As the first biologics for psoriasis in Japan, infliximab and adalimumab, anti‐tumor necrosis factor‐α antibodies, became available in the field of dermatology in 2010, followed by ustekinumab, an ...anti‐interleukin (IL)‐12/IL‐23p40 antibody, which was launched in Japan in 2011. Since 2015, three IL‐17 inhibitors of secukinumab and ixekizumab, anti‐IL‐17A antibodies, and brodalumab, an anti‐IL‐17 receptor antibody, and two anti‐IL‐23p19 antibodies of guselkumab and risankizumab, have also been launched. It is important for physicians to select appropriate biologic therapy for each psoriatic patient after due consideration of disease factors, treatment factors and patient background factors, sharing such information with patients. The following can be listed as points to be considered for the selection of biologics: drug effects (e.g. strength of effectiveness, time to onset of effectiveness, effectiveness against arthritis, primary failure, secondary failure), safety (e.g. infections, administration‐related reactions and relationships with other comorbidities), convenience for patients (e.g. hospital visit intervals, self‐injection, maintenance therapy at clinics, feasibility of drug discontinuation/re‐administration) and payment (medical costs) borne by patients. This guidance has been prepared with the aim of allowing dermatologists experienced in the treatment of psoriasis to use biologics appropriately according to the circumstances of individual patients after consideration of the above‐mentioned factors.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
This phase 2/3, double‐blind, placebo‐controlled study was designed to assess the safety and efficacy of ustekinumab in Japanese patients with moderate‐to‐severe plaque‐type psoriasis. Overall, 158 ...patients were randomized to receive ustekinumab 45 or 90 mg at weeks 0, 4, and every 12 weeks, or placebo with cross‐over to ustekinumab at week 12. The primary end‐point was the proportion of patients achieving at least 75% improvement in Psoriasis Area and Severity Index (PASI 75) at week 12. Physician’s Global Assessment (PGA), Dermatology Life Quality Index (DLQI), Nail Psoriasis Severity Index and joint pain Visual Analog Scale (VAS) were also measured. At week 12, 59.4% and 67.7% of ustekinumab 45 and 90 mg patients achieved PASI 75, respectively, compared with 6.5% in the placebo group (P < 0.0001 each). PASI 75 responses were maintained through week 64 in 65.0% and 78.6% of the ustekinumab‐treated patients, respectively. Placebo cross‐over patients had similar responses to ustekinumab‐treated patients. Significant improvements in PGA, DLQI and VAS scores were observed at week 12 and generally maintained over time. Adverse events during the placebo‐controlled period were similar among groups (45 mg, 65.6%; 90 mg, 59.7%; placebo, 65.6%). Serious adverse events were observed in 0%, 4.8% and 6.3% of patients, respectively. Through week 72, similar rates and types of adverse events and serious adverse events were reported in patients receiving 45 and 90 mg. Rates of injection site reactions and antibodies to ustekinumab were low. Ustekinumab was efficacious and generally well‐tolerated in Japanese patients with moderate‐to‐severe plaque‐type psoriasis through 72 weeks. These results are consistent with those reported in the global, phase 3 studies.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Since 1982, the Japanese Society for Psoriasis Research has conducted annual epidemiological surveys of patients with psoriasis. Kawada et al. have reported data for 1982–2001 and Takahashi et al. ...have reported data for 2002–2008. The present study evaluated 9290 psoriatic cases according to age and sex (2009–2012). The male : female ratio was 2.08:1 (6281 male patients 67.6% to 3009 female patients 32.4%). The most prevalent type was psoriasis vulgaris (85.6% of all cases), which was followed by psoriasis arthropathica (6.0%), psoriasis guttate acuta (3.2%), Zumbusch‐type generalized pustular psoriasis (1.8%) and psoriasis erythroderma (1.5%). Psoriasis vulgaris was the most prevalent type for all ages, while psoriasis arthropathica and psoriasis guttate acuta were most prevalent among patients aged less than 65 years. The present survey detected an increased number of cases with comorbid diabetes and/or arthritis symptoms compared with the previous surveys. We found that treatments frequently involved topical corticosteroids (89.7% of cases) and vitamin D3 ointments (78.0% of cases), with a notable increase in the use of vitamin D3 ointments. Systemic treatments were used in 33.3% of cases, including cyclosporin (33.6%), etretinate (19.5%), methotrexate (8.6%), infliximab (11.4%), adalimumab (10.9%) and ustekinumab (6.2%). Phototherapy was used in 30.9% of cases. Although psoralen plus ultraviolet A therapy was the predominant phototherapy during previous studies, the present survey revealed that narrowband ultraviolet B therapy was used in 84.5% of phototherapy‐treated cases. Thus, the present survey revealed major changes in treatment trends.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Keratoacanthoma (KA) is a self-limiting epidermal tumor for which histopathological examination sometimes suggests malignancy. Based on inconsistent clinical views, KA can be regarded as both a ...benign tumor and a variant of squamous cell carcinoma (SCC). Aberrant DNA methylation frequently occurs in malignant tumors but it scarcely occurs in benign tumors. Whether aberrant methylation occurs in KA has not been previously examined.
The aim is to elucidate whether aberrant methylation of CpG islands (CGI) containing a high density of cytosine-guanine dinucleotide (CpG) sites occurs in KA.
Five SCC cell lines, two cultured samples of normal human epidermal keratinocytes (NHEKs), 18 clinical SCC samples, and 21 clinical KA samples were analyzed with Infinium HumanMethylation450 BeadChips, quantitative real-time methylation-specific PCR (RT-MSP) and/or bisulfite sequencing.
Genome-wide analyses of NHEK, KA, and SCC indicated that there was a greater number of aberrantly hypermethylated CGIs in SCC than in KA and there were aberrantly hypermethylated CGIs which are common in both. Among the common hypermethylated CGIs, RT-MSP and bisulfite sequencing targeting CGIs located on CCDC17, PVR, and MAP3K11 gene bodies also showed that methylation levels were significantly higher in KA than in normal epidermis. Statistical analyses suggested that the methylation level of CGI located on PVR in SCC might be correlated to lymph node metastasis (P = 0.013, Mann-Whitney U test) and that the methylation level of CGI in MAP3K11 in KA might be correlated to age (P = 0.031, linear regression analysis).
Aberrant DNA methylation occurs in KA.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recent studies indicate the presence of systemic inflammation in psoriatic patients, and this inflammatory status is significantly associated with a range of comorbidities. The aim of this study was ...to evaluate the clinical significance of novel inflammatory biomarkers, neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR) and mean platelet volume (MPV) in Japanese patients with plaque‐type psoriasis (PsV) and psoriatic arthritis (PsA). One hundred and eighty‐six patients with PsV and 50 patients with PsA treated with biologics, including infliximab, adalimumab and ustekinumab, were retrospectively analyzed before and after treatment. At baseline, NLR and PLR, as well as C‐reactive protein (CRP), were significantly higher in PsA patients than those in PsV patients, and a significant correlation was found between NLR and PLR. In PsV patients, the NLR‐high and PLR‐high subgroups exhibited significantly higher Psoriasis Area and Severity Index scores compared with the NLR‐low and PLR‐low subgroups, respectively, and the NLR‐high subgroup also showed higher CRP levels. MPV value was negatively associated with the presence of arthritis, but its association with inflammation was less clear than that of NLR or PLR. After treatment of the patients with biologics for up to 12 months, NLR and PLR decreased promptly in parallel with a decrease of CRP, irrespective of the type of biologics used. Altogether, these results indicate that both NLR and PLR may be useful markers to evaluate systemic inflammation in psoriatic patients. They may serve as simple, convenient and cost‐effective biomarkers to monitor the disease course after systemic therapy.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Methylation of a CpG island (CGI; a dense cluster of CpGs) located in the 5' region of a gene suppresses that gene's transcription. The expression of G0/G1 switch gene 2 (G0S2) is potentially ...associated with tumorigenesis. The aim of this study is to elucidate the methylation status of the CGI located in the 5' region of G0S2 (hereinafter called 5' G0S2 CGI) in cutaneous squamous cell carcinoma (SCC).
Quantitative real-time methylation-specific PCR (RT-MSP) and bisulfite sequencing were performed to evaluate the methylation statuses of cutaneous SCC and normal epithelial cell samples. Quantitative real-time reverse transcription-PCR was performed to evaluate RNA expression levels. Immunohistochemical analysis was performed to detect protein expression.
G0S2 was suppressed in the five SCC cell lines with 5' G0S2 CGI methylation levels of nearly 100.0% and was expressed in the two normal cultured keratinocytes with methylation levels of almost 0.0%. G0S2 was re-expressed in SCC cell lines treated with a demethylating agent. The in vivo methylation levels of 5' G0S2 CGI as determined by RT-MSP varied widely (0.0% to 77.7%) in 17 cutaneous SCC samples and narrowly (0.1% to 7.3%) in 6 normal epidermis samples. Nine cutaneous SCC samples exhibited higher methylation levels than the highest methylation level (7.3%) of the 6 normal epidermis samples. Bisulfite sequencing showed dense methylated CpG sites within 5' G0S2 CGI in these highly methylated cutaneous SCC samples. The methylation levels of the cutaneous SCC samples did not correlate with any clinical parameters investigated or with histopathological grading.
G0S2 is silenced by aberrant DNA methylation in a subset of cutaneous SCCs.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Brodalumab, an interleukin‐17 receptor A inhibitor, demonstrated rapid and robust efficacy with a favorable safety profile in patients with moderate to severe plaque psoriasis. Here, we present data ...from a multicenter, open‐label extension study in patients with plaque psoriasis with/without psoriatic arthritis who completed 64 weeks of treatment with brodalumab (140 or 210 mg, every 2 weeks Q2W). Patients were enrolled to evaluate the long‐term safety and efficacy of a modified dose of brodalumab. Eligible patients were switched to a reduced dose of brodalumab (140 mg every 4 weeks on day 1) in the extension study; the dose and dosing interval were modified sequentially at the physician’s discretion (minimum 140 mg every 8 weeks and maximum 210 mg Q2W) until drug approval, after which all patients were switched to 210 mg Q2W for postmarketing surveillance. Of the 129 patients enrolled, 107 (82.9%) completed the 108‐week or more extension study. All patients had psoriasis that was well controlled with brodalumab treatment on day 1. Improvement in psoriasis‐related symptoms, evaluated with the Psoriasis Area and Severity Index, Psoriasis Scalp Severity Index, Dermatology Life Quality Index, Nail Psoriasis Severity Index, and American College of Rheumatology 20, 50 and 70, was maintained during the 108‐week extension study. Brodalumab treatment was well tolerated throughout, and no new safety signals were identified. The most commonly reported treatment‐related adverse event was nasopharyngitis, followed by influenza and oral candidiasis. No cases of serious candida infection or Crohn’s disease were observed in this study. Serious treatment‐related adverse events, such as appendicitis, brain abscess, bacterial meningitis, colon cancer, immunoglobulin A nephropathy and tubulointerstitial nephritis, were reported in one patient each. No anti‐brodalumab‐binding antibodies or brodalumab‐neutralizing antibodies were detected in any patient throughout the extension study. Overall, the long‐term efficacy and safety of brodalumab were demonstrated over 108 weeks.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Silencing of metallothionein 1A gene in melanoma Nobeyama, Yoshimasa; Nakagawa, Hidemi
Journal of dermatological science,
November 2017, 2017-Nov, 2017-11-00, 20171101, Volume:
88, Issue:
2
Journal Article
Peer reviewed
Open access
•MT1A products chelate trace elements which are associated with tumorigenesis.•MT1A is regulated by DNA methylation in melanocytes and melanomas.•MT1A is methylated and silenced in some ...melanomas.•MT1A is not methylated in melanocytic nevi.•MT1A methylation status is associated with melanoma types.
When a CpG island (CGI; a dense cluster of CpGs) located in the 5′ region of a gene is methylated, its transcription is suppressed. Tumorigenesis of melanoma is associated with trace elements. Metallothionein 1A is closely associated with the metabolism of trace elements. However, little is known about the metallothionein 1A gene (MT1A) in melanoma.
The purpose is to reveal the methylation and expression status of MT1A in melanoma.
Quantitative real-time methylation-specific PCR (RT-MSP) and bisulfite sequencing were performed to examine MT1A methylation status. Quantitative real-time reverse transcription-PCR (RT-PCR) was performed to examine MT1A expression.
Some melanoma cell lines exhibited high methylation levels of the CGI located in the 5′ region of MT1A (5′ MT1A CGI) with suppression of MT1A. Other melanoma cell lines and normal cultured melanocytes exhibited low methylation levels of 5′ MT1A CGI with expression of MT1A. Treatment with a demethylating agent resulted in transcriptional induction of MT1A in the melanoma cell lines SK-MEL-5 and G-361 with high methylation levels prior to treatment. The methylation levels of 5′ MT1A CGI ranged widely from 0.0% to 91.4% in 21 clinical melanoma samples but showed a narrow, low range from 0.0% to 6.4% in 23 clinical melanocytic nevus samples. Data of bisulfite sequencing was generally compatible with those of RT-MSP. The methylation levels ranged according to the types of melanoma (Kruskal-Wallis test, P=0.047).
MT1A is aberrantly silenced by DNA methylation of 5′ MT1A CGI in melanoma.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The purpose of the present two phase 1 studies was to assess the safety, tolerability and pharmacokinetics for topical application of a novel Janus kinase (JAK) inhibitor, JTE‐052, in Japanese ...healthy adult male volunteers and Japanese adult patients with atopic dermatitis (AD). Additionally, exploratory investigation was performed on the efficacy for disease severity and pruritus score in AD patients. In the QBX1‐1 study, the cutaneous safety of JTE‐052 ointment by a patch test and a photo patch test was assessed in an intra‐individual comparative study using placebo ointment, white petrolatum and non‐application as comparators. The study demonstrated that JTE‐052 ointment would be associated with a low potential for phototoxicity but had no potential for skin irritation or photoallergy. In the QBX1‐2 study, it was revealed that the systemic exposure to JTE‐052 in both healthy volunteers with normal skin and AD patients with inflamed skin was low in application of not only 1% but also 3% JTE‐052 ointment. JTE‐052 ointments of 1% and 3% were generally safe and well tolerated in both populations. In a repeated twice‐daily application for 7 days, the efficacy of JTE‐052 ointment to AD patients was observed with both 1% and 3% ointments in the exploratory investigations evaluated by Eczema Area and Severity Index, Investigator's Global Assessment and Numeric Rating Scale assessments. The mean scores for each assessment declined from the baseline throughout the study. These results suggest that the treatment of JTE‐052 ointment is generally safe and effective in AD patients, although further large confirmatory studies are needed.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Incidence of psoriasis vulgaris in Asians is estimated at 0.05–0.3%. Studies in North America and Europe demonstrated that adalimumab, a fully human, recombinant, immunoglobulin G1 monoclonal ...antibody, was efficacious and well‐tolerated in patients with chronic plaque psoriasis. This 24‐week, placebo‐controlled study evaluated the efficacy and safety of three different dosing regimens of adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis (n = 169). Patients were randomized to receive adalimumab 40 mg every other week (eow), adalimumab 80‐mg loading dose at week 0 followed by adalimumab 40 mg eow starting at week 2, adalimumab 80 mg eow, or placebo eow given as s.c. injections. The primary efficacy endpoint was the percentage of patients achieving a 75% or greater improvement in Psoriasis Area and Severity Index (PASI 75) score at week 16. At week 16, PASI 75 response rates were significantly greater for all three adalimumab groups (40 mg eow: 57.9%, P < 0.001; 40 mg eow plus loading dose: 62.8%, P < 0.001; 80 mg eow: 81.0%, P < 0.001) versus placebo (4.3%). As early as week 4, the 40‐mg eow plus loading dose and 80‐mg eow groups achieved significantly greater PASI 75 response rates compared with placebo. Injection‐site reactions and hepatic events occurred in greater percentages of adalimumab‐treated patients compared with placebo. Adalimumab therapy demonstrated efficacy and safety at all three dosage regimens. Rapid response rate in patients receiving 40 mg eow plus loading dose supports using an 80‐mg loading dose in the treatment of psoriasis.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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