Cendakimab in Patients With Moderate to Severe Atopic Dermatitis: A Randomized Clinical Trial.

Importance: Cendakimab selectively targets interleukin (IL)-13, a type 2 cytokine implicated in atopic dermatitis (AD) pathogenesis, by inhibiting binding to its receptors (IL13R-α1 and IL13R-α2). Proof-of-concept work in AD supports using cendakimab for type 2 inflammatory diseases. Objective: To evaluate the efficacy and safety of cendakimab compared with placebo in patients with moderate to severe AD. Design, Setting, and Participants: This phase 2, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging clinical trial was conducted from May 2021 to November 2022. Adult patients with moderate to severe AD and inadequate response to topical medications were enrolled at 69 sites in 5 countries (US [n = 26], Japan [n = 17], Canada [n = 9], Poland [n = 9], and Czech Republic [n = 8]). Data were analyzed between April 25, 2023, and October 16, 2023. Interventions: Patients were randomized (1:1:1:1) to receive subcutaneous cendakimab, 360 mg, every 2 weeks; 720 mg, every 2 weeks; 720 mg, once weekly; or placebo. Main Outcome and Measure: Mean percentage change in Eczema Area and Severity Index scores from baseline to week 16. Hierarchical testing with multiplicity adjustment was performed for 720 mg, once weekly vs placebo, then 720 mg, every 2 weeks vs placebo, and then 360 mg, every 2 weeks vs placebo. Results: Overall, 221 patients were randomized, and 220 received study drug (95 women [43%]; mean [SD] age, 37.7 [13.9] years; 720 mg, once weekly [54 (24%)]; 720 mg, every 2 weeks [55 (25%)]; 360 mg, every 2 weeks [55 (25%)]; placebo [56 (26%)]). The primary efficacy end point was met for cendakimab, 720 mg, once weekly vs placebo (-84.4 vs -62.7; P = .003) but missed statistical significance for 720 mg, every 2 weeks (-76.0 vs -62.7; P = .06). The treatment effect for 360 mg, every 2 weeks (-16.3; nominal P = .03 vs placebo) was comparable with 720 mg, once weekly (-21.8); however, significance was not claimed because the hierarchical testing sequence was interrupted. Of patients with treatment-emergent adverse events leading to discontinuation, 4 (7.4%) received 720 mg, once weekly; 2 (3.6%) 720 mg, every 2 weeks; 1 (1.8%) 360 mg, every 2 weeks; and 2 (3.6%) placebo. Conclusions and Relevance: The results of this randomized clinical trial indicated that cendakimab was effective, generally safe, and well-tolerated in patients with moderate to severe AD. The primary end point was met with a significant reduction in Eczema Area and Severity Index scores with 720 mg, once weekly at week 16. Cendakimab demonstrated progressive AD improvement at all doses during 16 weeks of treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT04800315.

Exploratory Efficacy Evaluation of Apremilast for the Treatment of Japanese Patients with Palmoplantar Pustulosis: 32-Week Results from a Phase 2, Randomized, Placebo-Controlled Study.

INTRODUCTION: Palmoplantar pustulosis (PPP) is a pruritic, painful, chronic dermatitis that greatly impacts functioning and quality of life and can be difficult to treat. Approved treatment options for PPP are limited, and many patients do not fully respond to current treatments. METHODS: This was a randomized, double-blind, placebo-controlled, phase 2 study in Japanese patients with moderate to severe PPP and inadequate response to topical treatment. Patients were randomized 1:1 to receive apremilast 30 mg twice daily or placebo for 16 weeks followed by an extension phase where all patients received apremilast through week 32. PPP Area and Severity Index (PPPASI), modified PPPASI (which evaluates pustules and vesicles separately), and Palmoplantar Severity Index (PPSI) total scores and subscores (erythema, pustules/vesicles, and desquamation/scales) were evaluated over 32 weeks of apremilast treatment. Achievement of ≥ 50% improvement in PPPASI (PPPASI-50) was evaluated at week 16 among baseline demographic and clinical characteristic subgroups. RESULTS: At week 16, improvements in total score and subscores for PPPASI, modified PPASI, and PPSI, as well as rates of PPPASI-50 were at least moderately greater with apremilast than placebo. Mean PPPASI total score decreased by - 68.3% from baseline to week 32 with continued apremilast treatment. At week 32, mean change from baseline in PPPASI/modified PPPASI subscores ranged from - 58.5% to - 77.0% with apremilast. At week 32, PPSI total score for physician and patient assessments decreased by - 51.3% and - 40.0%, respectively, with continued apremilast treatment. PPPASI-50 response at week 16 was greater with apremilast versus placebo in most demographic and baseline characteristic subgroups. CONCLUSIONS: Improvements in all PPPASI and PPSI total scores and subscores observed with apremilast over 16 weeks were maintained through 32 weeks in patients with moderate to severe PPP and inadequate response to topical treatment. Rates of PPPASI-50 response at week 16 were mostly consistent across patient subgroups. CLINICALTRIALS: GOV: NCT04057937.

Interleukin-23 inhibitors decrease Fibrosis-4 index in psoriasis patients with elevated Fibrosis-4 index but not inteleukin-17 inhibitors.

Recent studies indicate that hepatic diseases are associated with psoriasis. Non-invasive tests, including the Fibrosis-4 (FIB-4) index, which can confidently rule out the presence of advanced fibrosis, are currently receiving attention. However, data on the FIB-4 index in psoriasis patients and the effects of biologics on the FIB-4 index are limited. We investigated the relationships between the FIB-4 index and demographic or clinical characteristics as well as the effects of biologics on the FIB-4 index in psoriasis patients. Psoriasis patients aged 36-64 years, whose treatment was initiated with interleukin (IL)-17 inhibitors or IL-23 inhibitors for psoriasis from May 2015 to December 2022, were consecutively included. Data were collected retrospectively from the patients' charts. A total of 171 psoriasis patients were included in this study. Thirty-four, 43, 21, 32, and 41 psoriasis patients were treated with secukinumab, ixekizumab, brodalumab, guselkumab, or risankizumab, respectively. In biologics-naïve patients, a significant but weak positive correlation was observed between the FIB-4 index and age (r = 0.3246, p = 0.0018). There was no significant correlation between the FIB-4 index and other demographic or clinical characteristics. Regarding the effects of biologics on the FIB-4 index, no significant change was observed in psoriasis patients treated with any biologics. However, in psoriasis patients with a baseline FIB-4 index of >1.3, patients treated with guselkumab and those treated with either IL-23 inhibitor showed significantly decreased FIB-4 index scores 6 months after initiating the biologics (p = 0.0323, p = 0.0212). In contrast, no change was observed in FIB-4 index scores in patients treated with IL-17 inhibitors. In conclusion, our study revealed that the FIB-4 index was correlated with age in psoriasis patients. Furthermore, IL-23 inhibitors (but not IL-17 inhibitors) decreased the FIB-4 index score at 6 months in psoriasis patients with elevated FIB-4 index scores at baseline. Further studies are needed to clarify whether IL-23 inhibitors improve liver fibrosis physiologically and functionally.

Dose escalation of biologic treatment in patients with moderate-to-severe psoriasis in Japan.

Patients receiving interleukin (IL)-inhibiting biologics for moderate-to-severe psoriasis (PsO) may be treated with escalated doses to optimize outcomes. This study evaluated escalation prevalence in a Japanese claims analysis of patients with PsO diagnosis preceding IL-inhibiting biologic treatment and ≥1 post-induction maintenance claim (index date) with sufficient data availability from January 2014 to May 2022. Patients with non-persistence were excluded. Expected daily dose (EDD) was calculated as the recommended maintenance dose divided by the treatment interval. Dose escalation was defined as ≥2 claims showing a ≥20% increase in the observed average daily dose (ADD) over the EDD (with sensitivities requiring ≥1 claim and ≥30%). Significant differences were tested using multivariable regressions. The study included 982 unique patients treated with brodalumab (BRO; n = 104), guselkumab (GUS; n = 207), ixekizumab (IXE; n = 159), risankizumab (RIS; n = 135), secukinumab (SEC; n = 215) and ustekinumab (UST; n = 196). Within 12 months, dose escalation was observed for all IL-inhibiting biologics other than GUS and RIS: 44.4% for UST, 37.2% for IXE, 3.4% for SEC and 1.4% for BRO. In multivariable-adjusted analyses, odds of dose escalation were significantly lower for all products relative to UST. In sensitivities, escalation was observed for all products except RIS.

Safety and effectiveness of guselkumab in Japanese patients with psoriasis: 20-week interim analysis of a postmarketing surveillance study.

A 52-week postmarketing surveillance study was initiated to evaluate the safety and effectiveness of guselkumab, a human anti-interleukin 23 subunit p19 monoclonal antibody, in Japanese patients with psoriasis vulgaris, psoriatic arthritis, generalized pustular psoriasis, and erythrodermic psoriasis in real-world practice. Here, we report results of the 20-week interim analysis of the ongoing postmarketing surveillance study. Patients who received guselkumab between May 2018 (the date of commercial launch in Japan) and October 2020 were registered in this study. In total, 411 and 245 patients were included in the safety and effectiveness analysis sets, respectively. Adverse drug reactions (ADRs) occurred in 6.6% (27 of 411) and serious ADRs in 2.2% (nine of 411) of patients. The most frequent ADRs by System Organ Class were "Infections and infestations" (2.4%), with nasopharyngitis being the most frequently observed ADR (0.7%). The mean Psoriasis Area Severity Index score decreased from 11.6 at baseline to 6.5 at week 4 and 2.2 at week 20, with improvements achieving statistical significance at each time point. Clinical Global Impression, Dermatology Life Quality Index, and Nail Psoriasis Severity Index outcomesalso showed substantial improvements. Our findings demonstrate that guselkumab is well tolerated and effective in Japanese patients with psoriasis through 20 weeks of treatment in real-world clinical practice, showing significant effectiveness observed as early as 4 weeks. The study was officially registered with the University Hospital Medical Information Network Clinical Trials Registry with the identifier UMIN000032969.

308-nm excimer light is effective for palmoplantar pustulosis regardless of the presence or absence of focal infection: Single-center real-world experience of treatment for palmoplantar pustulosis.

Palmoplantar pustulosis (PPP) is relatively rare and recognition of PPP is different in different countries. Therefore, real-world data are limited. Local phototherapy for the palms and the soles is commonly used to treat PPP due to tolerable safety. However, data on the effectiveness of 308-nm excimer light are limited. In our study, we retrospectively investigated the effectiveness of treatments for PPP, especially phototherapy (308-nm excimer light), in our department. In addition, we examined whether smoking status and focal infection affected responsiveness to treatment of PPP. Patients who were diagnosed with PPP by board-certified dermatologists and visited our hospital from April 2015 to August 2018 were analyzed in this study. We collected data on PPP area severity index (PPPASI) before treatment. We also collected data on PPPASI in May to August 2018 as "after treatment" from all patients. Patients who received any treatment for less than 3 months were excluded. Nineteen patients (16 women and three men) were analyzed in this study. In patients treated with phototherapy (n = 12), PPPASI significantly decreased from a mean ± SD of 16.5 ± 10.3 to 4.5 ± 3.6 (p = 0.004), whereas it did not in patients treated without phototherapy (n = 7). Patients who quit smoking showed a significant decrease in PPPASI after treatment (16.8 ± 12.7 to 2.4 ± 2.9, p = 0.008). Regarding focal infection, in patients treated without phototherapy, the reduction rate of PPPASI was significantly lower in patients with focal infection than in those without focal infection (17.7 ± 21.5%, 71.1 ± 19.3%, p = 0.035), indicating that focal infection is associated with intractability. Meanwhile, in patients treated with phototherapy, PPPASI decreased regardless of the presence or absence of focal infection. In conclusion, our study demonstrated the effectiveness of local phototherapy consisting of 308-nm excimer light, regardless of focal infection. Patients who quit smoking were responsive to any treatment, indicating the importance of smoking cessation.

Impact of 1-year treatment with dupilumab on work productivity in Japanese patients with atopic dermatitis.

Atopic dermatitis (AD) places a burden on work productivity. Recently, dupilumab was approved for AD, but its impact on work productivity in Japanese patients has not been reported. Furthermore, data on the effect of long-term treatment with dupilumab on work productivity are limited. We investigated the work productivity and activity in Japanese patients with moderate-to-severe AD, utilizing the Japanese version of the Work Productivity and Activity Impairment (WPAI-AD-Japan) questionnaire. Furthermore, we examined the impact of dupilumab on work productivity. Adult moderate-to-severe AD patients treated with dupilumab for more than 12 months from March 2020 to June 2022 who filled out the WPAI-AD-Japan questionnaire were included. Twenty-eight adult AD patients were analysed. Absenteeism was low (mean: 5.3%), but presenteeism, work productivity loss and activity impairment were high (36.8%, 39.7%, 48.9%, respectively). Significant positive correlations were observed between work productivity loss and visual analogue scale (VAS) score of pruritus and between activity impairment and dermatology life quality index (DLQI). Dupilumab treatment significantly reduced presenteeism, work productivity loss and activity impairment at both 6 and 12 months. The extent of their amelioration was numerically higher at 12 months than at 6 months. The reduction rates in presenteeism, work productivity loss and activity impairment were positively correlated with the reduction rates in DLQI and VAS score of pruritus at 12 months. Dupilumab improved work productivity in Japanese AD patients. Long-term remission of pruritus and improved quality of life are important for comprehensive improvement of work productivity.

Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, in Japanese patients with moderate to severe plaque, erythrodermic, or generalized pustular psoriasis: Efficacy and safety results from an open-label, phase 3 trial.

Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved in Japan for adult patients with plaque (PP), generalized pustular (GPP), and erythrodermic (EP) psoriasis who have had an inadequate response to conventional systemic therapies. This approval is based on results from the global phase 3 POETYK PSO-1 and PSO-2 trials in which deucravacitinib was associated with significantly improved efficacy outcomes compared with placebo in adults with moderate to severe plaque psoriasis, and results described here from POETYK PSO-4, an open-label, single-arm, phase 3 trial (NCT03924427), which evaluated the efficacy and safety of deucravacitinib 6 mg once daily in adult Japanese patients with PP, GPP, or EP. The coprimary endpoints were the proportion of patients achieving a ≥75% reduction from baseline in the Psoriasis Area and Severity Index (PASI 75) and a static Physician's Global Assessment score of 0 (clear) or 1 (almost clear) (sPGA 0/1) with at least a two-point improvement from baseline at week 16. Nonresponder imputation was used for missing data. Efficacy responses, adverse events (AEs), and serious AEs (SAEs) were recorded for up to 52 weeks. Seventy-four patients were treated (PP, n = 63; GPP, n = 3; EP, n = 8). At week 16, 76.2%, 66.7%, and 37.5% of patients with PP, GPP, and EP, respectively, had achieved PASI 75, and 82.5%, 0.0%, and 50.0% had achieved sPGA 0/1. Responses were overall maintained through week 52. AEs occurred in 74.6% of patients with PP, 100% of patients with GPP, and 87.5% of patients with EP. The most common AEs were nasopharyngitis and acne. Rates of SAEs and discontinuations were low. There were no deaths. Deucravacitinib was effective and well tolerated in Japanese patients with moderate to severe PP and in a limited number of patients with GPP or EP.

Treatment patterns and drug survival for generalized pustular psoriasis: A patient journey study using a Japanese claims database.

Generalized pustular psoriasis (GPP) is a potentially life-threatening skin disease. Although several medications are approved for treating GPP in Japan, there are limited data on real-world treatment patterns or drug survival (the number of prescribed days of treatment). This retrospective cohort study describes drug survival and treatment patterns of patients with newly diagnosed GPP (International Classification of Diseases, 10th Revision code L40.1), and ≥1 year of follow-up, using de-identified claims data (Medical Data Vision Co., Ltd.) from January 2016 to August 2021. Most (97.0%) of the 434 Japanese patients received first-line therapy of etretinate (26.4%), topical medications (14.7%), or cyclosporin (14.3%); 80.0% and 60.1% of patients received a second and third line of therapy (LOT), respectively. Use of etretinate (12.6%) and cyclosporin (5.9%) decreased in second-line therapies, whereas use of biologics (interleukin [IL]-17, 14.3%; IL-23 inhibitors, 7.6%) and topical medications (22.1%) increased or remained consistent. Approximately 50% of biologics were prescribed in combination with systemic medications or systemic corticosteroids. Median (range) time to next therapy (TTNT) was 2.8 (0.03-48.07) months for first-line therapy and 3.3 (0.03-52.97) months for all other LOTs. TTNT was longer for combination therapies (up to 16.5 months) compared with monotherapies (up to 7.5 months). Biologics exhibited longer drug survival with fewer treatment episodes compared with non-biologic systemic medications. Among frequently used therapies, the median (95% confidence interval) drug survival was 8.8 (5.8-11.8) months for etretinate, 4.3 (2.2-6.9) months for systemic corticosteroids, and 19.6 (16.1-26.7) months for secukinumab. Treatment patterns varied considerably, highlighting the need for treatment algorithms and effective, well-tolerated medications to support patients to help them remain on long-term therapy.

Treatment patterns of systemic drug use in Japanese patients with plaque psoriasis: A retrospective chart review.

Plaque psoriasis (PsO) is a chronic immune-mediated inflammatory disease with skin lesions accompanied by an inflammation-related comorbidity risk. The development of various oral drugs and biologics for PsO has provided increasing systemic treatment options for patients with PsO, and the guidance regarding the use of biologics and PsO treatment schemes are widespread in Japan. However, no comprehensive guidelines regarding systemic drug use are available, and the current treatment patterns of systemic drugs for PsO in Japan remain unclear. We conducted a retrospective chart review to clarify the current treatment patterns of systemic drugs for PsO. We enrolled 114 patients who started systemic drugs for PsO between January 2017 and December 2020 at four institutes, with a mean follow-up of 37.2 months. The mean disease duration was 7.8 (standard deviation 9.5) years at the systemic drug initiation. Of all the patients, 78.1% started with oral drugs (phosphodiesterase [PDE] 4 inhibitors 56.1%. calcineurin inhibitors 14.0%. vitamin A derivatives 7.9%), whereas 21.9% started with biologics (interleukin [IL]-17 inhibitors 9.6%. tumor necrosis factor inhibitors 7.0%. IL-23 inhibitors 3.5%. IL-12/23 inhibitors 1.8%). Oral drugs had shorter drug persistence than biologics: the 12-month persistence of the oral drugs vitamin A derivative, calcineurin inhibitor, and PDE4 inhibitor, was 35.5%, 25.8%, and 60.1%, respectively, compared with that of the biologics IL-23 and IL-17 inhibitors, which was 85.6% and 84.7%, respectively. During the study period, the incidence of treatment changes was 59.1/100 patient-years. Lack of efficacy was the most common reason for treatment changes from monotherapy (34.1%). This retrospective medical chart review allowed us to understand the real-world, long-term treatment patterns of systemic drugs for PsO and the relationships between the reasons for treatment changes and subsequent treatment selection, indicating that there is still room for improvement in the appropriate use of systemic drugs for PsO in Japan.

Real-World Discontinuation and Switching Patterns for Interleukin-Inhibitor Treatments in Patients with Moderate-to-Severe Psoriasis in Japan.

INTRODUCTION: Patients with moderate-to-severe psoriasis (PsO) treated with interleukin (IL)-inhibitors may require treatment modification to achieve disease control. This study evaluated discontinuation and switching of IL-inhibitors for PsO patients in Japan. METHODS: Japan Medical Data Center claims (1/2005-5/2022) were used to identify patients with PsO diagnosis preceding a first IL-inhibitor claim (index date) with ≥ 6 months of eligibility prior. Treatment switch (claim for another biologic) and discontinuation (gap in care ≥ 150% of the days' supply of the preceding prescription) were assessed up to 24 months following initiation. Censored Kaplan-Meier time-to-event analyses calculated rates, and Cox proportional hazards models estimated hazard ratios (HRs) adjusting for baseline characteristics. RESULTS: The study included 1481 unique patients treated with brodalumab (BRO; n = 159), guselkumab (GUS; n = 360), ixekizumab (IXE; n = 279), risankizumab (RIS; n = 327), secukinumab (SEC; n = 366), tildrakizumab (n = 40; excluded due to limited data), and ustekinumab (UST; n = 262). At 12/24 months, 25.9%/38.6% of patients overall had discontinued their index IL-inhibitor and 13.5%/21.2% had switched to another biologic. Discontinuation at 12/24 months was lowest for RIS (11.2%/17.4%), followed by UST (17.9%/32.2%), IXE (27.0%/37.0%), GUS (29.8%/43.0%), SEC (35.6%/53.8%), and BRO (37.2%/47.2%). Switching showed a similar trend: RIS (5.7%/10.7%), UST (11.2%/19.9%), SEC (14.7%/25.7%), IXE (14.8%/21.5%), GUS (16.9%/23.2%), and BRO (19.7%/26.8%). HRs of discontinuation relative to RIS were 2.07 for UST, 2.59 for IXE, 2.70 for GUS, 3.65 for BRO, and 3.69 for SEC (all P ≤ 0.001). HRs of switching relative to RIS were 2.05 for IXE, 2.45 for GUS, 2.67 for SEC, 2.73 for UST, and 2.77 for BRO (all P ≤ 0.01). CONCLUSION: Treatment modification of IL-inhibitors for PsO was commonly observed and could indicate insufficient disease control and/or incremental economic burden. Discontinuation and switching rates were lowest for RIS regardless of time point and adjustment for patient characteristics.

Crosstalk: keratinocytes and immune cells in psoriasis.

In the past, psoriasis was considered a skin disease caused only by keratinocyte disorders. However, the efficacy of immunosuppressive drugs and biologics used to treat psoriasis proves that psoriasis is an immune-mediated disease. Indeed, a variety of immune cells are involved in the pathogenesis of psoriasis, including dendritic cells, Th17 cells, and resident memory T cells. Furthermore, keratinocytes play a role in the development of psoriasis as immune cells by secreting antibacterial peptides, chemokines, tumor necrosis factor-α, interleukin (IL)-36, and IL-23. These immune cells and skin cells interact and drive the aberrant differentiation and proliferation of keratinocytes. This crosstalk between keratinocytes and immune cells critical in the pathogenesis of psoriasis forms an inflammatory loop, resulting in the persistence or exacerbation of psoriasis plaques.

Minimum data set for treatment effectiveness in pyoderma gangrenosum (MIDSTEP): an international protocol of an e-Delphi study to develop a clinical physician-driven treatment effectiveness registry on behalf of the UPGRADE initiative.

Pyoderma gangrenosum (PG) is a rare inflammatory condition with an immense disease burden that remains understudied. With limited approved treatments and low-quality clinical evidence, PG continues to have poor patient outcomes. Unfortunately, improvement in PG treatments and patient care is based on additional research endeavors that can only be developed from existing high-quality data. The following protocol outlines the development of the Minimum Data Set for Treatment Effectiveness in Pyoderma gangrenosum (MIDSTEP), a core set of domains and domain items for the Pyoderma Gangrenosum Treatment Effectiveness (PyGaTE) international registry. The outcomes and benefits are focused on providing real-world data for physicians to improve their clinical decisions on PG treatment and inform clinical trial design, promoting clinical research among the international scientific community. MIDSTEP is a multi-phase project. The first phase will produce a domain item list from a literature review to take into the second phase which would finalize the core data set by an e-Delphi exercise. There will be a single stakeholder group participating together in the e-Delphi consisting of PG experts (healthcare providers, researchers, methodologists, industry representatives, and regulators), ulcerative PG patients, and PG patient advocates. The methodology outlined in the protocol is a systematic method based on several guidelines through COMET and established dermatologic registries and outcome sets with systematic methodologies of their own. The third phase will identify the instruments for the items, the 'when to measure' the items, and the platform for the registry. The last phase is the implementation and continued maintenance of the international registry PyGaTE. By solidifying a consensus on standardized outcomes and collecting information on PG treatment effectiveness in a centralized database, existing treatments can be compared more systematically and analyzed with increased evidence. MIDSTEP and the PyGaTE international registry will have the ambitious goal to generate and disseminate real-world data that can be used by all stakeholders to improve health outcomes for PG patients. Future potential for the outcome of this project includes the development of a gold-standard PG treatment.

Expression of interleukin-36 receptor antagonist in a patient with generalized pustular psoriasis harboring the p.Pro82Leu variant in the IL36RN gene.

It has recently been revealed that mutation of the IL36RN gene contributes to the development of generalized pustular psoriasis (GPP). The IL36RN gene encodes interleukin (IL)-36 receptor antagonist (IL-36Ra), which has antagonistic roles against IL-36α, -36ß, and -36γ. Previously, sanger sequencing performed in 62 Chinese GPP patients to identify IL36RN mutations revealed a new variant, c.245C>T (p.Pro82Leu), in a single heterozygous state in a patient with adult-onset GPP with psoriasis vulgaris. Since this p.Pro82Leu variant was not found in the psoriasis vulgaris or control groups in their study, they speculated that this variant might lead to exacerbated inflammatory responses. Meanwhile, Sorting Intolerant From Tolerant and PolyPhen-2, pathogenicity prediction tools, predict this variant as tolerated and benign. To date, its pathogenicity is unknown. We experienced a patient with GPP harboring the p.Pro82Leu variant, and investigated mRNA and protein expressions of IL-36Ra. Polymerase chain reaction conducted on hair follicle samples obtained from the scalp of the patient with GPP harboring the p.Pro82Leu using primers to detect mRNA of exons 2 and 5 in IL36RN demonstrated mRNA expression of IL36RN. Immunohistochemical staining revealed IL-36Ra expression in the keratinocytes of the patient with GPP harboring the p.Pro82Leu as in those of a GPP patient without the mutation (positive control). Furthermore, quantitative analysis of the immunofluorescent staining by ImageJ revealed that the expression level of IL-36Ra in the keratinocytes of the patient with GPP harboring p.Pro82Leu was higher than that in the healthy control and not lower than that in the GPP patients without the mutation. Our results indicate no aberrant splicing in this variant. In addition, according to the 1000 Genomes Project, this variant could be a founder mutation. Considering these factors together, this variant is unlikely to be associated with the development of GPP.

Real-world retention rates and effectiveness of secukinumab in psoriasis: Results from a multicenter cohort study (RAILWAY).

Psoriasis is a chronic, immune-mediated inflammatory skin disease with a high negative impact on patient's quality of life. Secukinumab, the first interleukin 17A inhibitor, has been used for the systemic treatment of psoriasis, but its long-term, real-world retention rates in Japan have not been fully investigated. In this multicenter, noninterventional, retrospective chart review study, the retention rate of secukinumab and its effectiveness among patients with psoriasis in Japan was evaluated up to 5 years. Data of patients who received secukinumab after December 26, 2014, were collected from medical charts obtained from seven sites, all certified for biologics use by the Japanese Dermatological Association. Patient characteristics, secukinumab retention, factors affecting secukinumab retention, reason for drug discontinuation, and effectiveness data were collected. The primary end point was secukinumab retention rate at week 52. A total of 123 patients were included in the analysis. Of these, 27 patients discontinued secukinumab by week 52, yielding a 78.0% (95% confidence interval, 69.6-84.4) retention rate at week 52. For patients whose Psoriasis Area and Severity Index (PASI) score was available, mean ± standard deviation PASI at baseline and at week 52 were 9.21 ± 7.37 and 1.4 ± 2.6, respectively. During the entire study period, "insufficient response" was the most common reason for discontinuation, and "history of biologics use" was a factor significantly associated with secukinumab discontinuation (hazard ratio, 1.72; p = 0.018). This study demonstrates the real-world retention rate and effectiveness of secukinumab in patients with psoriasis in Japan for up to 5 years and provides clinical insights into psoriasis treatment strategies.