Mitsuha Hayashi

Efficacy and safety of ustekinumab treatment in elderly patients with psoriasis

The ratio of the elderly among psoriasis patients has been increasing. However, satisfactory long‐term management of psoriasis for the elderly is challenging because of the more frequent presence of comorbidities, and the higher risk of adverse events from systemic therapeutic agents than younger patients. The use of ustekinumab (UST) appears to be an appropriate systemic treatment because it is considered less likely to cause adverse events than other systemic treatments, as well as necessitating fewer hospital visits. Our retrospective study aimed to evaluate the efficacy and safety profile of UST in elderly patients with psoriasis. The study included 24 patients aged over 65 years (range, 65–88 years; mean, 73.1 years) with moderate to severe plaque psoriasis with impaired quality of life. Efficacy and safety were assessed over a 1‐year period using the Psoriasis Area and Severity Index (PASI) and the Dermatology Live Quality Index (DLQI). The efficacy was evaluated by the proportion of subjects who achieved ≥75% reduction in PASI score (PASI 75). PASI 75 responses were 56.5% at week 16, 59.1% at week 28, and 60.0% at week 52. None of the patients developed any serious infection during the 1‐year treatment. The mean DLQI score at weeks 0, 16, 28, and 52 was 7.8 ± 6.0, 2.5 ± 3.4, 1.4 ± 1.7, and 1.2 ± 1.7, respectively. UST showed sufficient efficacy for elderly patients with psoriasis without any serious infection over the 1‐year treatment. Our results suggest that UST is the preferable agent for the treatment of elderly patients with psoriasis.

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

Successful treatment of ustekinumab in a severe psoriasis patient with human immunodeficiency virus infection.

myeloma, the diagnosis of AL amyloidosis was initially made by dermatological evaluation and skin biopsy. Among patients with multiple myeloma, 15% may develop some form of amyloidosis. Dermatologists should be aware that periorbital papules, purpura/ecchymosis and macroglossia are suggestive for systemic amyloidosis and require biopsy. First priority in handling amyloidosis is to identify and treat underlying disease.

Biologic treatments for elderly patients with psoriasis

The number of elderly patients with psoriasis is increasing in Japan. However, biologic treatment is generally considered to be challenging in elderly patients, due to their increased risk of complications compared with younger patients. Our retrospective study aimed to evaluate the safety profile and efficacy of biologics in senior elderly patients (≥75 years old) with psoriasis. The study involved a cohort of 27 patients aged 75–88 years who were being treated with biologics over a period of more than 1 year. Initial biologics administrated to were adalimumab (five cases) and ustekinumab (22 cases). Eight patients discontinued treatment: two developed cancer; one was transferred to hospital; and five others experienced either bone fracture, interstitial pneumonia, cerebral hemorrhage resulting in death, decrepitude or developed hepatopathy following prophylactic tuberculosis treatment. Efficacy, evaluated by the percentage of patients achieving 75% reduction of Psoriasis Area and Severity Index score, was 76.9% at week 16 (n = 26), 88.0% at week 24 (n = 25) and 90.5% at week 52 (n = 21). Biologic treatments thus show clear efficacy in elderly patients with psoriasis, however, the increased frequency of adverse events requires rigorous patient observation.

Impact of anti-tumor necrosis factor-α agents on serum levels of KL-6 and surfactant protein-D in patients with psoriasis

We longitudinally examined the influence of anti‐tumor necrosis factor (TNF)‐α treatment on serum levels of KL‐6 and surfactant protein‐D (SP‐D). The study group comprised 22 patients with psoriasis treated with infliximab or adalimumab and with no history of interstitial lung disease (ILD). KL‐6 and SP‐D levels were measured in serum samples. Twelve of the 22 patients (55%) showed at least a 20% increase in KL‐6 levels compared with baseline. Of these 12 patients, none exhibited any signs of ILD on chest computed tomography and nine who showed an increase in KL‐6 levels (75%) showed at least a 20% increase in SP‐D levels. Some patients showed simultaneous increases in KL‐6 and SP‐D levels after treatment with anti‐TNF‐α agents. Although these patients may have undetectable or subtle alveolar damage, careful observation is needed.

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.

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.

Genetic polymorphism in the TRAF3IP2 gene is associated with psoriasis vulgaris in a Japanese population.

[2] Sano S, Chan KS, Carbajal S, Clifford J, Peavey M, Kiguchi K, et al. Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model. Nat Med 2005;11:43–9. [3] Nakajima K, Kanda T, Takaishi M, Shiga T, Miyoshi K, Nakajima H, et al. Distinct roles of IL-23 and IL-17 in the development of psoriasis-like lesions in a mouse model. J Immunol 2011;186:4481–9. [4] Kunz S, Wolk K, Witte E, Witte K, Doecke WD, Volk HD, et al. Interleukin (IL)19, IL-20 and IL-24 are produced by and act on keratinocytes and are distinct from classical ILs. Exp Dermatol 2006;15:991–1004. [5] He M, Liang P. IL-24 transgenic mice: in vivo evidence of overlapping functions for IL-20, IL-22, and IL-24 in the epidermis. J Immunol 2010;184: 1793–8. [6] Chan JR, Blumenschein W, Murphy E, Diveu C, Wiekowski M, Abbondanzo S, et al. IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent [10] Cai Y, Shen X, Ding C, Qi C, Li K, Li X, et al. Pivotal role of dermal IL-17-producing gammadelta T cells in skin inflammation. Immunity 2011;35:596–610.

Serum levels of soluble programmed death-1 and programmed death ligand-1 in systemic sclerosis: Association with extent of skin sclerosis.

The interaction of programmed death‐1 (PD‐1) with its ligand, programmed death ligand‐1 (PD‐L1), has been considered to play a key role in the negative regulation of immune responses. Patients with diffuse cutaneous systemic sclerosis (SSc) had higher levels of soluble PD‐1 (sPD‐1) than those with limited cutaneous SSc and healthy individuals. Serum sPD‐1 levels positively correlated with the severity of skin sclerosis. In contrast, serum sPD‐L1 levels were significantly increased in patients with SSc compared with healthy individuals. Moreover, serum sPD‐L1 levels were not associated with the extent of skin sclerosis and were elevated not only in patients with diffuse cutaneous SSc, but also in those with limited cutaneous SSc. These results suggested that serum sPD‐1 levels may increase in patients with SSc and correlate with the severity of skin sclerosis. PD‐1/PD‐L1 interaction may contribute to the development of skin sclerosis in SSc.