Improvement of the Ocular Prognosis of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis: A National Survey in Japan.

PURPOSE: To investigate the incidence and prognostic factors of ocular sequelae in Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) cases arising between 2016 and 2018 in Japan, and compare the findings with those presented in the previous 2005-2007 survey. DESIGN: Retrospective, national trend survey . METHODS: Dermatological case report forms (CRFs) (d-CRFs) were sent to 257 institutions that treated at least 1 SJS/TEN case, and 508 CRFs were collected from 160 institutions. Ophthalmological CRFs (o-CRFs) regarding patient demographic data, onset date, ocular findings (first appearance, day of worst severity, and final follow-up), topical treatment (betamethasone), outcome (survival or death), and ocular sequelae (visual disturbance, eye dryness) were sent to the ophthalmologists in those 160 institutions. The results of this survey were then compared with that of the previous 2005-2007 survey. RESULTS: A total of 240 cases (SJS/TEN: 132/108) were included. The incidence of ocular sequelae incidence was 14.0%, a significant decrease from the 39.2% in the previous survey (SJS/TEN: 87/48). In 197 (82.1%) of the cases, systemic treatment was initiated within 3 days after admission, an increase compared to the previous survey (ie, treatment initiated in 82 [60.7%] of 135 cases). Of the 85 cases with an Acute Ocular Severity Score of 2 and 3, 62 (72.9%) received corticosteroid pulse therapy and 73 (85.9%) received 0.1% betamethasone therapy; an increase compared to the 60.0% and 70.8%, respectively, in the previous survey. Ocular-sequelae-associated risk factors included Acute Ocular Severity Score (P < 0.001) and specific year in the survey (P < 0.001). CONCLUSIONS: The ophthalmologic prognosis of SJS/TEN has dramatically improved via early diagnosis, rapid assessment of acute ocular severity, and early treatment.

A large-scale prospective registration study of the safety and efficacy of sorafenib tosylate in unresectable or metastatic renal cell carcinoma in Japan: results of over 3200 consecutive cases in post-marketing all-patient surveillance.

OBJECTIVE: Real-life safety and efficacy of sorafenib in advanced renal cell carcinoma in a nationwide patient population were evaluated by post-marketing all-patient surveillance. METHODS: All patients with unresectable or metastatic renal cell carcinoma in Japan who started sorafenib therapy from February 2008 to September 2009 were registered and followed for up to 12 months. Baseline characteristics, treatment status, tumor response, survival and safety data were recorded by the prescribing physicians. RESULTS: Safety and efficacy were evaluated in 3255 and 3171 patients, respectively. The initial daily dose was 800 mg in 78.2% of patients. Median duration of treatment was 6.7 months and the mean relative dose intensity was 68.4%. Overall, 2227 patients (68.4%) discontinued the treatment by 12 months, half of which (52.0% of discontinued patients) were due to adverse events. The most common adverse drug reactions were hand-foot skin reaction (59%), hypertension (36%), rash (25%) and increase in lipase/amylase (23%). The median progression-free survival was 7.3 months (95% confidence intervals: 6.7-8.1), and the overall survival rate at 1 year was 75.4% (73.5-77.1). Prognostic factors for overall survival were mostly consistent with those in previous clinical trials in the univariate analysis and largely similar to those for progression-free survival and duration of treatment in the multivariate analysis. CONCLUSIONS: Sorafenib for the treatment of advanced renal cell carcinoma under the labeled dose was feasible in daily medical practice, for its acceptable toxicity profile and favorable clinical benefit that were consistent with those in clinical trials.

Predictive Factors Associated With Acute Ocular Involvement in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.

PURPOSE: To suggest an objective score for grading the acute ocular severity of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), and to determine predictive factors for severe acute ocular involvement such as ocular surface epithelial defect and/or pseudomembrane formation. DESIGN: Retrospective cohort study. METHODS: The medical records of SJS (n = 87) and TEN (n = 48) patients between 2005 and 2007 were reviewed. An acute ocular severity score was determined on a scale from 0 to 3 (none, mild, severe, and very severe) according to the existence of hyperemia, corneal or conjunctival epithelial defect, and pseudomembrane formation. The associations between the severe acute ocular involvement and factors such as patient age, exposed drugs, systemic severity, and the prevalence of ocular sequelae were examined. RESULTS: The number of cases with score grade 0, 1, 2, and 3 was 19 (21.8%), 31 (35.6%), 22 (25.3%), and 15 (17.2%) in 87 SJS cases and 12 (25.0%), 11 (22.9%), 17 (35.4%), and 8 (16.7%) in 48 TEN cases. Multivariate logistic regression analysis revealed that patient age (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.96-0.99; P = .007) and nonsteroidal anti-inflammatory drugs NSAIDs or cold remedies (OR, 2.58; 95% CI, 1.26-5.29; P = .010) were predictive factors for severe acute ocular involvement. The prevalence of visual disturbance and eye dryness increased according to the increase of acute ocular severity (P = .001 and P = .007 in SJS; P = .007 and P = .014 in TEN, respectively). CONCLUSIONS: At the onset of SJS/TEN, strict attention should be paid to ocular involvement in young patients and in patients exposed to NSAIDs or cold remedies.

Sequelae in 145 patients with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms: survey conducted by the Asian Research Committee on Severe Cutaneous Adverse Reactions (ASCAR).

Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) is a severe adverse drug reaction caused by specific drug. It is characterized by visceral organ involvement and reactivation of various human herpesviruses. Although sporadic reports have documented certain conditions that appear after the resolution of DIHS/DRESS, little information is available on sequelae after resolution of DIHS/DRESS in a large patient population. The Asian Research Committee on Severe Cutaneous Adverse Reactions, comprised of doctors from Japan and Taiwan, conducted a survey on sequelae and deterioration of the underlying disease in patients with DIHS/DRESS. This was achieved by directly interviewing patients who had been followed-up by experts or through a questionnaire mailed to patients. Questions were asked about new onset cardiovascular disease, collagen disease or autoimmune disease, gastrointestinal disease, renal disease, respiratory disease, neoplasms, and other diseases such as herpes zoster and diabetes mellitus, as well as deterioration of the underlying disease. A total of 145 patients were analyzed in this study. The following newly developed diseases after recovery from DIHS/DRESS were observed: Graves' disease (n = 2), Hashimoto's disease (n = 3), painless thyroiditis (n = 2), fulminant type 1 diabetes mellitus (n = 5), and infectious diseases (n = 7). Several DIHS/DRESS patients with pre-existing renal dysfunction required lifelong hemodialysis. DIHS/DRESS is a condition that increases the risk of new onset of disease. Long-term observation of DIHS/DRESS can provide an opportunity to investigate substantial diseases from onset to the full-blown stage. Patients with DIHS/DRESS require careful long-term follow-up.

Identification of thymus and activation-regulated chemokine (TARC/CCL17) as a potential marker for early indication of disease and prediction of disease activity in drug-induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS).

BACKGROUND: Drug-induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS) is a serious acute drug reaction with fever, cutaneous eruption, lymphadenopathy, and several visceral dysfunctions. Eosinophilia is a common hematological abnormality in DIHS/DRESS suggesting that the Th2-type immune response is involved. Thymus and activation-regulated chemokine (TARC/CCL17) is a family of CC chemokines known to play an important role in Th2-mediated immune-inflammatory processes. OBJECTIVE: We investigated the pathogenic role of TARC in patients with DIHS. METHODS: Sera were obtained from 8 patients with DIHS, 7 patients with Stevens-Johnson syndrome/Toxic epidermal necrolysis (SJS/TEN), and 14 patients with drug-induced maculopapular exanthema (MPE). Serum TARC levels were measured by ELISA. TARC levels were then compared with clinical symptoms and various hematological parameters. In addition, a biopsy was taken from the lesional skin of patients with DIHS and stained with anti-TARC Ab and anti-CD11c Ab. RESULTS: Serum TARC levels in patients with DIHS were significantly higher than those in patients with SJS/TEN and MPE during the acute phase. Serum TARC levels in DIHS patients correlated with skin eruptions, serum sIL-2R levels, eosinophil counts, and serum IL-5 levels. Immunohistochemical staining revealed that TARC was mainly expressed on CD11c+ dermal dendritic cells in patients with DIHS. CONCLUSION: Serum TARC levels may be associated with the initial presentation of DIHS as well as disease activity during the course. Thus, they could be useful as an indicator for early diagnosis and assessment of disease activity in DIHS. CD11c+ dendritic cells may be the main source of TARC in patients with DIHS.

Coexpression of CCR6 and CD146 (MCAM) is a marker of effector memory T-helper 17 cells.

Effector memory T (T(EM)) cells are a subpopulation of memory T cells that express receptors mediating migration to inflamed tissues and produce various cytokines. Effector memory T-helper (Th)17 (Th17(EM)) cells are thought to be essential for inflammation in Th17-mediated diseases, but have not been studied in detail. To identify superior surface markers to isolate a homogeneous population of Th17(EM) cells from peripheral blood, CD4(+) T cells were isolated from the peripheral blood of healthy donors based on the expression of CCR7, CCR6 and CD146 using six-color flow cytometry. After 4days of culture in the presence of anti-CD3/28 beads, intracellular cytokines were determined by flow cytometric analysis. To investigate the relevance of Th17(EM) cells in Th17-mediated disease, the frequencies of T(EM) -cell subsets in psoriasis were quantified using six-color flow cytometry. An enzyme-linked immunosorbent assay was performed to confirm the interleukin (IL)-17-producing capacity of T(EM) -cell subsets from the peripheral blood of a patient with psoriasis. CCR6(+) CD146(+) T(EM) (CD4(+) CD45RA(-) CCR7(-)) cells had a greater capacity to produce IL-17 than CCR6(+) CD146(-) or CCR6(-) CD146(+) T(EM) cells. Although the percentage of CCR6(+) CD146(+) cells in T(EM) cells was not significantly different between patients with psoriasis and controls, three of eight patients had a higher percentage of CCR6(+) CD146(+) T(EM) cells than the mean +5 standard deviations of the controls. Coexpression of CCR6 and CD146 is a useful marker for Th17(EM) cells. Increasing the number of CCR6(+) CD146(+) Th17(EM) cells in peripheral blood may facilitate estimation of systemic Th17-cell activity in Th17-mediated diseases.

Distinguishing between erythema multiforme major and Stevens-Johnson syndrome/toxic epidermal necrolysis immunopathologically.

The early clinical presentations of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are similar to that of erythema multiforme major (EMM). Cytotoxic molecules, especially granulysin, are expressed in the skin lesions of SJS/TEN and cause extensive keratinocyte death. It is postulated that the function of regulatory T cells (Treg) in SJS/TEN is inadequate. This study examined whether an immunohistological examination of cytotoxic molecules and the immunophenotype of Treg is useful for discriminating SJS from EMM in the early period. Over the past 9 years, the lesional skin of 14 patients with SJS/TEN and 16 patients with EMM was biopsied. Double immunofluorescence labeling of CD8 and granulysin, perforin, or granzyme B was performed, and immunohistochemical analyses of granulysin, perforin, granzyme B, CD1a, CD3, CD4, CD8, CD68 and Foxp3 were conducted using a highly sensitive indirect immunoperoxidase technique. The number of cells positive for each antibody per five high-power fields was counted. The proportions of granulysin(+) cells/CD8(+) cells (P = 0.012) and perforin(+) cells/CD8(+) cells (P = 0.037) in SJS/TEN were significantly higher than in EMM. The number of Foxp3(+) cells/five high-power fields in SJS/TEN was significantly lower than in EMM (P = 0.004). Similarly, the number of CD4(+) cells/five high-power fields in SJS/TEN was significantly lower than in EMM (P = 0.0017). These data suggest that these panels of antibodies for labeling cytotoxic molecules, CD4 and Treg are useful for discriminating early SJS/TEN and EMM with a skin biopsy.

Critical factors differentiating erythema multiforme majus from Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN).

Erythema multiforme majus (EMM) and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) are severe cutaneous reactions characterised by targetoid erythematous lesions and mucocutaneous involvement. The initial skin manifestations are similar, making early diagnosis difficult. We retrospectively reviewed 36 cases of EMM and 18 cases of SJS/TEN and also evaluated 6 patients with unclassified EMM. 13 patients in the EMM group and 16 patients in the SJS/TEN group presented with a high fever (>38.5̊C; p<0.001). Two or more mucous membranes were affected in 6 patients in the EMM group and 18 patients in the SJS/TEN group. Significantly more SJS/TEN than EMM patients had high levels of C-reactive protein and severe hepatic dysfunction. Thirteen EMM and 13 SJS/TEN cases were caused by medications/drugs. Skin biopsy samples showed stronger mononuclear cell infiltration in the EMM than in the SJS/TEN group (p<0.001). The mean dose of initial systemic corticosteroid used to treat EMM was lower than that used to treat SJS/TEN. No patients died in either group. Clinically, the unclassified cases mostly behaved like EMM. The results of our investigation suggest that EMM and SJS/TEN are distinct conditions and they help in differentiating these syndromes at an early stage.

A novel splicing variant of CADM2 as a protective transcript of psoriasis.

CADM2, a candidate gene for psoriasis, was identified by a genome-wide association study using microsatellites in the Japanese population (561 cases and 561 controls). Moreover, haplotype analysis included an additional 68 SNPs and indicated that a 110-kb haplotype block was detected for the protective risk haplotype of psoriasis. We also identified an initial exon of novel splicing variants in this haplotype block. A functional analysis by qRT-PCR using RNAs from the blood of 56 cases and 64 controls significantly demonstrated an inverse correlation between expression frequencies in a novel splicing variant and the number of alleles associated with psoriasis. To confirm these results, we must perform replication studies using other ethnic groups and more functional analysis particularly for skin tissues.

Sorafenib-associated hand-foot syndrome in Japanese patients.

Sorafenib (Nexavar) is an oral multi-kinase inhibitor that targets tumor growth and angiogenesis, having encouraging efficacy and tolerability in patients with metastatic renal cell carcinoma (RCC) and other tumors. However, hand-foot syndrome (HFS), a frequently reported adverse event under sorafenib treatment, sometimes causes interruption of the treatment or dose reduction. This study was conducted to review sorafenib-associated HSF in Japanese patients, to facilitate improvement of the management of HFS in clinical practice. We reviewed the combined results on HFS in three sorafenib studies in Japanese patients: (A) a phase II study of metastatic renal cell carcinoma; (B) a phase I study of solid tumor; and (C), phase I study of hepatocellular carcinoma. Severity of HFS was graded as 1-3 based on the modified grading scale of National Cancer Institute - Common Toxicity Criteria version 2.0 and Common Terminology Criteria for Adverse Events version 3.0. A total of 189 patients were included for analyses. The incidence of all-grade HFS was 51% (55% in A, 39% in B and 44% in C), and the incidence of grade 3 HFS was 7% (9% in A, 0% in B and 7% in C). Incidence of HFS seemed dose-dependent. These events were observed within 3-9 weeks after initiation of sorafenib treatment. The majority of HFS was manageable with symptomatic treatment and HFS caused permanent discontinuation of sorafenib in only one patient (in study A). The incidence of sorafenib-associated HFS is high compared to other adverse events. However, the present analyses showed that HFS under sorafenib treatment is well manageable in Japanese patients.

Metal patch test results from 1990-2009.

Although metals are common contact allergens, clinical findings of metal contact dermatitis have varied. Such patients have subsequently become rare in Japan as gold dermatitis caused by ear piercing or baboon syndrome by broken thermometers. To evaluate such clinical findings and to determine the frequency of metal allergy, we analyzed the results of patch testing with 18 metals from 1990-2009. Nine hundred and thirty-one patients (189 men and 742 women, mean age 39.0years [standard deviation±17.8]) were tested. Metals were applied on the back for 2days, and the results read with the International Contact Dermatitis Research Group (ICDRG) scoring system 3days after application. Reactions of + to +++ were regarded as positive. Differences of positive rates between men and women, and patients from 1990-1999 and those from 2000-2009 were analyzed with the χ(2) -test. Differences were considered significant at P<0.05. The metal to which the most patients reacted was 5% nickel sulfate (27.2%), irrespective of sex and phase. Significantly more women reacted to nickel sulfate (P<0.01), mercuric chloride (P<0.05) and gold chloride (P<0.01) than men. Significantly more patients in the 1990s reacted to palladium chloride, mercuric chloride and gold chloride (all P<0.01) than from 2000-2009. Nickel has been the most common metal allergen and mercury-sensitivity has decreased over 19years in Japan.

Genome-wide association study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population.

An anticonvulsant, carbamazepine (CBZ), is known to show incidences of cutaneous adverse drug reactions (cADRs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS). To identify a gene(s) susceptible to CBZ-induced cADRs, we conducted a genome-wide association study (GWAS) in 53 subjects with the CBZ-induced cADRs, including SJS, TEN and DIHS, and 882 subjects of a general population in Japan. Among the single nucleotide polymorphisms (SNPs) analyzed in the GWAS, 12 SNPs showed significant association with CBZ-induced cADRs, and rs1633021 showed the smallest P-value for association with CBZ-induced cADRs (P = 1.18 × 10⁻¹³). These SNPs were located within a 430 kb linkage disequilibrium block on chromosome 6p21.33, including the HLA-A locus. Thus, we genotyped the individual HLA-A alleles in 61 cases and 376 patients who showed no cADRs by administration of CBZ (CBZ-tolerant controls) and found that HLA-A*3101 was present in 60.7% (37/61) of the patients with CBZ-induced cADRs, but in only 12.5% (47/376) of the CBZ-tolerant controls (odds ratio = 10.8, 95% confidence interval 5.9-19.6, P = 3.64 × 10⁻¹5), implying that this allele has the 60.7% sensitivity and 87.5% specificity when we apply HLA-A*3101 as a risk predictor for CBZ-induced cADRs. Although DIHS is clinically distinguished from SJS and TEN, our data presented here have indicated that they share a common genetic factor as well as a common pathophysiological mechanism. Our findings should provide useful information for making a decision of individualized medication of anticonvulsants.