Alitretinoin versus phototherapy as the first-line treatment in adults with severe chronic hand eczema: the ALPHA RCT.

Background: Hand eczema is common and a cause of morbidity and occupational disability. When education, irritant/contact allergen avoidance, moisturisation and topical corticosteroids are insufficient to control chronic hand eczema, ultraviolet therapy or systemic immune-modifying drugs are used. There is no treatment pathway generally accepted by UK dermatologists. Primary objective: Compare alitretinoin and ultraviolet therapy as first-line therapy in terms of disease activity at 12 weeks post planned start of treatment. Design: Prospective, multicentre, open-label, two-arm parallel group, adaptive randomised controlled trial with one planned interim analysis, and an economic evaluation. Setting: UK secondary care dermatology outpatient clinics. Participants: Patients with severe chronic hand eczema unresponsive to at least 4 weeks of treatment with potent topical corticosteroids. Primary end point: Natural logarithm of the Hand Eczema Severity Index + 1, 12 weeks post planned start of treatment. Randomisation: Participants randomised 1 : 1 by minimisation to alitretinoin or ultraviolet therapy for 12 to 24 weeks. Blinding: Blinded primary end-point assessor. Results: Intention-to-treat population: 441 (100.0%) participants; 220 (49.9%) alitretinoin and 221 (50.1%) ultraviolet therapy. At least one dose was received by 212 (96.4%) alitretinoin and 196 (88.7%) ultraviolet therapy participants. Primary outcome: The unadjusted median (interquartile range) relative change in hand eczema severity index at 12 weeks was 30% (10-70%) of that at baseline for alitretinoin compared with 50% (20-100%) for ultraviolet therapy. There was a statistically significant benefit of alitretinoin compared with ultraviolet therapy at 12 weeks, with an estimated fold change or relative difference (95% confidence interval) = 0.66 (0.52 to 0.82), p = 0.0003 at 12 weeks. There was no evidence of a difference at 24 or 52 weeks, with the estimated fold change (95% confidence interval) equal to 0.92 (0.798 to 1.08) and 1.27 (0.97 to 1.67), respectively. Primary analysis results were consistent for secondary end points: Fifty-nine per cent allocated to alitretinoin and 61% allocated to ultraviolet therapy achieved a clear/almost clear assessment during the trial period. Differential treatment compliance observed: 145 (65.9%) alitretinoin and 53 (24.0%) ultraviolet therapy participants confirmed compliance (≥ 80% received, no treatment breaks > 7 days during first 12 weeks). High levels of missing data were observed. Safety: One hundred and thirty-five reportable adverse events across 79 participants, 55 (25.0%) alitretinoin and 24 (10.9%) ultraviolet therapy. Four serious adverse events (two alitretinoin, two ultraviolet therapy). Four pregnancies reported (three alitretinoin, one ultraviolet therapy). No new safety signals were detected. Conclusion: As a first-line therapy, alitretinoin showed more rapid improvement and superiority to ultraviolet therapy at week 12. This difference was not observed at later time points. Alitretinoin is cost-effective at weeks 12 and 52. Ultraviolet therapy is cost-effective after 10 years, with a high degree of uncertainty. Hand eczema severity index may be a useful primary outcome measure for hand eczema trials; ALPHA results will inform future trials. Limitations: Treatment compliance was poor for ultraviolet therapy. Regular twice weekly treatment was not received by most patients. Assessment of long-term effects of randomised treatments was complicated by use of second-line treatments post treatment phase. Further work: Further analysis of substudies and pilot data will provide valuable information for future studies. A clear need for better therapeutic approaches for severe chronic hand eczema remains. Future studies will need to further address long-term benefits of treatments given. Trial registration: This trial is registered as ISRCTN80206075. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/186/01) and is published in full in Health Technology Assessment; Vol. 28, No. 59. See the NIHR Funding and Awards website for further award information.

The main question was which treatment was better at easing symptoms of severe hand eczema after 12 weeks. The two treatments compared were ones used most often by UK dermatologists. The first is a tablet called alitretinoin, which is taken once a day. The second is called ultraviolet therapy, where hands are soaked in a special liquid and placed under ultraviolet light twice a week at a hospital. We treated 220 patients with alitretinoin and 221 patients with ultraviolet therapy. Patients received treatment for 12 to 24 weeks depending on how well their hand eczema responded. Patients could have different treatments afterwards, and we collected information on their hand eczema symptoms for up to 1 year. After 12 weeks, severe hand eczema symptoms improved for both groups of patients but improved most for patients who took alitretinoin. However, 1 year after joining the trial, there was no evidence of a difference between alitretinoin and ultraviolet therapy as a first-line treatment. More patients stopped ultraviolet therapy early compared with patients who received alitretinoin. Different treatments may have been prescribed after the first treatment. Alitretinoin provides a convenient, instant relief or a 'quick fix' for patients with severe hand eczema. Alitretinoin is more convenient for lots of people, but it is important to have other options available for people who would prefer not to, or are unable to, take alitretinoin. For example, people who take alitretinoin can experience unwanted side effects, and people who are able to become pregnant must also use contraception. Long-term control of severe hand eczema is important. Individual discussions on the pros and cons of each treatment for hand eczema symptoms is needed. Providing flexible options to attend ultraviolet therapy appointments could be helpful (e.g. weekend/evenings).

Novel Chimeric Peptides Based on the Enolase Peptide Antigen (CEP-1) Bearing Three Post-Translational Modifications (Citrullination, Homocitrullination and Acetylation) for Determining the Diagnosis and Severity of Rheumatoid Arthritis.

With the aim of improving the uncertainties associated with the correct diagnosis of seronegative rheumatoid arthritis (RA) and identifying those at risk of developing interstitial lung disease (ILD), we have designed new peptide antigens bearing three post-translational modifications (PTMs) (citrulline, homocitrulline and acetyl-lysine) related to RA that could complement existing tests based on anti-citrullinated peptide/protein antibodies (ACPAs). Several chimeric peptides were synthesized and comparatively tested as antigens in ELISAs with two cohorts of sera: 178 RAs and 110 healthy blood donors. The results indicated that although chimeric peptides containing all three PTMs and vimentin and enolase domains do not significantly outperform existing ACPA tests in terms of sensitivity and specificity, they show potential to complement current assays, especially when detecting antibodies in some seronegative patients. Furthermore, the presence of these autoantibodies significantly identified patients with RA and ILD. We can conclude that the identification of specific autoantibody profiles using synthetic antigens containing peptide domains derived from proteins present in the human joint could help in the early detection of the risk of ILD in patients with RA and be useful for adapting follow-up strategies and guiding decisions during treatment.

Saikosaponin A Recovers Impaired Filaggrin Levels in Inflamed Skin by Downregulating the Expression of FRA1 and c-Jun.

Filaggrin (FLG) is an essential structural protein expressed in differentiated keratinocytes. Insufficient FLG expression contributes to the pathogenesis of chronic inflammatory skin diseases. Saikosaponin A (SSA), a bioactive oleanane-type triterpenoid, exerts anti-inflammatory activity. However, the effects of topically applied SSA on FLG expression in inflamed skin remain unclear. This study aimed to evaluate the biological activity of SSA in restoring reduced FLG expression. The effect of SSA on FLG expression in HaCaT cells was assessed through various biological methods, including reverse transcription PCR, quantitative real-time PCR, immunoblotting, and immunofluorescence staining. TNFα and IFNγ decreased FLG mRNA, cytoplasmic FLG protein levels, and FLG gene promoter-reporter activity compared to the control groups. However, the presence of SSA restored these effects. A series of FLG promoter-reporter constructs were generated to investigate the underlying mechanism of the effect of SSA on FLG expression. Mutation of the AP1-binding site (mtAP1) in the -343/+25 FLG promoter-reporter abrogated the decrease in reporter activities caused by TNFα + IFNγ, suggesting the importance of the AP1-binding site in reducing FLG expression. The SSA treatment restored FLG expression by inhibiting the expression and nuclear localization of FRA1 and c-Jun, components of AP1, triggered by TNFα + IFNγ stimulation. The ERK1/2 mitogen-activated protein kinase signaling pathway upregulates FRA1 and c-Jun expression, thereby reducing FLG levels. The SSA treatment inhibited ERK1/2 activation caused by TNFα + IFNγ stimulation and reduced the levels of FRA1 and c-Jun proteins in the nucleus, leading to a decrease in the binding of FRA1, c-Jun, p-STAT1, and HDAC1 to the AP1-binding site in the FLG promoter. The effect of SSA was evaluated in an animal study using a BALB/c mouse model, which induces human atopic-dermatitis-like skin lesions via the topical application of dinitrochlorobenzene. Topically applied SSA significantly reduced skin thickening, immune cell infiltration, and the expression of FRA1, c-Jun, and p-ERK1/2 compared to the vehicle-treated group. These results suggest that SSA can effectively recover impaired FLG levels in inflamed skin by preventing the formation of the repressor complex consisting of FRA1, c-Jun, HDAC1, and STAT1.

Recombinant filaggrin-2 improves skin barrier function and attenuates ultraviolet B (UVB) irradiation-induced epidermal barrier disruption.

The integrity of the skin barrier is essential for maintaining skin health, with the stratum corneum and filaggrin 2 (FLG-2) playing a key role. FLG-2 deficiency or mutation has been linked to diseases such as atopic dermatitis, while external stressors such as ultraviolet B (UVB) radiation further damage the epidermal barrier. This study investigated the effects of recombinant filaggrin (rFLG) on skin barrier function and UVB induced epidermal destruction. Cell experiments showed that 10 µg/mL of rFLG could increase the mobility of HaCaT cells from 20 % to 42 %, increase the epithelial resistance (TEER) value by about 2 times, and up-regulate the tight junction associated protein by about 2 times. In mouse models of UVB-induced epidermal barrier destruction, rFLG at concentrations of 0.5, 1, and 2 mg/mL showed effective cell uptake and skin penetration, alleviating erythema, and reducing skin thickness in mice by 1.5-3 times. Among them, 2 mg/mL of rFLG treatment restored the expression of tight junction proteins (LOR, ZO-1, and caspase-14), reduced collagen degradation, and reduced oxidative stress by normalizing serum hydroxyproline and superoxide dismutase levels. In addition, 2 mg/mL of rFLG inhibited UVB-induced upregulation of matrix metalloproteinases (MMP-3 and MMP-9) and reduced pro-inflammatory factors (IL-10, IL-1α, IL-6, and TNF-α) and apoptotic markers (P38, Bax, and Bcl-2) to normal levels. These findings suggested that rFLG effectively enhanced skin barrier integrity and mitigated UVB-induced epidermal barrier destruction, highlighting its potential as a therapeutic agent for diseases associated with skin barrier dysfunction.

Human Placenta Extract (HPH) Suppresses Inflammatory Responses in TNF-α/IFN-γ-Stimulated HaCaT Cells and a DNCB Atopic Dermatitis (AD)-Like Mouse Model.

Atopic dermatitis (AD), a chronic inflammatory disease, severely interferes with patient life. Human placenta extract (HPH; also known as human placenta hydrolysate) is a rich source of various bioactive substances and has widely been used to dampen inflammation, improve fatigue, exert anti-aging effects, and promote wound healing. However, information regarding HPH's incorporation in AD therapies is limited. Therefore, this study aimed to evaluate HPH's effective potential in treating AD using tumor necrosis factor (TNF)-α/interferon (IFN)-γ-stimulated human keratinocytes (HaCaT), immunized splenocytes, and a 2,4-dinitrochlorobenzene (DNCB)-induced AD mouse model. In TNF-α /IFN-γ-stimulated HaCaT cells, HPH markedly reduced the production of reactive oxygen species (ROS) and restored the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), superoxide dismutase 1(SOD1), catalase, and filaggrin (FLG). HPH reduced interleukin (IL)-6; thymus- and activation-regulated chemokine (TARC); thymic stromal lymphopoietin (TSLP); and regulated upon activation, normal T cell expressed and presumably secreted (RANTES) levels and inhibited nuclear factor kappa B phosphorylation. Additionally, HPH suppressed the T helper 2 (Th2) immune response in immunized splenocytes. In the AD-like mouse model, it significantly mitigated the DNCB-induced elevation in infiltrating mast cells and macrophages, epidermal thickness, and AD symptoms. HPH also reduced TSLP levels and prevented FLG downregulation. Furthermore, it decreased the expression levels of IL-4, IL-5, IL-13, TARC, RANTES, and immunoglobulin E (IgE) in serum and AD-like skin lesion. Overall, our findings demonstrate that HPH effectively inhibits AD development and is a potentially useful therapeutic agent for AD-like skin disease.

Trajectories of egg sensitization in childhood: Two birth cohorts in Asia and Europe.

BACKGROUND: Hen's egg exposure through impaired skin barrier is considered a major mechanism of sensitization to eggs. However, the impact of filaggrin (FLG) gene loss-of-function mutations on the natural history of egg sensitization lacks consensus among studies. OBJECTIVE: To evaluate the association between the natural course of egg sensitization and FLG mutations. METHODS: We used Japanese and the UK birth cohorts (CHIBA and MAAS) to identify the longitudinal patterns of egg sensitization until mid-school age and examined the relationship between the identified patterns and FLG mutations. Sensitization was assessed using egg white-specific IgE levels or skin prick tests (SPTs). Egg allergy was confirmed by parental reports and sensitization. Latent class growth analysis identified longitudinal patterns. RESULTS: Three similar patterns of egg sensitization (persistent, early-onset remitting, and no/low grade classes) were identified in both cohorts, with differing prevalence estimates. The proportion of children with egg allergy in the persistent class at 7 or 8 years of age was 23% (CHIBA) and 20% (MAAS). Consistently in both cohorts, FLG mutations were significantly associated only with the persistent class. Children with FLG mutations had an approximately four-fold increased risk of being in the persistent sensitization class (RRRs: 4.3, 95%C.I. (1.2-16.0), p = .03 in CHIBA; 4.3 (1.3-14.7), p = .02 in MAAS). CONCLUSION: FLG loss-of-function mutations are associated with persistent egg sensitization in both Japanese and European ethnicities, and the mutations might be a potential biomarker for identifying the risk of persistent egg sensitization/allergy in early infancy. Future studies should incorporate oral food challenges to confirm this relationship.

Benvitimod upregulates filaggrin, involucrin and loricrin expressions via aryl hydrocarbon receptor-OVO-like 1 axis.

Benvitimod has been successfully used in the treatment of psoriasis and atopic dermatitis (AD). However, the mechanism remains to be clarified. We aim to assess the effects of benvitimod on MC903-induced dermatitis in mice and to investigate the effects of benvitimod on filaggrin (FLG), involucrin (IVL), and loricrin (LOR) expressions and possible mechanism. MC903-induced mouse AD model was used to evaluate the effects of benvitimod. Filaggrin, involucrin, and loricrin protein and mRNA expressions in lesions of mice dermatitis were measured by Western blot and quantitative real-time PCR. In vitro, normal human epidermal keratinocytes (NHEKs) were cultured and benvitimod was used to treat NHEKs primed with IL-4 and IL-13. Then AHR and OVOL1 in NHEKs were knocked down to evaluate the role of AHR and OVOL1 in the effects of benvitimod. Topical treatment of benvitimod repaired skin barrier and alleviated skin inflammation in mouse AD model. This effect was inhibited by pretreatment with an AHR antagonist. Benvitimod upregulated the filaggrin, involucrin, and loricrin expressions in lesions of mouse AD model. In addition, benvitimod upregulated the filaggrin, involucrin, and loricrin expressions in NHEKs. Knockdown of AHR or OVO-like (OVOL)1 abrogated the upregulation of filaggrin, involucrin, and loricrin induced by benvitimod. Benvitimod attenuated MC903-induced mouse dermatitis and upregulated filaggrin, involucrin, and loricrin expressions via AHR-OVOL1 axis.

Symmetrical acral keratoderma associated with new variants in the filaggrin gene.

Symmetrical acral keratoderma (SAK) is a rare skin disorder with symmetric hyperkeratotic patches on the acral regions. Variants in the filaggrin gene (FLG) have been associated with SAK since 2020. To explore the clinical and genetic basis in six patients with SAK. Whole-exome sequencing, direct sequencing, and prediction of protein structure and function were performed. In this study, we identified two novel variants, c.3320del and c.4909del, and seven previously reported variants, c.3099C>G, c.4544C>A, c.6950_6957del, c.7264G>T, c.7945del, c.8117C>G, c.12064A>T. The findings of this study bolster the existing evidence implicating FLG variants in SAK, introducing two novel variants to the database of FLG variants associated with the condition.

Emollient application from birth to prevent eczema in high-risk children: the BEEP RCT.

Background: Atopic eczema is a common childhood skin problem linked with asthma, food allergy and allergic rhinitis that impairs quality of life. Objectives: To determine whether advising parents to apply daily emollients in the first year can prevent eczema and/or other atopic diseases in high-risk children. Design: A United Kingdom, multicentre, pragmatic, two-arm, parallel-group randomised controlled prevention trial with follow-up to 5 years. Setting: Twelve secondary and four primary care centres. Participants: Healthy infants (at least 37 weeks' gestation) at high risk of developing eczema, screened and consented during the third trimester or post delivery. Interventions: Infants were randomised (1 : 1) within 21 days of birth to apply emollient (Doublebase Gel®; Dermal Laboratories Ltd, Hitchin, UK or Diprobase Cream®) daily to the whole body (excluding scalp) for the first year, plus standard skin-care advice (emollient group) or standard skin-care advice only (control group). Families were not blinded to allocation. Main outcome measures: Primary outcome was eczema diagnosis in the last year at age 2 years, as defined by the UK Working Party refinement of the Hanifin and Rajka diagnostic criteria, assessed by research nurses blinded to allocation. Secondary outcomes up to age 2 years included other eczema definitions, time to onset and severity of eczema, allergic rhinitis, wheezing, allergic sensitisation, food allergy, safety (skin infections and slippages) and cost-effectiveness. Results: One thousand three hundred and ninety-four newborns were randomised between November 2014 and November 2016; 693 emollient and 701 control. Adherence in the emollient group was 88% (466/532), 82% (427/519) and 74% (375/506) at 3, 6 and 12 months. At 2 years, eczema was present in 139/598 (23%) in the emollient group and 150/612 (25%) in controls (adjusted relative risk 0.95, 95% confidence interval 0.78 to 1.16; p = 0.61 and adjusted risk difference -1.2%, 95% confidence interval -5.9% to 3.6%). Other eczema definitions supported the primary analysis. Food allergy (milk, egg, peanut) was present in 41/547 (7.5%) in the emollient group versus 29/568 (5.1%) in controls (adjusted relative risk 1.47, 95% confidence interval 0.93 to 2.33). Mean number of skin infections per child in the first year was 0.23 (standard deviation 0.68) in the emollient group versus 0.15 (standard deviation 0.46) in controls; adjusted incidence rate ratio 1.55, 95% confidence interval 1.15 to 2.09. The adjusted incremental cost per percentage decrease in risk of eczema at 2 years was £5337 (£7281 unadjusted). No difference between the groups in eczema or other atopic diseases was observed during follow-up to age 5 years via parental questionnaires. Limitations: Two emollient types were used which could have had different effects. The median time for starting emollients was 11 days after birth. Some contamination occurred in the control group (< 20%). Participating families were unblinded and reported on some outcomes. Conclusions: We found no evidence that daily emollient during the first year of life prevents eczema in high-risk children. Emollient use was associated with a higher risk of skin infections and a possible increase in food allergy. Emollient use is unlikely to be considered cost-effective in this context. Future research: To pool similar studies in an individual patient data meta-analysis. Trial registration: This trial is registered as ISRCTN21528841. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/67/12) and is published in full in Health Technology Assessment; Vol. 28, No. 29. See the NIHR Funding and Awards website for further award information.

Eczema is a troublesome itchy skin condition affecting 1 in 5 children and 1 in 10 UK adults. There is no cure and affected children are more likely to develop food allergies. We wanted to see if we could prevent eczema by protecting the skin of babies at higher risk of developing eczema (with an immediate relative with eczema, asthma or hay fever) with moisturisers used to treat dry skin. Previous research suggested that protecting the skin barrier might also prevent food allergy. One thousand three hundred and ninety-four families took part in a study; half of them were asked to apply moisturiser every day to their newborn baby for the first year and half to look after their baby's skin in the normal way. At the age of 2 years, we did not see any difference in how common eczema was between the two groups: 23% had eczema in the moisturiser group and 25% in the normal care group. It did not matter how we defined eczema ­ whether examined by a researcher or parent report. We did not find any differences in related conditions like asthma or hay fever either. We found that children using moisturisers had seen their doctor slightly more often for mild skin infections. There was a hint that food allergy might have been increased in the moisturiser group, but there was not enough data to be sure. We followed up the children to age 5 years, but we still did not find any benefits from using moisturisers in early life. Since this study, other similar research has been done using newer types of moisturisers, but their results are the same. This study shows that using daily moisturisers on healthy babies with a high risk of eczema does not prevent eczema. It is one less thing for busy families to worry about.

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.

Evaluation of OVOL1 and Filaggrin immunohistochemical expression and clinical relevance in psoriasis.

BACKGROUND: Psoriasis is a disease of overactive immune system. OVOL1 and Filaggrin have been associated with many inflammatory skin lesions. To the best of our knowledge, the correlation between OVOL1 and Filaggrin in psoriasis was not previously investigated. This work aims to search the immunohistochemical expression and correlation between OVOL1 and Filaggrin in psoriasis. MATERIALS AND METHODS: Slides cut from paraffin blocks of 30 psoriasis cases and 30 control subjects were stained with OVOL1 and Filaggrin. Clinicopathological data were correlated with the results of staining. RESULTS: OVOL1 and Filaggrin expression in epidermis showed a significant gradual reduction from normal skin to peri-lesional and psoriasis biopsies (P < 0.001). In contrast, psoriasis dermis showed a significant overexpression of OVOL1 in inflammatory cells in relation to peri-lesional biopsies (P < 0.002). OVOL1 demonstrated a significant direct correlation with Filaggrin expression in psoriasis (r = 0.568, P < 0.004). OVOL1 and Filaggrin expression in psoriasis skin epidermis demonstrated a statistically significant negative correlation with PASI score. CONCLUSION: OVOL1 and Filaggrin might be involved in psoriasis-associated inflammation and skin hyperproliferation. OVOL1 might have a protective barrier function in the skin and could be used to stratify progressive disease. Filaggrin may play a role in progression of psoriasis. OVOL1 inhibition could be considered in suppression of Filaggrin function. OVOL1 agonists may be beneficial in psoriasis treatment.

Skin colonization by Staphylococcus aureus in hemodialysis patients with pruritus and the effect of Staphylococcus aureus-secreted α-toxin on filaggrin expression.

Staphylococcus aureus (S. aureus) commonly reside on human skin in residents in long-term care facilities, yet its colonization and impact on the skin of hemodialysis (HD) patients have yet to be studied. The aim of the present study was to investigate the colonization of S. aureus on the skin of pruritic and non-pruritic HD patients, and the influence of S. aureus and S. aureus-secreted α-toxin on skin barrier function-related protein expression. In this study, a higher relative S. aureus count in pruritic HD patients compared to non-pruritic HD patients and healthy subjects were revealed by real-time polymerase chain reaction. S. aureus and α-toxin decreased mRNA and protein expression levels of aryl hydrocarbon receptor (AHR), ovo-like transcriptional repressor 1 (OVOL1), and filaggrin (FLG) in keratinocytes. In addition, anti-alpha-hemolysin (anti-hla) was used as an α-toxin neutralizer, and it successfully abrogated S. aureus-induced AHR, OVOL1, and FLG mRNA and protein expression downregulation. Mechanistically, α-toxin could decrease FLG activity by preventing the recruitment of AHR to the FLG promoter region. In conclusion, pruritic HD patients had higher S. aureus colonization, with S. aureus-secreted α-toxin suppressing FLG expression through the AHR-FLG axis.

Ethnic and Racial Disparities in Clinical Manifestations of Atopic Dermatitis.

Atopic dermatitis is a heterogenous inflammatory skin illness that may last for long time and affect people of different racial and ethnic backgrounds. The condition primarily appears in infants and young children. There are people living with atopic dermatitis in every country and every ethnic group, although the frequency of the disease varies greatly. Due to the varied clinical presentations that atopic dermatitis can have, it can be challenging to characterize and diagnose the disease, particularly in adults. Nevertheless, there exists a dearth of information pertaining to the various presentations of atopic dermatitis among individuals from diverse racial and cultural groups. This critical review article offers a succinct and comprehensive overview of the current findings on the epidemiology of atopic dermatitis with regards to ethnic and racial disparities. The findings hold potential significance in advancing the development of targeted treatments for personalized medicine approaches and enhancing the quality of life for patients with atopy.

Rare Filaggrin Variants Are Associated with Pustular Skin Diseases in Asians.

Reactive pustular eruptions (RPEs) can manifest in a variety of conditions, including pustular psoriasis (PP) and adult-onset immunodeficiency syndrome due to anti-interferon-γ autoantibody (AOID). These RPEs can be attributed to different causes, one of which is genetic factors. However, the genetic basis for pustular skin diseases remains poorly understood. In our study, we conducted whole-exome sequencing on a cohort of 17 AOID patients with pustular reactions (AOID-PR) and 24 PP patients. We found that 76% and 58% of the AOID-PR and PP patients, respectively, carried rare genetic variations within the filaggrin (FLG) gene family. A total of 12 out of 21 SNPs on FLG had previously received clinical classifications, with only p.Ser2706Ter classified as pathogenic. In contrast, none of the FLG3 SNPs identified in this study had prior clinical classifications. Overall, these variations had not been previously documented in cases of pustular disorders, and two of them were entirely novel discoveries. Immunohistochemical analysis of skin biopsies revealed that FLG variants like p.Ser860Trp, p.Gly3903Ter, p.Gly2440Glu, and p.Glu2133Asp caused reductions in FLG levels similar to the pathogenic FLG p.Ser2706Ter. These results highlight rare FLG variants as potential novel genetic risk factors contributing to pustule formation in both AOID and PP.

Stressors in Atopic Dermatitis.

As with other inflammatory skin disorders, atopic dermatitis has a tendency to cause stress and also be exacerbated by it. Patients with atopic dermatitis have several disease-associated stressors, some of which include physical discomfort due to itching and altered appearance due to flare-ups. These stressors have been shown to effect patients psychosocially by altering sleep patterns, decreasing self-esteem, and interfering with interpersonal relationships. In combination with its direct effect on patients, atopic dermatitis also causes stress for parents and caregivers. Studies suggest that atopic dermatitis is strongly correlated with co-sleeping habits, which can negatively impact the health and mood of parents or caregivers. It has also been reported to interfere with the formation of a strong mother-child relationship. In order to optimize treatment for patients with atopic dermatitis, it is important to note the impact that it has on quality of life. By implementing patient counseling, sleep-targeted therapies, and the use of quality of life (QoL) indices, atopic dermatitis patients and caregivers have the potential to experience greater satisfaction with treatment.

The stratum corneum barrier: impaired function in relation to associated lipids and proteins.

The skin is the largest organ of the human body and is widely considered to be the first-line defense of the body, providing essential protection against mechanical, physical, and chemical damage. Keratinocytes are the primary cells of the outer layer of the epidermis, which acts as a mechanical and permeability barrier. The epidermis is a permanently renewed tissue where undifferentiated keratinocytes located at the basal layer proliferate and migrate to the overlying layers. Here we report that some components of keratinocytes affect the formation and differentiation of the stratum corneum, which is the most specialized layer of the epidermis.

Atopic Dermatitis: Disease Background and Risk Factors.

Multiple risk factors have been associated with the development of atopic dermatitis (AD). Recent advances in understanding the role of genetics in this disease have been made, with discovery of the filaggrin (FLG) gene as the most notable so far. In addition to FLG gene mutations as a risk factor for AD, a positive family history of atopic or allergic disease in either parent has been shown to confer a greater risk of developing AD. Atopic dermatitis usually presents early in life and is thought to represent the initial step in the "atopic march," which is characterized by the development of other atopic diseases later in life such as asthma, allergic rhinitis, and/or rhinoconjunctivitis, food allergies, and hay fever. Other comorbid diseases that have been associated with AD include increase risk of viral and bacterial skin infections, neuropsychiatric diseases such as attention-deficit hyperactivity disorders (ADHD), and autistic spectrum disorder (ASD). Patients with AD have also been found to have worse sleep quality overall compared to patients without AD. In this chapter, we will discuss the risk factors associated with development of atopic dermatitis as well as the most commonly reported comorbidities in patients with this disease.

A Novel Recombinant Human Filaggrin Segment (rhFLA-10) Alleviated a Skin Lesion of Atopic Dermatitis.

Atopic dermatitis (AD), a prevalent chronic inflammatory skin disorder, is marked by impaired skin barrier function and persistent pruritus. It significantly deteriorates patients' quality of life, making it one of the most burdensome non-lethal skin disorders. Filaggrin plays a crucial role in the pathophysiology of barrier disruption in AD, interacting with inflammatory mediators. It is an integral part of the extracellular matrix architecture, serving to protect the skin barrier and attenuate the inflammatory cascade. In this study, we engineered a novel recombinant human filaggrin (rhFLA-10) expression vector, which was subsequently synthesized and purified. In vitro and ex vivo efficacy experiments were conducted for AD. rhFLA-10, at low concentrations (5 to 20 µg/mL), was non-toxic to HACaT cells, significantly inhibited the degranulation of P815 mast cells, and was readily absorbed by cells, thereby exerting a soothing therapeutic effect. Furthermore, rhFLA-10 demonstrated anti-inflammatory properties (p < 0.05). In vivo, efficacy experiments further substantiated that rhFLA-10 could effectively ameliorate AD in mice and facilitate the repair of damaged skin (p < 0.001). These findings underscore the considerable potential of rhFLA-10 in the treatment of AD.

Atopic Dermatitis Disease Complications.

This chapter will describe infectious complications of atopic dermatitis, including bacterial, viral, and fungal infections and the evolving understanding of the relationship between atopic dermatitis and infectious disease. The underlying immunological dysregulation and poor skin barrier function associated with atopic dermatitis not only increase the likelihood of infectious complications but also lend atopic dermatitis skin vulnerable to flares induced by environmental triggers. Thus, this chapter will also highlight the impact of common external environmental agents on precipitating flares of disease. Lastly, this chapter will discuss complications that can arise from treatments and the association of atopic dermatitis with more serious conditions such as lymphoma.

Immunolabeling for filaggrin and acidic keratins in the granular layer of mammalian epidermis indicates that an acidic-basic interaction is involved in cornification.

The soft epidermis of mammals derives from the accumulation of keratohyaline granules in the granular layer, before maturing into corneocytes. Main proteins accumulated in the granular layer are pro-filaggrin and filaggrin that determine keratin clumping and later moisturization of the stratum corneum that remains flexible. This soft epidermis allows the high sensitivity of mammalian skin. Presence and thickness of the stratum granulosum varies among different species of mammals and even between different body regions of the same animal, from discontinuous to multilayered. These variations are evident using antibodies for filaggrin, a large protein that share common epitopes among placentals. Here we have utilized filaggrin antibodies (8959 and 466) and an acidic keratin antibody (AK2) for labeling placental, marsupial and monotreme epidermis. AK2 labeling appears mainly to detect K24 keratin, and less likely other acidic keratins. Immunoreactivity for filaggrin is absent in platypus, discontinuous in Echidna and in the tested marsupials. In placentals, it is inconstantly or hardly detected in the thin epidermis of bat, rodents, and lagomorphs with a narrow, mono-stratified and/or discontinuous granular layer. In contrast, where the granular layer is continuous or even stratified, both filaggrin and AK2 antibodies decorate granular cells. The ultrastructural analysis using the AK2 antibody on human epidermis reveals that a weak labeling is associated with keratohyalin granules and filamentous keratins of transitional keratinocytes and corneocytes. This observation suggests that basophilic filaggrin interacts with acidic keratins like K24 and determines keratin condensation into corneocytes of the stratum corneum.