T helper 2 polarization in senile erythroderma with elevated levels of TARC and IgE.

BACKGROUND: Some cases of senile erythroderma tend to be diagnosed as senile atopic dermatitis (AD) based on elevated levels of immunoglobulin E (IgE) and thymus and activation-regulated chemokine (TARC). However, there are few studies that describe the detailed characteristics of senile erythroderma and senile AD. OBJECTIVE: We examined the association of erythroderma with AD. METHODS: In this retrospective observational study, 68 patients over 65 years of age who presented with erythroderma at Osaka University Hospital were enrolled. Patient data were collected through medical records and descriptive statistics. RESULTS: 47% of the patients were classified as having idiopathic erythroderma and 53% as having secondary erythroderma. In both idiopathic and secondary senile erythroderma patients, serum IgE and TARC levels were elevated. 84% of idiopathic erythroderma patients fulfilled the Japanese Dermatological Associations criteria for AD; however, only 4 patients were finally definitely diagnosed with senile AD. CONCLUSION: Many senile erythroderma patients showed AD-like symptoms due to T helper 2 polarization.

Psoriatic inflammation facilitates the onset of arthritis in a mouse model.

Psoriatic arthritis (PsA) is a seronegative, inflammatory joint disease associated with psoriasis. In most patients with PsA, skin lesions precede arthritis; however, the causality of skin inflammation for the development of arthritis remains unclear. Gp130F759/F759 knock-in (F759) mice develop autoimmune arthritis after 1 year of age through persistent signal transducer and activator of transcription 3 (Stat3) activation due to impairment in SOCS3-dependent negative regulation. Here, we crossed F759 mice with K5.Stat3C transgenic mice, in which keratinocytes express constitutive active Stat3 (Stat3C), leading to generation of psoriasis-like skin change. F759 mice harboring the K5.Stat3C transgene not only had aggravated skin lesions but also spontaneously developed arthritis with high penetrance in adjacent paws as early as 3 weeks of age. The joint lesions included swelling of the peripheral paws and nail deformities contiguous with the skin lesions, closely resembling PsA. Histopathologic study revealed enthesitis and bone erosions, with mononuclear cell infiltrates. Quantitative reverse transcriptase-PCR (RT-PCR), immunohistochemical analyses, and flow cytometry showed upregulation of the IL-23/T helper type 17 (Th17) pathway in affected joints. Furthermore, enforced generation of psoriasis-like skin inflammation by topical treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) in F759 mice induced swelling of the underlying joints. This animal model renders psoriatic inflammation as the driver of arthritis and helps to further understand the pathogenesis of PsA.

Immunohistochemical Analysis of Interleukin-17 Producing T Helper Cells and Regulatory T Cells Infiltration in Annular Erythema Associated with Sjögren's Syndrome.

BACKGROUND: Peculiar erythema known as annular erythema associated with Sjögren's syndrome (AESS) can be differentiated from autoimmune annular erythema and subacute cutaneous lupus erythematosus, both clinically and histologically. However, there are no detailed investigations on immune competent cells infiltration. OBJECTIVE: Preferential infiltration of interleukin-17-producing T helper (Th17) cells and regulatory T (Treg) cells into the labial salivary gland is reported to play a role in maintaining mucoepithelitis in patients with Sjögren's syndrome. In this study, we evaluated Th17 and Treg cell infiltration into the lesional skin of AESS. METHODS: We analyzed the numbers and infiltration patterns of Th17 and FoxP3 (+) Treg cells in seven cases of AESS using immunohistochemistry. Seven patients with systemic lupus erythematosus (SLE), atopic dermatitis (AD) and psoriasis vulgaris (PV), which are representatives of Th17 cell-involved skin disorders, were enrolled as disease controls. RESULTS: Periappendageal and epidermal changes, such as follicular plugging and liquefaction, were evident in the annular erythema of SLE, not AESS, tissue samples. In AESS tissue samples, dense perivascular and periappendageal infiltration of lymph cells was observed in the middle-to-deep dermis, as previously described, in contrast to the superficial infiltration pattern observed in both AD and PV samples. While the total number of infiltrated lymphocytes was similar between AESS and SLE tissue samples, Th17 cells were found to be preferentially infiltrated in the middle-to-deep dermis in AESS samples. CONCLUSION: These results suggest that an increased number and distribution of infiltration of Th17 cells is a preferential feature of AESS, rather than a characteristic feature of annular erythema of SLE.

A rare case of male bullous lupus erythematosus complicated with subsequent annular hypopigmentation.

A 57-year-old male had been suffering from an itchy map-shaped symmetrical erosive erythema with a crust that was attached to his upper arm and buttock, and occasionally he suffered from spiking fever. Laboratory examinations showed neither anti-desmoglein 1/3 antibodies nor anti-BP 180 antibodies, and he fulfilled the criteria for a diagnosis of systemic lupus erythematosus (SLE). Histologically, there was eosinophilic necrosis of keratinocytes, liquefaction and degradation with severe lymphocyte infiltration into the epidermis and subepidermal blister formation, suggestive of a variant of SLE, bullous lupus erythematosus (BLE). One month after remission of BLE, peculiar annular hypopigmentation appeared on the peripheral borders. An immunohistochemical analysis showed a decrease in Melan A-positive melanocytes and concomitant pigment incontinentia, with dense infiltration of CD8(+) T cells and IL-17A(+) Th17 cells. An ultrastructural analysis revealed a decrease, but not a complete disappearance, of both melanocytes and melanosomes, and no impairment in melanosomal transfer. In this case report, we would like to introduce the development of annular depigmentation complicated with BLE, and discuss the effects of lupus condition on melanocyte damage based on immunohistological and electromicroscopic findings of those vitiliginous lesions.

Decreased sudomotor function is involved in the formation of atopic eczema in the cubital fossa.

BACKGROUND: Eczema in the cubital fossa, which is susceptible to sweat, is frequently observed in atopic dermatitis (AD). However, there has been no direct evidence that sweating causes eczema in the cubital fossa. METHODS: To investigate this issue, axon reflex-mediated sweating volume (AXR) and skin barrier function in the cubital fossa were measured in subjects with AD and in healthy volunteers, and were applied to clinical feature of the cubital fossa. RESULTS: AXR in the cubital fossa decreased in AD subjects; it positively correlated only with water-holding capacity in healthy subjects but not in patients with in AD. Furthermore, AD subjects with lichenoid eczema and either prurigo or papules over the cubital fossa showed extremely decreased AXR. CONCLUSIONS: These results suggest that decreased sweating is a major source of water in the stratum corneum, and decreased sudomotor function may be involved in both the cause and aggravation of representative atopic eczema in the cubital fossa.

Barrier abnormality due to ceramide deficiency leads to psoriasiform inflammation in a mouse model.

It has been recognized that ceramides are decreased in the epidermis of patients with psoriasis and atopic dermatitis. Here, we generated Sptlc2 (serine palmitoyltransferase long-chain base subunit 2)-targeted mice (SPT-cKO mice), thereby knocking out serine palmitoyltransferase (SPT), the critical enzyme for ceramide biosynthesis, in keratinocytes. SPT-cKO mice showed decreased ceramide levels in the epidermis, which impaired water-holding capacity and barrier function. From 2 weeks of age, they developed skin lesions with histological aberrations including hyperkeratosis, acanthosis, loss of the granular layer, and inflammatory cell infiltrates. Epidermal Langerhans cells showed persistent activation and enhanced migration to lymph nodes. Skin lesions showed upregulation of psoriasis-associated genes, such as IL-17A, IL-17F, IL-22, S100A8, S100A9, and ß-defensins. In the skin lesions and draining lymph nodes, there were increased numbers of γδ T cells that produced IL-17 (γδ-17 cells), most of which also produced IL-22, as do Th17 cells. Furthermore, IL-23-producing CD11c(+) cells were observed in the lesions. In vivo treatment of SPT-cKO mice with an anti-IL-12/23p40 antibody ameliorated the skin lesions and reduced the numbers of γδ-17 cells. Therefore, we conclude that a ceramide deficiency in the epidermis leads to psoriasis-like lesions in mice, probably mediated by IL-23-dependent IL-22-producing γδ-17 cells.

Prevalence and impact of past history of food allergy in atopic dermatitis.

BACKGROUND: Increases in allergic diseases have been reported from various epidemiological surveys. However, a few reports demonstrate the comorbidity of food allergy (FA) and allergic march. The aim of this study was to assess the prevalence and comorbidity of allergic diseases in Japanese students. METHODS: First-year students (n = 3,321; 2,209 male and 1,112 female) at Osaka University were asked about allergic diseases using postal interview sheets. Personal and family histories of doctor-diagnosed allergic diseases, clinical courses, and aggravating factors were included in the questionnaires. RESULTS: The lifetime prevalence of allergic rhinitis (AR), atopic dermatitis (AD), bronchial asthma (BA), and FA was 35.7%, 16.5%, 9.9%, and 7.0%, respectively. Disease-specific family histories existed for AR, AD, and BA. There was a positive correlation between the number of family histories of allergic disease and comorbidity (R = 0.370, P < 0.001). Comorbidity with AD significantly lowered the onset age of both BA (P = 0.010) and AR (P < 0.001). In addition, the onset age of AD was remarkably lowered by comorbidity with FA (P < 0.001). Comorbidity with FA was the highest risk factor for the progression of allergic march. Although most students showed improvement in AD, BA, and AR over time, the peak recurrence period was observed in adolescence. CONCLUSIONS: These findings indicate that AD associated with FA accelerates the subsequent progression of allergic march. Early appropriate management for genetically high-risk groups is important for the prevention of allergic march.

Prevalence and Impact of Past History of Food Allergy in Atopic Dermatitis.

BACKGROUND: Increases in allergic diseases have been reported from various epidemiological surveys. However, a few reports demonstrate the comorbidity of food allergy (FA) and allergic march. The aim of this study was to assess the prevalence and comorbidity of allergic diseases in Japanese students. METHODS: First-year students (n = 3,321; 2,209 male and 1,112 female) at Osaka University were asked about allergic diseases using postal interview sheets. Personal and family histories of doctor-diagnosed allergic diseases, clinical courses, and aggravating factors were included in the questionnaires. RESULTS: The lifetime prevalence of allergic rhinitis (AR), atopic dermatitis (AD), bronchial asthma (BA), and FA was 35.7%, 16.5%, 9.9%, and 7.0%, respectively. Disease-specific family histories existed for AR, AD, and BA. There was a positive correlation between the number of family histories of allergic disease and comorbidity (R = 0.370, P <0.001). Comorbidity with AD significantly lowered the onset age of both BA (P = 0.010) and AR (P <0.001). In addition, the onset age of AD was remarkably lowered by comorbidity with FA (P <0.001). Comorbidity with FA was the highest risk factor for the progression of allergic march. Although most students showed improvement in AD, BA, and AR over time, the peak recurrence period was observed in adolescence. CONCLUSIONS: These findings indicate that AD associated with FA accelerates the subsequent progression of allergic march. Early appropriate management for genetically high-risk groups is important for the prevention of allergic march.

Periostin facilitates skin sclerosis via PI3K/Akt dependent mechanism in a mouse model of scleroderma.

OBJECTIVE: Periostin, a novel matricellular protein, is recently reported to play a crucial role in tissue remodeling and is highly expressed under fibrotic conditions. This study was undertaken to assess the role of periostin in scleroderma. METHODS: Using skin from patients and healthy donors, the expression of periostin was assessed by immunohistochemistry and immunoblotting analyses. Furthermore, we investigated periostin(-/-) (PN(-/-)) and wild-type (WT) mice to elucidate the role of periostin in scleroderma. To induce murine cutaneous sclerosis, mice were subcutaneously injected with bleomycin, while untreated control groups were injected with phosphate-buffered saline. Bleomycin-induced fibrotic changes were compared in PN(-/-) and WT mice by histological analysis as well as by measurements of profibrotic cytokine and extracellular matrix protein expression levels in vivo and in vitro. To determine the downstream pathway involved in periostin signaling, receptor neutralizing antibody and signal transduction inhibitors were used in vitro. RESULTS: Elevated expression of periostin was observed in the lesional skin of patients with scleroderma compared with healthy donors. Although WT mice showed marked cutaneous sclerosis with increased expression of periostin and increased numbers of myofibroblasts after bleomycin treatment, PN(-/-) mice showed resistance to these changes. In vitro, dermal fibroblasts from PN(-/-) mice showed reduced transcript expression of alpha smooth actin and procollagen type-I alpha 1 (Col1α1) induced by transforming growth factor beta 1 (TGFß1). Furthermore, recombinant mouse periostin directly induced Col1α1 expression in vitro, and this effect was inhibited by blocking the αv integrin-mediated PI3K/Akt signaling either with anti-αv functional blocking antibody or with the PI3K/Akt kinase inhibitor LY294002. CONCLUSION: Periostin plays an essential role in the pathogenesis of Bleomycin-induced scleroderma in mice. Periostin may represent a potential therapeutic target for human scleroderma.

Abnormal axon reflex-mediated sweating correlates with high state of anxiety in atopic dermatitis.

BACKGROUND: Sweating plays a key role in skin homeostasis, including antimicrobial and moisturizing effects, and regulation of skin surface pH. Impaired axon reflex-mediated (AXR) sweating has been observed in patients with atopic dermatitis (AD). However, the mechanism of such abnormal sudomotor axon reflex remains to be revealed. METHODS: To investigate this mechanism, sudomotor function was analyzed using a quantitative sudomotor axon reflex test (acetylcholine iontophoresis) in patients with AD (n = 26) and healthy volunteers (n = 12). Correlation between sudomotor function and certain background factors, including Spielberger State Trait Anxiety Inventory score, Severity Scoring of Atopic Dermatitis (SCORAD) score, number of circulating eosinophils, and serum concentrations of thymus and activation-regulated chemokine and immunoglobulin E radioimmunosorbent test, was validated. RESULTS: Latency time was significantly prolonged in AD (p = 0.0352), and AXR sweating volume (mg/0-5 min) was significantly lower in AD patients than in healthy controls (p = 0.0441). Direct sweating volume (mg/0-5 min) was comparable in AD patients and healthy controls. A significant correlation between the evaluation results of quantitative sudomotor axon reflex tests and certain background factors was not observed. The latency time in non-lesioned and lesioned areas for AD patients versus continuous anxiety value in the Spielberger State Trait Anxiety Inventory and the AXR versus SCORAD showed significant correlations (p = 0.0424, p = 0.0169, and p = 0.0523, respectively). CONCLUSIONS: Although the number of study subjects was little, abnormal AXR sweating in patients with AD was observed. Correlative analysis suggests possible involvement of continuous anxiety and the immune system in such abnormal sudomotor function.

Blockade of interleukin-6 receptor alleviates disease in mouse model of scleroderma.

Activation of fibroblasts by interleukin-6 (IL-6) is implicated in the pathogenesis of scleroderma, suggesting that the inhibition of fibroblast activation may be a promising scleroderma treatment. In this study, we used an IL-6 blocking antibody (Ab) and Il-6 knockout (Il-6KO) mice to examine the role of IL-6 in the bleomycin (BLM)-induced mouse model of scleroderma. BLM was administered to C57BL/6 and Il-6KO mice to induce dermal sclerosis. BLM-treated and control phosphate-buffered saline-treated mice were treated with anti-mouse IL-6 receptor monoclonal Ab (MR16-1). Disease severity was evaluated by measuring dermal thickness and skin hardness, by counting the numbers of α-smooth muscle actin-positive cells and mast cells, and by examining the cutaneous draining lymph nodes. C57BL/6 mice with BLM induced scleroderma had elevated serum IL-6 levels and more severe dermal sclerosis than Il-6KO mice. Weekly administration of MR16-1, but not control Ab, prevented and improved dermal sclerosis, and also attenuated swelling of the draining lymph nodes. MR16-1 suppressed α-smooth muscle actin induction in IL-6-stimulated Il-6KO fibroblasts. Our results indicate that IL-6 contributes to BLM induced dermal sclerosis and that IL-6 receptor-specific monoclonal Ab may improve the symptoms of scleroderma by suppressing fibroblast activation.

Four cases of atopic dermatitis complicated by Sjögren's syndrome: link between dry skin and autoimmune anhidrosis.

We report four adult cases of atopic dermatitis (AD) complicated by Sjögren's syndrome (SS). The patients fulfilled diagnostic criteria for AD and SS. All cases showed persistent itchy dry skin and eczematous lesions complicated by sicca symptoms including dry eyes and dry mouth with moderate joint pain. One case manifested annular erythema and another manifested widespread discoid erythema. To investigate the underlying cause of dry skin in these cases, sweating function was evaluated using a quantitative sudomotor axon reflex test (QSART) in which the axon reflex is stimulated by acetylcholine iontophoresis. The sweating latency time was significantly prolonged in eczematous skin of AD and AD/SS compared to normal controls. Axon reflex (AXR) sweat volume was also significantly reduced in AD (normal and eczematous skin) and AD/SS (normal and eczema) compared to normal control. In contrast, the direct sweat volume of lesional or non-lesional AD skin induced by direct stimulation with acetylcholine was only slightly reduced compared to that in normal controls, but not in SS and lesional skin of AD/SS patients. These results suggest that the impaired sweat response in AD is attributable to an abnormal sudomotor axon reflex, which is accelerated and modulated when complicated by SS resulting in dry skin in the present cases.

Cedar pollen aggravates atopic dermatitis in childhood monozygotic twin patients with allergic rhino conjunctivitis.

We report a case of 7-year-old monozygotic twin patients with atopic dermatitis. The HLA haplotypes were HLA A2, A11, B27, B61, DR1, and DR4. Both serum IgE levels and cedar pollen radioallergosorbent test (RAST) scores were high in the twins (elder/younger sister: IgE: 5170/3980 IU/ml and Japansese cedar pollen: >100/64.0) in contrast to low mite and food RAST scores (Dermatophagoides Pterygonium; 0.59/0.4 and egg white 9.24/4.6). The patients showed positive immediate (20 min in both sisters) and delayed (24 hours in elder sister, 24, 48, 72 hours in younger sister) reactions to a scratch test with Japanese cedar pollen. Skin lesions on the face were aggravated and extended to the trunk and extremities during the Japanese cedar pollen season and gradually subsided in summer. Oral provocation with egg white or cow milk showed no exacerbations, and topical corticosteroid did not improve the eczema. In contrast, successful protection from severe scratching behaviors was achieved by use of topical anti-allergic eye drops and wearing nightgowns made by the mother.

A case of disseminated DLE complicated by atopic dermatitis and Sjögren's syndrome: link between hypohidrosis and skin manifestations.

We report an unusual case of disseminated discoid lupus erythematosus (DLE) complicated by pre-existing atopic dermatitis (AD) and late-onset Sjögren's syndrome (SS). Disseminated DLE lesions were sparse on the expected sites for AD, such as the medial region of the extremities or v-neck area. The patient fulfilled the diagnostic criteria for AD and SS but not for systemic lupus erythematosus. Histopathological analysis of the crusted erythematous lesions revealed typical DLE with few FoxP3(+) cells and a moderate number of IL-17(+) cells. A quantitative sweating test showed impaired sweating of both lesional and non-lesional skin due to underlying hypohidrosis that was related to AD and SS. This finding suggests that dissemination of DLE was triggered by scratching and a Köbner phenomenon-like effect related to hypohidrotic and xerotic skin. To the best of our knowledge, this is the first reported case of disseminated DLE complicated by AD and SS.

The skin of patients with systemic sclerosis softened during the treatment with anti-IL-6 receptor antibody tocilizumab.

OBJECTIVE: SSc is an autoimmune disease characterized by fibrosis of the skin and internal organs. Although the aetiology remains uncertain, many reports have suggested that IL-6 is involved in SSc pathogenesis. Tocilizumab, an anti-IL-6 receptor antibody, is an anti-arthritis medicine that works through the blockade of IL-6 functions. To examine the effect of tocilizumab on SSc, we administered tocilizumab to two SSc patients. METHODS: Two dcSSc patients were administered tocilizumab at 8 mg/kg once a month for 6 months. One patient had pulmonary fibrosis assessed by CT and spirometry, and the other had chronic renal failure caused by scleroderma renal crisis. Their skin condition was monitored with a Vesmeter and the modified Rodnan total skin score (mRTSS). Skin biopsies were obtained before and after the tocilizumab treatment to investigate the histological changes. RESULTS: After tocilizumab treatment, both patients showed softening of the skin with reductions of 50.7 and 55.7% in the total z-score of Vesmeter hardness and 51.9 and 23.0% in the mRTSS, respectively. Histological examination showed thinning of the collagen fibre bundles in the dermis. The creatinine clearance in the patient with chronic renal failure improved from 38 to 55 ml/min. However, the fibrotic changes in the lung in the other patient remained unchanged. CONCLUSIONS: In the two cases of SSc that we report here, softening of the skin was observed during the treatment with tocilizumab.

Impact of sedative and non-sedative antihistamines on the impaired productivity and quality of life in patients with pruritic skin diseases.

BACKGROUND: The impairment that pruritic skin diseases have on patient productivity at work, in the classroom, and in daily activities is substantial and needs to be characterized. The objective of this study was to determine how pruritic skin diseases impact patient productivity and quality of life (QOL), in order to improve the measurement of these endpoints to allow the influence of treatment options including sedative and non-sedative antihistamines to be analyzed. METHODS: The impact of pruritic skin diseases and the effect of antihistamine therapy on work, classroom, and daily productivity were evaluated using the Work Productivity Assessment Index-Allergy Specific Questionnaire. The intensity of itch and patient QOL were assessed using a visual analogue scale and Skindex-16, respectively. RESULTS: Pruritic skin diseases resulted in significant impairment of work, classroom, and daily productivity. The severity of overall work impairment in atopic dermatitis (AD), urticaria, and prurigo was higher than for other diseases analyzed. However, classroom activity was more adversely affected in patients with urticaria relative to other diseases. All pruritic diseases in this study negatively impacted daily activity to a similar degree. Impaired productivity was significantly improved in patients taking non-sedative antihistamines for 1 month, and the improvements correlated with the alleviation of itch and improved QOL. CONCLUSIONS: These results indicate that pruritic skin diseases reduce patient productivity at work, in the classroom, and during daily activities, and that non-sedative antihistamines may offer an advantage over sedative antihistamines for alleviating certain negative consequences of these skin diseases.