Increased loss-of-function filaggrin gene mutation prevalence in atopic dermatitis patients across northern latitudes indicates genetic fitness: A systematic review and meta-analysis.

Loss-of-function (LoF) mutations in the filaggrin gene (FLG) constitute the strongest genetic risk for atopic dermatitis (AD). A latitude-dependent difference in the prevalence of LoF FLG mutations was systematically evaluated. A systematic review and meta-analysis were performed to estimate the prevalence of LoF FLG mutations in AD patients and the general population by geography and ethnicity. Risk of bias was assessed by Newcastle-Ottawa Scale and Jadad score. StatsDirect, version 3 software was used to calculate all outcomes. PubMed and EMBASE were searched until 9th December 2021. Studies were included if they contained data on the prevalence of LoF FLG mutations in AD patients or from the general population or associations between AD and LoF FLG mutations and were authored in English. Overall, 248 studies and 229 310 AD patients and individuals of the general population were included in the quantitative analysis. The prevalence of LoF FLG mutations was 19.1% (95% CI, 17.3-21.0) in AD patients and 5.8% (95% CI, 5.3-6.2) in the general population. There was a significant positive association between AD and LoF FLG mutations in all latitudes in the Northern hemisphere, but not in all ethnicities. The prevalence of LoF FLG mutations became gradually more prevalent in populations residing farther north of the Equator but was negligible in Middle Easterners and absent in most African populations. FLG LoF mutations are common and tend to increase with northern latitude, suggesting potential clinical implications for future AD management. The existence of possible genetic fitness from FLG LoF mutations remains unknown.

Psychosocial and mental impact of alopecia areata: Analysis of the Danish Skin Cohort.

IMPORTANCE: Alopecia areata (AA) carries a psychological burden for patients beyond hair loss. However, quality-of-life measurement tools such as EQ-5D used in clinical trials may not adequately capture the burden of AA, the perceived stigmatization or the psychosocial impact of AA. OBJECTIVE: To investigate the potential association between disease severity and the degree of social isolation, perceived stigmatization, anxiety and depression, alcohol consumption and work absenteeism using multiple PRO measures in patients with AA. DESIGN, SETTING AND PARTICIPANTS: Using the Danish Skin Cohort, the study included adult patients diagnosed with AA. The study included multiple PRO measures, including Skindex-16, EQ-5D-5L, Work Productivity and Activity Impairment (WPAI), Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) and the Alopecia Areata Symptom Impact Scale (AASIS). The questionnaires were dispatched to the patients in January 2023. The severity of AA was determined based on scalp involvement using a modified Alopecia Areata Scale. Multiple multivariate linear regressions were conducted using Skindex-16, AASIS and WPAI, while multivariate logistic regressions were applied to HADS, AUDIT-C and EQ-5D-5L. RESULTS: A total of 376 patients were included, of which 177 (47%) had severe disease, 41 (11%) had moderate disease, 94 (25%) had mild disease, and 64 (17%) were in remission. The median age of patients was 55 (IQR, 47-66 years) and most were female (70%). Skindex-16 and AASIS were the only PRO measures able to distinguish between severity. For these scores, moderate and severe diseases, female sex, and involvement of eyebrows increased the score and negatively impacted patient quality of life. CONCLUSION AND RELEVANCE: The results indicate the importance of using the proper tool for the intended measurement of quality of life and that factors such as the severity of AA, as well as female sex and involvement of the eyebrows, may potentially increase the psychosocial burden of AA.

An update on the use of antihistamines in managing chronic urticaria.

INTRODUCTION: Urticaria, a mast cell-mediated skin disease, manifests as acute or chronic, with the latter divided into spontaneous and inducible types and requires individualized management, including identifying triggers and comorbidities. Antihistamines, particularly the second generation group, form the mainstay of primary treatment plans consisting of dosage adjustments and/or in combination with other treatment modalities depending on underlying disease control. AREAS COVERED: A literature search was conducted using 'antihistamines,' 'urticaria,' 'pharmacogenomics,' 'genomics,' 'biomarkers' and 'treatment response' as key words. In this review, we focus on the comprehensive understanding and application of antihistamines in managing adult and adolescent patients with chronic urticaria. EXPERT OPINION: Using antihistamines to treat urticaria is set to change significantly, focusing more on personalized medicine and identifying key biomarkers to enhance treatment response prediction. These changes aim to make treatments more specific and cost-effective by avoiding unnecessary tests. Applying new approaches in everyday clinical care faces challenges like proving the biomarkers' reliability, updating current guidelines, and incorporating individualized treatments into standard procedures. Efforts should now concentrate on finding easy-to-use biomarkers, improving access to pharmacogenomics, understanding why some patients are resistant to treatment, and creating more specific treatment options based on patient needs.

Biomarkers of systemic inflammation are associated with disease severity and metabolic syndrome in patients with hidradenitis suppurativa.

Background: Biomarkers associated with disease severity and comorbid metabolic syndrome (MetS) in patients with hidradenitis suppurativa (HS) are lacking. Objective: To identify biomarkers associated with disease severity and comorbid MetS in patients with HS. Methods: Data on hospital outpatients with HS were obtained through clinical examination and interviews. Indicators of systemic inflammation; C-reactive protein (CRP), erythrocyte sedimentation-rate (ESR), neutrophil/lymphocyte-ratio (NLR), platelet/lymphocyte-ratio (PLR), monocyte/lymphocyte-ratio (MLR), platelet/neutrophil-ratio (PNR), pan-immune-inflammation-value (PIV), and systemic-immune-inflammatory-index (SII), were calculated from blood samples. Results: Seven hundred patients were included; of those 444 (63.4%) and 256 (36.6%) were female and male, respectively, with a median age of 38.3 years (IQR = 27.9-51.0). Increasing CRP, ESR, NLR, PIV, and SII (P < .001) were significantly associated with increasing Hurley-stage and international hidradenitis suppurativa severity score system 4 (IHS4)-score in adjusted analysis. A doubling in CRP (OR 1.59 (1.36-1.85), P < .001), ESR (OR 1.39 (1.17-1.66), P < .001) and PIV (OR 1.41 (1.12-1.77) P = .002) was associated with MetS in adjusted analysis. ESR was the best estimator for severe IHS4-score (AUC = 0.72 (0.66-0.77), P < .001) and Hurley III (AUC = 0.79 (0.73-0.85), P < .001) whereas CRP was best for MetS (AUC = 0.67 (0.62-0.72), P < .001). Limitations: Patients in a hospital setting tend to have more severe disease. Conclusion: Biomarkers like CRP, ESR, and PIV measuring systemic inflammation were associated with disease severity and comorbid MetS in patients with HS.

Experiences with pre-graduate research among Danish medical students and doctors.

INTRODUCTION: Pre-graduate research is popular among medical students. Concerns about time constraints and lack of mentorship have been raised in international studies. The extent to which these issues affect Danish medical students remains unclear. We therefore aimed to assess the conditions and outcomes of pre-graduate research among medical students from the University of Copenhagen. METHODS: A descriptive, cross-sectional, questionnaire-based survey on experiences from pre-graduate research was distributed to medical students and recently graduated medical doctors from the University of Copenhagen who had engaged in full-time pre-graduate research. The survey covered 1) working hours and income, 2) publications and authorship and 3) work environment and well-being. RESULTS: A total of 437 pre-graduate researchers participated in the survey. Pre-graduate research often involved a period outside of medical school (88%) and typically lasted a year (56%), with clinical research being the most common focus (68%). Almost a third worked longer hours (29%) than agreed and additional hours were commonly provided after the research period. Scholarships of 10,000 DKK a month were the primary source of income (72%). Most participants achieved their publication goals (62%) and experiences on work environment and well-being were generally positive. CONCLUSION: Pre-graduate research provides a conducive environment for medical students to engage in scientific research. Hovewer, engaging in pre-graduate research entails long working hours, is inadequately remunerated and often requires students to take leave from medical school. FUNDING: None. TRIAL REGISTRATION: Not relevant.

Characteristics and drivers of fatigue in patients with psoriasis and psoriatic arthritis: A cross sectional study.

BACKGROUND: A multitude of factors may influence fatigue in psoriasis and psoriatic arthritis (PsA); however, their individual fatigue components have not been thoroughly examined. OBJECTIVES: To explore characteristics of fatigue and its potential drivers in a cohort of patients with psoriasis with or without PsA. METHODS: Adults with psoriasis and a nonpsoriasis control group completed the Multidimensional Fatigue Inventory-20 questionnaire. Patients with psoriasis also reported joint pain intensity, pruritus, skin pain, and sleep problems using a numerical rating scale. Linear regression models were applied to continuous outcomes, and beta coefficients (ß) for the slopes were estimated with 95% confidence intervals (CIs). RESULTS: Among 2741 adults with psoriasis (of which 593 also had PsA) and 3788 controls, the impact on total fatigue was greatest for PsA (ß = 5.22; 95% CI, 3.55-6.90), followed by psoriasis (ß = 2.10; 95% CI, 0.96-3.25), compared with the general population (Ptrend < .0001). Among patients with psoriasis with or without PsA, increasing joint pain intensity was associated with overall fatigue (ß = 2.23 [95% CI, 2.03-2.44] for each 1-point increase in joint pain numerical rating scale score). LIMITATIONS: We lacked information on the effect of pharmacotherapy. CONCLUSIONS: These findings highlight the importance of a symptom-based approach when treating psoriasis, rather than focusing on objective severity measures alone.

CRUSE® -An innovative mobile application for patient monitoring and management in chronic spontaneous urticaria.

BACKGROUND: Chronic spontaneous urticaria (CSU) is unpredictable and can severely impair patients' quality of life. Patients with CSU need a convenient, user-friendly platform to complete patient-reported outcome measures (PROMs) on their mobile devices. CRUSE® , the Chronic Urticaria Self Evaluation app, aims to address this unmet need. METHODS: CRUSE® was developed by an international steering committee of urticaria specialists. Priorities for the app based on recent findings in CSU were defined to allow patients to track and record their symptoms and medication use over time and send photographs. The CRUSE® app collects patient data such as age, sex, disease onset, triggers, medication, and CSU characteristics that can be sent securely to physicians, providing real-time insights. Additionally, CRUSE® contains PROMs to assess disease activity and control, which are individualised to patient profiles and clinical manifestations. RESULTS: CRUSE® was launched in Germany in March 2022 and is now available for free in 17 countries. It is adapted to the local language and displays a country-specific list of available urticaria medications. English and Ukrainian versions are available worldwide. From July 2022 to June 2023, 25,710 observations were documented by 2540 users; 72.7% were females, with a mean age of 39.6 years. At baseline, 93.7% and 51.3% of users had wheals and angioedema, respectively. Second-generation antihistamines were used in 74.0% of days. CONCLUSIONS: The initial data from CRUSE® show the wide use and utility of effectively tracking patients' disease activity and control, paving the way for personalised CSU management.

Adverse events from topical corticosteroid use in chronic hand eczema - Findings from the Danish Skin Cohort.

Background: Topical corticosteroids (TCS) are used to treat most patients with chronic hand eczema (CHE), but knowledge about TCS-related adverse events in CHE is limited. Objectives: To investigate patient-reported adverse events to TCS in CHE patients. Methods: Data on adverse events related to TCS use in patients with CHE were analyzed from the Danish Skin Cohort; a prospective survey of a hospital cohort. We assessed patients' knowledge about TCS use and adverse event risks, and preference of TCS versus a nonsteroidal topical alternative. Results: Of 724 adults with CHE (64.0% women; mean age 57.5 [standard deviation 12.8] years), 64.1% reported skin atrophy, 41.4% cracks/fissures, 23.9% bleeding, 45.9% pain/stinging sensation, 40.0% reduced hand dexterity, and 40.2% worsening of CHE signs or symptoms from using TCS. We observed CHE-severity-dependent associations (all groups; P < .0001). Most patients (76.4%) would prefer a nonsteroidal option, 10.9% were neutral/indifferent, and 12.7% would prefer TCS for CHE. The median numerical rating scale-score (ranging from 0 to 10) was 10 (interquartile range 6-10) for preferring a nonsteroidal topical treatment. Limitations: Differences across TCS formulations were unexplored. Conclusion: TCS-related cutaneous adverse events were common. There is a desire from patients for novel steroid-free topical alternatives for CHE treatment.

Risk Factors that Impact Treatment with Oral Janus Kinase Inhibitors Among Adult Patients with Atopic Dermatitis: A Nationwide Registry Study.

The European Medicines Agency recently limited the use of oral Janus kinase inhibitors in certain patient populations, including those with atopic dermatitis. This cross-sectional study used the Danish national registers and Danish Skin Cohort to assess the prevalence of risk factors that potentially impact choice of treatment with oral Janus kinase inhibitors in adult patients with atopic dermatitis. From the Danish national registers and Danish Skin Cohort, 18,618 and 3,573 adults with atopic dermatitis, respectively, were identified. Half of the patients (49.5%) had, at some point, been registered to have at least 1 risk factor that could impact treatment with oral Janus kinase inhibitors. Non-modifiable risk factors recorded were cancer (5.6%), major adverse cardiovascular events (2.6%), venous thromboembolism (2.0%), smoking history (15.6%), and age ≥ 65 years (12.4%). Among patients ≥ 65 years of age, the mean (standard deviation) number of risk factors were 3 (1.4), and almost half of these patients had, at some point, been registered to have 1 or more non-modifiable risk factors in addition to their age. In conclusion, risk factors that may impact treatment with oral Janus kinase inhibitors were frequent in Danish adults with atopic dermatitis, especially among older individuals. Dermatologists need support and continuously updated long-term safety data when risk-evaluating patients with atopic dermatitis prior to initiation of advanced.

Evaluating the inhibition of IL-17A and TNFα in a cartilage explant model cultured with Th17-derived cytokines.

Introduction: T-helper 17 (Th17) cells produce IL-17A playing a critical role in activating the pathogenic chain leading to joint tissue inflammation and destruction. Elevated levels of Th17 cells and IL-17A have been detected in skin lesions, blood, and synovial fluid from patients with psoriatic arthritis (PsA) and ankylosing spondylitis (AS). Moreover, IL-17A inhibitors suppress disease activity in psoriasis, PsA and AS, supporting the evidence of IL-17A contributing to the disease pathogenesis. Although, IL-17A inhibitors are widely approved, it remains unclear how the inhibitory effect of IL-17A alters the extracellular matrix (ECM) of the joint in a Th17-conditioned inflammatory milieu. Therefore, the aim of this study was to establish a cartilage model cultured with conditioned medium from Th17 cells and inhibitors to explore the effect of IL-17A inhibition on joint tissue remodeling. Methods: Naïve CD4+ T cells from healthy human buffy coat were differentiated into Th17 cells, followed by Th17 cell activation to secrete Th17-related cytokines and molecules into media. The activated Th17 cells were isolated from the conditioned media (CM) and analyzed using flow cytometry to verify Th17 cell differentiation. The CM were assessed with ELISA to quantify the concentrations of cytokines secreted into the media by the Th17 cells. Healthy bovine cartilage explants were cultured with the Th17-CM and treated with IL-17A and TNFα inhibitors for 21 days. In harvested supernatant from the cartilage cultures, MMP- and ADAMTS-mediated biomarker fragments of type II collagen, aggrecan, and fibronectin were measured by ELISA to investigate the ECM remodeling within the cartilage tissue. Results: Th17-CM stimulated a catabolic response in the cartilage. Markers of type II collagen and aggrecan degradation were upregulated, while anabolic marker of type II collagen formation remained on similar levels as the untreated explants. The addition of IL-17A inhibitor to Th17-CM decreased the elevated type II collagen and aggrecan degradation, however, degenerative levels were still elevated compared to untreated group. The addition of TNFα inhibitor completely reduced both type II collagen and aggrecan degradation compared to untreated explants. Moreover, the TNFα inhibitor treatment did not alter the type II collagen formation compared to untreated group. Conclusion: This study suggests that inhibition of IL-17A in Th17-conditioned cartilage tissue only partially reduced the MMP-mediated type II collagen degradation and ADAMTS-mediated aggrecan degradation, while the TNFα inhibitor treatment fully reduced both MMP- and ADAMTS-mediated ECM degradation. This exploratory study where ECM biomarkers are combined with Th17-conditioned ex vivo model may hold great potential as output for describing joint disease mechanisms and predicting structural effects of treatment on joint tissue.

Prevalence and characteristics of pain in patients with lower-extremity ulcers-A cross-sectional study.

The study aimed to investigate the prevalence and characteristics of pain in different ulcer types and to identify factors associated with pain experience in patients with lower-extremity ulcers. A cross-sectional single-centre study was performed, including 130 newly referred outpatients with lower-extremity ulcers. Pain intensity was measured with a visual analog scale (VAS) and pain characteristics with the short form mcgill pain questionnaire-2 (SF-MPQ-2). The mean pain intensity was 29.5 (SD 31.8) at rest and 35.5 (SD 34.1) during movement (0-100 VAS). 61.5% of the patients experienced pain (VAS > 0) at rest and 70.8% during movement. Moderate to severe pain at rest was seen in 39.2% and in 43.8% of patients during movement. The mean total score on SF-MPQ-2 (range 0-220) was 35.9 (SD 32.6). Most of the patients described pain as intermittent (mean 11.8 SD 13.9). Analgesics were prescribed for 78% of the patients. Ulcer type (i.e., arterial, immunological, pressure and venous) and age were associated with pain severity, and women had a significantly lower well-being score than men. Prevalence of pain in patients with lower-extremity ulcers was high across different ulcer aetiologies. Pain intensity and quality must be assessed to obtain adequate pain management.

The Agreement between Consumer-Driven Self-Assessment of Psoriasis Severity and Physician-Assessed Severity Based on Patient-Taken Photographs Is Weak: A Cross-Sectional Study.

INTRODUCTION: Digital advancements have given access to huge amounts of real-world data (RWD) widely used for dermatological research. OBJECTIVES: The objective of this study was to investigate the agreement between consumer-driven self-assessed psoriasis severity and physician-assessed severity based on photographs. METHODS: Customer IDs in the NØIE database (Danish skincare company) from 2009 to 2022 with a smartphone photograph of psoriasis vulgaris on the body and a corresponding completed questionnaire were included. Smartphone photographs were evaluated by a physician-assessing erythema, induration, and scaling on a scale from 0 to 4 based on Psoriasis Area Severity Index (PASI). Self-assessment was done on a scale from 0 to 10 and converted to 0-4 scale (0 converted to 0; 1-3 to 1; 4-6 to 2; 7-8 to 3; and 9-10 to 4). Intraclass correlation coefficients with 95% confidence intervals (CIs) were calculated. RESULTS: In total, 187 patients (63% women) with mean age of 38 years were included. Self-assessment scores were higher than physicians' assessment scores for all groups, and scaling was closest to the physicians' assessment, while erythema and induration had a greater distance between the physicians' and patients' assessment. The correlation between self-assessed and physician-assessed psoriasis severity for all patients was 0.23 (95% CI: 0.0-0.92); 0.34 (95% CI: 0.0-0.95) for chronic patients; and 0.09 (-0.01 to 0.82) for non-chronic patients. The agreement was better for men (0.53 [-0.02 to 0.98]) than for women (0.12 [-0.01 to 0.84]). CONCLUSION: There was weak agreement between self-assessed psoriasis severity and photographically assessed severity by the physician. Consumer-driven RWD should be interpreted with caution.