Setsuko Matsukura

Periostin levels correlate with disease severity and chronicity in patients with atopic dermatitis

Recent findings indicate that periostin, an extracellular matrix protein induced by T helper 2 cytokines, plays a critical role in the pathogenesis of atopic dermatitis (AD).

Two cases of wheat-dependent anaphylaxis induced by aspirin administration but not by exercise.

Background.  Aspirin and other nonsteroidal anti‐inflammatory drugs (NSAIDs) have been reported to enhance the symptoms of wheat‐dependent exercise‐induced anaphylaxis (WDEIA). In contrast to many reports on WDEIA, there have been only a few reports of wheat‐dependent aspirin‐induced anaphylaxis not induced by the combination of wheat and exercise.

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.

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-β (p = 0.03). Ratios of change for serum TGF-β 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.

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.

Effects of TNCB sensitization in DS-Nh mice, serving as a model of atopic dermatitis, in comparison with NC/Nga mice.

Background: It has been predicted that a type-1 and type-2 helper T cell (Th1/Th2) imbalance exists in atopic dermatitis (AD). In DS-Nh mice, an AD mouse model, Staphylococcus aureus increases on the skin surface. Objective: To investigate whether the Th1-dominant response has an influence on the development of AD, we induced chronic allergic hypersensitivity with 2,4,6-trinitrochlorobenzene (TNCB ) in two AD mouse models: NC/Nga mice and DS-Nh mice. Th1 and Th2 cytokine production of splenocytes was assessed under stimulation with staphylococcal enterotoxin B (SEB) which induces a Th1 response in DS-Nh mice with or without TNCB sensitization. Methods: We examined clinical skin changes, transepidermal water loss (TEWL), the number of S. aureus on the skin and the serum IgE levels in these mice treated repeatedly with TNCB under conventional conditions (free of fur mites). The splenocytes of DS-Nh mice were cultured with SEB and the cytokine levels in the supernatants were measured by enzyme-linked immunosorbent assay (ELISA). Results: Significant skin changes were observed on the skin even where TNCB was not applied in both mice treated with TNCB. Increases in S. aureus on the skin and serum IgE levels were detected in DS-Nh mice, but not in NC/Nga mice. In DS-Nh mice, IFN-γ and IL-13 production of splenocytes increased in the mice treated with TNCB. Conclusion: These results suggest that there might be a different mechanism of dermatitis induction between NC/Nga and DS-Nh mice. Th1 responses might play an important role in the development of dermatitis and increase in serum IgE levels in DS-Nh mice through an increase in IL-13 production.

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.

Evaluation of serum cytokine levels in toxic epidermal necrolysis and Stevens-Johnson syndrome compared with other delayed-type adverse drug reactions.

Dear Editor, Toxic epidermal necrolysis (TEN) and Stevens–Johnson syndrome (SJS) are life-threatening disorders characterized by destruction of the epidermis and mucosal epithelium. They are mainly observed as consequences of adverse drug reactions (ADR) and are considered variants of the same disorder differentiated by the extent of the body surface area involved. It has been suggested that several pathways are implicated in the widespread apoptosis of keratinocytes in SJS ⁄TEN. Involvement of cytotoxic T cells and the molecular cytotoxicity of Fas and cytotoxic enzymes including granzyme B, perforine and granulysin have been shown in SJS ⁄TEN. Cytokines including tumor necrosis factor (TNF)-a and interferon (IFN)-c were found to be overexpressed in the lesional skin. It has also been shown that IFN-c can activate production of TNF-a by keratinocytes in the skin. Plasma exchange has been reported as a useful method of TEN treatment. In TEN patients, plasma exchange can effectively remove from patients’ serum not only drugs and drug metabolites, but also increased amounts of soluble Fas ligand and cytokines. However, in patients with SJS ⁄TEN, production of these cytokines were shown mainly in the skin lesions and blister fluids and only a few reports have shown an increase of these cytokines in the patient serum. In addition, there are few reports published about cytokine production other than IFN-c and TNF-a in SJS ⁄TEN patients. The aim of the present study was to evaluate a possible role of serum cytokines in SJS ⁄TEN by comparing their concentration levels among delayedtype ADR. Eight SJS (male : female ratio, 4:4; mean age, 52.9 years; age range, 23–74 years) and three TEN (three males; mean age, 51.0 years; age range, 4–75 years) patients were included in this study. These patients were admitted to either one of our two hospitals and treated with corticosteroid therapy with or without plasma exchange. Maximum epidermal detachment was 30–70% of body surface area in the TEN patients. All of these patients recovered. Sera were obtained from these patients at the onset (within 3 days of hospitalization) before starting treatment with high-dose systemic corticosteroids and plasma exchange. One SJS patient with systemic lupus erythematodes had been treated with daily 20 mg prednisolone for 1 year before initiating SJS treatment. In order to compare the cytokine levels among ADR types, 34 patients with other types of generalized delayed-type ADR were also included in this study. Their final diagnoses were as follows; macropapular type (MP), 15 patients (male : female ratio, 7:8; mean age, 58.4 years), erythema multiforme type (EM), 12 patients (male : female ratio, 6:6; mean age, 60.7 years), and drug-induced hypersensitivity syndrome (DIHS) or drug rash with eosinophilia and systemic symptoms (DRESS), which is another systemic life-threatening ADR that is mostly associated with reactivation of human herpesvirus 6, six patients (male : female ratio, 3:3; mean age, 48.7 years). Obtained sera were stored at )80 C until cytokine measurement. The cytokine levels were measured using the BioPlex suspension array system (Bio-Rad, San Francisco, CA, USA). Results were expressed as the mean ± standard error of the mean. Statistical analysis was performed using Mann–Whitney’s U-test, with P < 0.05 considered significant. Serum cytokine levels in normal volunteers (n = 13) were as follows: IFN-c, 54.9 ± 16.8 pg ⁄mL; TNF-a, 13.6 ± 10.0 pg ⁄mL; interleukin (IL)-10, 3.8 ± 4.4 pg ⁄mL; IL-1

Recalcitrant pemphigus herpetiformis with high titer of immunoglobulin G antibody to desmoglein 1 and positive IgG antibody to desmocollin 3, elevating thymus and activation-regulated chemokine

Pemphigus herpetiformis (PH) is a rare variant of pemphigus. The most frequent antibody in PH is anti-desmoglein 1 (Dsg1) antibody. Whereas desmocollin 1 (Dsc1) is recognized by immunoglobulin A (IgA) autoantibodies in subcorneal pustular dermatosis type IgA pemphigus, the presence of IgG anti-Dsc autoantibodies is still controversial, and antibodies to Dsc2 and Dsc3 have not been clearly identified. In order to accummulate data, we herein describe PH with IgG antibodies to Dsg1 and Dsc3. As far as we know, the only similar antibody profile in PH to have been reported is that by Kozlowska et al. Three desmocollins (Dsc1–3) and four desmogleins (Dsg1–4), transmembrane proteins of the cadherin family, form the adhesive core of desmosomes. Recently, an important role of Dsc3 in the integrity of murine epidermis was demonstrated in animals with conditional epidermal Dsc3 deficiency that suffered from severe intraepidermal blister formation comparable with the phenotype of the autoimmune bullous skin disease pemphigus vulgaris. In addition, Spindler et al. reported that the loss of heterophilic Dsg1/Dsc3 binding may contribute to pemphigus skin blistering. The present case seems to indicate the clinical importance of Dsg1/Dsc3 binding.

Effects of photocatalytic agent on DS-Nh mice, developing atopic dermatitis-like eruption with an increase of Staphylococcus aureus.

Background:Staphylococcus aureus(S. aureus) is thought to play a significant role in the exacerbation of atopic dermatitis (AD). DS-Nh mice, a non-hair-bearing mouse model of AD, spontaneously develop dermatitis under conventional conditions. A remarkable increase in S. aureus is considered to strongly relate to the induction and aggravation of this dermatitis. A topical use of anatase-type titanium dioxide (TiO2) followed by UV irradiation, acting as photocatalyst, is believed to have antibacterial activity. We investigated the bactericidal effect of TiO2 with UV irradiation on DS-Nh mice to prevent the aggravation of the dermatitis. Methods: Ten-week-old DS-Nh mice were treated with TiO2 in petrolatum on the back, followed by UVA irradiation, for 11 weeks. The severity of dermatitis was assessed by evaluating individual lesions using a 4-grade scale and expressed as the total skin score. S. aureus colonizing the mouse skin was counted after isolation and incubation with agar medium. The skin barrier dysfunction was evaluated by measuring transepidermal water loss (TEWL). Results:The mice treated with TiO2 and UV irradiation showed a significant increase in total skin scores, the number of S. aureus and TEWL values, compared with non-treated mice. In contrast, these parameters were significantly lower in the mice treated with petrolatum and UV irradiation. Conclusions: A significant increase in S. aureus was recognized on the skin together with the aggravation of AD-like dermatitis in our mice model. Skin barrier dysfunction induced by TiO2 and UV irradiation seems to facilitate the increase in S. aureus.