culprit drugs have been developed; however, it is particularly challenging for Stevens‒Johnson syndrome-toxic epidermal necrolysis. In this study, we enrolled 63 patients (39 with Stevens‒Johnson syndrome-toxic epidermal necrolysis, 13 with drug reaction with eosinophilia and systemic symptoms, and 11 with morbilliform drug eruption) and 30 tolerant controls to examine the performance of lymphocyte activation tests by measuring the expression of granulysin, granzyme B, and IFN-γ. Granulysin-based lymphocyte activation tests displayed the best sensitivity and specificity to identify the causality: 73.9% sensitivity and 96.7% specificity for carbamazepine and 68.2% sensitivity and 96.7% specificity for phenytoin. Oxcarbazepine and lamotrigine show weak antigenicity. Granulysin-based lymphocyte activation tests expanded predominantly memory cytotoxic T lymphocytes with characteristics of drug-specific T-cell receptor, major histocompatibility complex I dependence, and cross reactivity to different aromatic AEDs. Among 29 follow-up patients, 28 alternatively used nonaromatic AEDs, and none developed cutaneous adverse drug reactions. Our data suggest that granulysin-based lymphocyte activation tests represent in vitro cytotoxic T-lymphocyte memory response to offending drugs and are useful to confirm drug causality of AED-induced severe cutaneous adverse reactions. Implementing these tests will improve the AED-induced severe cutaneous adverse reactions prevention and clinical care.

Immunogenicity and skin clearance recapture in clinical studies of brodalumab.

BACKGROUND: Antidrug antibodies (ADAs) may change pharmacokinetic or pharmacodynamic profiles of biologic therapies, potentially decreasing efficacy. OBJECTIVE: To evaluate the potential effects of brodalumab immunogenicity on safety, efficacy, and retreatment. METHODS: Data from 1 phase 2 and 3 phase 3 studies of brodalumab in psoriasis were analyzed. RESULTS: Overall, 2.7% of patients had positive test results for binding ADAs after receiving brodalumab; ADAs were transient in 1.4% of patients, and there were no neutralizing ADAs. Among ADA-positive patients, 60.0% (3/5) achieved a static physician's global assessment score of 0 or 1 at week 12 in the group receiving the brodalumab 210 mg every 2 weeks, compared with 79.1% (1131/1429) of ADA-negative patients. All patients (100%) who experienced return of disease and were retreated with brodalumab 210 mg every 2 weeks (none were ADA positive) achieved at least a 75% improvement in Psoriasis Area And Severity Index, ≥90% of whom regained response by week 8 of retreatment. Hypersensitivity reactions were less frequent with brodalumab than with placebo. Injection site reactions occurred in 1.8% of patients treated with brodalumab versus 2% of patients treated with ustekinumab. LIMITATIONS: Retreatment could be assessed in only 1 phase 3 brodalumab study. CONCLUSION: Brodalumab compares favorably with other biologics in terms of immunogenicity and high rates of efficacy recapture upon retreatment.

Increased Type 2 Innate Lymphoid Cells in Patients with Drug Reaction with Eosinophilia and Systemic Symptoms Syndrome.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a life-threatening disorder with an estimated mortality rate of 2%. Recently, type II innate lymphoid cells (ILC2s) have been implicated as an important contributor to the pathogenesis of allergic disorders. However, the roles of ILC2s and ILC2-associated cytokines in DRESS remain unclear. Herein, we enrolled 54 participants (including 24 patients with DRESS syndrome and 30 healthy controls), and identified the increased ST2+ILC2s population in skin lesions/blood. In addition, serum soluble ST2 (sST2), IL-5, and TSLP levels were significantly elevated at the acute stage of patients with DRESS. Decreased ILC2s population, serum sST2, and IL-5, accompanied with rash, eosinophilia, and alanine aminotransferase improvement were observed after steroid treatment. In the delayed-responders group (n = 13), serum IL-33, sST2, IL-5, and TSLP levels were significantly increased at the acute phase, but only sST2 levels correlated with alanine aminotransferase and eosinophil improvement at the 4-week follow-up visit. Serum sST2 levels were also correlated with IL-33 (ρ = 0.49; P = 0.02) and alanine aminotransferase levels (ρ = 0.65; P < 0.01) at the onset of DRESS. Our results demonstrated high IL-33/ST2 expression in ILC2 cells plays a role in skin inflammation of drug hypersensitivity, and serum sST2 levels can be as a potential biomarker to predict liver involvement in patients with DRESS syndrome.

Markers of systemic involvement and death in hospitalized cancer patients with severe cutaneous adverse reactions.

BACKGROUND: Severe cutaneous adverse reactions (SCARs) are frequent in inpatient oncology. Early intervention might reduce morbidity, mortality, and hospitalization costs; however, current clinical and histologic features are unreliable SCAR predictors. There is a need to identify rational markers of SCARs that could lead to effective therapeutic interventions. OBJECTIVE: To characterize the clinical and serologic features of hospitalized patients with cancer who developed SCARs. METHODS: Retrospective review of 49 hospitalized cancer patients with a morbilliform rash, recorded testing for serum cytokines (interleukin [IL] 6, IL-10, and tumor necrosis factor [TNF] α) or elafin, and a prior dermatology consultation. Patients were categorized as having a simple morbilliform rash without systemic involvement or complex morbilliform rash with systemic involvement. RESULTS: Fifteen out of 49 patients (30.6%) were deceased at 6 months from time of dermatologic consultation. Elafin, IL-6, and TNF-α were significantly higher in patients who died compared with patients who were still alive at 6 months. IL-6 and IL-10 were significantly higher in patients with a drug-related complex rash. LIMITATIONS: Retrospective design, limited sample size, and high-risk patient population. CONCLUSION: In cancer patients with SCARs, elafin, IL-6, and TNF-α levels might predict a poor outcome. Agents directed against these targets might represent rational treatments for the prevention of fatal SCARs.

Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms due to lamotrigine differs from that due to other drugs.

Drug-induced hypersensitivity syndrome (DIHS), also referred to as drug reaction with eosinophilia and systemic symptoms (DRESS), is a multi-organ systemic drug reaction characterized by hematological abnormalities and reactivation of human herpesvirus-6 (HHV-6). DIHS/DRESS is typically associated with a limited number of drugs, such as the anticonvulsants. Our group has treated 12 patients for DIHS/DRESS due to lamotrigine (LTG), but their presentation differed from that of patients with DIHS/DRESS caused by other drugs. The aim of the present study was to identify significant differences between DIHS/DRESS caused by LTG versus other drugs. We retrospectively reviewed data of 12 patients with DIHS/DRESS caused by LTG and 32 patients with DIHS/DRESS due to other drugs. The increase in alanine aminotransferase level was significantly milder in the LTG group than the DIHS/DRESS group due to other drugs. The percentage of atypical lymphocytes in the blood during DIHS/DRESS was lower in the LTG group. Serum levels of lactate dehydrogenase and thymus and activation-regulated chemokine were also lower in the LTG group. There were fewer DIHS/DRESS patients with HHV-6 reactivation in the LTG group than in the group treated with other drugs. Lymphocyte transformation after DIHS/DRESS onset was faster in the LTG group. The two groups did not differ with respect to the interval from first drug intake to rash, white blood cell count, blood eosinophilia or DRESS score. There were no significant histopathological differences between the two groups. The features of LTG-associated DIHS/DRESS and DIHS/DRESS due to other drugs differ.

Characteristics of patients hospitalized for Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) at a Level 1 trauma center.

The purpose of this study is to further characterize the population that is hospitalized for a severe cutaneous drug reaction or that developed once during their hospitalization. We conducted a chart review of patients seen by a dermatologist at the University of California Davis Medical Center for the diagnosis of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Between January 2000 and July 2018, 25 cases of DRESS were diagnosed using RegiSCAR criteria. Twenty-two patients recovered, two were deceased, and one was transferred to another hospital. The most commonly implicated drugs in the development of DRESS were nafcillin (N=3) and carbamazepine (N=3). Of the 25 patients in our care, 88% developed eosinophilia, 50% developed renal involvement, and 44% had liver involvement. There was a positive correlation between age and creatine (P=0.01) and age and eosinophils (P=0.02). There was a negative correlation between age and liver enzyme abnormalities (AST P=0.01; ALT P=0.0003). Carbamazepine and nafcillin were commonly implicated drugs in DRESS. There was no significant difference between treatment group and patient outcome. Those who develop DRESS at an older age were more likely to have elevated creatinine and more profound eosinophilia, but were less likely to develop liver involvement.

C-Reactive Protein and Procalcitonin in Case Reports of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome.

BACKGROUND: The spectrum of inflammatory marker response in DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome has not been systematically characterized. METHODS: An epidemiological biomarker study of C-reactive protein (CRP) and procalcitonin (PCT) values in patients with DRESS syndrome reported at 2 regional pharmacovigilance centers in Switzerland or published in the medical literature 2008-2016 was performed. RESULTS: Ninety-four DRESS cases were studied. All cases showed a CRP value > 10 mg/L (the upper limit of normal). The mean CRP value was 109.2 ± 79.4 mg/L. CRP values were significantly higher in 22 cases where a cause of inflammation besides DRESS could not be excluded (mean 162.1 vs. 92.9 mg/L; p = 0.003). Receiver operator characteristics curve analysis showed a moderate performance with a CRP cut-off value of 99.4 mg/L (AUC 0.717) to distinguish between patients with and without a possible additional cause of inflammation. The mean and median PCT values were 2.44 ± 5.94 and 0.69 ng/mL, respectively (n = 25 patients). Patients in whom an additional cause of inflammation besides DRESS could not be excluded showed a median PCT of 1.37 ng/mL (n = 9) versus 0.67 ng/mL (n = 16) in patients with DRESS only. PCT values were above the normal cut-off of 0.1 ng/mL, suggestive of bacterial infection in all but 1 case. Furthermore, there was a correlation between PCT values and hepatic enzyme measurements. CONCLUSIONS: Evaluating CRP and PCT values might be of use in helping physicians to distinguish between cases of DRESS syndrome with and without concurrent infection or other causes of inflammation. Further prospective investigation is required to define the use of these inflammatory markers in the management of DRESS.

DRESS syndrome with thrombotic microangiopathy revealing a Noonan syndrome: Case report.

RATIONALE: The life-threatening drug rash with eosinophilia and systemic symptoms (DRESS) syndrome occurs most commonly after exposure to drugs, clinical features mimic those found with other serious systemic disorders. It is rarely associated with thrombotic microangiopathy. PATIENT CONCERNS: We describe the unique case of a 44-year-old man who simultaneously experienced DRESS syndrome with thrombotic microangiopathy (TMA) after a 5 days treatment with fluindione. DIAGNOSES: Clinical evaluation leads to the discovery of an underlying lymphangiomatosis, due to a Noonan syndrome. INTERVETIONS: The anticoagulant was withdrawn, and corticosteroids (1 mg/kg/day) and acenocoumarol were started. OUTCOMES: Clinical improvement ensued. At follow-up the patient is well. LESSONS: The association of DRESS with TMA is a rare condition; we believe that the presence of the underlying Noonan syndrome could have been the trigger. Moreover, we speculate about the potential interrelations between these entities.

Case of lamotrigine-induced drug adverse reaction under tocilizumab treatment with clinical and virological features of drug-induced hypersensitivity syndrome.

The pathological mechanisms and immunological kinetics of drug-induced hypersensitivity syndrome (DIHS), including the relevance of interleukin (IL)-6, remain unclear. We report a case of drug adverse reaction that does not fulfill the diagnostic criteria of DIHS but mimics its characteristic features. Because the patient was under anti-IL-6 therapy at the onset, some symptoms typically seen in DIHS were absent, such as fever and leukocyte count abnormalities. However, the characteristic features of DIHS were clearly observed in the subsequent course, including the repeated recurrence of skin rash, prolonged liver dysfunction and reactivation of herpes viruses. This case suggested that IL-6 role at the onset is not a main factor to determine the subsequent pathomechanism of DIHS and attention should be paid to the preceding therapy for achieving accurate diagnosis.