Emi Nishida

The Majority of Generalized Pustular Psoriasis without Psoriasis Vulgaris Is Caused by Deficiency of Interleukin-36 Receptor Antagonist

Generalized pustular psoriasis (GPP) is a rare inflammatory skin disease that can be life-threatening. Recently, it has been reported that familial GPP is caused by homozygous or compound heterozygous mutations of IL36RN. However, the majority of GPP cases are sporadic and it is controversial whether IL36RN mutations are a causative/predisposing factor for sporadic GPP. We searched for IL36RN mutations in two groups of GPP patients in the Japanese population in this study: GPP without psoriasis vulgaris (PV), and GPP with PV. Eleven cases of GPP without PV (GPP alone) and 20 cases of GPP accompanied by PV (GPP with PV) were analyzed. Surprisingly, 9 out of 11 cases of GPP alone had homozygous or compound heterozygous mutations in IL36RN. In contrast, only 2 of 20 cases of GPP with PV had compound heterozygous mutations in IL36RN. The two cases of GPP with PV who had compound heterozygous mutations in IL36RN are siblings, and both cases had PV-susceptible HLA-A*0206. We determined that GPP alone is a distinct subtype of GPP and is etiologically distinguished from GPP with PV, and that the majority of GPP alone is caused by deficiency of the interleukin-36 receptor antagonist due to IL36RN mutations.

Photo(chemo)therapy Reduces Circulating Th17 Cells and Restores Circulating Regulatory T Cells in Psoriasis

Background Photo(chemo)therapy is widely used to treat psoriasis, the pathogenesis of which might be caused by an imbalance of Th17 cells/regulatory T cells (Treg). In the present study, we evaluated the effects of photo(chemo)therapy on the Th17/Treg balance and Treg function. Methods Peripheral blood was obtained from psoriasis patients treated with bath-psoralen ultraviolet A (UVA, n = 50) or narrowband ultraviolet B (UVB, n = 18), and age-matched healthy volunteers (n = 20). CD3+CD4+IL-17A+ or CD4+CD25+Foxp3+cells were analyzed to estimate Th17 or Treg number by fluorescence–activated cell sorting. Moreover, CD4+ CD25− T cells from patients treated with PUVA(n = 14) were incubated in CFSE and activated with or without CD4+ CD25+T cells, and the suppressive function of CD4+ CD25+T cells were analyzed. Results Photo(chemo)therapy significantly reduced Th17 levels from 5.66±3.15% to 2.96±2.89% in patients with increased Th17 (Th17/CD4>3.01% [mean+SD of controls]). In contrast, photo(chemo)therapy significantly increased Treg levels from 2.77±0.75 to 3.40±1.88% in patients with less than 4.07% Treg level, defined as the mean of controls. Furthermore, while Treg suppressed the CD4+CD25− T cell proliferation to a greater extent in controls (Treg Functional Ratio 94.4±4.28%) than in patients (70.3±25.1%), PUVA significantly increased Treg Functional Ratio to 88.1±6.47%. Th17 levels in severe patients (>30 PASI) were significantly higher as compared to controls. Th17 levels that were left after treatment in the patients not achieving PASI 50 (3.78±4.18%) were significantly higher than those in the patients achieving PASI 75 (1.83±1.87%). Treg levels in patients achieving PASI 90 (4.89±1.70%) were significantly higher than those in the patients not achieving PASI 90 (3.90±1.66%). Treg levels prior to treatment with Th17 high decreased group (5.16±2.20%) was significantly higher than that with Th17 high increased group (3.33±1.39%). Conclusion These findings indicate that Treg is dysfunctional in psoriasis patients, and photochemotherapy restores those dysfunctional Treg. Photo(chemo)therapy resolved the Th17/Treg imbalance in patients with psoriasis.

Role of the aryl hydrocarbon receptor in tobacco smoke extract–induced matrix metalloproteinase‐1 expression

Findings from large epidemiologic studies indicate that there is a link between smoking and extrinsic skin ageing. We previously reported that matrix metalloproteinases (MMPs) mediate connective tissue damage in skin exposed to tobacco smoke extracts. Tobacco smoke contains more than 3800 constituents, including numerous water‐insoluble polycyclic aromatic hydrocarbons (PAHs) that trigger aryl hydrocarbon receptor (AhR) signalling pathways. To analyse the molecular mechanisms involved in tobacco smoke–induced skin ageing, we exposed primary human fibroblasts and keratinocytes to tobacco smoke extracts. Hexane‐ and water‐soluble tobacco smoke extracts significantly induced MMP‐1 mRNA in both human cultured fibroblasts and keratinocytes in a dose‐dependent manner. To clarify the involvement of the AhR pathway, we used a stable AhR‐knockdown HaCaT cell line. AhR knockdown abolished the increased transcription of the AhR‐dependent genes CYP1A1/CYP1B1 and MMP‐1 induced by either of the tobacco smoke extracts. Furthermore, the tobacco smoke extracts induced 7‐ethoxyresorufin‐O‐deethylase activity, which was almost completely abolished by AhR knockdown. Likewise, treating fibroblasts with AhR pathway inhibitors, that is, the flavonoids 3‐methoxy‐4‐nitroflavone and α‐naphthoflavone, blocked the expression of CYP1B1 and MMP‐1. These findings suggest that the tobacco smoke extracts induce MMP‐1 expression in human fibroblasts and keratinocytes via activation of the AhR pathway. Thus, the AhR pathway may be pathogenetically involved in extrinsic skin ageing.

Phototherapy reduces serum resistin levels in psoriasis patients

This study investigated phototherapy‐induced changes in certain adipokine levels in patients with psoriasis. Patients with psoriasis (n=36) were recruited and body mass index (BMI) and disease severity (Psoriasis Area and Severity Index) were recorded. Serum resistin and leptin levels before and after bath‐psoralen and ultraviolet (UV) A or narrow‐band UVB therapy were examined by enzyme‐linked immunosorbent assay. Serum leptin levels correlated positively with BMI. Phototherapy induced no remarkable change in the leptin levels, but significantly decreased serum resistin levels from 9.02±8.83 to 4.86±3.30 ng/ml. Serum resistin levels might be involved in insulin resistance and inflammation, and correlate with disease severity in patients with psoriasis. The reduction in serum resistin induced by phototherapy might be related to the clinical efficacy of this treatment for psoriasis.

A new targeted blue light phototherapy for the treatment of acne

Background: The effects of blue light phototherapy on inflammatory acne lesions were recently investigated. Many reports have used high‐intensity, narrow‐band 420 nm UV‐free blue light delivery systems. The aim of this study was to evaluate a new blue light system (MultiClear™) for targeted blue light phototherapy.

Efficacy of excimer light therapy (308 nm) for palmoplantar pustulosis with the induction of circulating regulatory T cells

Abstract:  In this open‐label study, we investigated the efficacy of excimer light (308 nm) with a filter to cut off wavelengths below 297 nm for the treatment of palmoplantar pustulosis (PPP). Twenty patients with PPP were recruited and treated once a week for a total of 30 sessions. Patient response was assessed every 10 sessions based on the Palmoplantar Pustulosis Area and Severity Index (PPPASI) score. Levels of Th17 cells and regulatory T cells (Treg) in the peripheral blood in patients with PPP were also evaluated. Mean PPPASI score was 19.5 at baseline, 13.2 at 10 treatments, 10.9 at 20 treatments and 9.5 at 30 treatments. Th17 levels after excimer therapy were not significantly different from those at baseline. In contrast, Treg levels after excimer therapy were significantly higher than those at baseline.

Feasibility and accuracy of a newly developed hand-held device with a flat-type fluorescent lamp for measuring the minimal erythema dose for narrow-band UVB therapy

Background: Narrow‐band ultraviolet B (NB‐UVB) for the treatment of refractory skin diseases, such as psoriasis and atopic dermatitis, requires an adequate irradiation protocol based on the minimal erythema dose (MED) to establish an optimal dosage schedule. Although MED can be measured using a systemic‐type irradiation unit, there are difficulties associated with this device. There is no standardized device available to determine the MED for NB‐UVB. Here, we compared a conventional device with a newly developed device for measuring MED.

Successful treatment of psoriasis vulgaris with targeted narrow-band ultraviolet B therapy using a new flat-type fluorescent lamp

Narrow‐band ultraviolet B (NB‐UVB) therapy is widely used for refractory skin diseases. Targeted phototherapy is now being used to reduce the number of sessions and to avoid exposing normal skin. We developed a targeted NB‐UVB therapy using a flat‐type lamp emitting a wavelength similar to that of the TL‐01 fluorescent lamp. Six Japanese patients with psoriasis were recruited and treated with the flat‐type NB‐UVB device with an initial dose of 70% of the minimal erythema dose, with a 20% increase at each subsequent session. The plaque severity score was determined. All lesions of the tested patients were responsive to NB‐UVB therapy using the flat‐type lamp. The mean percent reduction of the lesion was 58.3 ± 17.7%. The mean cumulative dose was 20.8 ± 10.8 J/cm2. No side effects were observed during treatment. The flat‐type targeted NB‐UVB device is compact and convenient, and highly effective for the treatment of limited psoriasis lesions.

Clinical effect of low-energy double-pass 1450 nm laser treatment for acne in Asians

Background: While the 1450 nm diode laser is highly effective for the treatment of acne, its use is associated with considerable pain. Low‐energy, double‐pass irradiation was attempted as an alternative to prevent the occurrence of pain as an adverse effect.

Bath-PUVA therapy improves impaired resting regulatory T cells and increases activated regulatory T cells in psoriasis

BACKGROUND Bath-psoralen plus ultraviolet light A (PUVA) therapy is an effective, safe, and inexpensive treatment for psoriasis. Psoriasis might be due to an unbalanced ratio of Th17 cells and regulatory T cells (Treg). The Treg functional ratio is significantly lower in patients with psoriasis compared with controls and is inversely correlated with the Psoriasis Area and Severity Index score. We previously reported that bath-PUVA therapy significantly increases the number of Treg and restores Treg function to almost normal in most patients with psoriasis. OBJECTIVES We examined the effects of bath-PUVA therapy on three distinct Foxp3+ subsets: activated Treg (aTreg), resting Treg (rTreg), and cytokine-secreting non-suppressive T cells. METHODS We enrolled 15 patients with psoriasis and 11 healthy controls. We examined aTreg, rTreg, and cytokine-secreting non-suppressive T cells in peripheral blood obtained from the psoriasis patients before and after every fifth bath-PUVA therapy session. RESULTS Levels of aTreg, which are considered to have the strongest suppressive activity in patients with psoriasis, were significantly increased in the early bath-PUVA therapy sessions, and then diminished. Levels of rTreg were lower in psoriasis patients than in healthy controls, and increased during bath-PUVA therapy. CONCLUSIONS Bath-PUVA therapy induced aTreg and rTreg concomitantly with an improvement in the psoriatic lesions, suggesting a mechanism for the effectiveness of bath-PUVA therapy for psoriasis patients.