Sota Kikuchi

IL-10-producing regulatory B cells are decreased in patients with psoriasis

BACKGROUNDS Interleukin (IL)-10-producing regulatory B cells (B10 cells) have been shown to ameliorate psoriasis in mice. Human B10 progenitor cells are characterized as CD19(+)CD24(hi)CD38(hi) B cells that exert their regulatory functions via the production of IL-10. However, the role of B10 cells in the pathogenesis of psoriasis remains unclear. OBJECTIVES We examined B10 cells in patients with psoriasis and healthy controls. METHODS Peripheral blood mononuclear cells were isolated from psoriasis patients without a history of receiving any immunosuppressants during the 6-month period before enrollment in the study. Using flow cytometry, we determined the frequencies of blood B cell subsets, B10 progenitor cells, and B10 cells for 31 patients with psoriasis and 26 healthy controls. RESULTS Both psoriasis patients and healthy controls showed similar frequencies of total B cells, IgD(+)CD27(-) naïve B cells, and IgD(-)CD27(+) memory B cells. However, the frequency of CD19(+)CD24(hi)CD38(hi) B10 progenitor cells was significantly higher in patients with psoriasis than in the healthy controls. In contrast, the frequency of B10 cells in patients with psoriasis was significantly lower than that in healthy controls. Furthermore, treatment with immunosuppressants resulted in a decrease in B10 progenitor cells and an increase in B10 cells. CONCLUSION B10 progenitor cells were increased, while IL-10-producing regulatory B10 cells were decreased in patients with psoriasis, suggesting that B10 cells may be functionally impaired in patients with psoriasis.

Novel IL36RN gene mutation revealed by analysis of 8 Japanese patients with generalized pustular psoriasis

[2] Tarutani M, Itami S, Okabe M, Ikawa M, Tezuka T, Yoshikawa K, et al. Tissuespecific knockout of the mouse Pig-a gene reveals important roles for GPIanchored proteins in skin development. Proc Natl Acad Sci U S A 1997;94:7400– 5. [3] Vasioukhin V, Degenstein L, Wise B, Fuchs E. The magical touch: genome targeting in epidermal stem cells induced by tamoxifen application to mouse skin. Proc Natl Acad Sci U S A 1999;96:8551–6. [4] Sano S, Itami S, Takeda K, Tarutani M, Yamaguchi Y, Miura H, et al. Keratinocytespecific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis. EMBO J 1999;18:4657–68. [5] Tarutani M, Nakajima K, Takaishi M, Ohko K, Sano S. Epidermal hyperplasia induced by Raf-MAPK signaling requires Stat3 activation. J Dermatol Sci 2013;72:110–5. [6] Ramirez A, Page A, Gandarillas A, Zanet J, Pibre S, Vidal M, et al. A keratin K5Cre Yujin Nakagawa, Gyohei Egawaa,*, Yoshiki Miyachi, Kenji Kabashima Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan; PRESTO, Japan Science and Technology Agency, 7 Gobancho, Chiyoda-ku, Tokyo 102-0075, Japan

Synergistic effect of PDGF and FGF2 for cell proliferation and hair inductive activity in murine vibrissal dermal papilla in vitro

BACKGROUND The dermal papilla is composed of a small clump of mesenchymal cells, called dermal papilla cells (DPCs). DPCs closely interact with epidermal cells to give rise to hair follicles and shafts during hair follicle development and the hair cycle. DPCs are promising cell sources for hair regeneration therapy for alopecia patients. However, once DPCs are put into conventional two-dimensional culture conditions, they quickly lose their capability to produce hair follicles. OBJECTIVE We aimed to expand a sufficiently large population of DPCs that retain their hair inductive activity. METHODS Murine DPCs were cultured in the presence of platelet-derived growth factor-AA (PDGF-AA) and fibroblast growth factor 2 (FGF2). Expressions of follicular-related genes were analyzed by real time PCR and hair inductive activity was determined by patch assay and chamber assay in vivo. RESULTS FGF2 significantly increased the expression of platelet-derived growth factor receptor alpha (PDGFRα) in cultured vibrissal DPCs. PDGF-AA, a ligand of PDGFRα, promoted proliferation of DPCs synergistically when utilized with FGF2 and enhanced the expression of several follicular-related genes in DPCs. Hair reconstitution assays revealed that DPCs treated with both PDGF-AA and FGF-2 were able to maintain their hair inductive activity better than those treated with FGF2 alone. CONCLUSION Both cell proliferation and hair inductive activity in murine DPCs are maintained by the synergistic effect of FGF2 and PDGF-AA.

Switching of biologics in psoriasis: Reasons and results.

Efficacy and safety profiles of biologics have been established for moderate to severe psoriasis. However, inefficacy or adverse events sometimes require changing the treatment to other biologics. Here, we examine the effectiveness of this strategy. We retrospectively investigated cases requiring switching biologics. We enrolled 275 psoriatic patients treated with biologics between January 2010 and December 2014 in our hospital. Of these, 51 required a switch to another biologic. First‐line therapies were infliximab (IFX, n = 26), adalimumab (ADA, n = 18) and ustekinumab (UST, n = 7), and second‐line therapies were IFX (n = 5), ADA (n = 21) and UST (n = 25). Reasons for switching were inefficacy (n = 38), adverse events (n = 11) and others (n = 2). The details were primary failure (n = 15), secondary failure (n = 23) and infusion reactions (n = 8). In 49 patients who switched biologics due to inefficacy and adverse events, the mean Psoriasis Area and Severity Index (PASI) score at week 16 was 4.3 for first‐line therapies and 2.9 for second‐line therapies (P < 0.05). Switching to a second biologic therapy to address the firsts inefficacy or adverse events often results in significant improvement in moderate to severe psoriasis.

Interstitial pneumonia in two patients with psoriasis during ustekinumab treatment.

1 Nogita T, Aramo Y, Terajima S et al. The coexistence of psoriasis vulgaris, Sj€ ogren’s syndrome, and Hashimoto’s thyroiditis. J Dermatol 1992; 19: 302–305. 2 Kobayashi T, Naka W, Harada T, Nishikawa T. Association of the acral type of pustular psoriasis, Sj€ ogren’s syndrome, systemic lupus erythematosus, and Hashimoto’s thyroiditis. J Dermatol 1995; 22: 125–128. 3 Yamamoto T, Yokoyama A. Association of generalized pustular psoriasis, Sj€ ogren’s syndrome, and Hashimoto’s thyroiditis. J Dermatol 1996; 23: 64–65. 4 Cuesta-Montero L, Belinch on I. Connective tissue disease and psoriasis. Actas Dermosifiliogr 2011; 102: 487–497. 5 Tang X, Tian X, Zhang Y et al. Correlation between the frequency of Th17 cells and the expression of microRNA-206 in patients with dermatomyositis. Clin Dev Immunol 2013; 2013: 345–347.

Adalimumab markedly improves enthesitis in patients with psoriatic arthritis: Evaluation with a magnetic resonance imaging scoring system

Psoriatic arthritis (PsA), a seronegative arthropathy, may often result in progressive joint damage without treatment, leading to disability and impaired quality of life. Early therapeutic intervention of PsA is therefore crucial before the development of irreversible joint damage. Because psoriatic skin lesions generally precede the onset of PsA, dermatologists occupy an important position in treating patients with early PsA. This study aimed to evaluate the efficacy of adalimumab in treating joint disease in patients with PsA, using the PsA magnetic resonance imaging scoring system (PsAMRIS). Five adult Japanese male patients with active PsA were treated with adalimumab. Magnetic resonance imaging was obtained at baseline and 8–32 weeks with 2–3 time points following adalimumab treatment and assessed using PsAMRIS. Adalimumab treatment markedly improved clinical symptoms and disease activities of joint disease, which was confirmed by the reduction of PsAMRIS scores in all patients. Bone marrow edema and periarticular inflammation, reflecting the presence of enthesitis, were dramatically improved at week 8, while improvement of synovitis and flexor tenosynovitis was observed later, at week 24 or 32. However, bone erosion was not improved by adalimumab treatment during the follow‐up period. These results indicate that adalimumab treatment is associated with dramatic improvement of enthesitis in patients with PsA, whereas bone erosion may be resistant to such treatment. PsAMRIS appears to be useful for the evaluation of treatment efficacy in PsA.

Infliximab and adalimumab, unlike ustekinumab, increase serum KL‐6 levels in Japanese patients with psoriasis

thema began to improve after 4 months, and disappeared for 6 months (Fig. 1d). Morbihan disease is characterized by persistent lymphedema on the upper half of the face and regarded as a late-stage complication of rosacea. The characteristic features are chronic course, typical clinical manifestations, lack of specific laboratory and histological findings, and refractoriness to therapeutic measures. The diagnosis is made based on the combination of clinical and histopathological findings, including dilated blood vessels, perifollicular fibrosis, perivascular and perifollicular lymphatic infiltration, and, rarely, an increased number of mast cells. We diagnosed our case with Morbihan disease from the characteristic clinical presentation and histopathological findings. There is no established guideline or satisfactory treatments for Morbihan disease. Many therapeutic options, including oral corticosteroids, tetracyclines, ketotifen, tranilast and antimycobacterium drugs, which are used alone or in combination with others, have been reported. However, clinical response with these therapies has been inadequate. Although long-term use of oral isotretinoin has been recently proposed as an effective treatment, isotretinoin is not available in Japan. We previously reported a case of Morbihan disease with massive mast cell infiltration treated successfully with longterm use of minocycline (100 mg/day for 4 months), in which we hypothesized that the treatment response was associated with the degree of mast cell infiltration. Although increased mast cell infiltration is one of the histological features, it is not found in all cases. Tetracycline has been described as suppressing cytokine production of mast cells in vitro. This is the second report of Morbihan disease with mast cell infiltration successfully treated with long-term use of minocycline. Pitting edema remained in the previous case probably due to the delay of the initiation of minocycline treatment; however, the present case achieved a significant improvement without leaving pitting edema. Although further investigation is needed, the present case is compatible with our speculation that the long-term use of tetracycline is effective in cases with increased mast cell infiltration.

Ustekinumab treatment in patients with psoriasis undergoing hemodialysis

Patients with psoriasis undergoing hemodialysis have additional difficulties in treatment compared with general patients. Conventional treatments such as cyclosporin, retinoids and methotrexate are not widely administrated due to the chances of an increase in adverse effects and the possibility of risk to patient survival. Recently, biologic treatments have been recognized as having sufficient efficacy for severe psoriasis with low incidence of organ toxicities. For this reason, biologic treatments may be more preferable for patients on hemodialysis; however, there is not sufficient evidence. We have treated three patients with psoriasis with ustekinumab for 1 year, who had been undergoing hemodialysis. They were previously treated with conventional treatments before ustekinumab treatments; however, they did not respond to these treatments sufficiently. Following treatment with ustekinumab, rapid and maintained improvement in psoriasis was observed. Over the course of treatments, two of the three patients encountered no adverse events during their first year of treatment. The other patient discontinued ustekinumab due to elevated levels of C‐reactive protein. These findings suggest that ustekinumab may be an appropriate treatment for patients undergoing hemodialysis who are suffering from psoriasis. However, the risk of developing infection remains higher than in general patients.

Algorithm for Selecting Ideal Biologic Treatment for Psoriasis

Biologics are the standard treatment for moderate-to-severe psoriasis due to their efficacy and safety. However, the selection of appropriate biologics is complicated by patient characteristics, treatment regimen, and cost. We constructed an algorithm to select biologics based on psoriasis type (psoriasis vulgaris or psoriasis arthritis), Psoriasis Area and Severity Index (PASI) score (≥ 20 or <20) and body mass index (≥ 25 or <25). To validate our algorithm, we retrospectively analyzed 134 patients treated with biologics. Based on the algorithm, patients were categorized into the following treatment groups: infliximab-appropriate (IFX-ap), n=33; adalimumab-appropriate (ADA-ap), n=44; and ustekinumab-appropriate (UST-ap), n=57. The relationship between each agent-appropriate group and the efficacy of each agent was analyzed. Among IFX-ap patients (n=33), the reduction in PASI with each treatment was as follows: inflximab (n=13), 93.2 ± 7.4%; adalimumab (n=10), 61.3 ± 29.2%; and ustekinumab (n=10), 87.4 ± 12.8%, with significant differences between infliximab and adalimumab. Among ADA-ap patients (n=44), the reduction in PASI with each treatment was as follows: infliximab (n=10), 83.3 ± 23.3%; adalimumab (n=12), 84.9 ± 23.6%; and ustekinumab (n=14), 73.0 ± 29.8%, with no significant differences between treatments. Among UST-ap patients, the reduction in PASI with each treatment was as follows: infliximab (n=15), 94.9 ± 6.0%; adalimumab (n=14), 73.0 ± 23.0%; and ustekinumab (n=28), 87.2 ± 18.0%, with a significant difference between treatment with adalimumab and ustekinumab. These results suggest that appropriate biologics selection results in increased efficacy of treatment.

Pathological findings of lymphadenopathy in drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic syndrome (DRESS): similarities with angioimmunoblastic T-cell lymphoma

Drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic syndrome (DRESS) is a severe systemic drug reaction known to be associated with lymphadenopathy. However, the pathological findings of lymphadenopathy in DIHS/DRESS are less defined. Here, we report a case of DIHS/DRESS using lymph node (LN) biopsy for the exclusive diagnosis of lymphoproliferative disorders.A 34-year-old Japanese woman was referred to us with generalized confluent erythema, involving mainly [...]