Patch testing with the Japanese baseline series 2015: A 4-year experience.

BACKGROUND: The Japanese baseline series (JBS), established in 1994, was updated in 2008 and 2015. The JBS 2015 is a modification of the thin-layer rapid-use epicutaneous (TRUE) test (SmartPractice Denmark, Hillerød, Denmark). No nationwide studies concerning the TRUE test have previously been reported. OBJECTIVES: To determine the prevalence of sensitizations to JBS 2015 allergens from 2015 to 2018. METHODS: We investigated JBS 2015 patch test results using the web-registered Skin Safety Care Information Network (SSCI-Net) from April 2015 to March 2019. RESULTS: Patch test results of 5865 patients were registered from 63 facilities. The five allergens with the highest positivity rates were gold sodium thiosulfate (GST; 25.7%), nickel sulfate (24.5%), urushiol (9.1%), p-phenylenediamine (PPD; 8.9%), and cobalt chloride (8.4%). The five allergens with the lowest positivity rates were mercaptobenzothiazole (0.8%), formaldehyde (0.9%), paraben mix (1.1%), mercapto mix (1.1%), and PPD black rubber mix (1.4%). CONCLUSIONS: Nickel sulfate and GST had the highest positivity rates. The JBS 2015, including a modified TRUE test, is suitable for baseline series patch testing.

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.

Serum levels of squamous cell carcinoma antigens 1 and 2 reflect disease severity and clinical type of atopic dermatitis in adult patients.

BACKGROUND: Recent studies have indicated that serum levels of squamous cell carcinoma antigen (SCCA) 1 and 2 induced by type 2 cytokines such as IL-4 and IL-13, are increased in patients with atopic dermatitis (AD). However, no clinical studies have analyzed serum levels of SCCA2 in larger series of AD patients or their association with various clinical characteristics. This study was performed to clarify whether serum levels of SCCA2 are associated with disease severity and clinical phenotypes of adult AD patients. METHODS: An enzyme-linked immunosorbent assay was performed to examine serum SCCA2 levels in 240 adult patients with AD and 25 healthy controls in this study. Serum SCCA2 levels were analyzed with clinical characteristics and laboratory parameters including thymus and activation-regulated chemokine (TARC), lactate dehydrogenase (LDH), blood eosinophils, total IgE, and specific IgE (Japanese cedar pollen, Dermatophagoides farina, Candida, malassezia, Staphylococcal enterotoxin B). Expression of SCCA2 in AD eruption was examined by immunohistochemistry. The effect of treatment on serum SCCA2 was also assessed. RESULTS: Serum SCCA2 level showed a positive correlation with disease severity, levels of TARC, LDH, eosinophil counts, and IgE levels. Robust expression of SCCA2 was detected in the supra basal keratinocytes in the epidermis of AD patients. Serial measurements of serum SCCA2 revealed decreased levels of SCCA2 after treatment for AD. CONCLUSIONS: Serum SCCA2 levels reflected disease severity and clinical type of AD. Serum SCCA2 may thus be a relevant biomarker for AD.

A randomized double-blind trial of intravenous immunoglobulin for bullous pemphigoid.

BACKGROUND: Patients with steroid-resistant bullous pemphigoid (BP) require an appropriate treatment option. OBJECTIVE: A multicenter, randomized, placebo-controlled, double-blind trial was conducted to investigate the therapeutic effect of high-dose intravenous immunoglobulin (IVIG; 400mg/kg/day for 5days) in BP patients who showed no symptomatic improvement with prednisolone (≥0.4mg/kg/day) administered. METHODS: We evaluated the efficacy using the disease activity score on day15 (DAS15) as a primary endpoint, and changes in the DAS over time, the anti-BP180 antibody titer, and safety for a period of 57days as secondary endpoints. RESULTS: We enrolled 56 patients in this study. The DAS15 was 12.5 points lower in the IVIG group than in the placebo group (p=0.089). The mean DAS of the IVIG group was constantly lower than that of the placebo group throughout the course of observation, and a post hoc analysis of covariance revealed a significant difference (p=0.041). Furthermore, when analyzed only in severe cases (DAS≥40), the DAS15 differed significantly (p=0.046). The anti-BP180 antibody titers showed no difference between the two groups. CONCLUSION: IVIG provides a beneficial therapeutic outcome for patients with BP who are resistant to steroid therapy.

Retrospective analysis of Stevens-Johnson syndrome and toxic epidermal necrolysis in 87 Japanese patients--Treatment and outcome.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe adverse drug reactions with high mortality. METHODS: To present the clinical characteristics of SJS and TEN in Japan and evaluate the efficacy of treatments, we retrospectively analyzed cases of SJS and TEN treated in 2 university hospitals during 2000-2013. RESULTS: Fifty-two cases of SJS (21 males and 31 females; average age, 55.1 years) and 35 cases of TEN (17 males and 18 females; average age, 56.6 years) were included in this study. Twenty-eight cases of SJS (53.8%) and all cases of TEN were caused by drugs. Hepatitis was the most common organ involvement in both SJS and TEN. Renal dysfunction, intestinal disorder, and respiratory disorder were also involved in some cases. The major complication was pneumonia and sepsis. All cases except for 3 cases were treated systemically with corticosteroids. Steroid pulse therapy was performed in 88.6% of TEN. Plasmapheresis and/or immunoglobulin therapy was combined with steroid therapy mainly in TEN after 2007. The mortality rate was 6.9% and the rates for SJS and TEN were 1.9% and 14.3%, respectively. These were much lower than predicted mortality according to a severity-of-illness scoring system for TEN prognosis (SCORTEN) score. When comparing the mortality rate between 2000-2006 and 2007-2013, it was decreased from 4.5% to 0.0% in SJS and from 22.2% to 5.3% in TEN. CONCLUSIONS: Treatment with steroid pulse therapy in combination with plasmapheresis and/or immunoglobulin therapy seems to have contributed to prognostic improvement in SJS/TEN.

Development of a simple genotyping method for the HLA-A*31:01-tagging SNP in Japanese.

AIM: To construct a simple, low-cost typing method for the surrogate marker of HLA-A*31:01, a risk factor for carbamazepine (CBZ) related Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). MATERIALS & METHODS: DNAs from Japanese SJS/TEN patients were used for genotyping and developing the assay. RESULTS: HLA-A*31:01 was confirmed to be significantly associated with definite/probable cases of CBZ-related SJS/TEN (p = 0.0040). Three single nucleotide polymorphisms, rs1150738, rs3869066 and rs259945, were in absolute linkage disequilibrium with HLA-A*31:01 in 210 Japanese SJS/TEN patients. Robust genotyping of rs3869066 in ZNRD1-AS1 was developed using polymerase chain reaction-restriction fragment length polymorphism assays. CONCLUSION: Single nucleotide polymorphism genotyping is less time consuming and cheaper than conventional HLA typing, and would be useful for identifying Japanese patients at risk of CBZ-related SJS/TEN.

Efficacy of additional i.v. immunoglobulin to steroid therapy in Stevens-Johnson syndrome and toxic epidermal necrolysis.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and life-threatening cutaneous adverse drug reactions. While there is no established therapy for SJS/TEN, systemic corticosteroids, plasma exchange and i.v. immunoglobulin (IVIG) have been used as treatment. The efficacy of IVIG is still controversial because total doses of IVIG used vary greatly from one study to another. The aim of this study was to evaluate the efficacy of IVIG, administrated for 5 days consecutively, in an open-label, multicenter, single-arm study in patients with SJS or TEN. IVIG (400 mg/kg per day) administrated for 5 days consecutively was performed as an additional therapy to systemic steroids in adult patients with SJS or TEN. Efficacy on day 7 of IVIG was evaluated. Parameters to assess clinical outcome were enanthema including ophthalmic and oral lesions, cutaneous lesions and general condition. These parameters were scored and recorded before and after IVIG. We enrolled five patients with SJS and three patients with TEN who did not respond sufficiently to systemic steroids before IVIG administration. All of the patients survived and the efficacy on day 7 of the IVIG was 87.5% (7/8 patients). Prompt amelioration was observed in skin lesions and enanthema in the patients in whom IVIG therapy was effective. Serious side-effects from the use of IVIG were not observed. IVIG (400 mg/kg per day) administrated for 5 days consecutively seems to be effective in patients with SJS or TEN. IVIG administrated together with steroids should be considered as a treatment modality for patients with refractory SJS/TEN. Further studies are needed to define the therapeutic efficacy of IVIG.

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.

Paraneoplastic pemphigus associated with fatal bronchiolitis obliterans and appearance of anti-BP180 antibodies in the late stage of the disease.

Paraneoplastic pemphigus (PNP) is an autoimmune bullous disease, which associates mainly with lymphoproliferative neoplasms. Bronchiolitis obliterans (BO) with progressive respiratory failure is a significant cause of death in PNP. We report a case of PNP associated with follicular lymphoma and BO, which showed findings suggesting coexistence of bullous pemphigoid (BP). The patient showed bullous and ulcerative lesions on the lips and oral cavity, and flaccid blisters on the trunk and thighs associated with anti-desmoglein (Dsg)3 antibodies. At later disease stage after commencement of treatment, anti-BP180 antibodies and tense blister formation were observed. It was proposed that persistent interface dermatitis is the first event in PNP, and subsequently induce the production of autoantibodies to Dsg and components of the basement membrane zone, resulting in both intraepidermal and subepidermal blisters. We speculate that interface dermatitis caused by autoreactive T cells induced autoantibody production against Dsg3, and subsequently against BP180.

Effects of oral administration of Lactobacillus acidophilus L-92 on the symptoms and serum cytokines of atopic dermatitis in Japanese adults: a double-blind, randomized, clinical trial.

OBJECTIVES: Several studies on lactobacilli have demonstrated they are effective against atopic dermatitis (AD) in children, but there are very few reports of their effects in adults. We investigated the changes in AD symptoms in adults after the ingestion of the Lactobacillus acidophilus strain L-92 (L-92), which has been shown to have a curative effect on AD in children. METHODS: A double-blind, parallel-group, placebo-controlled comparison was performed on 49 AD patients aged ≥16 years using heat-killed L-92. Skin lesions were assessed using the SCORing AD (SCORAD) index before the start of L-92 ingestion and 4 and 8 weeks after ingestion. Serum cytokine and blood marker levels were measured 8 weeks after the start of L-92 ingestion. RESULTS: The group that ingested L-92 had lower SCORAD scores than the controls (p = 0.002). The L-92 group also had decreased ratios of change for eosinophil count (p = 0.03) and increased ratios of change for serum TGF-ß (p = 0.03). Ratios of change for serum TGF-ß rose significantly (p = 0.04) in patients showing mitigated symptoms with L-92 administration. CONCLUSIONS: Administration of heat-killed L-92 was effective for AD symptoms in adults. L-92 may contribute to the suppression of Th2-dominant inflammation. Our preliminary trial is the first to report the effects of L-92 on adult AD.

Morbihan disease and extrafacial lupus miliaris disseminatus faceie: a case report.

Lupus miliaris disseminatus faciei (LMDF) is characterized by discrete dome-shaped papules on the bilateral face and neck. We report the first case of LMDF with a widespread distribution of extrafacial papules and concomitant bilateral eyelid edema. A unique case of a 30-year-old man presented with nonpruritic, painless, papular eruptions (3-5 mm in diameter) involving the bilateral trunk and upper extremities, along with bilateral eyelid edema. There was no facial eruption involved. The outbreak initially involved the back, and gradually spread to the chest and wrists. The histologic examination of the eyelids revealed histiocytic epitheloid cells, dermal intercellular edema, and an expanded vascular space, which led to the diagnosis of Morbihan disease. The immunohistochemical staining of the truncal eruption revealed nodular inflammatory changes involving the middle to lower dermis around the follicles, containing histiocytes, multinucleated giant cells, and small lymphocytes. This led to the diagnosis of LMDF. The truncal papular eruption ultimately improved with roxithromycin treatment, but the eyelid edema required surgical treatment.

Effect of a single-cycle alternative dosing regimen for rituximab for recalcitrant pemphigus: a case series of 9 patients.

BACKGROUND: There is increasing evidence that a single cycle of rituximab (375 mg per square meter [corrected] of body surface area once weekly for 4 weeks) is efficacious in patients with severe pemphigus. The approved protocol in rheumatoid arthritis is 1 g on days 1 and 15. We report herein on the efficacy and safety of this latter protocol for rituximab in 9 patients with pemphigus. OBSERVATIONS: Nine patients with recalcitrant pemphigus were treated with prednisone, immunosuppressive agents, and/or intravenous immunoglobulin. Rituximab, 1 g, was infused on days 1 and 15. Each patient was observed for a minimum of 6 months. Reepithelialization of at least 50% of the affected areas occurred in all patients within 16 weeks. Three of 6 patients (50%) discontinued intravenous immunoglobulin therapy. A significant decrease in the pemphigus severity score and the mean dosage of prednisone was observed at 3 and 6 months. Relapses were observed in 4 patients between 5 and 13 months after rituximab treatment; these patients completed a second cycle of rituximab. There were no serious adverse effects observed during the follow-up period. CONCLUSIONS: A single cycle of rituximab, 1 g on days 1 and 15, is an effective treatment for pemphigus. Further studies are needed to determine the efficacy and safety of repeated treatment courses in patients who experience recurrences.

[Analysis of treatments and deceased cases of severe adverse drug reactions--analysis of 46 cases of Stevens-Johnson syndrome and toxic epidermal necrolysis].

BACKGROUND: Systemic administration of corticosteroid, plasmapheresis and high-dose immunoglobulin therapy (IVIG) are the main treatment of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). OBJECTIVE: To evaluate the effects of the treatments of SJS and TEN. METHODS: Twenty-seven cases of SJS and 19 cases of TEN treated in our hospitals from 2000 to 2007 were analyzed. RESULTS: Corticosteroid was administered systemically in all cases except one case of TEN which developed methicillin resistant staphylococcus aureus (MRSA) pneumoniae before the onset of the eruption. Methylprednisolone (mPSL) pulse therapy (1000 mg/day) or mini pulse therapy (less than 600 mg/day of mPSL) was selected by 8 cases of SJS and 9 cases of TEN. Combination of plasmapheresis or IVIG with corticosteroid therapy was performed in 3 cases of SJS and 8 cases of TEN. The mortality rate of patient with SJS was 3.7% (1 case), and with TEN was 21.1% (4 cases). The deceased case of SJS had been treated with corticosteroid alone and died for acute respiratory disorder after 24 days from the onset of the eruption. Four deceased cases of TEN were treated with corticosteroids with or without IVIG, and 2 of them merged sepsis. CONCLUSIONS: Although corticosteroids may enhance the risk of sepsis, prompt treatment with systemic corticosteroids seems to reduces morbidity and improves outcome of SJS and TEN patients.

Late-onset anaphylaxis after ingestion of Bacillus Subtilis-fermented soybeans (Natto): clinical review of 7 patients.

BACKGROUND: Allergic reactions after ingestion of fermented soybeans have rarely been reported. Fermented soybeans were recently reported to be a causative food of IgE-mediated, late-onset anaphylaxis without early phase responses. The objectives of our study are to clarify the clinical and laboratory features and to characterize the allergens in allergy due to fermented soybeans. METHODS: Seven patients with suspected hypersensitivity to fermented soybeans, from whom informed consent had been obtained, underwent skin prick-prick tests with fermented soybeans and challenge test with fermented soybeans. Additionally, specific IgE against fermented soybeans and the allergens of fermented soybeans were detected by ELISA and IgE-immunoblotting, respectively. RESULTS: Seven male patients, aged 26 to 42 years (mean age, 33.1 years), participated. All patients reported generalized urticaria and dyspnea; 5, loss of consciousness; 2, collapse; 2, vomiting; and 2, diarrhea after fermented soybean ingestion. The interval between fermented soybean ingestion and onset of symptoms was 5 to 14 hours (mean, 9.6 hours). All patients were positive on skin prick-prick tests with fermented soybeans. In 2 patients, oral challenge with fermented soybeans was positive 5.5 and 13 hours after ingestion. In ELISA, all 5 patients tested showed elevated IgE levels to the fermented soybean extract. Furthermore, IgE-immunoblotting using 5 patients' sera showed six bands, of which three bands at 38, 28, and 26-kd were bound to sera from 4 patients. CONCLUSIONS: Cases with hypersensitivity after ingestion of fermented soybeans most frequently correspond to IgE-mediated, late-onset anaphylactic reactions due to fermented soybeans.