Supportive care in the acute phase of Stevens-Johnson syndrome and toxic epidermal necrolysis: an international, multidisciplinary Delphi-based consensus.

BACKGROUND: Supportive care is the cornerstone of management of adult and paediatric Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). However, consensus on the modalities of supportive care is lacking. OBJECTIVES: Our aim in this international multicentric Delphi exercise was to establish a multidisciplinary expert consensus to standardize recommendations regarding supportive care in the acute phase of SJS/TEN. METHODS: Participants were sent a survey via the online tool SurveyMonkey, consisting of 103 statements organized into 11 topics: multidisciplinary team composition, suspect drug management, infection prevention, fluid resuscitation and prevention of hypothermia, nutritional support, pain and psychological distress management, management of acute respiratory failure, local skincare, ophthalmological management, management of other mucosa, and additional measures. Participants evaluated the level of appropriateness of each statement on a scale of 1 (extremely inappropriate) to 9 (extremely appropriate). The results were analysed according to the RAND/UCLA Appropriateness Method. RESULTS: Forty-five participants from 13 countries (on three continents) participated. After the first round, a consensus was obtained for 82.5% of the 103 initially proposed statements. After the second round, a final consensus was obtained for 102 statements. CONCLUSIONS: We have reached an international Delphi-based consensus on best supportive care practice for SJS/TEN. Our expert consensus should help guide physicians in treating patients with SJS/TEN and thereby improve short-term prognosis and the risk of sequelae.

The risk of anti-osteoporotic agent-induced severe cutaneous adverse drug reactions and their association with HLA.

BACKGROUND: There is increasing use of anti-osteoporotic agents (AOA) worldwide for prevention or management of patients with osteoporosis. However, there have been reports of severe cutaneous adverse reactions (SCAR) induced by AOA. A recent study showed weak association between HLA and strontium ranelate (SR)-SCAR. OBJECTIVE: To characterize patients with AOA-SCAR and investigate the HLA association and utility of in vitro diagnostic methods. METHODS: We enrolled 16 cases with AOA-cutaneous adverse drug reactions (cADR), including SCAR (n = 10: 8 with Stevens-Johnson syndrome [SJS] and 2 with drug rash with eosinophilia and systemic symptoms [DRESS]) and maculopapular exanthema (MPE) (n = 6) from Taiwan and Hong Kong. We analysed the clinical characteristics, outcomes, HLA alleles and in vitro testing of AOA-SCAR, and tolerability to alternative drugs. We further performed literature review and meta-analysis on the HLA association of AOA-SCAR. RESULTS: Our data showed strontium ranelate is the most common causality of AOA-SCAR in Asian populations. There was no cross-hypersensitivity of SR-SCAR with other AOA. HLA genotyping showed that SR-SJS was most significantly associated with HLA-A*33:03 (Pc = 5.17 × 10-3 , OR: 25.97, 95% CI: 3.08-219.33). Meta-analysis showed that HLA-A*33:03 was associated with SR-SJS (P = 5.01 × 10-5 ; sensitivity: 85.7%) in Asians. The sensitivity of lymphocyte activation test (LAT) for identifying the culprit drug of SR-SJS was 83.3%. CONCLUSIONS: Strontium ranelate is identified as the most notorious AOA associated with SCAR. The HLA-A*33:03 genetic allele and LAT testing may add benefits to the diagnosis of SR-SCAR in patients whose reaction developed while taking multiple drugs.

Serum and blister-fluid elevation and decreased epidermal content of high-mobility group box 1 protein in drug-induced Stevens-Johnson syndrome/toxic epidermal necrolysis.

BACKGROUND: High-mobility group box 1 (HMGB1) is a damage-associated molecular-pattern protein. Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) are serious, immune-mediated skin-blistering conditions. OBJECTIVES: To determine serum and/or blister-fluid total HMGB1 levels in SJS/TEN cohorts, and HMGB1 expression in formalin-fixed, paraffin-embedded (FFPE) SJS/TEN skin vs. healthy and maculopapular exanthema (MPE) skin. Methods Serum HMGB1 was quantified in Malawian nevirapine-induced hypersensitivity, Taiwanese SJS/TEN and Spanish SJS/TEN cohorts. FFPE skin (healthy skin, MPE, SJS/TEN) was stained and assessed for HMGB1 expression. RESULTS: Serum total HMGB1 was not significantly elevated in patients with nevirapine-induced SJS/TEN (3·98 ± 2·17 ng mL-1 ), MPE (3·92 ± 2·75 ng mL-1 ) or drug reaction with eosinophilia and systemic symptoms (4·73 ± 3·00 ng mL-1 ) vs. tolerant controls (2·97 ± 3·00 ng mL-1 ). HMGB1 was significantly elevated in Taiwanese patients with SJS/TEN, highest during the acute phase (32·6 ± 26·6 ng mL-1 ) vs. the maximal (19·7 ± 23·2 ng mL-1 ; P = 0·007) and recovery (24·6 ± 25·3 ng mL-1 ; P = 0·027) phases. In blister fluid from Spanish patients with SJS/TEN, HMGB1 (486·8 ± 687·9 ng mL-1 ) was significantly higher than in serum (8·8 ± 7·6 ng mL-1 ; P <0·001). Preblistered SJS/TEN skin showed decreased epidermal nuclear HMGB1 expression in upper epidermis vs. healthy or MPE skin but retained basal/suprabasal expression. CONCLUSIONS: Epidermal HMGB1 expression was decreased in SJS/TEN skin. Retained basal/suprabasal epidermal HMGB1 expression may exacerbate localized injury in SJS/TEN.

Delayed-type hypersensitivity reactions induced by proton pump inhibitors: A clinical and in vitro T-cell reactivity study.

BACKGROUND: Proton pump inhibitors (PPIs) have been known to induce type I hypersensitivity reactions. However, severe delayed-type hypersensitivity reactions (DHR) induced by PPI, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug rash with eosinophilia and systemic symptoms (DRESS), are rarely reported. We conducted a study of a large series of PPI-related DHR, followed up their tolerability to alternative anti-ulcer agents, and investigated the T-cell reactivity to PPI in PPI-related DHR patients. METHODS: We retrospectively analyzed patients with PPI-related DHR from multiple medical centers in Taiwan during the study period January 2003 to April 2016. We analyzed the causative PPI, clinical manifestations, organ involvement, treatment, and complications. We also followed up the potential risk of cross-hypersensitivity or tolerability to other PPI after their hypersensitivity episodes. Drug lymphocyte activation test (LAT) was conducted by measuring granulysin and interferon-γ to confirm the causalities. RESULTS: There were 69 cases of PPI-related DHR, including SJS/TEN (n=27) and DRESS (n=10). The LAT by measuring granulysin showed a sensitivity of 59.3% and specificity of 96.4%. Esomeprazole was the most commonly involved in PPI-related DHR (51%). Thirteen patients allergic to one kind of PPI could tolerate other structurally different PPI without cross-hypersensitivity reactions, whereas three patients developed cross-hypersensitivity reactions to alternative structurally similar PPI. The cross-reactivity to structurally similar PPI was also observed in LAT assay. CONCLUSIONS: PPIs have the potential to induce life-threatening DHR. In patients when PPI is necessary for treatment, switching to structurally different alternatives should be considered.

Periorbital erythema and swelling as a presenting sign of lupus erythematosus in tertiary referral centers and literature review.

Background Cutaneous lupus erythematosus (CLE) includes a broad range of dermatologic manifestations. Periorbital involvement, however, is a relatively rare clinical presentation of CLE. Objectives This clinical study aimed to investigate the characteristics of this unique presentation of CLE in tertiary medical centers. Methods We enrolled patients with periorbital erythema and swelling as the presenting sign of lupus erythematosus, from January 2003 to November 2017, using the data of 553 pathologically proven CLE cases from the registration database of the Chang Gung Memorial Hospitals in Taiwan. Results We enrolled a total of 25 patients. The mean age was 46.7 years and 68% of the patients were female. Most of the patients (84.0%) presented with unilateral involvement, with the left orbit involved in 15 patients (60%); the upper eyelid was the most frequently involved (72%). Mean duration between the onset of clinical manifestations and the diagnosis of CLE was approximately 59 weeks. Nineteen patients had been previously misdiagnosed. All patients had features compatible with CLE on histopathological examination. In contrast, laboratory analysis of the autoimmune profile often revealed negative results, including those for antinuclear antibodies (25%). Notably, anti-SSA/SSB (45.5%) showed the highest positive rate. During follow-up, six patients developed systemic lupus erythematosus (SLE) and two patients developed Sjögren syndrome. Conclusions The diagnosis of CLE presenting as periorbital erythema and swelling is often delayed because of clinical mimicry and the high proportion of negative results on autoantibody tests. Increased clinical suspicion and prompt histopathological examination are crucial for early diagnosis. Moreover, one-fourth of the patients ultimately developed SLE, which highlights the importance of clinical awareness.

Association of HLA-B*15:13 and HLA-B*15:02 with phenytoin-induced severe cutaneous adverse reactions in a Malay population.

Phenytoin (PHT) is a common cause of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Although HLA-B*15:02 is associated with PHT-induced SJS/TEN (PHT-SJS/TEN) in Han Chinese and Thais, the genetic basis for susceptibility to PHT-induced SCARs (PHT-SCAR) in other populations remains unclear. We performed a case-control association study by genotyping the human leukocyte antigen (HLA)-B alleles of 16 Malay PHT-SCAR patients (13 SJS/TEN and 3 DRESS), 32 PHT-tolerant controls and 300 healthy ethnicity-matched controls. A novel genetic biomarker, HLA-B*15:13, showed significant association with PHT-SJS/TEN (53.8%, 7/13 cases) (odds ratio (OR) 11.28, P=0.003) and PHT-DRESS (100%, 3/3 cases) (OR 59.00, P=0.003) when compared with PHT-tolerant controls (9.4%, 3/32 controls). We also confirmed HLA-B*15:02 association with PHT-SJS/TEN (61.5%, 8/13 cases vs 21.9%, 7/32 controls; OR 5.71, P=0.016) when compared with PHT-tolerant controls. These alleles may serve as markers to predict PHT-SCAR in Malays.

Identification of differentially expressed genes in longissimus muscle of pigs with high and low intramuscular fat content using RNA sequencing.

Intramuscular fat (IMF) content in pork is an important element of consumer preference and is positively correlated with meat quality, including tenderness and juiciness. With advances in RNA sequencing technologies, transcriptome-related differences can be associated with specific traits in animals. The objective of this study was to investigate differentially expressed genes (DEGs) closely related to IMF content in porcine longissimus muscle using RNA sequencing. A total of 107 Berkshire pigs were used for IMF content measurements, and significant differences between extremely high (H, n = 3) and low (L, n = 3) IMF content groups were found (P < 0.0001). From multi-dimensional scaling analyses, it was observed that the relationships between H and L groups were similar to each other. Here, we identified a total of 134 genes that were differentially expressed between the groups (false discovery rate <0.05; fold change ≥2). Functional analyses with DEGs revealed that lipid metabolism (SCD and FASN) was one of the significant biological processes related to IMF content determination. In addition, we found that DEGs related to muscle regeneration (MYOG and VEGFA) and extracellular matrix (COL1A1, COL1A2, COL5A1, COL14A1 and COL15A1) were changed among individuals with extreme IMF contents. These results will aid in understanding the regulation of IMF content in pigs.

Secular trends in caesarean section rates over 20 years in a regional obstetric unit in Hong Kong.

INTRODUCTION: Although caesarean section rates have been increasing over the years in both public and private sectors in Hong Kong, there has been a paucity of formal surveys on local trends in such rates. This study aimed to examine the trends in caesarean section rates over a 20-year period at a public regional obstetric unit in Hong Kong using the Robson's Ten-group Classification System. METHODS: All deliveries in a single obstetric unit during a 20-year period (1995-2014) were classified into 10 subgroups according to the Robson's classification. The annual caesarean section rate for each subgroup was calculated and then stratified into 5-year intervals to analyse any significant trends. RESULTS: The caesarean section rates in a total of 86 262 births with complete data were analysed. The overall caesarean section rate increased modestly from 15.4% to 24.6% during the study period. There was an obvious increasing trend for caesarean section in those with previous caesarean section (Robson's category 5), breech presentation at delivery (category 6 and 7), multiple pregnancy (category 8), and preterm labour (category 10). A gradual fall in caesarean section rate from 14.4% to 10.8% was seen in primiparous women with term spontaneous labour (category 1). Statistically significant differences (P<0.001) in these trends were confirmed when the data were stratified into 5-year intervals for comparison. CONCLUSION: The rising caesarean section rate may be associated with clinical management policies that allow women with relative risk factors (such as breech, previous caesarean section, or multiple pregnancy) to opt for caesarean section. This rise was counterbalanced by a decrease in primary caesarean section rate in primiparous women with spontaneous labour. The trend for caesarean section was more in line with patient expectations rather than evidence-based practice.

[Diagnostic criteria for Menière's disease according to the Classification Committee of the Bárány Society]. / M. Menière: Diagnostische Kriterien des Internationalen Klassifikationskomitees der Bárány-Gesellschaft.

This paper presents diagnostic criteria for Menière's disease jointly formulated by the Classification Committee of the Bárány Society, The Japan Society for Equilibrium Research, the European Academy of Otology and Neurotology (EAONO), the Equilibrium Committee of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) and the Korean Balance Society. The classification includes two categories: definite Menière's disease and probable Menière's disease. The diagnosis of definite Menière's disease is based on clinical criteria and requires the observation of an episodic vertigo syndrome associated with low- to medium-frequency sensorineural hearing loss and fluctuating aural symptoms (hearing, tinnitus and/or fullness) in the affected ear. Duration of vertigo episodes is limited to a period between 20 min and 12 h. Probable Menière's disease is a broader concept defined by episodic vestibular symptoms (vertigo or dizziness) associated with fluctuating aural symptoms occurring in a period from 20 min to 24 h.

Stevens-Johnson syndrome and toxic epidermal necrolysis in patients with malignancies.

BACKGROUND: Malignancy is known to be associated with an increased mortality rate in patients with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). However, risk factors contributing to the poor prognosis of patients with SJS/TEN with malignancies remain undefined. OBJECTIVES: To explore the potential involvement of malignancy and its related factors contributing to the poor outcome of SJS/TEN, in a retrospective study. METHODS: In total 517 patients with SJS/TEN were enrolled. Forty-seven who sustained various types of malignancies were analysed for numerous malignancy-related factors, including cancer types, clinical stages and chemotherapies given or not before the onset of SJS/TEN. RESULTS: We found that the mortality rate of patients with SJS/TEN with malignancies was higher than that of patients without malignancies (32%, 15/47 vs. 8·5%, 40/470, respectively) (P < 0·001). The use of phenytoin was significantly higher in the malignancy group. The presence of hepatocellular carcinoma (80%, four of five; P < 0·001; odds ratio 43) and colorectal cancer (67%, two of three; P = 0·022; odds ratio 21·5) significantly increased the death rate of patients with SJS/TEN, whereas lung cancer and urothelial carcinoma did not. Patients who had received ongoing or recent chemotherapy showed higher mortality than those without chemotherapy (P = 0·022; odds ratio 4·95). Furthermore, among the 47 patients with SJS/TEN with malignancies, lower serum albumin, haemoglobin and platelet count were detected in the deceased patients than in the surviving patients before the onset of SJS/TEN. CONCLUSIONS: Our results suggest that several factors related to malignancies, such as specific cancer types, chemotherapy and malnutrition, may contribute to poor prognosis in patients with malignancies developing SJS/TEN.

HLA-A*31:01 and different types of carbamazepine-induced severe cutaneous adverse reactions: an international study and meta-analysis.

HLA-A*31:01 was reported to be associated with carbamazepine (CBZ)-induced severe cutaneous adverse reactions (SCAR), including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We conducted an international study using consensus diagnosis criteria to enroll a total of 93 patients with CBZ-SCAR from Europe or Asia. We found that HLA-A*31:01 showed a significant association with CBZ-DRESS in Europeans (P<0.001; odds ratio (OR) (95% confidence interval (CI))=57.6 (11.0-340)), and the strong association was also found in Chinese (P<0.001; OR (95% CI)=23.0 (4.2-125)). However, HLA-A*31:01 had no association with CBZ-SJS/TEN in neither Chinese nor Europeans. By comparison, HLA-B*15:02 showed a strong association with CBZ-SJS/TEN in Chinese (P<0.001, OR (95% CI)=58.1 (17.6-192)). A meta-analysis of this and other published studies confirmed that in all populations, HLA-A*31:01 had an extremely strong association with CBZ-DRESS (P<0.001, a pooled OR (95% CI)=13.2 (8.4-20.8)), but a much weaker association with CBZ-SJS/TEN (P=0.01, OR (95% CI)=3.94 (1.4-11.5)). Our data revealed that HLA-A*31:01 is a specific predictor for CBZ-DRESS but not for CBZ-SJS/TEN. More studies are needed to investigate the genetic determinant of CBZ-SJS/TEN in Europeans. Considering the potential clinical utility, the cost-effectiveness of the combined HLA-A*31:01 and HLA-B*15:02 genetic test to prevent CBZ-SCAR in Chinese needs further investigation.

Strontium ranelate related Stevens-Johnson syndrome: a case report.

Strontium ranelate is a relatively new medication with good safety profile for the treatment of postmenopausal osteoporosis. However, severe cutaneous adverse drug reactions have been reported, such as drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). We report the case of a 70-year-old woman who developed multiple itching erythematous macules and plaques about 1 month after beginning strontium ranelate medication. The cutaneous lesions progressed over the entire body with severe oral and ocular mucosa involvement. Probable mild SJS was diagnosed, compatible with the pathology findings, and strontium ranelate was discontinued immediately. Systemic methylprednisolone was administered to suppress the overactive immune system and ameliorate cutaneous symptoms. With early recognition and prompt treatment, the patient's prognosis was good.

Histopathological analysis and clinical correlation of drug reaction with eosinophilia and systemic symptoms (DRESS).

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe cutaneous adverse drug reaction. However, its histopathological features have not been well defined. OBJECTIVES: To identify the clinicohistopathological findings of DRESS, and analyse the cutaneous histopathological changes observed in DRESS compared with those observed in maculopapular exanthema (MPE). METHODS: In a retrospective study, conducted at Chang Gung Memorial Hospital (Taiwan) between 2001 and 2011, we compared the clinicohistopathological features of 32 patients with probable/definite DRESS (defined by the RegiSCAR scoring system) with those of 17 patients with MPE. RESULTS: The major pathological changes observed in patients with DRESS included dyskeratosis (97%), epidermal spongiosis (78%), interface vacuolization (91%), perivascular lymphocytic infiltration (97%) and eosinophilic infiltration (72%). Many pathological features were common to both MPE and DRESS. However, severe dyskeratosis, epidermal spongiosis and severe interface vacuolization were significantly more prominent in cases of DRESS (P < 0·05). The presence of severe dyskeratosis was significantly associated with the clinical severity of renal impairment (P = 0·01). CONCLUSIONS: The severe dyskeratosis detected in patients with DRESS may correlate with a greater extent of systemic involvement compared with that noted in MPE. However, the histopathological changes associated with DRESS are not entirely specific.

Unilateral segmentally arranged basaloid follicular hamartomas with osteoma cutis and hypodontia: a case of Happle-Tinschert syndrome.

Happle-Tinschert syndrome (HTS) is a rare syndrome characterized by segmentally arranged basaloid follicular hamartomas (BFH) associated with ipsilateral osseous, dental and cerebral abnormalities. Happle and Tinschert first reported this disorder in 2008, and three cases with similar presentations have since been reported. We report another case, that of a 40-year-old man, presenting with the characteristic clinical features of HTS.

SCORTEN and impaired renal function related to mortality of toxic epidermal necrolysis syndrome patients in the Asian population.

BACKGROUND: Toxic epidermal necrolysis syndrome (TEN) is a rare, life-threatening, drug-related skin reaction with a high mortality rate. To date, only a few studies with insufficient sample sizes have been conducted to analyse SCORTEN in Asian populations with TEN. OBJECTIVE: To analyse SCORTEN and other related factors that affect TEN patients in Taiwan. METHODS: A retrospective review of medical records of 101 patients with TEN from 1992 to 2009. RESULTS: There were 62 cases of adverse reactions to a single medication and 39 cases of idiopathic reaction, from multiple medications, or infectious pathogens, of 101 TEN patients. Of the seven individual SCORTEN parameters, only associate malignancy, detached or compromised body surface area >10%, serum urea and bicarbonate were statistically significant in the multivariate analysis. Factors such as 1.5 times baseline serum creatinine levels, urine output of less than 0.5 mL/kg for 6 h and acute renal failure were connected with subsequent mortality. CONCLUSION: The SCORTEN score is effective in predicting the outcome in Taiwanese TEN patients. A number of factors are predictors of mortality. In our study, we determine renal insufficiency and failure to be a marker for predicting a poor outcome.

A patch testing and cross-sensitivity study of carbamazepine-induced severe cutaneous adverse drug reactions.

BACKGROUND: The usefulness of the drug patch testing for Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) is still controversial. Recent studies have shown that HLA-B*1502 is strongly associated with CBZ-SJS/TEN in Chinese and Southeast Asian populations. OBJECTIVE: To evaluate the usefulness of patch tests for patients with carbamazepine (CBZ)-induced SJS, TEN and drug reaction with eosinophilia and systemic symptoms (DRESS) and the cross-reactivity in patch tests among the aromatic antiepileptic drugs. METHODS: We measure the frequency of positive patch test reactions and cross-sensitivity to structure-related aromatic anti-epileptic drugs (AEDs) for patients after SJS/TEN or DRESS episodes caused by CBZ. CBZ and other structure-related AEDs used for patch testing were prepared in 10% and 30% petrolatum. Secondary measures included the association of HLA-B*1502 genotype and frequency of possible side effects from the patch tests. RESULTS: Positive patch test reactions to 30% CBZ in the CBZ-SJS/TEN were 62.5% (10/16), and 70% (7/10) in the CBZ-DRESS. None of the 10 healthy controls displayed a positive reaction to tested agents. Cross-sensitivity to other aromatic AEDs was observed in both the CBZ-SJS/TEN and the CBZ-DRESS. Only the HLA-B*1502 genotype was present and strongly associated with the CBZ-SJS/TEN, but not with the CBZ-DRESS. CONCLUSION: Drug patch testing is a safe and useful method for the identification of CBZ as the culprit drug of SJS/TEN as well as DRESS. Testing of chemically or pharmacologically related AEDs may provide information on cross-reactivity for these patients.