Epidemiology, Treatment Patterns, and Healthcare Resource Utilization Study of Patients With Alopecia Areata in Taiwan's National Health Insurance Research Database.

OBJECTIVES: This study investigated the epidemiology, treatment patterns, and resource utilization in patients with alopecia areata (AA) in Taiwan using the National Health Insurance Research Database. AA severity was determined by treatment use and diagnostic codes in the year after enrollment (including corticosteroids, systemic immunosuppressants, topical immunotherapy, and phototherapy). METHODS: The cross-sectional analysis was conducted to estimate the incidence and prevalence of AA from 2016 to 2020. For the longitudinal analysis, 2 cohorts were identified: mild/moderate and severe. The cohorts were matched based on age, gender, and comorbidities. Patients were enrolled upon their first claim with an AA diagnosis during the index period of 2017-2018. RESULTS: The number of patients with AA increased from 3221 in 2016 to 3855 in 2020. The longitudinal analysis identified 1808 mild/moderate patients and 452 severe patients. Mild/moderate patients used higher levels of topical corticosteroids (82.41%) than severe patients (73.45%). Conversely, severe patients used more topical nonsteroids (41.81%) and systemic therapies (51.77%) than mild/moderate patients (0.44% and 16.15%, respectively). Oral glucocorticoids use was higher in severe patients (47.57%) relative to mild/moderate patients (14.88%), whereas the use of injectable forms was similar. The most used systemic immunosuppressants were methotrexate, cyclosporin, and azathioprine. Topical immunotherapy utilization decreased with subsequent treatment lines for severe patients. Treatment persistence at 6 months was low for all treatments. Severe patients had higher annual AA-related outpatient visits than the mild/moderate cohort. CONCLUSIONS: These findings highlight the need for additional innovations and therapies to address the clinical and economic burden of AA.

Use of biologics in Chinese pregnant patients with deficiency of interleukin-36 receptor antagonist (DITRA): A case series.

OBJECTIVE: Impetigo herpetiformis (IH) is a rare form of pustular psoriasis which may result in maternal and fetal morbidity and even mortality. Deficiency of interleukin-36 receptor antagonist (DITRA) is the most frequently identified genetic defect of IH. Currently there are no biologics approved for IH despite the revolutionary role of biologics in the treatment of plaque and pustular psoriasis. Anecdotal reports of biologics use in DITRA patients with IH are also limited. CASE REPORTS: We present herein a case series of 6 Chinese IH patients harboring IL36RN gene c.115+6T>C mutation during 8 pregnancies, treated with various biologics, including adalimumab, etanercept and secukinumab. CONCLUSION: Most pregnancy courses were uneventful, except for one woman who had recurrent episodes of decreased fetal heart rate variability after adalimumab injections, which subsided after switching to etanercept. The treatment effectiveness and safety demonstrated in our cases suggested the role of biologics for the treatment of IH in patients with DITRA.

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.

Acquired diffuse palmoplantar erythema with keratoderma in Chinese patients with pustular psoriasis: A predictor for IL36 receptor antagonist c.115+6T>C mutation?

Several studies have suggested that mutation of the interleukin 36 receptor antagonist gene (IL36RN) is related to generalized pustular psoriasis (GPP), and the presence of IL36RN mutation may affect the clinical manifestations and treatment responses. However, genetic testing is not routinely available in clinical practice for the diagnosis of GPP. Previously, GPP patients with acrodermatitis continua of Hallopeau (ACH) were found to have a high percentage of carrying IL36RN mutation. In this study, we reported six patients with pustular psoriasis presenting as diffuse palmoplantar erythema with keratoderma among 60 patients who carried IL36RN mutation. ACH was present in five patients and five patients had acute flare of GPP. This unique presentation may serve as a predictor for IL36RN mutation in patients with pustular psoriasis, similar to ACH.

Drug- or Vaccine-Induced/Aggravated Psoriatic Arthritis: A Systematic Review.

INTRODUCTION: Drugs and vaccines have been less studied as inducing or aggravating factors for psoriatic arthritis (PsA) compared with psoriasis. Thus, the present study collected and summarized the publications to date about this issue. METHODS: We conducted a systematic literature search through the PubMed, Embase, and Cochrane databases to identify all reports on potential drug- and vaccine-related PsA events until 28 February 2023. RESULTS: In total, 179 cases from 79 studies were eligible for study. Drugs commonly reported include coronavirus disease 2019 (COVID-19) mRNA vaccines (6 cases), bacillus Calmette-Guerin (BCG) vaccine (3 cases), interferon (18 cases), immune-checkpoint inhibitors (ICI) (19 cases), and biologic disease-modifying antirheumatic drugs (bDMARDs) (127 cases). Drugs causing psoriasis may also induce or aggravate PsA (6 cases). BDMARD-related PsA mostly occurred in a "paradoxical" setting, in which the bDMARDs approved for the treatment of psoriasis induce or aggravate PsA. The reported latency may be delayed up to 2 years. Peripheral arthritis (82.3%) was the most common manifestation of drug- and vaccine-related PsA, followed by dactylitis (29.1%), enthesitis (23.4%), and spondyloarthritis (17.7%). CONCLUSIONS: Drugs and vaccines may be implicated in the aggravation of PsA. Possible mechanisms include cytokine imbalance, immune dysregulation, or inadequate PsA treatment response compared with psoriasis. Most reports are case based without controls, so more studies are needed to further prove the causality. However, early recognition of factors causing or aggravating PsA is important to prevent the irreversible joint damage.

Clinical advances in biological therapy for generalized pustular psoriasis: a review.

INTRODUCTION: In 2022, U.S. Food and Drug Administration (FDA) approved the first biologics, intravenous spesolimab, for acute flare of generalized pustular psoriasis (GPP). The drug works by blocking IL-36 signaling, the key pathway of GPP. Among the known mutations causing GPP, IL36RN mutations are most common, and the presence of IL36RN mutations had been found to affect the clinical manifestations and treatment response of GPP. AREAS COVERED: Literature search was conducted in PubMed, Embase and ClinicalTrials.gov for relevant studies discussing biologic treatment for GPP with special emphasis on larger studies, pediatric group, pregnant women, and the influence of IL36RN mutation on the effectiveness of biologics. EXPERT OPINION: The approval of spesolimab for GPP flare treatment marks a new era. However, whether spesolimab will be placed as the treatment of choice remains unknown, considering its higher cost, lack of direct comparison with existing biologics, and uncertain effects on co-existing plaque-type psoriasis. However, the demonstration of numerically better efficacy for patients carrying pathogenic IL36RN mutations suggests the role of pharmacogenetics in the choices of GPP treatment. Future randomized studies are warranted to investigate the effectiveness and safety of biologics for GPP in pediatric and pregnant groups.

A Review of Dupilumab-Induced Adverse Events to Dermatologists and the Potential Pathogenesis in the Treatment of Atopic Dermatitis.

Dupilumab, a monoclonal antibody targeting interleukin-4 antibody, is approved for use in many type 2 inflammatory diseases, including atopic dermatitis. It is generally well tolerated with no need of routine laboratory monitoring. However, several adverse events have been reported during real-world practice and in pivotal trials. We conducted a systematic literature research of the PubMed, Medline, and Embase databases to identify articles recording the clinical manifestation and potential pathogenesis of these adverse events with interests (AEIs) to dermatologists. In total, 547 cases from 134 studies have developed 39 AEIs 1 day to 2.5 years after dupilumab treatment. The most common AEIs are facial and neck dermatitis (299 cases), psoriasis (70 cases), arthralgia (56 cases), alopecia (21 cases), cutaneous T cell lymphoma (19 cases), severe ocular diseases (19 cases), and drug eruption (6 cases). Most of the AEIs recorded in this review resolved or improved after dupilumab discontinuation or the addition of another treatment, whereas 3 of the cases died of severe AEI. The potential pathogenesis included T help type 1 (Th1)/T help type 2 (Th2) imbalance, Th2/T help type 17 (Th17) imbalance, immune reconstitution, hypersensitivity reaction, transient hypereosinophilia related, and Th1 suppression. Clinicians should be alert of these AEIs for timely diagnosis and appropriate treatment.

Combination of methotrexate with oral disease-modifying antirheumatic drugs in psoriatic arthritis: a systematic review.

Background: Oral conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), especially methotrexate, are the cornerstone of treating psoriatic arthritis (PsA). The use of csDMARDs with biologics has increased their efficacy in psoriasis. However, the combination of two oral DMARDs in patients with PsA has not been adequately reviewed. In this study, we explore the combinational use of methotrexate with DMARDs in PsA patients. Materials & methods: A review was conducted using Medline (PubMed), Embase, Web of Science and the Cochrane Library, covering articles up to February 2023. Results & conclusion: Nine studies comprising 1993 participants were included. The evidence supporting combination therapy remains limited. Combinational therapy could be considered in patients with inadequate response to monotherapy or no access to biologics.

This study aimed to determine whether combining two different medicines could serve as an option for patients with psoriatic arthritis (PsA). Typically, doctors prescribe just one medicine, but sometimes its efficacy is limited. After reviewing nine studies with 1993 participants, it appears that using two medicines together might be an alternative option for PsA patients who do not experience sufficient relief from a single medicine. This research contributes to our understanding of using this combination approach for PsA and suggests that further larger studies could confirm its potential as a beneficial method for improving the health of these patients.

Pressure and Skin: A Review of Disease Entities Driven or Influenced by Mechanical Pressure.

Skin perceives and reacts to external mechanical forces to create resistance against the external environment. Excessive or inappropriate stimuli of pressure may lead to cellular alterations of the skin and the development of both benign and malignant skin disorders. We conducted a comprehensive literature review to delve into the pressure-induced and aggravated skin disorders and their underlying pressure-related mechanisms. Dysregulated mechanical responses of the skin give rise to local inflammation, ischemia, necrosis, proliferation, hyperkeratosis, impaired regeneration, atrophy, or other injurious reactions, resulting in various disease entities. The use of personal devices, activities, occupations, weight bearing, and even unintentional object contact and postures are potential scenarios that account for the development of pressure-related skin disorders. The spectrum of these skin disorders may involve the epidermis (keratinocytes and melanocytes), hair follicles, eccrine glands, nail apparatuses, dermis (fibroblasts, mast cells, and vasculature), subcutis, and fascia. Clarifying the clinical context of each patient and recognizing how pressure at the cellular and tissue levels leads to skin lesions can enhance our comprehension of pressure-related skin disorders to attain better management.

Effectiveness of Biologics, Patient-Reported Outcomes, and Clinical Photography in a Subset of Patients with Moderate-to-Severe Psoriasis: Week 12 Results from the Psoriasis Study of Health Outcomes (PSoHO).

Purpose: Since skin is highly accessible, clinical photography is a useful tool to visually substantiate the real-world effectiveness outcomes of biologic-treated adults with moderate-to-severe psoriasis (PsO). We report the effectiveness and patient-reported outcomes at Week 12 between anti-interleukin (IL)-17A biologics and other biologics as well as ixekizumab and guselkumab in patients with available clinical photography at baseline and Week 12. Patients and Methods: The Psoriasis Study of Health Outcomes (PSoHO) is an international, non-interventional, cohort study investigating the effectiveness of biologics in adults with moderate-to-severe psoriasis at Week 12. Outcomes included the proportion of patients who achieved 90% improvement in Psoriasis Area and Severity Index (PASI90) and/or static Physician Global Assessment (sPGA) 0/1 (primary endpoint), PASI100, PASI90, Dermatology Life Quality Index (DLQI), and Itch Numeric Rating Scale (NRS) (secondary endpoints) at Week 12. Data are reported descriptively. Results: This analysis included 59 biologic-treated (23 anti-IL-17A; 36 other biologics) patients with available clinical photographs from the overall PSoHO study (n=1981). At baseline, the mean (standard deviation [SD]) age was 45.7 (11.1) years, 71.2% were male, 52.5% were bio-experienced and the median (interquartile range) duration of disease was 10.5 (12.4) years. Mean (SD) PASI was 16.9 (9.3) and sPGA was 3.5 (0.8). At Week 12, 65.2%/47.2% of the anti-IL-17A/other biologics cohort achieved the primary outcome. Response rates for PASI90/100 were numerically higher with anti-IL-17A than with other biologics. Patients receiving anti-IL-17A had numerically better outcomes for DLQI 0/1 and Itch NRS than those receiving other biologics at Week 12. Clinical photographs confirmed skin improvements in ixekizumab- and guselkumab-treated patients. Conclusion: This subgroup analysis showed that anti-IL-17A biologics are effective at rapidly improving signs and symptoms of PsO and improving quality of life. Additionally, serial photography provided visual evidence of biologic treatment response over time.

Predictors for the effectiveness of 75 mg risankizumab in treating psoriasis-A real-word evidence from a 52-week retrospective study.

In the registration trial of risankizumab for patients with moderate-to-severe psoriasis in Japan, similar Psoriasis Area Severity Index (PASI) responses were observed for 75 mg or 150 mg risankizumab at most time points up to 52 weeks, except for PASI 100 at week 16. The use of 75 mg risankizumab offers an attractive option considering the high cost of risankizumab. However, it is unknown whether patients with mild-to-moderate psoriasis respond similarly, and the efficacy data of non-Japanese patients is also lacking. We retrospectively included 30 consecutive Chinese patients receiving half-dose (75 mg) risankizumab as scheduled up to 52 weeks. Compared with biologic-experienced group, biologic-naive group had a significantly higher PASI 50/75/90/100 achievement (p = 0.0098/0.0039/0.0016/0.0054) at week 52. PASI 50/75/90/100 curves in biologic-naive group (p = 0.0117/0.0239/0.0143/0.0269) were also significantly higher when analysed generalized estimating equations (GEE) model. Though there was no statistically significant difference in terms of PASI 50/75/90/100 responses at any time points between those with body weight ≦ 65 kg and those >65 kg, a tendency of secondary failure was noted in those >65 kg from week 40 onwards. Patients who were both biologic-naive and weighed ≦ 65 kg achieved sustained PASI 50/75/90 responses from week 16/28/40 onwards, respectively, indicating that they could be considered as potential candidates for 75 mg risankizumab. Though PASI 75 curve in patients without diabetes mellitus (DM) surpassed that in patient without DM, curves of other parameters did not reach significance when analysed by GEE model. There was no HBV, HCV or TB reactivation, nor other new safety signals during the 52-week observational period. Providing risankizumab with flexible dosing options is beneficial in clinical practice considering the high cost of this medication.

Efficacy and Safety of Spesolimab in Patients with Generalized Pustular Psoriasis: A Subgroup Analysis of Chinese Patients in the Effisayil 1 Trial.

INTRODUCTION: Generalized pustular psoriasis (GPP) is a rare and potentially life-threatening skin disease. The global Effisayil 1 study investigated the efficacy and safety of spesolimab, a humanized monoclonal antibody targeting the IL-36 receptor, in patients experiencing GPP flare. This analysis aimed to explore the efficacy and safety of spesolimab in the Chinese subgroup of Effisayil 1. METHODS: Effisayil 1 was a multicenter, randomized, double-blind, placebo-controlled phase II study. Eligible patients with a GPP flare were randomly assigned (2:1) to receive a single intravenous dose of spesolimab (900 mg) or placebo on day 1. On day 8, patients who had persistent symptoms that met a predefined criterion could receive open-label spesolimab. After day 8, patients with recurrent flares following clinical response could receive rescue treatment with open-label spesolimab. The primary end point was a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation sub-score of 0 at week 1. The key secondary end point was a GPPGA total score of 0 or 1 at week 1. RESULTS: Eleven Chinese patients were randomized, with five patients receiving spesolimab and six receiving placebo. At week 1, 60.0% (3/5) of patients in the spesolimab group and 16.7% (1/6) of patients in the placebo group achieved a GPPGA pustulation sub-score of 0 (risk difference 43.3%; 95% CI -22.6, 86.2); 60.0% and 16.7% of patients in the spesolimab and placebo group, respectively, achieved a GPPGA total score 0 or 1 (risk difference 43.3%; 95% CI -22.6, 86.2). Overall, four patients in each group of the spesolimab and the placebo groups reported at least one adverse event (AE) by week 1, with two and three reporting drug-related AEs, respectively. One patient reported a serious AE that was not considered to be drug related. No death occurred during the study period. CONCLUSION: In the Chinese subgroup of the Effisayil 1 study, more patients receiving spesolimab experienced lesion clearance than those on placebo at week 1, with an acceptable safety profile that was consistent with the global study population. TRIAL REGISTRATION: NCT03782792.

The Pressurized Skin: A Review on the Pathological Effect of Mechanical Pressure on the Skin from the Cellular Perspective.

Since human skin is the primary interface responding to external mechanical stimuli, extrinsic forces can disrupt its balanced microenvironment and lead to cutaneous lesions. We performed this review to delve into the pathological effects of mechanical pressure on skin from the cellular perspective. Fibroblasts of different subsets act as heterogeneous responders to mechanical load and express diverse functionalities. Keratinocytes relay mechanical signals through mechanosensitive receptors and the ensuing neurochemical cascades to work collaboratively with other cells and molecules in response to pressure. Mast cells release cytokines and neuropeptides, promoting inflammation and facilitating interaction with sensory neurons, while melanocytes can be regulated by pressure through cellular and molecular crosstalk. Adipocytes and stem cells sense pressure to fine-tune their regulations of mechanical homeostasis and cell differentiation. Applying mechanical pressure to the skin can induce various changes in its microenvironment that potentially lead to pathological alterations, such as ischemia, chronic inflammation, proliferation, regeneration, degeneration, necrosis, and impaired differentiation. The heterogeneity of each cellular lineage and subset from different individuals with various underlying skin conditions must be taken into consideration when discussing the pathological effects of pressure on the skin. Thus, elucidating the mechanotransduction and mechanoresponsive pathways from the cellular viewpoint is crucial in diagnosing and managing relevant dermatological disorders.