International Consensus Definition and Diagnostic Criteria for Generalized Pustular Psoriasis From the International Psoriasis Council.

Importance: Generalized pustular psoriasis (GPP) lacks internationally accepted definitions and diagnostic criteria, impeding timely diagnosis and treatment and hindering cross-regional clinical and epidemiological study comparisons. Objective: To develop an international consensus definition and diagnostic criteria for GPP using the modified Delphi method. Evidence Review: The rarity of GPP presents a challenge in acquiring comprehensive published clinical data necessary for developing standardized definition and criteria. Instead of relying on a literature search, 43 statements that comprehensively addressed the fundamental aspects of the definitions and diagnostic criteria for GPP were formulated based on expert reviews of 64 challenging GPP cases. These statements were presented to a panel of 33 global GPP experts for voting, discussion, and refinements in 2 virtual consensus meetings. Consensus during voting was defined as at least 80% agreement; the definition and diagnostic criteria were accepted by all panelists after voting and in-depth discussion. Findings: In the first and second modified Delphi round, 30 (91%) and 25 (76%) experts participated. In the initial Delphi round, consensus was achieved for 53% of the statements, leading to the approval of 23 statements that were utilized to develop the proposed definitions and diagnostic criteria for GPP. During the second Delphi round, the final definition established was, "Generalized Pustular Psoriasis is a systemic inflammatory disease characterized by cutaneous erythema and macroscopically visible sterile pustules." It can occur with or without systemic symptoms, other psoriasis types, and laboratory abnormalities. GPP may manifest as an acute form with widespread pustules or a subacute variant with an annular phenotype. The identified essential criterion was, "Macroscopically visible sterile pustules on erythematous base and not restricted to the acral region or within psoriatic plaques." Conclusions and Relevance: The achievement of international consensus on the definition and diagnostic criteria for GPP underscores the importance of collaboration, innovative methodology, and expert engagement to address rare diseases. Although further validation is needed, these criteria can serve as a reference point for clinicians, researchers, and patients, which may contribute to more accurate diagnosis and improved management of GPP.

Spesolimab Efficacy and Safety in Patients with Moderate-to-Severe Palmoplantar Pustulosis: A Multicentre, Double-Blind, Randomised, Placebo-Controlled, Phase IIb, Dose-Finding Study.

INTRODUCTION: We evaluated the anti-interleukin-36 receptor antibody spesolimab in patients with moderate-to-severe palmoplantar pustulosis (PPP). METHODS: This phase IIb trial comprised a loading dose period to week (W) 4, then maintenance dosing to W52. Patients were randomised 2:1:1:1:2 to subcutaneous spesolimab 3000 mg to W4 then 600 mg every 4 weeks (q4w), spesolimab 3000 mg to W4 then 300 mg q4w, spesolimab 1500 mg to W4 then 600 mg q4w, spesolimab 1500 mg to W4, 300 mg q4w to W16 then 300 mg every 8 weeks (q8w), or placebo switching to spesolimab 600 mg q4w at W16. The primary efficacy endpoint was percentage change from baseline in Palmoplantar Pustular Area and Severity Index (PPP ASI) at W16. Secondary endpoints included a Palmoplantar Pustular Physician's Global Assessment (PPP PGA) score of 0/1. Safety (including adverse events [AEs], local tolerability) was assessed. RESULTS: 152 patients were treated. The primary endpoint was not met; mean differences for spesolimab versus placebo ranged from - 14.6% (95% confidence interval [CI]: - 31.5%, 2.2%) to - 5.3% (95% CI: - 19.1%, 8.6%); none reached significance. At W16, 23 (21.1%) and two (4.7%) patients in the combined spesolimab and placebo groups, respectively, achieved PPP PGA 0/1 (mean difference 16.4%; 95% CI: 3.8%, 25.7%), increasing to 59 (54.1%; combined spesolimab) and 12 (27.9%; placebo switch to spesolimab) patients at W52. Non-Asian patients had significant improvements in the primary endpoint (mean difference - 17.7%; nominal P = 0.0394) and PPP PGA 0/1 at W16 with spesolimab versus placebo. Rates of AEs and AE-related discontinuations were similar for spesolimab and placebo. Local tolerability events and injection-site reactions were more frequent with spesolimab than placebo. CONCLUSION: The primary objective to demonstrate a non-flat dose-response relationship and proof-of-concept was not achieved; improvements with spesolimab occurred in secondary endpoints and in non-Asian patients, indicating potential modest benefits. Spesolimab was generally well tolerated (ClinicalTrials.gov NCT04015518).

A clinical trial of spesolimab for patients with palmoplantar pustulosis. Palmoplantar pustulosis (PPP) is a painful, difficult-to-treat skin disease that is found on patients' palms and the soles of their feet. In this clinical trial, we studied an injected medicine called spesolimab for treating patients with PPP. Patients were split into five groups; four groups received different doses of spesolimab and one received placebo (an injection without spesolimab). After 16 weeks, patients receiving placebo switched to spesolimab. We measured the body area affected by PPP and how severe PPP was at week 16. Patients' doctors also assessed skin affected by PPP. At 16 weeks of treatment, there was no significant difference between spesolimab and placebo in terms of the PPP-affected area and severity. However, more patients had clear or almost clear skin with spesolimab than placebo. Among non-Asian patients, more showed an improvement in their PPP with spesolimab than with placebo; this was not the case with Asian patients. Patients taking spesolimab or placebo reported side effects, of which the most common were colds, aches and headaches. More patients receiving spesolimab reported a reaction at the injection site compared with placebo. We monitored patients for up to 1 year, and results remained similar. We showed that spesolimab may have a modest effect on the body area affected by PPP, as well as the severity of PPP, and did not seem to cause more side effects than placebo, except for reactions at the injection site.

Real-world safety and effectiveness of adalimumab in patients with hidradenitis suppurativa: A 52-week analysis of a postmarketing surveillance study in Japan.

Adalimumab is a human monoclonal antibody against tumor necrosis factor-α that was approved in Japan for the treatment of hidradenitis suppurativa (HS), a chronic recurrent inflammatory skin disease. We report the results of the final analysis of the postmarketing surveillance (PMS) study (ClinicalTrials.gov: NCT03894956), which evaluated the 52-week safety and efficacy of adalimumab for HS treatment in real-world clinical practice in Japan. This multicenter, prospective, open-label, observational study (March 2019 to May 2021) included patients with HS treated with subcutaneous adalimumab at doses following the package insert. The primary endpoint was safety, and the secondary endpoints were effectiveness, including HS clinical response (HiSCR), C-reactive protein (CRP), skin pain, and Dermatology Life Quality Index (DLQI). Of the 84 patients registered at 65 sites, 83 patients were included in the analyses. Adverse drug reactions (ADRs) were reported by 10 (12.0%) patients; two patients reported a serious ADR, including one patient with serious infection. Other safety events of special interest reported were liver disorder and dermatitis psoriasiform (one patient each). Almost all patients with ADRs were recovering or had recovered, except for one patient who experienced a serious ADR of liver disorder and died. At 12 weeks, 55.4% of patients achieved HiSCR; this increased to 60.5% and 62.8% at 24 and 52 weeks of adalimumab treatment, respectively. Significant reductions from baseline in CRP (P < 0.05), skin pain (P < 0.0001), and DLQI (P < 0.0001) were observed at all time points. The results from this PMS study demonstrated that long-term adalimumab treatment is well tolerated and effective in patients with HS in real-world clinical practice in Japan.

Recent Advances in Clinical Research on Rare Intractable Hereditary Skin Diseases in Japan.

Our Research Group for Rare and Intractable Skin Diseases operates within the Project for Research on Intractable Diseases of the Ministry of Health, Labour, and Welfare of Japan and is conducting research on eight rare intractable skin diseases. Five of these are monogenic disorders (epidermolysis bullosa, congenital ichthyoses, oculocutaneous albinism, pseudoxanthoma elasticum, and hereditary angioedema), and for a sixth [generalized pustular psoriasis (GPP)], genetic predisposing factors are important. This review introduces our activities for raising public awareness of these six intractable hereditary skin diseases and summarizes our recent achievements in clarifying the situation of medical treatments for these diseases in Japan. We note our current progress in elucidating the pathogeneses of these diseases and in developing new treatment methods, and we discuss our progress in establishing clinical practice guidelines. A nationwide survey on epidermolysis bullosa and a clinical survey on congenital ichthyoses are progressing. The Angioedema Activity Score and the Angioedema Quality-of-Life Questionnaire, the latter of which is a quality-of-life evaluation tool, have been established for hereditary angioedema. Registries of patients with oculocutaneous albinism and pseudoxanthoma elasticum have been created, and the registry for the latter has achieved its target of 170 cases. For GPP, the results of our survey on clinical practice were published in 2021. Information regarding all six of these hereditary skin diseases has been disseminated to academic societies, medical professionals, patients, and the general public.

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

BACKGROUND: Palmoplantar pustulosis (PPP) is a pruritic, painful, recurrent, and chronic dermatitis with limited therapeutic options. OBJECTIVE: To evaluate the efficacy and safety of apremilast for the treatment of Japanese patients with PPP and inadequate response to topical treatment. METHODS: This phase 2, randomized, double-blind, placebo-controlled study enrolled patients with Palmoplantar Pustulosis Area and Severity Index (PPPASI) total score ≥ 12 and moderate or severe pustules/vesicles on the palm or sole (PPPASI pustule/vesicle severity score ≥ 2) at screening and baseline with an inadequate response to topical treatment. Patients were randomized (1:1) to apremilast 30 mg twice daily or placebo for 16 weeks, followed by a 16-week extension phase during which all patients received apremilast. The primary endpoint was achievement of PPPASI-50 response (≥ 50% improvement from baseline in PPPASI). Key secondary endpoints included change from baseline in PPPASI total score, Palmoplantar Pustulosis Severity Index (PPSI), and patient's visual analog scale (VAS) for PPP symptoms (pruritus and discomfort/pain). RESULTS: A total of 90 patients were randomized (apremilast: 46; placebo: 44). A significantly greater proportion of patients achieved PPPASI-50 at week 16 with apremilast versus placebo (P = 0.0003). Patients receiving apremilast showed greater improvement in PPPASI at week 16 versus placebo (nominal P = 0.0013), as well as PPSI and patient-reported pruritus and discomfort/pain (nominal P ≤ 0.001 for all). Improvements were sustained through week 32 with apremilast treatment. The most common treatment-emergent adverse events included diarrhea, abdominal discomfort, headache, and nausea. CONCLUSIONS: Apremilast treatment demonstrated greater improvements in disease severity and patient-reported symptoms versus placebo at week 16 in Japanese patients with PPP with sustained improvements through week 32. No new safety signals were observed. CLINICALTRIALS: GOV: NCT04057937.

Safety of Ixekizumab in Adult Patients with Moderate-to-Severe Psoriasis: Data from 17 Clinical Trials with Over 18,000 Patient-Years of Exposure.

INTRODUCTION: We report a comprehensive summary of the safety outcomes in adult patients with moderate-to-severe psoriasis with up to 5 years of exposure to ixekizumab. METHODS: Long-term safety of the IL-17A antagonist ixekizumab was assessed from 17 randomized trials. Treatment-emergent adverse events (TEAEs)-adjusted incidence rates (IRs) per 100 patient-years (PY) within 1-year time periods through 19 March 2021 were calculated for all patients treated with at least one dose of ixekizumab. Reported cases of major adverse cerebro-cardiovascular events (MACE) and inflammatory bowel disease (IBD) were adjudicated. RESULTS: A total of 6892 adult patients with a cumulative exposure of 18,025.7 PY were included. The IRs per 100 PY for any TEAE and serious adverse events (AEs) were 32.5 and 5.4. IR of discontinuation because of AE was 2.9. A total of 36 deaths were reported. IR of serious infections was low (1.3). There were no confirmed cases of reactivation of tuberculosis (TB). IR of Candida infections (IR 1.9) was low; most cases of Candida were localized, and no systemic cases were reported. IRs of injection site reactions and allergic/hypersensitivity were 5.9 and 5.6, respectively. No confirmed cases of anaphylaxis were observed. IRs were low for malignancies, depression, cytopenia, and MACE (all ≤ 1.2). IBD events were uncommon, although a total of 31 patients (IR 0.2) had confirmed IBD (ulcerative colitis, n = 18; Crohn disease, n = 13). Across safety topics, IRs decreased or remained constant over time. CONCLUSIONS: The long-term safety profile for ixekizumab is consistent with that previously reported in patients with psoriasis. No new or unexpected safety events were detected.

Real-world safety and effectiveness of adalimumab in patients with hidradenitis suppurativa: 12-week interim analysis of post-marketing surveillance in Japan.

Hidradenitis suppurativa (HS) is a painful chronic skin disease characterized by abscesses, nodules, and tunnels in the skin. Adalimumab, a monoclonal antibody against tumor necrosis factor-α, is approved for the treatment of HS in Europe, the USA, and Japan. This multicenter, open-label, post-marketing, observational study (ClinicalTrials.gov: NCT03894956) evaluated the safety and effectiveness of adalimumab in routine clinical practice in Japan (March 2019-May 2021). Patients with HS were treated with s.c. doses of adalimumab according to the dosage described in the package insert. The primary end-point was safety (data cut-off, December 2020). Secondary end-points assessed effectiveness, including HS Clinical Response (HiSCR), skin pain, Dermatology Life Quality Index (DLQI), and C-reactive protein (CRP). Here, we report 12-week interim effectiveness results. A total of 84 eligible patients from 65 sites were enrolled; 83 patients were included in this analysis. Mean age was 42.0 years, mean body mass index was 26.9 kg/m2 , 78.3% of patients were male, 61.4% had Hurley stage III disease, 39.8% had a disease duration ≥10 years, and 7.2% had a family history of HS. The most common affected sites were the axilla (60.2%), buttocks (59.0%), and the inguinal and femoral regions (47.0%). Mean abscess and inflammatory nodule count was 13.0 (standard deviation, 12.0). Among patients with a comorbidity (57.8%), the most common were diabetes mellitus, hypertension, and chronic kidney disease. No patient reported a serious infection or any safety event of special interest. One patient died from a serious adverse event of cardiac failure unrelated to adalimumab. At week 12, 57.4% of patients achieved HiSCR, and significant reductions from baseline in skin pain, DLQI (both p < 0.0001), and CRP (p = 0.0029) were observed. These results support the administration of adalimumab as a well-tolerated and effective treatment for Japanese patients with HS in real-world clinical practice.

English version of guidelines for the management of asteatosis 2021 in Japan.

This is the English version of guidelines for the management of asteatosis 2021 in Japan. Asteatosis is a synonym of xerosis found in a wide range of diseases that induce dry skin through impaired functions of either water retention of the stratum corneum or skin covering with acid mantle. Patients with asteatosis may be accompanied by pruritus. Moisturizers are the first-line treatment for asteatosis and their adequate use must be recommended. The main purpose of the present guidelines is to define skin symptoms requiring treatment with moisturizers for medical use in patients with asteatosis. If the deterioration of marked scaling or scratch marks is predicted, therapeutic intervention with moisturizers for medical use should be considered even in the absence of pruritus. Regarding six important points requiring decision-making in clinical practice (clinical questions), we evaluated the balance between the benefits and harm of medical interventions in reference to previous reports of clinical research, and presented the recommendation grades and evidence levels to optimize the patient outcome by medical interventions.

Sustained efficacy and safety of guselkumab in patients with palmoplantar pustulosis through 1.5 years in a randomized phase 3 study.

The safety and efficacy of guselkumab for palmoplantar pustulosis (PPP) have been established through week (W)52; however, no sufficient information is available beyond 1 year. This study was conducted to assess the efficacy and safety of guselkumab through W84, and to explore factors associated with the sustainability of its efficacy in Japanese PPP patients. Patients received guselkumab 100 or 200 mg at W0, W4, W12, and every 8 weeks (q8w) until W60, or placebo at W0, W4, and W12. At W16, patients receiving placebo were re-randomized to receive guselkumab 100/200 mg at W16, W20, and q8w until W60. Efficacy end-points included PPP Area and Severity Index (PPPASI), PPP Severity Index (PPSI), Physician's Global Assessment scores, and patient reported outcomes (PRO) (Dermatology Life Quality Index, EuroQoL-5 Dimensions, and 36-item Short Form Health Survey). Post-hoc comparison of patient characteristics was performed between PPPASI-75/90 responders and non-responders at W60, and sustained responders and non-responders at W84. Safety was evaluated through W84. A total of 45, 43, 21, and 24 patients from the guselkumab 100 mg, guselkumab 200 mg, placebo→guselkumab 100 mg, and placebo→guselkumab 200 mg groups, respectively, completed the study through W84. Overall, the mean improvement in the guselkumab groups from baseline in the PPPASI and PPSI total scores at W84 was ~79% and ~66%, respectively. All PRO improved through W84. The proportion of responders through W60 was higher in patients who had not received prior phototherapy and non-biologic systemic therapy for PPP. Non-smokers and patients with no prior non-biologic systemic treatment tended numerically towards sustained efficacy through W84. The majority of treatment-emergent adverse events (TEAE) were mild to moderate (~88%) with low incidence of serious TEAE (7.6%). Overall, guselkumab showed sustained efficacy and safety with improvement in the health-related quality of life through W84 in Japanese PPP patients.

Serum level of hemokinin-1 is significantly lower in patients with chronic spontaneous urticaria than in healthy subjects.

BACKGROUND: We previously reported upregulation of expression of Mas-related G protein-coupled receptor X2 (MRGPRX2) on mast cells (MCs) in the skin of patients with severe chronic spontaneous urticaria (CSU). Serum levels of substance P (SP) were reportedly significantly elevated, in correlation with the severity of CSU. Hemokinin-1 (HK-1) reportedly induced histamine release from LAD2 cells via MRGPRX2. We aimed to investigate HK-1's role in CSU. METHODS: The concentrations of HK-1 and SP were measured using ELISAs. Skin- and synovium-derived cultured MCs were generated by culturing dispersed skin and synovial cells, respectively, with stem cell factor. MRGPRX2 expression in the MCs was reduced using a lentiviral shRNA silencing technique. RESULTS: Anti-SP Ab used in the SP ELISA showed 100% cross-reactivity to HK-1, but anti-HK-1 Ab showed 0% cross-reactivity to SP. The serum level of HK-1 was significantly lower in patients with CSU (n = 151) than in non-atopic healthy control (NC) subjects (n = 114). The EC50 of histamine release from MCs induced by HK-1 (5056 nM) was 12-fold higher than by SP (426 nM). Brief pretreatment of MCs with HK-1 at concentrations of 3.0-10 µM significantly reduced histamine release by 0.1 µM SP. However, brief incubation of MCs with HK-1 did not elicit rapid MRGPRX2 internalization. CONCLUSIONS: In NC subjects, high HK-1 concentrations may desensitize MGRPRX2-mediated MC activation, thereby preventing MC degranulation by SP.

miR103a-3p in extracellular vesicles from FcεRI-aggregated human mast cells enhances IL-5 production by group 2 innate lymphoid cells.

BACKGROUND: Mast cells (MCs) are key regulators of IgE-mediated allergic inflammation. Cell-derived extracellular vesicles (EVs) contain bioactive compounds such as microRNAs. EVs can transfer signals to recipient cells, thus using a novel mechanism of cell-to-cell communication. However, whether MC-derived EVs are involved in FcεRI-mediated allergic inflammation is unclear. OBJECTIVE: We sought to investigate the effect of EVs derived from FcεRI-aggregated human MCs on the function of human group 2 innate lymphoid cells (ILC2s). METHODS: Human cultured MCs were sensitized with and without IgE for 1 hour and then incubated with anti-IgE antibody, IL-33, or medium alone for 24 hours. EVs in the MC supernatant were isolated by using ExoQuick-TC. RESULTS: Coculture of ILC2s with EVs derived from the FcεRI-aggregated MCs significantly enhanced IL-5 production and sustained upregulation of IL-5 mRNA expression in IL-33-stimulated ILC2s, but IL-13 production and IL-13 mRNA expression were unchanged. miR103a-3p expression was upregulated in IL-33-stimulated ILC2s that had been cocultured with EVs derived from anti-IgE antibody-stimulated MCs. Transduction of an miR103a-3p mimic to ILC2s significantly enhanced IL-5 production by IL-33-stimulated ILC2s. miR103a-3p promoted demethylation of an arginine residue of GATA3 by downregulating protein arginine methyltransferase 5 (PRMT5) mRNA. Reduction of protein arginine methyltransferase 5 expression in ILC2s by using a small interfering RNA technique resulted in upregulation of IL-5 production by IL-33-stimulated ILC2s. Furthermore, the level of miR103a-3p expression was significantly higher in EVs from sera of patients with atopic dermatitis than in EVs from nonatopic healthy control subjects. CONCLUSION: Eosinophilic allergic inflammation may be exacerbated owing to ILC2 activation by MC-derived miR103a-3p.