Background Guttate psoriasis (GP) is associated with streptococcal throat infection. Neutrophils are the first immune cells to respond to Group A Streptococcal (GAS) infection, but detailed analysis of their contribution to GP pathogenesis is lacking. The study primarily focuses on phenotyping the neutrophils located at the site of inflammation in GP skin and understanding their specific contribution to the pathogenesis of the disease. Methods Here, we performed a comprehensive immunophenotypic and transcriptomic analysis of neutrophils from blood and inflamed GP skin using high-dimensional single-cell protein and RNA analyses. Ex vivo stimulation of neutrophils and co-culture with CD4+ T cells was performed to validate the function of neutrophil subsets upon GAS stimulation. Findings We uncovered high diversity of human neutrophils in GP, with enrichment of an immature subset in GP skin that exhibited antigen processing and presentation signature. A similar subset in healthy controls was observed only upon ex vivo stimulation of neutrophils with GAS bacteria. Additionally, the GAS-induced neutrophil subset was found to induce CD4+ T cell proliferation mediated by HLA-DR. Other neutrophil subsets that expanded in GP were characterised by enrichment of genes related to neutrophil migration, formation of neutrophil extracellular traps and phagocytosis. Interpretation Our study depicts the landscape of neutrophils in GP skin and highlights HLA-DR+ neutrophils with possible role in disease pathogenesis. Funding This work was supported by HudFonden, Psoriasisfonden, Gösta A Karlssons 60-års fond, Magnus Bergvall stiftelse, Åke Wibergs stiftelse, and Karolinska Institute. AP was supported by HudFonden. PA was partially supported by Karolinska Institute’s doctoral funding (KID). LPM was supported by grants from Svenska Sällskapet för Medicinsk Forskning (SSMF) and European Society of Clinical Microbiology and Infectious Diseases (ESCMID). UN was supported by grants from the Swedish Research Council. JL was supported by Region Stockholm (clinical postdoctoral appointment). ML was supported by the Swedish Childhood Cancer research fund and the Karolinska Institute. Part of the data handling was enabled by resources at project number SNIC-2021/22-49 provided by the Swedish National Infrastructure for Computing (SNIC), partially funded by the Swedish Research Council through grant agreement no. 2018-05973.

Background: Up to one-third of people living with psoriasis develop psoriatic arthritis (PsA), and the majority have active psoriasis prior to the development of arthritis. Clinical risk factors, such as nail involvement, in conjunction with novel blood biomarkers, could improve PsA risk monitoring and early diagnosis. Objectives: The aim of the HIPPOCRATES Prospective Observational Study (HPOS— www.hpos.study ) is to follow a cohort living with psoriasis and identify risk factors for the development of PsA. Design: HPOS is a patient-driven online prospective European observational cohort. Methods: Adult participants with psoriasis but with no prior diagnosis of PsA are eligible. Participants are invited to provide consent and join the study online. They complete a semi-structured questionnaire to collect data on demographics, psoriasis, comorbidities, risk factors for PsA, and the Psoriasis Epidemiology Screening Tool screening questionnaire. Follow-up is conducted through a questionnaire every 6 months. The primary outcome is the new onset of PsA confirmed by a diagnosis from their doctor. The study will also collect peripheral blood samples from a subset of participants for biomarker identification. Ethics: This study follows the principles of the Declaration of Helsinki. To date, ethical approval has been granted by independent ethical committees in 10 countries. Discussion: Studying a cohort of individuals with psoriasis will allow us to identify risk factors for arthritis development and to develop a risk calculator. This can support focused efforts on screening, patient education, and even studies looking to delay or prevent the onset of arthritis. This study, run via remote online data collection, provides an efficient way to recruit a large cohort (25,000) across multiple countries. However, challenges have had to be addressed with some key changes in study design, ethical review, and recruitment strategies required for each individual country. Trial registration: HPOS, Clinicaltrials.gov ID: NCT05858528, IRAS number 325080; https://clinicaltrials.gov/study/NCT05858528?locStr=United%20Kingdom&country=United%20Kingdom&cond=Psoriasis&term=HPOS&aggFilters=status%3Anot%20rec&rank=1 .

BACKGROUND:Psoriasis is a common chronic inflammatory skin disease characterized by recurrent flares at previously affected locations. Although biologics targeting IL-17 or IL-23 effectively suppress active disease, they rarely result in long-term remission, suggesting that clinically resolved skin retains molecular changes predisposing to relapse. OBJECTIVE:The STEPIn main study indicated that early intervention with secukinumab, an anti-IL-17A monoclonal antibody, may modify the course of psoriasis. This mechanistic substudy sought to define cellular and molecular changes in psoriatic skin lesions during treatment. METHODS:Psoriatic skin was sampled at baseline and at up to 52 weeks of secukinumab treatment in new-onset (≤1 year) and long-standing (≥5 years) cohorts. Biopsy samples were evaluated histologically by immune profiling, global gene expression, and genome-wide DNA CpG methylation analyses. RESULTS:Treatment with secukinumab resulted in marked molecular differences between new-onset and long-standing psoriasis despite similar clinical improvement. Gene expression normalized faster in new-onset disease but ultimately resolved in both cohorts. In contrast, disease-associated CpG methylation detected at baseline persisted despite treatment, but only in long-standing psoriasis. Baseline methylation differences were enriched for AP-1 transcription factor binding sites in long-standing disease and persistent methylation changes mapped to genes enriched for small GTPase pathways. Notably, AP-1 components were found to amplify IL-17A and TNF-α responses in keratinocytes, and a subset of these persistent methylation sites overlapped with accessible chromatin regions in psoriatic keratinocytes. CONCLUSIONS:Early secukinumab intervention may prevent formation of an epigenetic scar that persists in long-standing psoriasis even after clinical resolution. CLINICAL TRIAL REGISTRATION:NCT03020199.

IntroductionPsoriasis is a common chronic inflammatory skin disease. Treatments lead to Q6 substantial improvement of most psoriasis plaques. However, it can be challenging to reach disease resolution in certain hard to treat areas such as scalp, and lower extremity. Here we map histologic and spatial transcriptomic differences between psoriasis lesions across different anatomical locations, to understand if differences can be linked to plaque-site specific treatment resistance.MethodsQuantitative immunohistochemical analysis and transcriptomic digital spatial profiling were performed on skin punch biopsies obtained from unaffected areas on the trunk, lesional (LS) areas of the scalp, upper extremity and lower extremity of 12 patients with psoriasis. Histological analysis showed no significant differences in epidermal thickness among LS skin from different body locations.ResultsImmunohistochemical markers (CD3, CD4, CD8, CD103, CD207, IL-12RB1, IL-17A, IL-23R, RORγt, FOXP3, and MPO) did not differ significantly between LS sites. Whole transcriptome spatial RNA profiling identified several differentially expressed genes that revealed site-specific transcriptomic differences. Notably, IL-23 signaling was significantly enriched in the lower extremity epidermis, and IL-17 signaling was more pronounced in the epidermis of LS samples.DiscussionThese findings highlight minimal histological and immunohistochemical variation, yet significant transcriptomic and pathway differences between psoriasis body locations, suggesting potential targets for site-specific therapeutic strategies.

BACKGROUND:Benefits of early intervention with secukinumab in patients with new-onset plaque psoriasis (disease duration: ≤1 year) were investigated in STEPIn study (NCT03020199). OBJECTIVE:To evaluate the proportion of patients maintaining sustained skin clearance in the treatment-free follow-up period up to week (W) 104 following withdrawal of secukinumab and narrow band ultraviolet B at W52. METHODS:Wald test was used for analysis of proportion of patients achieving PASI 90 (key secondary endpoint) from W52 through W104. Missing values were imputed using nonresponder imputation approach. RESULTS:Overall, 93.5% (72/77) of patients completed 52 weeks in the secukinumab arm. At W104, 20.8% of patients who previously received secukinumab sustained PASI 90 responses. At W104, 11.7%, 22.1%, and 24.7% of patients previously treated with secukinumab sustained a PASI 100 response, IGA mod 2011 0/1 and PASI <3. Among secukinumab treated patients, 44% (29/66) who entered the treatment-free follow-up period at W52 did not relapse (loss of 50% of the maximum improvement in PASI following treatment cessation) until W104. LIMITATION:Absence of blinding due to open-label nature of the study. CONCLUSIONS:Early intervention with secukinumab maintains efficacy in a subset of patients with new-onset moderate to severe psoriasis, 1-year following treatment withdrawal.

Numerous patients with psoriasis will associate disease triggers to changes in disease activity over time. Modern treatments induce remission, but relapse is common if the treatment is stopped. Exploring patients’ first-hand experiences is a key starting point to identify triggers that may influence disease relapse. A cross-sectional digital questionnaire was distributed to 2716 individuals with psoriasis in Chile, Denmark, Sweden, and the Netherlands. 71% of participants reported psoriatic disease triggers. Triggers were classified into 24 subgroups dominated by stress (55.3%), infections (17.7%) and alcohol (10.8%). The majority (65%) of the participants experienced seasonal variation in disease activity, and approximately half reported fluctuating disease activity with periods of flare-ups. The self-reported trigger prevalence varied by gender, disease manifestation (skin psoriasis and/or psoriatic arthritis), and country of residence. The female participants more often reported stress and infections as triggers. Alcohol consumption is more often reported as a trigger in males. Chileans more often reported stress and less frequently reported infections as triggers. Insights into patient-reported disease variations and triggers can be used to aid patient-physician conversations and patient phenotyping during routine clinical practice. Trigger assessment and management could potentially contribute to patient counselling and motivate lifestyle changes.

The "hot topics" session of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2024 annual meeting and trainee symposium explored the integration of artificial intelligence (AI) in managing psoriatic diseases (PsD) and the underlying mechanisms of inflammatory memory that drive recurrence in psoriasis and psoriatic arthritis. Drs. April Armstrong and Denis Poddubnyy discussed the transformative role of AI in enhancing diagnostic accuracy, assessing disease severity, and predicting treatment responses, particularly through deep learning models such as convolutional neural networks. AI systems have shown promise in providing objective, standardized assessments for psoriasis, with applications expanding across dermatology and rheumatology. Dr. Liv Eidsmo presented insights into inflammatory memory, a phenomenon sustained by both immune and nonimmune cells, including tissue-resident memory cells and epigenetically altered keratinocytes. Eidsmo emphasized the importance of understanding the cellular and molecular pathways that contribute to disease persistence. Both AI and inflammatory memory highlight key challenges and opportunities in PsD management; future research is needed to integrate technological advancements, with a deeper understanding of the biological processes affecting treatment outcomes.

The journey of early-career researchers (ECRs) in immunology is marked by many challenges but also exciting prospects. Here we bring a snapshot of the recent ECR workshop organized by the Young European Federation of Immunology Societies (yEFIS) during the 7th European Congress of Immunology (ECI), which took place in Dublin Ireland from September 1 to 4, 2024. This article brings forward the unique experiences and perspectives of eight Principal Investigators (PIs) and the events that shaped their careers in immunology. Navigating challenges, from mastering intricate laboratory techniques, securing tenure, or moving countries, to finding the right balance between family and research life; their stories reveal the diverse paths to independence within academia. This series celebrates scientific accomplishments acknowledging the non-linearity of career paths and the value of passion for discovery, self-confidence, resilience, and perseverance in their academic journeys.

Secukinumab and Dead Sea treatment result in clear skin for many psoriasis patients, through distinct mechanisms. However, recurrence in the same areas after treatments suggests the existence of a molecular scar. We aimed to compare the molecular and genetic differences in psoriasis patients who achieved complete response from secukinumab and Dead Sea climatotherapy treatments. We performed quantitative immunohistochemical and transcriptomic analysis, in addition to digital spatial profiling of skin punch biopsies. Histologically, both treatments resulted in a normalization of the lesional skin to a level resembling nonlesional skin. Interestingly, the transcriptome was not normalized by either treatments. We revealed 479 differentially expressed genes between secukinumab and Dead Sea climatotherapy at the end of treatment, with a psoriasis panel identifying SERPINB4, SERPINB13, IL36G, IL36RN, and AKR1B10 as upregulated in Dead Sea climatotherapy compared with secukinumab. Using digital spatial profiling, pan-RAS was observed to be differentially expressed in the microenvironment surrounding CD103+ cells, and IDO1 was differentially expressed in the dermis when comparing the two treatments. The differences observed between secukinumab and Dead Sea climatotherapy suggest the presence of a molecular scar, which may stem from mechanistically different pathways and potentially contribute to disease recurrence. This may be important for determining treatment response duration and disease memory.

Background Hidradenitis suppurativa (HS) is a chronic inflammatory and scarring disease with a wide spectrum of disease severity. The amount of scarring is proportional to the preceding tissue damage and poses a challenge to patients. Severe HS is most often treatment recalcitrant, but hypothetically avoidable through early biologic treatment. Early prediction of individual risk of disease progression is therefore essential for patient management. Objectives To investigate risk factors associated with disease progression and to design an algorithm capable of predicting disease progression. Methods A prospective cohort study of 335 Hurley III-na & iuml;ve patients with HS, not treated with biologics, was followed for a median of 2 years. Potential risk factors covered basic demographics, HS anamnestic factors and clinical HS factors collected during physical examination. Two separate Cox proportional hazard regression (CPHR) analyses were conducted. A summated 'progression score' was calculated and used in the predictive algorithm of severe disease. Subsequent bootstrap sampling was used to validate the predictability of the predictive algorithm. Results The CPHR analysis of Transition to severe disease found that active smoking [hazard ratio (HR) 4.01, 95% confidence interval (CI) 1.71-9.40, P = 0.001]; body mass index (BMI) points > 25 at baseline (each point: HR 1.06, 95% CI 1.02-1.09, P < 0.001); active disease in 2 (HR 4.26, 95% CI 1.23-14.84, P = 0.02) and >= 3 areas (HR 6.54, 95% CI 1.89-22.72, P = 0.003) all constituted substantial risk factors. Conversely, the CPHR analysis of Disease progression did not yield results of clinical relevance. A 'progression score' of 3.04 was used as a threshold in the predictive algorithm of Transition to severe disease and achieved the following test specifics: sensitivity = 0.51, specificity = 0.86, positive predictive value = 0.50, negative predictive value = 0.86. Conclusions We found a disparity between factors increasing the risk of simple Disease progression and those increasing the risk of Transition to severe disease. For the latter, active smoking, BMI points > 25, active disease in 2 or >= 3 areas were all shown to be the clinically relevant factors that could be used to construct an algorithm that correctly predicted progression to severe HS in more than half of all instances.

The human skin forms a dynamic barrier to physical injuries and microbial invasion. Constant interactions between stroma and tissue-confined immune cells maintain skin homeostasis. However, the cellular interactions that maintain skin health also contribute to focal immunopathology. Psoriasis is a common disease that manifests with focal pathology induced by environmental triggers in genetically susceptible individuals. Within psoriasis plaques, cross-talk between skin-resident T cells and stroma cells leads to chronic inflammation. Inflammatory cytokines such as TNF-α, IL-17, IL-22, and IL-23 amplify the local chronic inflammation and sustain the well-demarcated thick and scaly plaques that characterize the disease. In resolved lesions, T cells remain poised for IL-17 and IL-22 production, and postinflammatory epigenetic modifications lower the threshold for initiation of local relapse. This review focuses on how tissue-resident memory T cells contribute to the onset, maintenance, resolution, and relapse of psoriasis.

Vitiligo is an autoimmune skin disease characterized by focal depigmentation due to melanocyte loss attributed to autoreactive T cells. Recent single cell studies highlight activation of IFNg pathways in both lesional and non-lesional skin and stressed keratinocytes with metabolic switch towards oxidative phosphorylation in lesional skin. In this integrative study we combine existing single cell datasets and put it into spatial context with 10x Visium spatial sequencing of 25 samples from non-, peri- and lesional vitiligo and healthy skin. We utilized bulk RNAseq to assess tissue responses to pan T cell stimulation and measure quantitatively deconvolution-derived cell types changes in health and vitiligo. Pigmented peri-lesional vitiligo was found to be a site of active IFNγ inflammation and oxidative phosphorylation, with IFNγ responses highly associated with Treg cell signal. In contrast, depigmented lesions displayed dormant IFNγ inflammation, that was revealed upon T cell stimulation. Besides IFNg responses, vitiligo epidermis reacted to T cell stimulation with local T cell proliferation. Lesional melanocytes had increased expression of the damage marker S100B and selenoamino acid metabolism, both previously proposed biomarkers of disease activity. Moreover, S100B protein was specifically upregulated in T cells-melanocytes colocalizations. The combined modality of the study revealed novel insights into spatially restricted disruptions of cellular environments in vitiligo.