Dupilumab-associated ocular surface disease is characterized by a shift from Th2/Th17 toward Th1/Th17 inflammation.

BACKGROUND: Dupilumab is used for the treatment of atopic dermatitis (AD). Approximately one third of AD patients develop a dupilumab-associated ocular surface disease (DAOSD), of which the pathomechanism is poorly understood. This study aimed at investigating inflammatory markers in tear fluids of patients on dupilumab therapy. METHODS: Tear fluids were collected from AD patients with DAOSD (ADwDAOSD), AD patients without DAOSD (ADw/oDAOSD), and non-AD patients before and during dupilumab therapy, and analyzed using a specialized proteomic approach quantifying inflammatory markers. The ocular surface microbiome was determined by next generation sequencing technology. RESULTS: Upon dupilumab therapy, an upregulation of 31 inflammatory markers was observed in DAOSD tear fluids compared to baseline in AD patients. While IL-12B was upregulated in both ADwDAOSD and ADw/oDAOSD groups, the pattern of inflammatory markers significantly differed between groups and over time. In the ADwDAOSD group, a shift from a mixed Th2/Th17 pattern at baseline toward a Th1/Th17 profile under dupilumab was observed. Furthermore, an upregulation of remodeling and fibrosis markers was seen in DAOSD. Semantic map and hierarchical cluster analyses of baseline marker expression revealed four clusters distinguishing between AD and non-AD as well as ADwDAOSD and ADw/oDAOSD patient groups. In a pilot study, dupilumab therapy was associated with a decrease in richness of the ocular surface microbiome. CONCLUSIONS: DAOSD is characterized by a Th1/Th17 cytokine profile and an upregulation of markers known to promote remodeling and fibrosis. The expression pattern of inflammatory markers in tear fluids at baseline might serve as a prognostic factor for DAOSD.

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.

UCRAID (Ukrainian Citizen and refugee electronic support in Respiratory diseases, Allergy, Immunology and Dermatology) action plan.

Eight million Ukrainians have taken refuge in the European Union. Many have asthma and/or allergic rhinitis and/or urticaria, and around 100,000 may have a severe disease. Cultural and language barriers are a major obstacle to appropriate management. Two widely available mHealth apps, MASK-air® (Mobile Airways Sentinel NetworK) for the management of rhinitis and asthma and CRUSE® (Chronic Urticaria Self Evaluation) for patients with chronic spontaneous urticaria, were updated to include Ukrainian versions that make the documented information available to treating physicians in their own language. The Ukrainian patients fill in the questionnaires and daily symptom-medication scores for asthma, rhinitis (MASK-air) or urticaria (CRUSE) in Ukrainian. Then, following the GDPR, patients grant their physician access to the app by scanning a QR code displayed on the physician's computer enabling the physician to read the app contents in his/her own language. This service is available freely. It takes less than a minute to show patient data to the physician in the physician's web browser. UCRAID-developed by ARIA (Allergic Rhinitis and its Impact on Asthma) and UCARE (Urticaria Centers of Reference and Excellence)-is under the auspices of the Ukraine Ministry of Health as well as European (European Academy of Allergy and Clinical immunology, EAACI, European Respiratory Society, ERS, European Society of Dermatologic Research, ESDR) and national societies.

Proteomics of immune cells from liver tumors reveals immunotherapy targets.

Elucidating the mechanisms by which immune cells become dysfunctional in tumors is critical to developing next-generation immunotherapies. We profiled proteomes of cancer tissue as well as monocyte/macrophages, CD4+ and CD8+ T cells, and NK cells isolated from tumors, liver, and blood of 48 patients with hepatocellular carcinoma. We found that tumor macrophages induce the sphingosine-1-phospate-degrading enzyme SGPL1, which dampened their inflammatory phenotype and anti-tumor function in vivo. We further discovered that the signaling scaffold protein AFAP1L2, typically only found in activated NK cells, is also upregulated in chronically stimulated CD8+ T cells in tumors. Ablation of AFAP1L2 in CD8+ T cells increased their viability upon repeated stimulation and enhanced their anti-tumor activity synergistically with PD-L1 blockade in mouse models. Our data reveal new targets for immunotherapy and provide a resource on immune cell proteomes in liver cancer.

PPAR-γ regulates the effector function of human T helper 9 cells by promoting glycolysis.

T helper 9 (TH9) cells promote allergic tissue inflammation and express the type 2 cytokines, IL-9 and IL-13, as well as the transcription factor, PPAR-γ. However, the functional role of PPAR-γ in human TH9 cells remains unknown. Here, we demonstrate that PPAR-γ drives activation-induced glycolysis, which, in turn, promotes the expression of IL-9, but not IL-13, in an mTORC1-dependent manner. In vitro and ex vivo experiments show that the PPAR-γ-mTORC1-IL-9 pathway is active in TH9 cells in human skin inflammation. Additionally, we find dynamic regulation of tissue glucose levels in acute allergic skin inflammation, suggesting that in situ glucose availability is linked to distinct immunological functions in vivo. Furthermore, paracrine IL-9 induces expression of the lactate transporter, MCT1, in TH cells and promotes their aerobic glycolysis and proliferative capacity. Altogether, our findings uncover a hitherto unknown relationship between PPAR-γ-dependent glucose metabolism and pathogenic effector functions in human TH9 cells.

Inhibition of Melanoma Cell-Intrinsic Tim-3 Stimulates MAPK-Dependent Tumorigenesis.

T-cell immunoglobulin mucin family member 3 (Tim-3) is an immune checkpoint receptor that dampens effector functions and causes terminal exhaustion of cytotoxic T cells. Tim-3 inhibitors are under investigation in immuno-oncology (IO) trials, because blockade of T-cell-Tim-3 enhances antitumor immunity. Here, we identify an additional role for Tim-3 as a growth-suppressive receptor intrinsic to melanoma cells. Inhibition of melanoma cell-Tim-3 promoted tumor growth in both immunocompetent and immunocompromised mice, while melanoma-specific Tim-3 overexpression attenuated tumorigenesis. Ab-mediated Tim-3 blockade inhibited growth of immunogenic murine melanomas in T-cell-competent hosts, consistent with established antitumor effects of T-cell-Tim-3 inhibition. In contrast, Tim-3 Ab administration stimulated tumorigenesis of both highly and lesser immunogenic murine and human melanomas in T-cell-deficient mice, confirming growth-promoting effects of melanoma-Tim-3 antagonism. Melanoma-Tim-3 activation suppressed, while its blockade enhanced, phosphorylation of pro-proliferative downstream MAPK signaling mediators. Finally, pharmacologic MAPK inhibition reversed unwanted Tim-3 Ab-mediated tumorigenesis in T-cell-deficient mice and enhanced desired antitumor activity of Tim-3 interference in T-cell-competent hosts. These results identify melanoma-Tim-3 blockade as a mechanism that antagonizes T-cell-Tim-3-directed IO therapeutic efficacy. They further reveal MAPK targeting as a combination strategy for circumventing adverse consequences of unintended melanoma-Tim-3 inhibition. SIGNIFICANCE: Tim-3 is a growth-suppressive receptor intrinsic to melanoma cells, the blockade of which promotes MAPK-dependent tumorigenesis and thus counteracts antitumor activity of T-cell-directed Tim-3 inhibition.

Comorbidities in lichen planus by phenome-wide association study in two biobank population cohorts.

BACKGROUND: Lichen planus (LP) is a relatively frequent mucocutaneous inflammatory disease affecting the skin, skin appendages and mucosae, including oral mucosae, and less frequently the anogenital area, conjunctivae, oesophagus or larynx. OBJECTIVES: To estimate the association of LP, with emphasis on dermatological and gastrointestinal conditions, in two large independent population cohorts. MATERIALS AND METHODS: We performed a phenome-wide association study (PheWAS) and examined conditions associated with LP in two unrelated cohorts, i.e. the multicentre, community-based UK Biobank (UKB: 501 381 controls; 1130 LP subjects) and the healthcare-associated Penn Medicine BioBank (PMBB; 42 702 controls; 764 LP subjects). The data were analysed in 2021. The 'PheWAS' R package was used to perform the PheWAS analyses and Bonferroni correction was used to adjust for multiple testing. Odds ratios (ORs) were adjusted for age, sex and body mass index. RESULTS: In the UKB, PheWAS revealed 133 phenome codes (PheCodes) significantly associated with LP and most of them were confirmed in PMBB. Dermatological and digestive PheCodes were the most abundant: 29 and 34 of these disorders, respectively, were significantly overrepresented in LP individuals from both cohorts. The 29 dermatological and 12 oral disorders were often highly enriched, whereas hepatic, gastric, oesophageal and intestinal PheCodes displayed ORs in the range of 1·6-4·5. Several autoimmune disorders also exhibited OR > 5 in both cohorts. CONCLUSIONS: PheWAS in two large unrelated cohorts identified previously unknown comorbidities and may support clinical counselling of patients with LP. What is already known about this topic? Lichen planus (LP) is known to affect the skin, skin appendages and mucosae, including oral mucosae, and less frequently the anogenital area, conjunctivae, oesophagus or larynx. What does this study add? Our data provide the most comprehensive collection of associated dermatological, digestive and autoimmune disorders to date. Our findings are expected to be useful for the evaluation and management of patients with LP.

Transient injection site reaction to alirocumab during immune system activation: a case series.

Background: Injection site reactions (ISRs) are known side effects of the proprotein convertase subtilisin kexin 9 (PCSK9) inhibitor alirocumab. Transient ISR to alirocumab after a long phase of good tolerability have not been reported previously. Case summary: A 55-year-old woman (Patient 1) and a 77-year-old man (Patient 2) were treated with alirocumab for the management of dyslipidaemia. Both patients tolerated the treatment without side effects for 7 and 2 months, respectively. After an upper respiratory tract infection in Patient 1 and a first COVID-19 vaccination in Patient 2, both patients suddenly developed ISR with erythema, calor, and itching upon 2 (Patient 1) and 1 (Patient 2) subsequent injection(s), respectively. Symptoms resolved with local steroids, oral antihistamines, and cooling. After termination of the presumed immune system activated state, alirocumab was well tolerated again in both patients without recurrence of any ISR upon repeated applications. Discussion: These are the first cases to report transient ISR to a PCSK9 inhibitor, possibly triggered by activation of the immune system, after prolonged good tolerability. Based on the transient and benign nature of the reaction, such patients should be encouraged to continue supervised treatment, as tolerability may return after resolution of the pro-inflammatory state.

The Activation Pattern of Drug-Reacting T Cells Has an Impact on the Clinical Picture of Hypersensitivity Reactions.

Rationale: ß-lactam antibiotics cause drug hypersensitivity reactions (DHR) with various clinical pictures from minor affections like maculopapular exanthema (MPE) and urticaria to severe cutaneous adverse reactions and anaphylaxis. Currently, two different reactivity patterns have been shown to initiate an immune reaction by activating T cells-the hapten concept and the pharmacological interaction with immune receptor (p-i) concept. Objectives: In this study, the relationship between the reactivity pattern of drug-reacting T cells of drug allergic patients and their clinical picture has been investigated. Findings: Drug-reacting T-cell clones (TCCs) were isolated from patients hypersensitive to ß-lactams. Analysis of their reactivity pattern revealed an exclusive use of the hapten mechanism for patients with immediate reactions and for patients of MPE. In patients suffering from drug reactions with eosinophils and systemic symptoms, a severe DHR, analysis of isolated drug-reacting TCC identified the p-i concept as the unique mechanism for T-cell activation. Conclusions: The results show a shift from hapten pattern in mild allergic reactions to p-i pattern in severe life-threatening allergic reactions. They strongly argue against the current preclinical risk evaluation of new drugs based on the ability to form haptens.

T cells in the skin: Lymphoma and inflammatory skin disease.

T cells are established contributors to the pathogenesis of atopic dermatitis and psoriasis; yet, whether they are the key drivers or simply unwitting participants remains incompletely understood. Conversely, malignant T cells are the undisputed culprits of cutaneous T-cell lymphoma (CTCL), a group of diseases that share key clinical, histopathologic, and molecular features with inflammatory skin disease (ISD). Here, we compare the pathogenesis of ISD and CTCL and discuss the resulting insights. Recurrent, skin-limited disease implicates skin-resident memory T cells in both ISD and CTCL. In CTCL, malignant T cells recruit benign T cells into inflammatory skin lesions, a disease-amplifying function that has also been proposed for pathogenic T cells in ISD. Mechanistically, cytokines produced by malignant T cells in CTCL and by pathogenic T cells in ISD, respectively, are likely both necessary and sufficient to drive skin inflammation and pruritus, which in turn promotes skin barrier dysfunction and dysbiosis. Therapies for ISD target T-cell effector functions but do not address the chronicity of disease, whereas treatments for CTCL target malignant T cells but not primarily the symptoms of the disease. Integrating our understanding of ISD and CTCL can result in important insights into pathogenesis and therapy that may improve the lives of patients in both of these disease groups.

Long-Term Effectiveness and Drug Survival of Apremilast in Treating Psoriasis: A Real-World Experience.

BACKGROUND: Apremilast is an oral phosphodiesterase 4 (PDE4) inhibitor used for the treatment of moderate to severe psoriasis. Long-term data on the effectiveness and drug survival of patients treated with apremilast are limited. OBJECTIVE: The aim of this study was to analyze the characteristics, effectiveness, and drug survival of patients treated with apremilast in a real-world setting. METHODS: We conducted a retrospective cohort study of patients with psoriasis who received at least 1 dose of apremilast between 2015 and 2018. We documented sex; age; type, duration, and severity (using Psoriasis Area Severity Index [PASI] and Dermatology Life Quality Index [DLQI]) of psoriasis; comorbidities; previous treatment modalities; adverse events; and reasons for therapy discontinuation. For drug survival, estimates and efficacy analysis with Kaplan-Meier statistics were used. RESULTS: The drug survival rate of the 93 reviewed patients was 69.5% at 6 months, 34.7% at 12 months, and 25.8% at 24 months after initiating therapy. The median survival duration was 8.0 months. Therapy was discontinued in 66.6 and 27.8% due to loss of efficacy and adverse events, respectively. At 24 months, 35.9% had achieved PASI75 response and 23.7% had achieved PASI90 response. Most observed adverse events were gastrointestinal issues, weight loss, and headache. CONCLUSIONS: Apremilast is an effective and well-tolerated therapy for patients with moderate to severe psoriasis, especially for patients with difficult-to-treat locations and/or contraindications to other biologics. Furthermore, apremilast was used for patients with a history of nonresponse to biologics and was favored for patients with relatively low PASI (<10) and a high DLQI.

Effect of topical application of platelet-rich plasma on chronic venous leg ulcerations.

Wound products that reliably support healing of chronic leg ulcers remain a huge unmet need in clinical practice. Due to the lack of standardized comparable protocols and different systems for platelet-rich plasma (PRP) preparation, there is limited data on healing rates in chronic venous ulcers. In our case series with a total of seven chronic leg ulcers in four patients, we investigated the healing rates based on standardized digital photographs of chronic venous ulcers after application of topical PRP using a digital imaging software. In 5 out of 7 ulcers, the PRP-treated wound half showed faster healing as compared the control half of the wound. In this case series, PRP-treated sides of chronic venous leg ulcers showed a tendency for accelerated healing as compared to nontreated collateral wound side. Our data support the evaluation of topical PRP treatment in the management of chronic venous leg ulcers.

IL-12 regulates type 3 immunity through interfollicular keratinocytes in psoriasiform inflammation.

Psoriasis is a chronic inflammatory skin disorder underpinned by dysregulated cytokine signaling. Drugs neutralizing the common p40 subunit of interleukin-12 (IL-12) and IL-23 represented a therapeutic breakthrough; however, new drugs that block the IL-23p19 subunit and spare IL-12 are more effective, suggesting a regulatory function of IL-12. To pinpoint the cell type and underlying mechanism of IL-12­mediated immune regulation in psoriasis, we generated a conditional Il12rb2-knockout (KO)/reporter mouse strain. We detected Il12rb2 expression in T cells and a specific subset of interfollicular (IF) keratinocytes. Analysis of single-cell RNA-sequencing (scRNAseq) data from patients with psoriasis confirmed a similar expression pattern in the human skin. Deletion of Il12rb2 across the hematopoietic compartment did not alter the development of Aldara-induced psoriasiform inflammation. However, depletion of Il12rb2 in keratinocytes exacerbated disease development, phenocopying the Il12rb2 germline knockout. Protective IL-12 signaling blocked the hyperproliferation of keratinocytes, maintained skin barrier integrity, and diminished disease-driving IL-23/type 3 immune circuits. In line, specific IL-23p19 blockade led to a more profound reduction of psoriatic keratinocyte expression signatures in the skin of patients with psoriasis than combined IL-12/IL-23 inhibition. Collectively, we provide a potential explanation for the superior efficacy of IL-23p19 inhibitors in psoriasis and describe an unperceived role of IL-12 in maintaining skin epithelial cell homeostasis.

The Concept of Pathogenic TH2 Cells: Collegium Internationale Allergologicum Update 2021.

T helper (TH) cells have evolved into distinct subsets that mediate specific immune responses to protect the host against a myriad of infectious and noninfectious challenges. However, if dysregulated, TH-cell subsets can cause inflammatory disease. Emerging evidence now suggests that human allergic disease is caused by a distinct subpopulation of pathogenic TH2 cells. Pathogenic TH2 cells from different type-2-driven diseases share a core phenotype and show overlapping functional attributes. The unique differentiation requirements, activating signals, and metabolic characteristics of pathogenic TH2 cells are just being discovered. A better knowledge of this particular TH2 cell population will enable the specific targeting of disease-driving pathways in allergy. In this review, we introduce a rational for classifying TH cells into distinct subsets, discuss the current knowledge on pathogenic TH2 cells, and summarize their involvement in allergic diseases.

Prurigo Pigmentosa: Demographics and Characteristics in 14 Caucasian Patients.

BACKGROUND: Prurigo pigmentosa (PP) is an inflammatory dermatosis typically reported in young Asian women and characterized by recurrent papulovesicular lesions resolving with a postinflammatory reticulated hyperpigmentation. METHODS: We have included all consecutive patients with PP diagnosed in our tertiary center between 2013 and 2020. The clinical information was retrospectively collected from medical records. RESULTS: We identified 14 patients with PP. The median age at the time of diagnosis was 29.5 years (range 17-43 years), while the female-to-male ratio was 13:1. Diagnostic delay varied from 10 days to 10 years (mean of 25 months). Light microscopy studies consistently showed presence of a lymphohistiocytic infiltrate in combination in 40% of cases with neutrophils. Interface changes were found in 60% of cases. In 6 (43%) of 14 cases, there was a chronological relationship between the starting of a new diet and the development of the first flares. Treatment with doxycycline in 9 patients resulted in a complete regression of the lesions. LIMITATION: This was a retrospective study in a tertiary referral hospital. CONCLUSIONS: Our observations indicate that PP is not so rare in Europe as previously thought and is often diagnosed after a long delay. Demographics, clinical characteristics and triggering factors in Caucasian patients are similar to those described in the Asian population. Diagnosis is based on the peculiar recurrent course and distinctive clinicopathological features. Tetracyclines represent the first-line therapy in PP.