Allergic Rhinitis in Children: An Underestimated Disease.

Allergic rhinitis affects approximately 40% of children. This study aimed at determining the prevalence, sociodemographic features, comorbid illnesses, complications and quality of life in children referred to the outpatient clinic of "Allergic Rhinitis" in Penteli Children Hospital, Athens, Greece. We analyzed 590 pediatric patients referred to the outpatient clinic of "Allergic Rhinitis" in Penteli Children Hospital, Athens, Greece from 26/01/2012 to 20/11/2022. Allergic rhinitis was recorded as the one and only allergic disease in 59% of the children diagnosed with allergic rhinitis, concomitant asthma in 16% of them, atopic dermatitis in 8% and allergic conjunctivitis in 5%. 54% of asthmatic children was diagnosed allergic rhinitis, while 16% of allergic rhinitis children was diagnosed asthma. Skin tests were important diagnostic tools, not being necessary the measurement of total IgE in plasma. Eosinophils from nasal secretions were increased in 19% of the children with non-diagnostic cases and the diagnosis was local allergic rhinitis (LAR). Clinical presentations of allergic rhinitis were mainly nasal blockage, runny nose, recurrent sneezing and nasal itching. The most common complication was acute or chronic sinusitis 35%. Major associated comorbid illnesses among were tonsils hypertrophy, adenoid hypertrophy and inferior turbinate hypertrophy. Allergic rhinitis was reported in 78% of studied children and was frequently characterized by significant morbidity. Allergic rhinitis affected all paediatric age group and was peaked at age group 11-14 years and 5-7 years. There were associated epidemiological features, clinical manifestations, comorbid illnesses, complications and affectation of the quality of life in children.

Atopic Dermatitis: Molecular Alterations between Lesional and Non-Lesional Skin Determined Noninvasively by In Vivo Confocal Raman Microspectroscopy.

Atopic dermatitis (AD)/atopic eczema is a chronic relapsing inflammatory skin disease affecting nearly 14% of the adult population. An important pathogenetic pillar in AD is the disrupted skin barrier function (SBF). The atopic stratum corneum (SC) has been examined using several methods, including Raman microspectroscopy, yet so far, there is no depth-dependent analysis over the entire SC thickness. Therefore, we recruited 21 AD patients (9 female, 12 male) and compared the lesional (LAS) with non-lesional atopic skin (nLAS) in vivo with confocal Raman microspectroscopy. Our results demonstrated decreased total intercellular lipid and carotenoid concentrations, as well as a shift towards decreased orthorhombic lateral lipid organisation in LAS. Further, we observed a lower concentration of natural moisturising factor (NMF) and a trend towards increased strongly bound and decreased weakly bound water in LAS. Finally, LAS showed an altered secondary and tertiary keratin structure, demonstrating a more folded keratin state than nLAS. The obtained results are discussed in comparison with healthy skin and yield detailed insights into the atopic SC structure. LAS clearly shows molecular alterations at certain SC depths compared with nLAS which imply a reduced SBF. A thorough understanding of these alterations provides useful information on the aetiology of AD and for the development/control of targeted topical therapies.

Targeting Metabolic Syndrome in Hidradenitis Suppurativa by Phytochemicals as a Potential Complementary Therapeutic Strategy.

Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by the appearance of painful inflamed nodules, abscesses, and pus-draining sinus tracts in the intertriginous skin of the groins, buttocks, and perianal and axillary regions. Despite its high prevalence of ~0.4-1%, therapeutic options for HS are still limited. Over the past 10 years, it has become clear that HS is a systemic disease, associated with various comorbidities, including metabolic syndrome (MetS) and its sequelae. Accordingly, the life expectancy of HS patients is significantly reduced. MetS, in particular, obesity, can support sustained inflammation and thereby exacerbate skin manifestations and the chronification of HS. However, MetS actually lacks necessary attention in HS therapy, underlining the high medical need for novel therapeutic options. This review directs attention towards the relevance of MetS in HS and evaluates the potential of phytomedical drug candidates to alleviate its components. It starts by describing key facts about HS, the specifics of metabolic alterations in HS patients, and mechanisms by which obesity may exacerbate HS skin alterations. Then, the results from the preclinical studies with phytochemicals on MetS parameters are evaluated and the outcomes of respective randomized controlled clinical trials in healthy people and patients without HS are presented.

Altered structure indicating reduced barrier function of lesional compared to non-lesional psoriatic skin-A non-invasive in vivo study of the human stratum corneum with confocal Raman micro-spectroscopy.

Psoriasis, one of the most common skin diseases affecting roughly 2%-3% of the world population, is associated with a reduced skin barrier function (SBF) that might play an important role in its pathophysiology. The SBF is provided primarily by the stratum corneum (SC) of the skin. Previous studies have revealed a higher trans-epidermal water loss, lower hydration, abnormal concentration and composition of intercellular lipids, as well as alterations in secondary keratin structure in the psoriatic SC. We compared on molecular level lesional psoriatic skin (LPS) with non-lesional psoriatic skin (nLPS) from 19 patients non-invasively in vivo, using confocal Raman micro-spectroscopy. By analysing the corresponding Raman spectra, we determined SBF-defining parameters of the SC depth-dependently. Our results revealed a lower total lipid concentration, a shift of lamellar lipid organisation towards more gauche-conformers and an increase of the less dense hexagonal lateral packing of the intercellular lipids in LPS. Furthermore, we observed lower natural moisturising factor concentration, lower total water as well as a strong tendency towards less strongly bound and more weakly bound water molecules in LPS. Finally, we detected a less stable secondary keratin structure with increased ß-sheets, in contrast to the tertiary structure, showing a higher degree of folded keratin in LPS. These findings clearly suggest structural differences indicating a reduced SBF in LPS, and are discussed in juxtaposition to preceding outcomes for psoriatic and healthy skin. Understanding the alterations of the psoriatic SC provides insights into the exact pathophysiology of psoriasis and paves the way for optimal future treatments.

Bimekizumab efficacy and safety in patients with moderate-to-severe plaque psoriasis who switched from adalimumab, ustekinumab or secukinumab: results from phase III/IIIb trials.

BACKGROUND: Discontinuation of biologics is common among patients with psoriasis due to treatment failure or adverse events. To achieve improvements in disease management, patients and clinicians may choose to switch biologics. OBJECTIVES: To evaluate the efficacy and safety of switching to bimekizumab from adalimumab, ustekinumab and secukinumab. METHODS: Data are reported for up to 80 weeks after patients switched to bimekizumab from adalimumab at week 24 in BE SURE, ustekinumab at week 52 in BE VIVID [upon entry into the BE BRIGHT open-label extension (OLE)] and secukinumab at week 48 in BE RADIANT (upon entry into the BE RADIANT OLE). Efficacy outcomes are reported by number of weeks after switching to bimekizumab and were split based on whether patients had achieved a ≥ 90% improvement from baseline in Psoriasis Area and Severity Index (PASI 90) at the time of switch. Treatment-emergent adverse events (TEAEs) are reported using exposure-adjusted incidence rates (EAIRs) per 100 patient-years. Trial registration: BE SURE (NCT03412747), BE VIVID (NCT03370133), BE BRIGHT (NCT03598790), BE RADIANT (NCT03536884). RESULTS: Rapid and durable improvements in clinical responses and benefits in health-related quality of life were observed among PASI 90 nonresponders who switched to bimekizumab. Most PASI 90 nonresponders achieved PASI 90 4 weeks after switching to bimekizumab from adalimumab (67%), ustekinumab (79%) and secukinumab (53%). After 48 weeks of bimekizumab, 91%, 90% and 79% of PASI 90 nonresponders had achieved PASI 90 after switching from adalimumab, ustekinumab or secukinumab, respectively. Durable improvements were also observed for PASI 100, Investigator's Global Assessment score 0/1, body surface area affected by psoriasis ≤ 1%, absolute PASI ≤ 2, and Dermatology Life Quality Index 0/1. Among PASI 90 responders, existing treatment responses were maintained or improved after switching to bimekizumab. The majority of TEAEs were mild or moderate. EAIRs were generally similar between active-comparator treatment periods and after switching to bimekizumab. EAIRs typically decreased with a longer duration of bimekizumab exposure. CONCLUSIONS: High proportions of patients who did not adequately respond to adalimumab, ustekinumab or secukinumab achieved high levels of skin clearance after switching to bimekizumab. Bimekizumab was well tolerated and there were no new safety findings.

Secukinumab in moderate-to-severe hidradenitis suppurativa (SUNSHINE and SUNRISE): week 16 and week 52 results of two identical, multicentre, randomised, placebo-controlled, double-blind phase 3 trials.

BACKGROUND: Few therapeutic options are available for patients with moderate-to-severe hidradenitis suppurativa. We aimed to assess the efficacy of secukinumab in patients with moderate-to-severe hidradenitis suppurativa in two randomised trials. METHODS: SUNSHINE and SUNRISE were identical, multicentre, randomised, placebo-controlled, double-blind phase 3 trials done in 219 primary sites in 40 countries. Patients aged 18 years old or older with the capacity to provide written informed consent and with moderate-to-severe hidradenitis suppurativa (defined as a total of ≥5 inflammatory lesions affecting ≥2 distinct anatomical areas) for at least 1 year were eligible for inclusion. Included patients also agreed to daily use of topical over-the-counter antiseptics on the areas affected by hidradenitis suppurativa lesions while on study treatment. Patients were excluded if they had 20 or more fistulae at baseline, had ongoing active conditions requiring treatment with prohibited medication (eg, systemic biological immunomodulating treatment, live vaccines, or other investigational treatments), or met other exclusion criteria. In both trials, patients were randomly assigned (1:1:1) by means of interactive response technology to receive subcutaneous secukinumab 300 mg every 2 weeks, subcutaneous secukinumab 300 mg every 4 weeks, or subcutaneous placebo all via a 2 mL prefilled syringe in a double-dummy method as per treatment assignment. The primary endpoint was the proportion of patients with a hidradenitis suppurativa clinical response, defined as a decrease in abscess and inflammatory nodule count by 50% or more with no increase in the number of abscesses or in the number of draining fistulae compared with baseline, at week 16, assessed in the overall population. Hidradenitis suppurativa clinical response was calculated based on the number of abscesses, inflammatory nodules, draining fistulae, total fistulae, and other lesions in the hidradenitis suppurativa affected areas. Safety was assessed by evaluating the presence of adverse events and serious adverse events according to common terminology criteria for adverse events, which were coded using Medical Dictionary for Regulatory Activities terminology. Both the SUNSHINE, NCT03713619, and SUNRISE, NCT03713632, trials are registered with ClinicalTrials.gov. FINDINGS: Between Jan 31, 2019, and June 7, 2021, 676 patients were screened for inclusion in the SUNSHINE trial, of whom 541 (80%; 304 [56%] women and 237 [44%] men; mean age 36·1 years [SD 11·7]) were included in the analysis (181 [33%] in the secukinumab every 2 weeks group, 180 [33%] in the secukinumab every 4 weeks group, and 180 [33%] in the placebo group). Between the same recruitment dates, 687 patients were screened for inclusion in the SUNRISE trial, of whom 543 (79%; 306 [56%] women and 237 [44%] men; mean age 36·3 [11·4] years) were included in the analysis (180 [33%] in the secukinumab every 2 weeks group, 180 [33%] in the secukinumab every 4 weeks group, and 183 [34%] in the placebo group). In the SUNSHINE trial, significantly more patients in the secukinumab every 2 weeks group had a hidradenitis suppurativa clinical response (rounded average number of patients with response in 100 imputations, 81·5 [45%] of 181 patients) compared with the placebo group (60·7 [34%] of 180 patients; odds ratio 1·8 [95% CI 1·1-2·7]; p=0·0070). However, there was no significant difference between the number of patients in the secukinumab every 4 weeks group (75·2 [42%] of 180 patients) and the placebo group (1·5 [1·0-2·3]; p=0·042). Compared with the placebo group (57·1 [31%] of 183 patients), significantly more patients in the secukinumab every 2 weeks group (76·2 [42%] of 180 patients; 1·6 [1·1-2·6]; p=0·015) and the secukinumab every 4 weeks group (83·1 [46%] of 180 patients; 1·9 [1·2-3·0]; p=0·0022) had a hidradenitis suppurativa clinical response in the SUNRISE trial. Patient responses were sustained up to the end of the trials at week 52. The most common adverse event by preferred term up to week 16 was headache in both the SUNSHINE (17 [9%] patients in the secukinumab every 2 weeks group, 20 [11%] in the secukinumab every 4 weeks group, and 14 [8%] in the placebo group) and SUNRISE (21 [12%] patients in the secukinumab every 2 weeks group, 17 [9%] in the secukinumab every 4 weeks group, and 15 [8%] in the placebo group) trials. No study-related deaths were reported up to week 16. The safety profile of secukinumab in both trials was consistent with that previously reported, with no new or unexpected safety findings detected. INTERPRETATION: When given every 2 weeks, secukinumab was clinically effective at rapidly improving signs and symptoms of hidradenitis suppurativa with a favourable safety profile and with sustained response up to 52 weeks of treatment. FUNDING: Novartis Pharma.

Neutrophilic granulocyte-derived B-cell activating factor supports B cells in skin lesions in hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by painful inflamed nodules, abscesses, and pus-draining tunnels appearing in axillary, inguinal, and perianal skin areas. HS lesions contain various types of immigrated immune cells. OBJECTIVE: This study aimed to characterize mediators that support lesional B/plasma cell persistence in HS. METHODS: Skin samples from several cohorts of HS patients and control cohorts were assessed by mRNA sequencing, quantitative PCR on reverse-transcribed RNA, flow cytometry, and immunohistofluorescence. Blood plasma and cultured skin biopsy samples, keratinocytes, dermal fibroblasts, neutrophilic granulocytes (neutrophils), monocytes, and B cells were analyzed. Complex systems biology approaches were used to evaluate bulk and single-cell RNA sequencing data. RESULTS: Proportions of B/plasma cells, neutrophils, CD8+ T cells, and M0 and M1 macrophages were elevated in HS lesions compared to skin of healthy and perilesional intertriginous areas. There was an association between B/plasma cells, neutrophils, and B-cell activating factor (BAFF, aka TNFSF13B). BAFF was abundant in HS lesions, particularly in nodules and abscesses. Among the cell types present in HS lesions, myeloid cells were the main BAFF producers. Mechanistically, granulocyte colony-stimulating factor in the presence of bacterial products was the major stimulus for neutrophils' BAFF secretion. Lesional upregulation of BAFF receptors was attributed to B cells (TNFRSF13C/BAFFR and TNFRSF13B/TACI) and plasma cells (TNFRSF17/BCMA). Characterization of the lesional BAFF pathway revealed molecules involved in migration/adhesion (eg, CXCR4, CD37, CD53, SELL), proliferation/survival (eg, BST2), activation (eg, KLF2, PRKCB), and reactive oxygen species production (eg, NCF1, CYBC1) of B/plasma cells. CONCLUSION: Neutrophil-derived BAFF supports B/plasma cell persistence and function in HS lesions.

High Tolerability, Favorable Safety, and Subjects' Preference for a Single 200 mg/2 mL Tildrakizumab Injection: A Phase I, Open-Label, Randomized Crossover Trial in Healthy Volunteers.

INTRODUCTION: Tildrakizumab 200 mg/2 mL pre-filled syringe is a new preparation of tildrakizumab that is developed to facilitate patients' compliance. This phase I clinical trial compares the local tolerability, safety, and subjects' preferred method of administration of tildrakizumab when administered as a new single 200 mg/2 mL subcutaneous injection or as two 100 mg/1 mL subcutaneous injections in healthy subjects. METHODS: Visual analogue scores were used to self-assess injection site pain immediately (< 1 min) after each administration and at 1 h and 48 h after each administration. Treatment injection site reactions were assessed at 1 h and 48 h after each administration. Treatment safety was monitored throughout the study period. Subjects' preferred method of administration was assessed 4 weeks after the last administration (day 56). RESULTS: No statistically significant difference in visual analogue scores and injection site reactions was detected between the two treatments. Treatment-emergent adverse events were mild, and there were no deaths or serious adverse events. Most subjects (61.5%) preferred the treatment when administered as a single 200 mg/2 mL subcutaneous injection rather than as two 100 mg/mL subcutaneous injections. CONCLUSIONS: Administration of 200 mg tildrakizumab as a single 2 mL subcutaneous injection was safe, well tolerated, and preferred over two separate 100 mg/1 mL subcutaneous injections by healthy subjects. Eudract No. 2020-000183-37.

Early identification of axial psoriatic arthritis among patients with psoriasis: a prospective multicentre study.

OBJECTIVES: To evaluate a dermatologist-centred screening tool followed by a structured rheumatological examination including MRI of sacroiliac joints and spine for the recognition of psoriatic arthritis with axial involvement (axPsA). METHODS: This was a prospective multicentre study. Adult patients with a confirmed diagnosis of psoriasis who had chronic back pain (≥3 months), onset <45 years and had not been treated with any biologic or targeted synthetic disease-modifying antirheumatic drug in the 12 weeks before screening were referred to a specialised rheumatology clinic. A rheumatological investigation including clinical, laboratory and genetic assessments as well as imaging with conventional radiography and MRI of sacroiliac joints and spine was performed. The primary outcome of the study was the proportion of patients diagnosed with axPsA among all referred patients with PsO. RESULTS: Rheumatologists examined 100 patients of those who qualified for referral. 14 patients (including 3 with both axial and peripheral involvement) were diagnosed with axPsA and 5 were diagnosed with peripheral PsA solely. All patients diagnosed with axPsA had active inflammatory and/or structural (post)inflammatory changes in the sacroiliac joints and/or spine on imaging. In five patients, MRI changes indicative of axial involvement were found only in the spine. All but one patient with PsA (13/14 with axPsA and 5/5 with pPsA) fulfilled the Classification Criteria for Psoriatic Arthritis criteria for PsA. The Assessment of SpondyloArthritis International Society criteria for axSpA were fulfilled in 9 (64.3%) patients diagnosed with axPsA. CONCLUSIONS: Applying a dermatologist-centred screening tool may be useful for the early detection of axPsA in at-risk patients with psoriasis .

Generalized pustular psoriasis: overview of the status quo and results of a panel discussion.

Generalized pustular psoriasis (GPP) is a rare, severe, potentially life-threatening, autoinflammatory, neutrophilic skin disease that may be accompanied by fever and leukocytosis. This paper describes the current state of knowledge on GPP in terms of classification, (differential) diagnosis and prevalence. We present a comparison of the genetics and pathoimmunology of GPP and psoriasis vulgaris with the central mechanisms of autoimmunology and autoinflammation. The currently available therapeutic options, expert recommendations for therapy, and data from early clinical trials investigating targeted therapies will be summarized. We present the results of our discussion with 13 experts for psoriasis vulgaris and GPP and give an integrated overview of indication and therapy based on our personal experience and present an outlook on further research questions. Collectively, this article highlights the high unmet need in GPP, as there exists no satisfactory method of diagnosis or treatment to date and new treatment options will be of great therapeutic benefit to those affected.

Follow-Up Comparison of Fluorescence Optical Imaging With Musculoskeletal Ultrasound for Early Detection of Psoriatic Arthritis.

Objectives: Early diagnosis of psoriatic arthritis (PsA) is crucial for a patient outcome but hampered by heterogenous manifestation and a lack of specific biomarkers. We recently showed that fluorescence optical imaging (FOI) can differentiate between patients with confirmed and suspected PsA. This study aims to follow-up (FU) patients with confirmed and suspected PsA focusing on patients with a change from suspected to confirmed PsA by the use of FOI in comparison with musculoskeletal ultrasound (MSUS). Methods: Follow-up examination of patients included in the study performed by Erdmann-Keding et al. in which FOI of both hands was performed in a standardized manner using three predefined phases (p1-p3) and PrimaVista Mode (PVM). The comparison was drawn to grayscale-power Doppler (GS/PD) MSUS of the clinically dominant hand (wrist, MCP, PIP, DIP 2-5) from dorsal or palmar. Results: Patients with a change from suspected to diagnosed PsA showed an increased prevalence of joints with pathological enhancement in FOI (p = 0.046) with an unchanged joint distribution pattern, especially with a dominant involvement of DIP joints. Compared to the baseline, these patients were three times more common to show enhancement in FOI p3 at FU. Newly detected pathologic joints by FOI (PVM, p2) and MSUS at FU were positively associated with the change of diagnosis from suspected to confirmed PsA (FOI: AUC 0.78; GSUS: AUC 0.77). Conclusion: Fluorescence optical imaging appears to be a helpful tool to detect early PsA and to distinguish between acute and chronic disease stages. It could thereby become a suitable tool as a screening method to select psoriasis patients with an indication for further rheumatological evaluation.

Skin Sodium Accumulates in Psoriasis and Reflects Disease Severity.

Sodium can accumulate in the skin at concentrations exceeding serum levels. A high sodium environment can lead to pathogenic T helper 17 cell expansion. Psoriasis is a chronic inflammatory skin disease in which IL-17‒producing T helper 17 cells play a crucial role. In an observational study, we measured skin sodium content in patients with psoriasis and in age-matched healthy controls by Sodium-23 magnetic resonance imaging. Patients with PASI > 5 showed significantly higher sodium and water content in the skin but not in other tissues than those with lower PASI or healthy controls. Skin sodium concentrations measured by Sodium-23 spectroscopy or by atomic absorption spectrometry in ashed-skin biopsies verified the findings with Sodium-23 magnetic resonance imaging. In vitro T helper 17 cell differentiation of naive CD4+ cells from patients with psoriasis markedly induced IL-17A expression under increased sodium chloride concentrations. The imiquimod-induced psoriasis mouse model replicated the human findings. Extracellular tracer Chromium-51-EDTA measurements in imiquimod- and sham-treated skin showed similar extracellular volumes, rendering excessive water of intracellular origin. Chronic genetic IL-17A‒driven psoriasis mouse models underlined the role of IL-17A in dermal sodium accumulation and inflammation. Our data describe skin sodium as a pathophysiological feature of psoriasis, which could open new avenues for its treatment.

Brodalumab Is Associated with High Rates of Complete Clearance and Quality of Life Improvement: A Subgroup Analysis of Patients with Psoriasis and Concomitant Psoriatic Arthritis.

BACKGROUND: Psoriatic arthritis (PsA) is a chronic inflammatory disease associated with psoriasis that significantly impairs physical function and quality of life (QoL). Prompt therapeutic intervention is crucial for limiting PsA progression and preventing disability. OBJECTIVES: The aim of this study was to compare the efficacy of brodalumab versus ustekin-umab and the impact on QoL in patients with moderate-to-severe plaque psoriasis, by concomitant PsA status. METHODS: This post hoc analysis of pooled data from the phase 3 AMAGINE-2 and -3 trials evaluated complete skin clearance (100% improvement of Psoriasis Area and Severity Index [PASI 100]), improvement in symptom severity (Psoriasis Symptom Inventory [PSI] response), and QoL (Dermatology Life Quality Index [DLQI] score of 0/1) by concomitant PsA status. A competing risk model assessed cumulative incidence over 52 weeks with outcomes of PASI 100 or inadequate response. RESULTS: This analysis included 929 patients with moderate-to-severe psoriasis. Concomitant PsA was present in 79/339 (23%) and 110/590 (19%) patients receiving brodalumab 210 mg and ustekinumab, respectively. At Week 52, odds ratios (ORs) (95% confidence intervals [CIs]) for complete clearance with brodalumab versus ustekin-umab were 3.15 (1.52-6.55, p = 0.0015) in patients with concomitant PsA and 3.05 (2.19-4.26, p < 0.0001) in patients without concomitant PsA. Corresponding Week 52 ORs (95% CIs) for DLQI 0/1 with brodalumab versus ustekinumab were 2.05 (1.07-3.90, p = 0.0277) and 1.83 (1.32-2.53, p = 0.0002); Week 52 ORs (95% CIs) for PSI ≤8 with brodalumab versus ustekinumab were 3.42 (1.43-8.18, p = 0.0036) and 1.40 (1.01-1.95, p = 0.0434). The 52-week cumulative incidence of patients achieving PASI 100 was significantly higher for brodalumab versus ustekinumab in patients with concomitant PsA (p = 0.0001) and in those without concomitant PsA (p < 0.0001). CONCLUSIONS: Treatment with brodalumab rapidly results in high levels of complete and sustained skin clearance and greater cumulative treatment benefit in patients with moderate-to-severe psoriasis versus ustekinumab, regardless of concomitant PsA status.

The Clinical Significance of Simultaneous IL-17A and IL-17F Blockade in Psoriasis Non-Responding to Anti-IL17A Therapy.

The better understanding of the immunopathogenesis of psoriasis has led to the development of highly efficacious targeted therapies with favorable safety profiles. Among them, the class of Interleukin (IL)-17 antibodies are well established for the treatment of psoriasis, psoriatic arthritis and axial spondyloarthritis. Bimekizumab is a new antibody that simultaneously neutralizes IL-17A and IL-17F. We present two patients with psoriasis, who lost response to several biologics, among them IL-17 antagonists such as secukinumab, ixekizumab or brodalumab. Besides plaque-type psoriasis, patients also had psoriasis in hard-to-treat areas such as scalp and groins or psoriatic arthritis. Remarkably, both patients already responded to the therapy with bimekizumab 4 weeks after the first injection and, one year thereafter, both patients sustained PASI100. No side effects were observed. The fast response to bimekizumab emphasizes the crucial role of IL-17F in the pathogenesis of psoriasis. Besides, due to the new mechanism of action, non-responders to other anti-IL-17 therapies could benefit when switched to bimekizumab.

The Effect of TNF-α Inhibitors on Nail Psoriasis and Psoriatic Arthritis-Real-World Data from Dermatology Practice.

Patients with psoriatic arthritis (PsA) often develop joint symptoms years after their initial diagnosis of psoriasis disease; therefore, dermatologists should test for and detect PsA early. In this study, we focused on patients with psoriasis with both nail and joint disease being treated with tumor necrosis factor-α inhibitors by dermatologists. We performed a noninterventional, prospective, multicenter, and open-label study to evaluate the effectiveness of adalimumab, etanercept, or infliximab over 24 months of continuous therapy in patients with moderate to severe plaque-type psoriasis (Pso) and PsA. Disease assessments with the Psoriasis Area and Severity Index, Nail Psoriasis Severity Index (NAPSI), joint assessment, Dermatology Life Quality Index (DLQI), and Health Assessment Questionnaire (HAQ) instruments were performed every 3 months for the first year and twice annually thereafter. The cohort included 100 patients with Pso, nail psoriasis, and PsA. A significant reduction of NAPSI was observed 3 months after therapy initiation compared with the baseline (mean ± SD, 22.9 ± 17.8 vs. 33.8 ± 21.4; p < 0.001). Similarly, the mean ± SD number of both tender and swollen joints decreased significantly within the first 3 months of treatment, from 10.8 ± 11.5 to 6.4 ± 10.3 (p < 0.001) and from 6.4 ± 9.5 to 3.1 ± 7.2 (p < 0.001), respectively. Additionally, the distal interphalangeal joint involvement improved throughout the observation time, and DLQI and HAQ scores decreased. Improvements in control of skin, nail, and joint symptoms were seen, as well as in patients' quality of life and functionality. Dermatologists have an important role not only in PsA diagnosis but also in PsA long-term care.

Increased Skin Clearance and Quality of Life Improvement with Brodalumab Compared with Ustekinumab in Psoriasis Patients with Aggravating Lifestyle Factors.

INTRODUCTION: Obesity, smoking, and alcohol consumption are prevalent in psoriasis patients and have been associated with increased disease severity and reduced treatment adherence and response. This post hoc analysis of pooled data from the phase 3 AMAGINE-2 and -3 trials compared the efficacy of brodalumab versus ustekinumab in psoriasis patients with aggravating and potentially treatment-confounding lifestyle risk factors. METHODS: This post hoc analysis evaluated complete skin clearance, as measured by a 100% reduction of Psoriasis Area and Severity Index (PASI100) and quality of life (QoL), as measured by a Dermatology Life Quality Index (DLQI) score of 0/1, by the presence of risk factors (obesity, tobacco or alcohol use). A competing risk model assessed cumulative incidence over 52 weeks with outcomes of PASI100 or inadequate response. RESULTS: This analysis included 929 patients (brodalumab 210 mg, n = 339; ustekinumab, n = 590) with moderate-to-severe psoriasis. At week 52, odds ratios (95% confidence intervals [CIs]) for complete clearance with brodalumab versus ustekinumab were 2.50 (1.14-5.46, P = 0.0186), 4.64 (2.80-7.69, P < 0.0001), 2.06 (1.25-3.40, P = 0.0045), and 2.55 (0.55-11.91, P = 0.2117) in patients with no, one, two, or three risk factors, respectively. Corresponding odds ratios (ORs) (95% CIs) for DLQI 0/1 with brodalumab versus ustekinumab were 1.72 (0.78-3.79, P = 0.1883), 2.49 (1.54-4.02, P < 0.0002), 1.57 (0.97-2.54, P = 0.0666), and 2.07 (0.45-9.57, P = 0.3438). The 52-week cumulative incidence of patients achieving PASI100 was consistently higher for brodalumab versus ustekinumab, regardless of number of risk factors (P < 0.0001 for one or two risk factors and P = 0.0029 for three risk factors). CONCLUSIONS: Higher levels of complete skin clearance and QoL were achieved and maintained with brodalumab versus ustekinumab in patients with moderate-to-severe psoriasis, regardless of the presence of lifestyle risk factors. CLINICAL TRIAL REGISTRATION: AMAGINE-2 (NCT01708603); AMAGINE-3 (NCT01708629).

Ambivalent Effects of Tumor Necrosis Factor Alpha on Apoptosis of Malignant and Normal Human Keratinocytes.

INTRODUCTION: Tumor necrosis factor alpha (TNFα) is a pro-inflammatory cytokine that may paradoxically induce either apoptosis or cell survival. It mediates its activity through binding of TNF-receptor (TNFR) 1 or 2. TNFR1 is mainly responsible for transmitting apoptotic signals. The activation of apoptotic mechanisms can either be intrinsic (mitochondrial) or extrinsic (death receptors). Death ligands such as TNF-related apoptosis-inducing ligand (TRAIL) specifically induce extrinsic apoptosis, while cytostatic drugs such as 5-fluorouracil (5FU) induce intrinsic apoptosis. OBJECTIVES: To investigate the effects of TNFα on apoptosis in malignant and normal human keratinocytes. METHODS: Human cutaneous squamous cell carcinoma (SCC) cell line SCC-13 and immortalized human keratinocytes HaCaT as well as primary normal human keratinocytes (PNHK) were stimulated with TNFα and then treated either with TRAIL or 5FU. Cell viability and cell proliferation, DNA fragmentation, apoptosis, and cytotoxicity were determined by WST-1 proliferation assay, ELISA, flow cytometry, and colorimetric analysis of lactate dehydrogenase, respectively. In addition, Western blotting was performed for analysis of caspase-3. RESULTS: TNFα affected viability of SCC-13 and HaCaT cells in combination with 5FU or TRAIL. In contrast, TNFα did not influence cell viability of PNHK. It enhanced the apoptotic effects of both extrinsic and intrinsic stimuli in SCC-13 and HaCaT. In clear contrast, TNFα protected PNHK against TRAIL- and 5FU-induced apoptosis. The effects were dose-dependent and TNFα-specific; furthermore, the apoptosis pathway was caspase-dependent. CONCLUSIONS: In summary, opposing effects of TNFα in malignant versus normal human keratinocytes were observed with possibly relevant clinical implications, when patients are treated with TNFα inhibitors.

Delayed Diagnosis of Hidradenitis Suppurativa and Its Effect on Patients and Healthcare System.

BACKGROUND: Hidradenitis suppurativa (HS) is a neglected chronic inflammatory disease with long delay in diagnosis. Besides pain, purulent discharge, and destruction of skin architecture, HS patients experience metabolic, musculoskeletal, and psychological disorders. OBJECTIVES: To determine the delay in HS diagnosis and its consequences for patients and the healthcare system. METHODS: This was a prospective, multicenter, epidemiologic, non-interventional cross-sectional trial carried out in Germany and based on self-reported questionnaires and medical examinations performed by dermatologists. In total, data of 394 adult HS patients were evaluated. RESULTS: The average duration from manifestation of first symptoms until HS diagnosis was 10.0 ± 9.6 (mean ± SD) years. During this time, HS patients consulted on average more than 3 different physicians - most frequently general practitioners, dermatologists, surgeons, gynecologists - and faced more than 3 misdiagnoses. Diagnosis delay was longer in younger and non-smoking patients. In most cases, HS was correctly diagnosed by dermatologists. The longer the delay of diagnosis, the greater the disease severity at diagnosis. Delayed HS diagnosis was also associated with an increased number of surgically treated sites, concomitant diseases, and days of work missed. CONCLUSION: This study demonstrates an enormous delay in the diagnosis of HS, which results in more severe disease. It also shows for the first time that a delay in diagnosis of a chronic inflammatory disease leads to a higher number of concomitant systemic disorders. In addition to the impaired health status, delayed diagnosis of HS was associated with impairment of the professional life of affected people.

Hidradenitis Suppurativa and Concurrent Psoriasis: Comparison of Epidemiology, Comorbidity Profiles, and Risk Factors.

INTRODUCTION: Hidradenitis suppurativa (HS) is a chronic, debilitating, and inflammatory skin disease. The epidemiology of HS varies greatly, with an estimated prevalence ranging from 0.03% to 4% worldwide. Similar to psoriasis (PsO), HS also exhibits a systemic inflammatory nature with a spectrum of systemic comorbidities. A large health insurance claims (HICs) database is analyzed to determine the demography and epidemiology of HS, PsO, and HS with concurrent PsO (HS-PsO) patients. Furthermore, the comorbidity profiles, including the comorbidity risk of these patient populations, are analyzed. METHODS: This is a noninterventional retrospective analysis of anonymized HICs data using a subset of the Institute of Applied Health Research Berlin (InGef) database. The primary outcome is the prevalence and incidence of HS, PsO, and HS-PsO. Secondary outcomes include comorbidity profiles and a comorbidity risk analysis. RESULTS: The prevalence and incidence of HS were 0.0681% and 0.0101%, respectively. The prevalence of HS-PsO was 0.004% (6% of the total HS population). HS patients frequently suffered from arterial hypertension (45%), nicotine dependence (46%), obesity (41%), and depression (36%), which were more common in HS-PsO patients compared with HS alone. HS patients had an increased prevalence of metabolic, psychiatric, immune-mediated, and cardiovascular diseases, e.g., overweight/obesity [odds ratio (OR): 2.65, 95% confidence interval (CI) 2.37-2.96], depression (OR: 1.55, 95% CI 1.42-1.76), or seronegative rheumatoid arthritis (OR: 2.82, 95% CI 1.61-4.94) compared with the overall population. The increased risk of myocardial infarction in HS patients (OR: 4.1, 95% CI 3.5-4.8, adjusting for age/sex) was largely attributed to patient's current smoking status (OR: 1.1, 95% CI 0.8-1.5, adjusting for smoking/age/sex). CONCLUSIONS: HS patients show a broad spectrum of inflammatory and metabolic syndrome-related comorbidities, with an increased risk by concurrent PsO. Important for clinical practice, the elevated cardiovascular risk of HS patients can be largely attributed to smoking.