Development and Validation of a Novel Score to Predict Mortality in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: CRISTEN.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening, severe mucocutaneous adverse reactions. Severity prediction at early onset is urgently required for treatment. However, previous prediction scores have been based on data of blood tests. OBJECTIVE: This study aimed to present a novel score that predicts mortality in patients with SJS/TEN in the early stages based on only clinical information. METHODS: We retrospectively evaluated 382 patients with SJS/TEN in a development study. A clinical risk score for TEN (CRISTEN) was created according to the association of potential risk factors with death. We calculated the sum of these risk factors using CRISTEN, and this was validated in a multinational survey of 416 patients and was compared with previous scoring systems. RESULTS: The significant risk factors for death in SJS/TEN comprised 10 items, including patients' age of ≥65 years, ≥10% body surface area involvement, the use of antibiotics as culprit drugs, the use of systemic corticosteroid therapy before the onset, and mucosal damage affecting the ocular, buccal, and genital mucosa. Renal impairment, diabetes, cardiovascular disease, malignant neoplasm, and bacterial infection were included as underlying diseases. The CRISTEN model showed good discrimination (area under the curve [AUC] = 0.884) and calibration. In the validation study, the AUC was 0.827, which was statistically comparable to those of previous systems. CONCLUSION: A scoring system based on only clinical information was developed to predict mortality in SJS/TEN and was validated in an independent multinational study. CRISTEN may predict individual survival probabilities and direct the management and therapy of patients with SJS/TEN.

Elevated serum osteopontin levels in patients with severe cutaneous adverse drug reactions.

Osteopontin (OPN) was initially described as a protein involved in bone metabolism, but the roles played by OPN in the immune system and allergic reactions have attracted increasing attention. Here, we clarify the OPN-related dynamics of severe cutaneous adverse drug reactions, and assess whether the OPN level has utility for classifying such reactions and serving as a biomarker of severity. Serum OPN levels in patients with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS), Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and erythema multiforme-type drug reaction (EM-DR) were quantified by ELISA. The OPN sources were analyzed by dual immunofluorescence assay of DIHS, SJS/TEN and EM-DR biopsy specimens. The serum OPN levels of DIHS/DRESS patients (489.1 ± 37.0 ng/mL) and SJS/TEN patients (508.5 ± 47.8 ng/mL) were significantly higher compared with controls (314.4 ± 14.3 ng/mL; p < 0.001). After treatment, the serum OPN level of DIHS/DRESS patients decreased to that of controls. In addition, OPN levels in DIHS/DRESS patients and SJS/TEN patients were higher than in patients with EM-DR (Mann-Whitney U test, p < 0.05). However, when the Kruskal-Wallis test was used to compare the OPN levels among the three groups of patients, the difference was not significant (p = 0.055). Dual immunofluorescence assay revealed that T lymphocytes and macrophages were the main OPN sources in DIHS, SJS/TEN and EM-DR patients. These data suggest that the OPN level can be used to evaluate the severity of inflammation in patients experiencing drug reactions.

Serum levels of C-C motif chemokine ligand 2 and interleukin-8 as possible biomarkers in patients with toxic epidermal necrolysis accompanied by acute respiratory distress syndrome.

Toxic epidermal necrolysis (TEN) is a fatal cutaneous adverse reaction that occasionally affects multiple organs. Acute respiratory distress syndrome (ARDS) is a rare complication that can cause rapid and potentially fatal pulmonary dysfunction. However, the mechanisms underlying TEN-induced ARDS remain unknown. This retrospective single-center study aimed to identify potential biomarkers for predicting ARDS onset in TEN patients. Pre-treatment serum samples were collected from 16 TEN patients and 16 healthy controls (HCs). The serum levels of cytokines/chemokines were determined using the Luminex Assay Human Premixed Multi-analyte kit. The expression levels of cytokines and chemokines in the skin were examined via immunohistochemistry. The serum levels of C-C motif chemokine ligand 2 (CCL2), interleukin (IL)-6, and IL-8 were significantly higher in TEN patients with ARDS than in those without ARDS and in HCs, whereas those of CCL2 and IL-8 were not significantly different between TEN patients without ARDS and HCs. There was no significant difference in CCL2 and IL-8 expression in the skin between TEN patients with and without ARDS. Interestingly, there were no significant differences in the cytokine/chemokine levels between TEN and other organ damage, other than ARDS and TEN without any organ damage. We further analyzed the changes in cytokine/chemokine levels before and after treatment in two TEN patients with ARDS. CCL2, IL-6, and IL-8 levels decreased after systemic treatment compared to their baseline levels before treatment at an early stage. These results suggest that IL-8 and CCL2 may be involved in the pathogenesis of TEN-induced ARDS and have potential application as predictive markers for ARDS onset.

Abnormal inflammatory traits and downregulated caveolin-1 expression in monocytes of psoriasis patients may be associated with psoriatic inflammation and atherosclerosis.

BACKGROUND: Monocytes and macrophages are implicated in inflammation and atherosclerosis, whereas monocytes are involved in psoriasis lesion formation. We previously reported a psoriatic inflammation-associated significant decrease in the membrane protein caveolin-1 (CAV-1) in psoriasis patient monocytes. However, the phenotype of circulating monocytes and their macrophage differentiation in psoriasis patients remain unclear. OBJECTIVE: We sought to clarify circulating monocyte and monocyte-derived macrophage (MDM) phenotypes in psoriasis patients with and without comorbidities. METHODS: Thirty-one patients with psoriasis vulgaris and 28 control subjects were included. Surface macrophage markers and inflammatory status were examined in circulating monocytes and MDMs from both groups. Expression of CD36, which mediates macrophage uptake of oxidized low-density lipoprotein (oxLDL), was evaluated in these cells. CAV-1-silenced monocytes were differentiated into macrophages to investigate the effects of CAV-1 downregulation on psoriatic inflammation and atherosclerosis. RESULTS: Macrophage surface markers were detectable in circulating monocytes. A significant M1 shift was detected in monocytes and MDMs in psoriasis patients, including those without cardiovascular disease risk factors, as compared to controls. MDMs of psoriasis patients had more CD36-expressing cells, which are associated with atherosclerosis risk. Additionally, CAV-1-silencing in monocytes increased the likelihood of M1-biased macrophage differentiation and increased pro-inflammatory cytokine production. CONCLUSIONS: Monocytes from psoriasis patients were more likely to differentiate into M1-dominant macrophages, correlating with inflammatory status and CAV-1 expression. These aberrant inflammatory monocytes not only contribute to psoriatic inflammation by producing psoriatic cytokines, but also have a phenotype that could increase atherosclerosis risk by uptake of oxLDL and formation of foam cells.

Risk factors for sepsis and effects of pretreatment with systemic steroid therapy for underlying condition in SJS/TEN patients: Results of a nationwide cross-sectional survey in 489 Japanese patients.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening severe cutaneous adverse reactions (SCARs). Sepsis has been shown to be the main cause of death in SJS/TEN. The European SCAR study reported that 14.8 % of SJS/TEN patients were receiving systemic steroid therapy for their underlying condition prior to onset. However, it remained unclear whether this factor affected the mortality rate. OBJECTIVE: This study was performed to identify risk factors for sepsis in SJS/TEN patients. In addition, we compared patients who had and had not received systemic steroid therapy for their underlying condition. METHODS: A primary survey regarding the numbers of SJS/TEN patients between 2016 and 2018 was sent to 1205 institutions in Japan. A secondary survey seeking more detailed information was sent to institutions reporting SJS/TEN patients. We analyzed 315 SJS patients and 174 TEN patients using a logistic regression model, Wilcoxon's rank-sum test, χ2 test, and Fisher's exact test. RESULTS: Significant risk factors for sepsis included TEN, diabetes, and intensive care unit (ICU) admission. The mortality rate was significantly higher among patients with sepsis. Patients who had received systemic steroid therapy had a lower incidence of fever, and showed a higher mortality rate. CONCLUSION: Based on a nationwide epidemiological survey of SJS/TEN in Japan, we identified risk factors for sepsis and found that patients who had received steroid therapy for their underlying condition had a lower incidence of fever and a higher mortality rate.

Recent Dermatological Treatments for Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Japan.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are serious conditions characterized by necrosis of the skin and mucus membranes, and are mainly caused by medication and infections. Although the exact pathomechanism of SJS/TEN remains unclear, keratinocyte death is thought to be triggered by immune reactions to these antigens. While there is no established therapy for SJS/TEN, corticosteroids and intravenous immunoglobulin (IVIG) have been utilized as immunomodulator. We previously conducted a study to evaluate the efficacy of IVIG therapy in Japanese patients with SJS/TEN. IVIG was administered at a dosage of 400 mg/kg/day for 5 consecutive days as an additional therapy with systemic steroids. Prompt amelioration was observed in seven of the eight patients. All patients survived without sequelae. Recently, we retrospectively analyzed 132 cases of SJS/TEN treated in our two hospitals. The mortality rates in the patients treated with methylprednisolone pulse were 0% (0/31) for SJS and 7.0% (3/43) for TEN, and 0% (0/10) in the TEN patients treated with methylprednisolone pulse in combination with IVIG. These results suggest that early treatment with high-dose steroids, including methylprednisolone pulse therapy, and IVIG together with corticosteroids are possible therapeutic options to improve the prognosis of SJS/TEN.

[A LONG PROSPECTIVE OBSERVATIONAL STUDY ON PREVALENCE OF ATOPIC DERMATITIS IN EARLY CHILDHOOD TO ADOLESCENCE].

BACKGROUND: There are few prospective observational studies on the prevalence of atopic dermatitis (AD) in children. We aimed to prospectively investigate the dynamics of change in the prevalence of AD from early childhood to adolescence. METHODS: We conducted a survey with a modified questionnaire to diagnose AD based on The International Study of Asthma and Allergies in Childhood questionnaire with 1230 13-year-old children who were born in the Minami ward, Yokohama City between May 2004 and June 2005 and had undergone physical examinations by dermatologists at 3 years of age. Among the 422 children who answered the questionnaire, 210 had undergone periodic physical examinations by dermatologists from 4 months to 3 years of age (Cohort 1), whereas 212 had undergone physical examinations only at 3 years of age (Cohort 2). RESULTS: The prevalence of AD was 16.9% in 422 children at 13 years of age, with 22.9%, 16.6%, 20.0% and 18.3% prevalence at 4 months, 18 months, 3 years and 13 years of age, respectively, in children who were followed up long-term. The frequency of AD occurrence per year decreased after the age of 3 years; a history of AD at this age was significantly related to AD at 13 years of age (Fisher's exact test, p<0.001). CONCLUSION: In conclusion, it was suggested that AD in 3-year-old children is one of the risk factors for the development of AD in 13-year-old children.

A pediatric case of Stevens-Johnson syndrome with acute liver failure, resulting in liver transplantation.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are fatal adverse skin reactions characterized by high fever, epidermal detachment, and mucositis. It is well known that SJS/TEN occasionally affects various organs, leading to permanent damage and death in some patients. Although acute liver dysfunction is a relatively common complication of SJS/TEN, severe acute liver dysfunction requiring liver transplantation is rare. We present the case of a 14-year-old girl with SJS complicated by severe and rapidly progressive liver dysfunction, specifically, acute liver failure (ALF) requiring liver transplantation. A lymphocyte transformation test showed positive results for acetaminophen and cefdinir. Furthermore, human leukocyte antigen (HLA) genotyping revealed the presence of the HLA-A*02:06 genotype, which is reported to be strongly associated with acetaminophen-related SJS/TEN with severe ocular complications. These results suggested that our patient may have presented with acetaminophen-induced SJS complicated by ALF, but no ocular complications. This is the first report of a pediatric patient with SJS who required liver transplantation. In rare instances, severe liver dysfunction requiring liver transplantation should be considered as a possible complication of SJS/TEN.

Downregulated IRF8 in Monocytes and Macrophages of Patients with Systemic Sclerosis May Aggravate the Fibrotic Phenotype.

Monocytes and macrophages may be involved in the pathogenesis of systemic sclerosis (SSc); however, the etiology and regulation of monocyte and macrophage function in SSc remain unknown. IRF8 is a transcriptional regulator that is essential for the differentiation and function of monocytes and macrophages and thus may be involved in the regulation of macrophage phenotypes in SSc fibrosis. In this study, we measured IRF8 levels in circulating monocytes of 26 patients with SSc (diffuse cutaneous SSc, n = 11; limited cutaneous SSc, n = 15) and 14 healthy controls. IRF8 levels were significantly suppressed in monocytes of patients with diffuse cutaneous SSc and correlated negatively with the modified Rodnan total skin thickness score. Next, we assessed expression levels of cell surface markers, cytokine profiles, and components of extracellular matrix in IRF8-silenced monocyte-derived macrophages. IRF8-silenced monocyte-derived macrophages displayed an M2 phenotype and significantly upregulated mRNA and protein levels of profibrotic factors and extracellular matrix components. Finally, we assessed skin fibrosis in myeloid cell-specific IRF8 conditional knockout (Irf8flox/flox; Lyz2Cre/+) mice and found upregulated mRNA levels of extracellular matrix components and increased bleomycin-induced skin fibrosis. In conclusion, altered IRF8 regulation in monocytes and macrophages may be involved in SSc pathogenesis.

The psychological effects of COVID-19 on hospital workers at the beginning of the outbreak with a large disease cluster on the Diamond Princess cruise ship.

The aim of the present study was to investigate the psychological effects of the COVID-19 outbreak and associated factors on hospital workers at the beginning of the outbreak with a large disease cluster on the Diamond Princess cruise ship. This cross-sectional, survey-based study collected demographic data, mental health measurements, and stress-related questionnaires from workers in 2 hospitals in Yokohama, Japan, from March 23, 2020, to April 6, 2020. The prevalence rates of general psychological distress and event-related distress were assessed using the 12-item General Health Questionnaire (GHQ-12) and the 22-item Impact of Event Scale-Revised (IES-R), respectively. Exploratory factor analysis was conducted on the 26-item stress-related questionnaires. Multivariable logistic regression analysis was performed to identify factors associated with mental health outcomes for workers both at high- and low-risk for infection of COVID-19. A questionnaire was distributed to 4133 hospital workers, and 2697 (65.3%) valid questionnaires were used for analyses. Overall, 536 (20.0%) were high-risk workers, 944 (35.0%) of all hospital workers showed general distress, and 189 (7.0%) demonstrated event-related distress. Multivariable logistic regression analyses revealed that 'Feeling of being isolated and discriminated' was associated with both the general and event-related distress for both the high- and low-risk workers. In this survey, not only high-risk workers but also low-risk workers in the hospitals admitting COVID-19 patients reported experiencing psychological distress at the beginning of the outbreak.

Allergic contact dermatitis due to the liquid skin adhesive Dermabond® predominantly occurs after the first exposure.

BACKGROUND: The clinical characteristics of patients with allergic contact dermatitis (ACD) due to a skin adhesive containing 2-octyl cyanoacrylate, Dermabond®, have not yet been elucidated. OBJECTIVE: To investigate the clinical characteristics of patients with ACD caused by Dermabond® application. METHODS: In this retrospective study, 577 patch tested patients were included. We identified patients with positive patch test results for Dermabond® and evaluated their results concerning (meth)acrylates and ethyl cyanoacrylate adhesive. RESULTS: Nine patients had positive patch test results to Dermabond®; six had developed secondary generalization.The mean time between Dermabond® application and ACD onset was 34 days (range, 27-44) in six patients with ACD after the first use, whereas, in the other three patients, it was 5.6 days (range, 4-8) after the second use. The time was significantly different between the two groups (P < .01). Positive reactions to ethyl cyanoacrylate adhesive (Aron Alpha) occurred in seven of nine patients, to ethyl cyanoacrylate 10% pet. in four of eight patients tested, and to 2-hydroxyethyl methacrylate in one of eight patients tested. CONCLUSIONS: Dermabond®-induced ACD is apparently characterized by a high prevalence of primary sensitization at first exposure to Dermabond®, secondary generalization is frequent, and most patients show cross-reactivity to ethyl cyanoacrylate.

Mortality and risk factors on admission in toxic epidermal necrolysis: A cohort study of 59 patients.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening disorders characterized by widespread epidermal necrosis of the skin and mucosa. The severity-of-illness scoring system for TEN (SCORTEN) was widely used since 2000 as a standard prognostic tool consisting of seven clinical values. METHODS: To evaluate the prognosis using current treatments and risk factors for mortality, we retrospectively analyzed 59 cases of TEN, including SJS/TEN overlap treated in two university hospitals from January 2000 to March 2020. RESULTS: The mortality rate of TEN was 13.6% (8/59). All patients treated with high-dose steroid administration in combination with plasma exchange and/or immunoglobulin therapy recovered. Logistic regression analysis showed nine clinical composite scores, namely: heart rate (≧120 bpm), malignancy present, percentage of body surface area with epidermal detachment (>10%), blood urea nitrogen (>28 mg/dL), serum bicarbonate level (<20 mEq/L), serum glucose level (>252 mg/dL), age (≧71 years), the interval between disease onset and treatment initiation at the specialty hospital (≧8 days), and respiratory disorder within 48 h after admission. The receiver operating characteristic curves confirmed a high potential for predicting the prognosis of TEN. CONCLUSIONS: Recent developments in treatment strategies have contributed to the improved prognosis of TEN patients. A modified severity scoring model composed of nine scores may be helpful in the prediction of TEN prognosis in recent patients. Further large-scale studies are needed to confirm mortality findings to improve prognostication in patients with TEN.

The nationwide epidemiological survey of Stevens-Johnson syndrome and toxic epidermal necrolysis in Japan, 2016-2018.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening severe cutaneous adverse reactions (SCARs). The first national epidemiological survey of SJS/TEN was carried out in 2008. We conducted a new survey to identify changes from the previous survey. OBJECTIVE: The present survey aimed to estimate the number of SJS/TEN patients in Japan between 2016 and 2018 (primary survey) and to clarify clinical epidemiological profiles (secondary survey). METHODS: A primary survey asking for numbers of SJS/TEN patients during the study period was sent to 1205 institutions nationwide. A secondary survey was sent to institutions reporting SJS/TEN patients, seeking detailed information. RESULTS: Yearly prevalence per million was 2.5 for SJS and 1 for TEN. The secondary survey allowed analysis of 315 SJS cases and 174 TEN cases from 160 institutions. Mean age was 53.9 years in SJS, and 61.8 years in TEN. Mortality rate was 4.1 % for SJS and 29.9 % for TEN. In TEN, mean age and mortality rates had increased from the previous survey. The ratio of expected to observed mortality calculated by SCORTEN score was lowest with high-dose steroid therapy (0.40), followed by steroid pulse therapy (0.52). CONCLUSION: The present findings suggest that the mortality rate of TEN has increased because of increases in mean ages of patients and patients with malignant neoplasm as underlying disease. When comparing the ratio of expected mortality to actual mortality, high-dose steroid therapy achieved the greatest reduction in mortality.

Increased level of high mobility group box 1 in the serum and skin in patients with generalized pustular psoriasis.

High-mobility group box 1 (HMGB-1) is a highly abundant pro-inflammatory protein associated with the pathogenesis of inflammatory and autoimmune diseases. HMGB-1 expression level increases in patients with psoriasis vulgaris (PV). However, HMGB-1 expression in patients with generalized pustular psoriasis (GPP) is unknown. In this study, we investigated HMGB-1 expression in GPP. HMGB-1 expression levels were examined in the skin and serum of patients with GPP, PV, atopic dermatitis (AD) and healthy controls (HC) using enzyme-linked immunosorbent assay and immunohistochemistry. The elevation in HMGB-1 expression was significantly higher in GPP patients than in PV, AD and HC patients. In addition, patients with GPP had elevated serum HMGB-1 levels compared with those with AD and HC. Furthermore, serum HMGB-1 levels were significantly decreased after systemic treatment. In the correlation analysis, a significant positive correlation was detected between serum HMGB-1 levels and the Japanese severity score for GPP. HMGB-1 may be involved in the pathogenesis of GPP and can be useful to evaluate disease severity and the effectiveness of GPP treatment.

Clinical significance of serum levels of anti-transcriptional intermediary factor 1-γ antibody in patients with dermatomyositis.

Dermatomyositis (DM) is an autoimmune inflammatory disease characterized by skin eruptions and myositis. Anti-transcriptional intermediary factor 1-γ antibody (anti-TIF1-γ Ab) is one of the most frequently detected myositis-specific autoantibodies and adults positive for anti-TIF1-γ have markedly higher rates of malignancy. Our aim was to determine the clinical associations of anti-TIF1-γ levels in 31 Japanese adult DM patients positive for anti-TIF1-γ. We determined associations between the anti-TIF1-γ index and patient characteristics and disease severities. Sixteen patients with anti-TIF1-γ Ab had concomitant malignancies. A mild positive correlation was found between the levels of serum creatine phosphokinase at the first visit and anti-TIF1-γ levels. In contrast, there was no significant difference in the anti-TIF1-γ Ab index between patients with and without malignancy. Dysphagia tended to be observed in patients with malignancy. On sequential analysis, anti-TIF1-γ levels in patients without malignancy were lower or turned negative after treatment for DM. Ab titers tended to be sustained in patients with stage IV malignancies. Interestingly, a re-increase in the Ab titer was observed on recurrence of malignancy or increase in DM activity. Four patients were completely cured of their malignancies, and anti-TIF1-γ levels in three patients turned negative with the loss of DM activity. These data suggest that higher anti-TIF1-γ titers may not directly indicate the presence of malignancy. Nevertheless, longitudinal changes in the anti-TIF1-γ index in individual patients may partially reflect activities of both DM and malignancy.