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Summary: Background: Conventional analyses present aggregate data, masking late responders and efficacy reductions. Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin (IL)‐17A, shows sustained efficacy in moderate‐to‐severe psoriasis. Objectives: To determine stability of response to secukinumab, changes in efficacy were assessed in individual patients. Methods: This is a post hoc analysis of two phase III randomized controlled trials, FIXTURE (trial registration: NCT01358578) and CLEAR (trial registration: NCT02074982). Patients received secukinumab 300 mg (FIXTURE and CLEAR), etanercept 50 mg (FIXTURE) or ustekinumab 45 or 90 mg (CLEAR) over 52 weeks. Mutually exclusive response categories were defined: ≥ 90% improvement in the Psoriasis Area and Severity Index (PASI 90) ('excellent'), ≥ 75% improvement in PASI (PASI 75) and < PASI 90 ('good') and < PASI 75 ('insufficient'). Reductions in efficacy were defined as shifts from higher to lower response categories between two consecutive visits maintained for a third consecutive visit. Loss of efficacy was defined as a reduction of efficacy resulting in 'insufficient' response. All comparisons are descriptive. Results: At 52 weeks, in CLEAR, 90·2% (303/336) of patients on secukinumab achieved stable efficacy without loss and 77·7% (261/336) showed stable efficacy without any reduction of response [74·3% (252/339) and 59·9% (203/339) of patients for ustekinumab]. In FIXTURE, 83·5% (273/327) and 66·4% (217/327) of patients on secukinumab had stable efficacy without loss or reduction of response [58·3% (190/326) and 42·6% (139/326) for etanercept]. Response was regained by continuing secukinumab treatment in 50% (8/16) of patients in CLEAR and 26% (9/34) in FIXTURE. Similar patterns were observed for other response definitions. Conclusions: Efficacy with secukinumab was stable over 52 weeks of treatment in most patients. Continued treatment with secukinumab resulted in regain of efficacy in some patients. Persistent loss of response was uncommon. What's already known about this topic? Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin (IL)‐17A, shows significant and sustained efficacy in the treatment of moderate‐to‐severe psoriasis.Secondary loss of response may be experienced by a minority of patients treated with secukinumab, as with other biologics, but the extent of this and the potential for regain of efficacy with continued treatment is not well understood. What does this study add? To determine stability of response to secukinumab and inform clinical practice, changes in efficacy were assessed at individual patient level using response categories.Efficacy with secukinumab was stable over 52 weeks of treatment in most patients, and continued treatment with secukinumab resulted in efficacy regain after loss in some patients. Persistent loss of response was uncommon.Patient factors such as body weight may affect the likelihood of loss of efficacy. Plain language summary available online Respond to this article [ABSTRACT FROM AUTHOR]

Background: Imbalances of T‐cell subsets are hallmarks of disease‐specific inflammation in psoriasis. However, the relevance of B cells for psoriasis remains poorly investigated. Objective: To analyse the role of B cells and immunoglobulins for the disease‐specific immunology of psoriasis. Methods: We characterized B‐cell subsets and immunoglobulin levels in untreated psoriasis patients (n = 37) and compared them to healthy controls (n = 20) as well as to psoriasis patients under disease‐controlling systemic treatment (n = 28). B‐cell subsets were analysed following the flow cytometric gating strategy based on the surface markers CD24, CD38 and CD138. Moreover, immunofluorescence stainings were used to detect IgA in psoriatic skin. Results: We found significantly increased levels of IgA in the serum of treatment‐naïve psoriasis patients correlating with disease score. However, IgA was only observed in dermal vessels of skin sections. Concerning B‐cell subsets, we only found a moderately positive correlation of CD138+ plasma cells with IgA levels and disease score in treatment‐naïve psoriasis patients. Confirming our hypothesis that psoriasis can develop in the absence of functional humoral immunity, we investigated a patient who suffered concomitantly from both psoriasis and a hereditary common variable immune defect (CVID) characterized by a lack of B cells and immunoglobulins. We detected variants in three of the 13 described genes of CVID and a so far undescribed variant in the ligand of the TNFRSF13B receptor leading to disturbed B‐cell maturation and antibody production. However, this patient showed typical psoriasis regarding clinical presentation, histology or T‐cell infiltrate. Finally, in a group of psoriasis patients under systemic treatment, neither did IgA levels drop nor did plasma cells correlate with IgA levels and disease score. Conclusion: B‐cell alterations might rather be an epiphenomenal finding in psoriasis with a clear dominance of T cells over shifts in B‐cell subsets. [ABSTRACT FROM AUTHOR]

Background: Pyoderma gangrenosum (PG) is rare neutrophil skin disease causing painful, progressively enlarging ulcers. Among the treatment options, intravenous immunoglobulin (IVIG) is a therapy of first choice for paraneoplastic PG. Otherwise, it is used in therapy-refractory courses., Objective: To assess the efficacy and safety of IVIG therapy in patients with PG., Methods: A retrospective chart review for patients in five dermatologic wound centres in Germany was performed., Results: Overall, 81 patients were included. IVIG was used as adjunct therapy with (methyl-) prednisolone and/or a steroid sparing therapy in 77 (95.1%) cases. Response to treatment (combined complete and partial, defined as tendency to heal and cessation of lesion progression, respectively) was 49.3% 1 month after initiation of IVIG. In total 18.8% had a complete response after 6 months. Statistically significantly higher response rates were observed in patients with diabetes mellitus and thyroid disease [odds ratio (OR) 3.49, confidence interval (CI) 1.13-10.80 and OR 6.64, CI 1.01-43.57, respectively]. Patients with solid malignancy tended to have better response (OR 4.36, CI 0.79-23.91). A higher IVIG dose was also associated with a tendency towards better response rates (OR 2.70, CI 0.84-8.63). In total, 1 (1.2%) severe adverse event (myocardial infarction with consequent death) was observed as well as three moderate adverse events, with two thromboembolic events (2.5%) and one acute kidney injury (1.2%). Other adverse events were mild or unlikely to be associated with IVIG therapy, with 14 events in 10 patients overall (12.3%)., Conclusions: This multicentre retrospective study shows the important role of adjunctive IVIG therapy in patients with PG with recalcitrant courses. Identifying subgroups with a higher probability of response could improve future response rates and save patients from ineffective treatment and potential adverse events., Competing Interests: Declarations. Funding: Open Access funding enabled and organized by Projekt DEAL. M.R. and L.S. were funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—493624887 (Clinician Scientist Program NOTICE). Conflicts of interest: None declared. Ethical approval: Reviewed and approved by the local ethics committee (ethics committee of the Friedrich-Alexander-Universität Erlangen-Nürnberg), # 23-430-Br. Data availability statement: The data that support the findings of this study are available from the corresponding author upon reasonable request. Patient consent to participate: Not applicable due to retrospective study design. Patient consent to publish: Not applicable due to retrospective study design. Code availability: Not applicable. Author contributions: M.R. carried out conceptualization, data curation, investigation, funding acquisition, methodology, project administration, visualization and writing—original draft preparation; L.S. carried out conceptualization, data curation, investigation, funding acquisition, methodology and writing—review and editing; M.V., L.W., M.K. and M.M. carried out data curation, investigation and writing—review and editing; J.D., E.S., F.L. and P.v.d.D. carried out supervision and writing—review and editing; C.E.-B. carried out conceptualization, supervision and writing—review and editing., (© 2024. The Author(s).)

Introduction: Studies directly comparing the effectiveness of different biologics over long observation periods are lacking. As many treatment guidelines are formulated based on drug class, there is a particular need to compare drug classes rather than specific biologic agents., Methods: This post hoc analysis compares the effectiveness and durability of biologics that target the interleukin (IL)-17 A ligands or the IL-17 receptor A (IL-17RA) relative to other approved drug classes in patients with moderate-to-severe plaque psoriasis, through 12 months in a real-world setting., Results: In the Psoriasis Study of Health Outcomes (PSoHO) (N = 1981), patients treated with anti-IL-17A/RA resulted in a higher proportion of patients who achieved the primary outcome [proportion of patients who had at least a 90% improvement in Psoriasis Area and Severity Index score (PASI90) and/or a score of 0 or 1 in static Physician Global Assessment (sPGA)] compared to anti-IL-23-, anti-IL-12/23-, and tumor necrosis factor (TNF)-α-treated patients at week 12, month 6, and month 12, except versus anti-IL-23 at month 12. Similar trends were observed for a 100% improvement in PASI score (PASI100), PASI90, and Dermatology Life Quality Index score of 0 or 1 [DLQI (0,1)]. At month 12, the unadjusted response rates across the drug classes were 53.5-69.1% for the primary outcome, 27.6-40.8% for PASI100, 41.7-55.9% for PASI90, and 31.8-33.0% for DLQI (0,1). Regarding the durability of effectiveness, anti-IL-17A/RA patients had the highest response rate, and for the adjusted analysis, using Frequentist Model Averaging (FMA), patients had 1.4-2.6 times higher odds of achieving the primary durability outcome compared to patients treated with any other drug class., Conclusion: Overall, anti-IL-17A/RA had the highest effectiveness of achieving early response to treatment and maintaining that response through 12 months compared to other drug classes., Trial Registration: The study was registered at the European Network of Centers for Pharmacoepidemiology and Pharmacovigilance (ENCEPP24207)., Competing Interests: Declarations. Conflict of Interest: Saakshi Khattri is a speaker for AbbVie, Janssen, Lilly, and UCB; serves as an advisory board member/consultant for AbbVie, Janssen, Lilly, Novartis, and UCB; and has received research grants from AbbVie, BMS, LEO, Novartis, and Pfizer; Álvaro González-Cantero has served as a consultant for and received speaker fees from AbbVie, Janssen, Novartis, Almirall, Celgene, UCB, L'Oreal, MSD and Leo Pharma; Burhan Engin and Sunil Dogra has no conflict of interest to declare; Caroline A. Murphy, Christopher Schuster, Naoto Tsujimoto, Georgia Martimianaki, Anastasia Lampropoulou, Aya Alsharafi and Bruce Konicek are employees and shareholders of Eli Lilly and Company; Felix Lauffer has received speaker or consultant fees from Abbvie, Novartis Pharma, LEO Pharma, Lilly, Roche, Sanofi, Almirall, Janssen-Cilag Pharma Amgen, UCB Pharma, Boehringer-Ingelheim, Bristol-Myers-Squibb, and Union Therapeutics. Ethical Approval: The protocol, amendments, and consent documentation were approved by local institutional review boards (IRBs). The study was registered at the European Network of Centers for Pharmacoepidemiology and Pharmacovigilance (ENCEPP24207) and was conducted according to International Conference on Harmonization, Good Clinical Practice guidelines, and the Declaration of Helsinki. All patients were required to give informed consent for participation in the study. We confirm that the necessary central or local IRB and/or ethics committee approvals have been obtained for this multi-site, international study by United BioSource LLC (UBC). Approvals can be provided on request., (© 2024. The Author(s).)

Lichen planus (LP) is a chronic inflammatory disease affecting the skin, mucosa, nail, and hair. Previous studies demonstrated a pivotal role of type 1 immunity in LP because infiltrating T cells trigger apoptosis and necroptosis in the epidermis. In this study, we investigated the role of DAPK1 in LP with special focus on its role in mediating cell death and inflammation. Bulk RNA sequencing of skin biopsies revealed a high expression of DAPK1 in LP compared with that in psoriasis and atopic dermatitis. DAPK1 expression in human keratinocytes was induced by IFN-γ, TNF, and IL-32. CRISPR/Cas9-mediated DAPK1 knockout led to a decreased rate of cell death and induction of proapoptotic proteins (BAX, cPARP) in human keratinocytes upon stimulation with the supernatant T cells derived from LP skin biopsies. Meanwhile, DAPK1 knockout resulted in an induction of kinases involved in necroptosis (RIPK3) and an upregulation of inflammatory genes (CXCL9, CXCL10, CXCL11, IL32, CCL2) after stimulation with LP supernatant T cells. In summary, we demonstrate that DAPK1 mediates keratinocyte apoptosis under type 1 inflammatory conditions and thereby counteracts necroptosis and regulation of inflammatory genes. These findings point toward previously unreported therapeutic approaches for activating or stabilizing DAPK1 in LP., (Copyright © 2025. Published by Elsevier Inc.)

Importance: Psoriasis is a chronic inflammatory skin disease with unmet needs for tailored treatment and therapy de-escalation strategies., Objective: To evaluate early intervention with and prolonging the dosing interval for guselkumab, a p19 subunit-targeted interleukin (IL)-23 inhibitor, in patients with moderate to severe psoriasis., Design, Setting, and Participants: The GUIDE clinical trial is an ongoing phase 3b, randomized, double-blinded trial conducted across 80 centers in Germany and France comprising 3 parts evaluating the impact of early disease intervention, prolonged dosing interval, and maintenance of response following treatment withdrawal among adults with moderate to severe plaque psoriasis. In study part 2, reported herein, first and last patient visits were September 2019 and March 2022, respectively., Interventions: In GUIDE part 1 (week [W]0-W28), patients received guselkumab, 100 mg, at W0, W4, W12, and W20. Those achieving a Psoriasis Area and Severity Index (PASI) of 0 at both W20 and W28 were termed super responders (SRes). In part 2 (W28-W68), SRes were randomized to guselkumab, 100 mg, every 8 weeks or every 16 weeks; non-SRes continued open-label guselkumab every 8 weeks., Main Outcomes and Measures: Primary objective was to demonstrate noninferiority (with a 10% margin) of guselkumab every 16 weeks vs every 8 weeks dosing among SRes for maintenance of disease control (PASI <3 at W68). Biomarker substudies assessed immunologic effects in skin and blood., Results: Overall, 822 patients received guselkumab in part 2 (297 [36.1%] SRes [every 8 weeks/every 16 weeks; n = 148/n = 149] and 525 [63.9%] non-SRes). Among SRes, mean (SD) age was 39.4 (14.1) years, 95 (32.0%) were female, and 202 (68.0%) were male. The primary end point of noninferiority for guselkumab every 16 weeks vs every 8 weeks in SRes was met (P = .001), with 91.9% (137/149; 90% CI, 87.3%-95.3%) of SRes receiving every 16 weeks and 92.6% (137/148; 90% CI, 88.0%-95.8%) of SRes receiving dosing every 8 weeks having PASI lower than 3 at W68. Clinical effects corresponded with immunologic changes; skin CD8-positive tissue-resident memory T (TRM)-cell count decreased quickly from baseline, remaining low in both dosing groups. Similarly, serum IL-17A, IL-17F, IL-22, and β defensin (BD)-2 levels decreased significantly from baseline, remaining low in both dosing groups to W68. Guselkumab was well-tolerated; no new safety signals were identified., Conclusions and Relevance: Psoriasis treatment guidelines lack or provide inconsistent advice on patient stratification and treatment de-escalation. We present the first randomized trial providing evidence that, in patients with early complete skin clearance at 2 consecutive visits (W20 and W28), extending the guselkumab dosing interval may control disease activity., Trial Registration: ClinicalTrials.gov Identifier: NCT03818035.

Background: Psoriasis was long regarded as an inflammatory disease limited to the skin. Data from dermatologic, rheumatologic and cardiologic research now show it to be a systemic disease, for which the term psoriatic disease is used., Methods: This paper is based on a selective literature search with special attention to the findings of clinical trials and other current publications, as well as the recommendations of international guidelines., Results: Immunologically mediated inflammation of the skin, arteries, bones, and joints is a central feature of psoriatic disease. Other diseases that are known to be associated with psoriatic disease include hypertension, metabolic syndrome, and depression. The main risk factor for the development of psoriatic disease is obesity, which also increases the likelihood of psoriatic arthritis. The main known trigger factors are stress, infection, and, less commonly, medication. Psoriatic disease is characterized by complex genetics and by a characteristic pattern of inflammation that involves elements of both innate and acquired immunity and, in particular, the cytokines interleukin 17 and 23. The inflammatory processes underlying psoriatic disease can now be targeted with modern biologic and other therapies., Conclusion: In view of the complexity of psoriatic disease, structured management is now recommended so that physicians and patients can work together to determine the optimal treatment strategy.

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases, with an increasing number of targeted therapies available. While biologics to treat AD exclusively target the key cytokines of type 2 immunity, Janus kinase inhibitors target a broad variety of cytokines, including IFN-γ. To better stratify patients for optimal treatment outcomes, the identification and characterization of subgroups, especially with regard to their IFNG expression, is of great relevance, as the role of IFNG in AD has not yet been fully clarified. This study aims to define AD subgroups based on their lesional IFNG expression and to characterize them based on their gene expression, T cell secretome and clinical attributes. RNA from the lesional and non-lesional biopsies of 48 AD patients was analyzed by RNA sequencing. Based on IFNG gene expression and the release of IFN-γ by lesional T cells, this cohort was categorized into three IFNG groups (high, medium, and low) using unsupervised clustering. The low IFNG group showed features of extrinsic AD with a higher prevalence of atopic comorbidities and impaired epidermal lipid synthesis. In contrast, patients in the high IFNG group had a higher average age and an activation of additional pro-inflammatory pathways. On the cellular level, higher amounts of M1 macrophages and natural killer cell signaling were detected in the high IFNG group compared to the low IFNG group by a deconvolution algorithm. However, both groups shared a common dupilumab response gene signature, indicating that type 2 immunity is the dominant immune shift in both subgroups. In summary, high and low IFNG subgroups correspond to intrinsic and extrinsic AD classifications and might be considered in the future for evaluating therapeutic efficacy or non-responders., Competing Interests: Sophia Wasserer has received honoraria and travel support from Novartis, Sanofi-Regeneron, Janssen and Lilly. Felix Lauffer has been an advisor and/or received speaker&rsquo;s honoraria and/or received grants and/or participated in clinical trials for the following companies: Abbvie, Almirall, Amgen, Biogen, Boehringer Inglheim, Bristol-Myers-Squibb, Janssen, LEO Pharma, Pfizer, Lilly, Novartis, Roche, Sanofi, UCB, Union Therapeutics and Biogen. Kristine E. Mayer has received travel support from Novartis. Kilian Eyerich has received grants and honoraria and has served as a speaker, investigator, consultant and/or advisor for AbbVie, Almirall, Boehringer Ingelheim, BMS, Celgene, Hexal, Galapagos, Galderma, Janssen, Eli Lilly, Pfizer, Novartis, Sanofi and UCB Pharma. Tilo Biedermann gave advice to and received honoraria for talks or research grants from the following companies: Abbvie, Alk-Abell&oacute;, Boehringer-Ingelheim, Celgene-BMS, Leo Pharma, Lilly Deutschland GmbH, Novartis, Sanofi-Genzyme, Regeneron and Viatris. No specific conflicts of interest were declared in relation to this article.