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.

Hydrochlorothiazide increases risk of nonmelanoma skin cancer in an elderly Japanese cohort with hypertension: The Shizuoka study.

Background: Hydrochlorothiazide (HCT), a widely used hypertensive drug, has photocarcinogenic potential, leading to concerns about the development of nonmelanoma skin cancers (SCs) after intake. Despite substantial numbers of observational studies, the results remain inconsistent especially among Asian countries. Objective: To assess the incidence of nonmelanoma SCs in hypertensive Japanese HCT users compared with nonusers. Methods: A population-based, cohort nested, propensity score-matched study was conducted using the Shizuoka Kokuho database. All participants were patients aged ≥60 years. Hazard ratios for SC incidence were calculated in the matched cohorts using the propensity scores of potential confounders, sex, age category, comorbidities, and administration of methotrexate, cyclosporin, and statins. Results: The risk of SC was higher in HCT users than in nonusers (hazard ratio, 1.58; 95% confidence interval, 1.04-2.40), with preferential sun-exposed location and a tendency to develop squamous cell carcinoma, but not basal cell carcinoma or Bowen disease. Limitations: No additional information was available from other than medical records. The data were confined to a Japanese population. Conclusion: HCT use increases the risk of SC in Japanese patients with hypertension and a dark skin type, highlighting the increased risk of SC among HCT users in the aging society worldwide.

Risk factors and drugs that trigger the onset of Stevens-Johnson syndrome and toxic epidermal necrolysis: A population-based cohort study using the Shizuoka Kokuho database.

Background: Evidence of factors associated with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) from population-based studies is scarce. Objective: We aimed to identify the incidence, risk factors, and drugs that trigger the development of SJS/TEN in the general population. Methods: A regional, population-based, longitudinal cohort with 2,398,393 Japanese individuals was analyzed using the Shizuoka Kokuho Database from 2012 to 2020. Results: Among 1,909,570 individuals, 223 (0.01%, 2.3 cases/100,000 person-years) patients were diagnosed with SJS/TEN during the observational period of a maximum of 7.5 years. In a multivariable analysis, the risks of SJS/TEN were an older age, and the presence of type 2 diabetes, peripheral vascular disease, and systemic autoimmune diseases. The administration of drugs, such as immune checkpoint inhibitors, insulin, and type 2 diabetes agents, triggered the onset of SJS/TEN. Limitations: The results may apply only to the Japanese population. Conclusion: In this cohort population from a database representing the general population, the risks of developing SJS/TEN were old age and a history of type 2 diabetes, peripheral vascular disease, and systemic autoimmune disease. Furthermore, in addition to previously reported drugs, the administration of immune checkpoint inhibitors, insulin, and type 2 diabetes agents, may trigger the development of SJS/TEN.

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.

Current Understanding of Immunological Skin Diseases: Atopic Dermatitis, Generalized Anhidrosis, and Drug Hypersensitivity.

Recent dermatological research has progressed, particularly novel technologies and analytical methodologies, providing great advances in the exploration of previously poorly understood interactions between the skin-the outermost surface of humans-and the external environment [...].

Immunoglobulin A vasculitis post-severe acute respiratory syndrome coronavirus 2 vaccination and review of reported cases.

Immunoglobulin (Ig)A vasculitis/nephropathy is a systemic immune complex-mediated vasculitis. Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is widely recommended in individuals without specific allergy to the vaccine components, it is arguable whether vaccination is advisable for patients with IgA vasculitis or for predisposed individuals. We and others have presented cases of IgA vasculitis occurring after SARS-CoV-2 vaccination. In total, these 19 cases, including ours, involved predominantly female patients, and half of them were suffering from de novo vasculitis onset. The most frequent manifestation was gross hematuria (89.5%) while skin lesions were relatively infrequent, occurring in only five cases (26.3%), of which three (15.8%) were confirmed to be IgA vasculitis. Taken together, these cases suggest that SARS-CoV-2 vaccination might be a trigger for development/deterioration of IgA vasculitis/nephropathy.

A new susceptibility index to predict the risk of severe herpes zoster-associated pain: A Japanese regional population-based cohort study, the Shizuoka study.

BACKGROUND: Approximately 7-20% of patients with herpes zoster (HZ) develop zoster-associated pain (ZAP). ZAP not only impairs quality of life and psychological well-being, but also can reduce work effectiveness, which has negative economic effects. Reports of ZAP risk factors are inconsistent. OBJECTIVE: To confirm risk factors for the development of severe ZAP in HZ patients in Japan using a large-scale database, the Shizuoka Kokuho Database. METHODS: A population-based cohort study using the Shizuoka Kokuho Database was conducted. Of 792,647 patients, 7491 (0.95%) experienced "severe ZAP" (as defined in this study). We developed a ZAP risk prediction scoring system by identifying risk factors using logistic regression analysis of several candidate risk factors for severe ZAP: age, sex, seasonality, and presence of comorbidities (using the Charlson comorbidity index), excluding HIV/AIDS. RESULTS: We identified peripheral vascular disease and the onset from October to December as novel risk factors for severe ZAP, in addition to the previously reported risk factors of age and comorbidities (cerebral vascular disease, chronic pulmonary disease, rheumatic disease, peptic ulcer, liver disease, diabetes, and malignant neoplasms with/without metastasis). In contrast, dementia was found to reduce ZAP risk. We developed a susceptibility index to predict the risk of ZAP. CONCLUSION: We newly demonstrated that peripheral vascular disease and the onset from October to December are ZAP risk factors. Our comorbidity findings support previous observations. The susceptibility index proposed here provides a new approach to the prevention of ZAP using early intervention for high-risk patients.

Is steroid pulse therapy a suitable treatment for drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms? A systematic review of case reports in patients treated with corticosteroids in Japan.

Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms is a life-threatening severe cutaneous adverse reaction, characterized by multiple organ involvement and reactivation of herpes viruses. Although the mainstay of treatment is a high dosage of corticosteroids delivered by pulse therapy or conventional oral administration, it remains debatable which mode is better. To clarify this issue, we reviewed publications in Japan of 299 cases of drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms treated with corticosteroids, to evaluate safety concerns with regards to these two modes of treatment. As a result, we found that patients treated with pulse therapy more frequently suffered cytomegalovirus reactivation, persistency, and high mortality but less frequently experienced herpesvirus 6 reactivation or type 1 diabetes compared with those undergoing conventional treatment, suggesting that the administration mode may differentially modulate inflammatory responses toward distinct consequences. This is the first statistical analysis revealing that steroid pulse therapy frequently resulted in severe sequelae with high mortality. In terms of the risk of serious consequences, we consider that steroid pulse therapy should be eschewed for the treatment of drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms.

Clinical characteristics of itch in cutaneous lupus erythematosus: A prospective, multicenter, multinational, cross-sectional study.

OBJECTIVE: Pruritus is an important symptom frequently accompanying various inflammatory skin conditions and some recent data indicated that it may be associated with autoimmune connective tissue diseases. The aim of this study was to assess the frequency and clinical presentation of itch in CLE. METHODS: A multinational, prospective, cross-sectional study was performed to assess the prevalence, intensity and clinical characteristic of pruritus in various subtypes of CLE. A total of 153 patients with active CLE lesions were included. Their age ranged between 17 and 82 years (mean 49.8 ± 15.4 years), and 115 patients (75.2%) were women. The disease activity and damage were assessed according to the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). Pruritus severity was assessed with Numeric Rating Scale (NRS) and the 12-Item Pruritus Severity Scale. Dermatology Life Quality Index and EQ-5D questionnaire were used to measure quality of life. RESULTS: Pruritus was present in 116 (76.8%) of patients of whom half had NRS scoring equal or above 4 points indicating moderate or severe pruritus. Most commonly itch was localized on the scalp, face (excluding ears and nose) and arms (40.5%, 36.2%, 31.9%, respectively). Sensations connected with pruritus were most frequently described as burning, tingling and like ants crawling feeling, but 31.9% patients described it as "pure itch". More than half of patients reported that pruritus was present every day, and it was most frequent during the evenings. The pruritus scoring and the CLASI activity score were significantly correlated (r = 0.42, p = 0.0001), while no correlation was found with the CLASI damage score (p = 0.16). Both the maximum and average itch intensity were correlated with systemic lupus erythematosus (SLE) activity measured with the Systemic Lupus Erythematosus Disease Activity Index. CONCLUSIONS: Pruritus is a common, but frequently overlooked symptom of CLE. Its intensity correlates with the activity of CLE, but not with the skin damage. In more than a half of patients it occurs on a daily basis. The correlation between the intensity of pruritus and the activity of the skin lesions and the systemic involvement indicate that pruritus could be an individual indicator of both SLE and CLE activity.

Cutaneous Coinfection of Cytomegalovirus and Mycobacterium chelonae Accelerated by Immunosuppression.

A mildly diabetic 58-year-old male had traumatic ulceration on the left popliteal fossa, and the lesion progressed to a painful 6 cm deep ulcer. After surgical debridement and skin grafting, ulceration recurred. Pyoderma gangrenosum was clinically diagnosed after the first biopsy, indicating a noninfective ulcer. Immunosuppressive therapy (prednisolone and cyclosporine A) induced complete epithelialization in three months. Four months later, subcutaneous nonulcerated nodules appeared on the anterior area of the left lower leg. Subcutaneous induration progressed and ulceration recurred, so that immunosuppressive therapy continued for one year. Cytomegalovirus (CMV) viremia was detected, and the second biopsy demonstrated CMV inclusions of endothelial and perivascular cells in fibrosing septolobular panniculitis. Cyclosporine A was cancelled, prednisolone was tapered, and ganciclovir started. Viremia soon disappeared, but the lesion progressed to large induration with multiple ulcers measuring up to 3 cm. The third biopsy disclosed infection of Gram-positive mycobacteria, accompanying fat droplet-centered suppurative granulomas without CMV infection. Microbial culture identified Mycobacterium chelonae. Clarithromycin with thermotherapy was effective. A review of the second biopsy confirmed coinfection of CMV and Gram-positive mycobacteria. Immunostaining using a panel of anti-bacterial antibodies visualized the mycobacteria in the lesion. Positive findings were obtained with antibodies to Bacillus Calmette-Guérin, Bacillus cereus, MPT64 (Mycobacterium tuberculosis-specific 24 kDa secretory antigen), LAM (Mycobacterium tuberculosis-related lipoarabinomannan), and PAB (Propionibacterium acnes-specific lipoteichoic acid).

Quinolone immediate hypersensitivity due to topical ophthalmic preparations: a case report and review of literature.

Ophthalmic quinolone preparations are widely used for the treatment of eye diseases; however, there are only a few reported cases of immediate hypersensitivity due to such medications. Here, we present a case of immediate hypersensitivity induced by an ophthalmic administration of quinolones in a 20-year-old female with bacterial conjunctivitis. The results of skin prick and basophil activation tests suggest that it involved a type Ib reaction associated with Mas-related G-protein coupled receptor X2. The present case cautions us to be aware of quinolone immediate hypersensitivity caused by topical ophthalmic preparations, which can easily be overlooked, because it may predict severe hypersensitivity reactions to systemic administration.

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.