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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: Guselkumab is an interleukin (IL)-23 inhibitor with demonstrated efficacy in patients with psoriasis., Objectives: Evaluate the impact of early disease intervention on clinical responses following 28 weeks of guselkumab treatment in patients with moderate-to-severe plaque psoriasis. Correlate clinical response and disease duration data with serum biomarker data., Methods: GUIDE is a phase IIIb randomized, double-blind, parallel-group, multicentre study of adults with moderate-to-severe plaque psoriasis. In study part 1, patients with a short disease duration (SDD [≤2 years]) or a long disease duration (LDD [>2 years]) received guselkumab 100 mg at Week (W) 0, 4, 12, and 20. Those achieving complete skin clearance at W20 and W28 were defined as a super responder (SRe). A multivariable logistic regression analysed the association between baseline factors and the likelihood of becoming an SRe. The relationship between clinical response, disease duration and serum biomarker data was assessed at W0 and 4., Results: In total, 880 patients were enrolled (SDD/LDD = 40.6%/59.4% of patients). More SDD than LDD patients achieved absolute Psoriasis Area and Severity Index (PASI) = 0 at W28 (51.8% vs. 39.4%) and were SRes (43.7% vs. 28.1% [overall 34.4%]). SDD patients also achieved PASI = 0 quicker than LDD patients (median 141 vs. 200 days). Disease duration and prior biologic use had the greatest impact on becoming an SRe, with no strong association among these independent variables. At baseline, there were no significant differences in the serum biomarker levels of IL-17A, IL-17F, IL-22 and β-defensin 2 between SDD and LDD patients, or between SRe and non-SRe patients. Guselkumab rapidly decreased these markers of systemic inflammation across all patient groups analysed at W4. Guselkumab was well tolerated., Conclusions: Guselkumab efficacy was consistent across subpopulations, on the skin and systemically. The proportion of SRes was higher in SDD than LDD patients, indicating early treatment intervention may improve clinical outcomes., (© 2023 Janssen Cilag GmbH and The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: PERSIST was a prospective, non-interventional, real-world study of guselkumab and ustekinumab in adult patients with moderate-to-severe plaque psoriasis in Germany., Objectives: To examine effectiveness, safety and quality-of-life (QoL) outcomes to Week (W) 104 of treatment with guselkumab and ustekinumab in patients with moderate-to-severe plaque psoriasis., Methods: Patients (≥18 years of age) received guselkumab or ustekinumab as per routine clinical practice. Outcomes to W104 were examined separately in guselkumab and ustekinumab recipients. An ad hoc exploratory analysis of outcomes with guselkumab versus ustekinumab was also performed following propensity score matching., Results: Overall, 302 and 313 patients received guselkumab and ustekinumab, respectively. Patients in both cohorts experienced improvements in disease activity and QoL that were maintained to W104, with 64.7% and 63.6% of guselkumab- and 54.6% and 64.4% of ustekinumab-treated patients achieving a Psoriasis Area and Severity Index (PASI) 90 response and a Dermatology Life Quality Index (DLQI) 0/1 score, respectively. Propensity score matching yielded well-balanced baseline characteristics except for prior biologic use, which was higher in guselkumab versus ustekinumab recipients (51.7% vs. 32.0%). Achievement of PASI ≤1 at W104 was more common in guselkumab versus ustekinumab recipients (58.7% vs. 49.7%). The W104 PASI90 response rate was 65.6% with guselkumab and 56.0% with ustekinumab; corresponding rates for PASI100 were 44.3% and 28.5%. In guselkumab recipients, response rates were higher in biologic-naïve versus biologic-experienced patients (PASI90, 77.1% vs. 53.4%; PASI100, 55.0% vs. 33.0%). A high level of response for QoL outcomes was observed for both treatments., Conclusions: Ustekinumab and guselkumab led to improvements in physician-assessed and patient-reported outcomes that were sustained for up to 2 years, with no new safety signals identified. Following propensity score matching, greater improvements in PASI outcomes were observed with guselkumab versus ustekinumab. Improvements with guselkumab were highest in biologic-naïve patients, highlighting the value of early treatment., (© 2023 Janssen-Cilag GmbH and The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: PERSIST was a prospective, non-interventional, long-term, German multicentre study of patients with moderate-to-severe psoriasis receiving guselkumab, an approved monoclonal antibody that binds to the p19 subunit of interleukin (IL)-23, in a real-world setting., Objectives: Evaluation of the efficacy and safety of guselkumab, and its effect on health-related quality of life (HRQoL), in patients with moderate-to-severe psoriasis who have received 52 weeks of treatment., Methods: Patients (≥18 years old) were prescribed guselkumab as per routine clinical practice. End points assessed include Psoriasis Area and Severity Index (PASI), Physician's Global Assessment (PGA), target Nail Psoriasis Severity Index (NAPSI), and the Dermatology Life Quality Index (DLQI)., Results: Overall, 303 patients were enrolled and treated with guselkumab. Mean disease duration was 21.0 years, and 77.2% and 51.2% of patients had received ≥1 prior conventional systemic or ≥1 prior biologic therapy, respectively. Mean PASI score decreased from 16.4 at baseline to 3.0 by Week (W) 28, and further decreased to 2.4 by W52, while the proportion of patients achieving an absolute PASI score of ≤1 increased from 1.3% at baseline, to 50.8% at W28 and to 58.4% by W52. PASI90 and PASI100 responses also showed marked improvements between W28 and W52, regardless of biologic treatment history. Clearance of psoriatic skin was observed in difficult-to-treat areas, with the percentage of patients achieving a PGA score ≤1 increasing between W28 and W52. Guselkumab improved HRQoL; mean DLQI score decreased from 13.7 at baseline to 2.8 by W28, and further decreased to 2.4 by W52. At W52, 64.6% of patients achieved a DLQI score ≤1. The cumulative probability of drug survival was 92.4% at W52., Conclusions: Guselkumab is efficacious and well tolerated regardless of previous biologic therapies, comorbidities or psoriasis manifestation in difficult-to-treat areas. No new safety signals were observed., (© 2022 Janssen-Cilag GmbH. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Introduction: Dimethyl fumarate (DMF) is an oral compound to treat plaque psoriasis. Data on the treatment of patients with psoriasis affecting impactful areas are scarce. In this interim analysis of the prospective, noninterventional SKILL study, we summarized results of DMF treatment regarding effectiveness (overall and in impactful areas) and safety., Methods: Data from 676 patients suffering from moderate-to-severe plaque psoriasis were analyzed after 52 weeks of DMF treatment. Of these, 257 had data available after 52 weeks. The considered impactful areas were nails, palms, soles, and scalp. Data analysis included observed cases (OC) and last observation carried forward (LOCF)., Results: All effectiveness parameters improved after 52 weeks. The Psoriasis Area and Severity Index score was reduced by 79.5% (OC) and 65.7% (LOCF). Compared with baseline, improvements were shown for 70.2% of the patients in their nail psoriasis [nail-Physician Global Assessment (PGA)] and for 57.3% in palmoplantar disease (palmoplantar-PGA). The proportion of patients with scalp-PGA 0/1 (clear/almost clear) increased significantly to 79.8% (OC) and 69.3% (LOCF, both p < 0.001) (versus 37.5% and 36.6% at baseline, respectively). Significant reduction of pruritus (p < 0.001) was also observed. No unexpected adverse drug reactions were observed., Conclusion: Long-term treatment with DMF in routine practice showed good overall effectiveness and safety, and a positive effect on plaque-psoriasis-affected impactful areas., (© 2022. The Author(s).)

Background: Guselkumab is an interleukin (IL)-23 pathway blocker with proven efficacy in patients with moderate-to-severe plaque psoriasis. Early intervention with guselkumab may result in changes to the clinical disease course versus later intervention., Methods and Analysis: Here we present the rationale and design of a phase 3b, randomised, double-blind, multicentre study (GUIDE), comparing treatment effects of guselkumab in patients with short (≤2 years) or longer (>2 years) duration of plaque-type psoriasis, measured from first appearance of psoriatic plaques. Participants achieving skin clearance (Psoriasis Area and Severity Index (PASI)=0) by week 20 and maintaining complete clearance at week 28 visit ('super-responders' (SRe)) will be randomised to continue approved maintenance dosing every 8 weeks (q8w) versus an investigational maintenance dosing interval of 16 weeks (q16w) until week 68. Primary endpoint: proportion of participants in the q8w vs q16w arms with absolute PASI <3 at week 68. Participants with PASI <3 at week 68 will be withdrawn from guselkumab treatment for up to 48 weeks. Participants not achieving SRe criteria (non-SRe) will remain in the study with q8w guselkumab dosing through week 68. Additional to serum samples obtained from all patients, skin biopsies and whole-blood samples will be taken from SRe and non-SRe participants at various time points in optional substudies. Analyses include: genetics; immunophenotyping (fluorescence-activated cell sorting); gene and protein expression profiling; immunohistology. By merging clinical endpoints with mechanistic findings, this study aims to elucidate how IL-23 blockade with guselkumab can modify the disease course by altering molecular and cellular drivers that cause relapse after treatment withdrawal, particularly among SRe., Ethics and Dissemination: Approval obtained from ethics committee Medical Council Hamburg, Germany (PVN5925). GUIDE is compliant with the Declaration of Helsinki., Trial Registration Number: Registered at ClinicalTrials.gov (NCT03818035). All primary endpoint results (prespecified analyses) will be submitted to peer-reviewed, international journals within 18 months after primary completion date., Competing Interests: Competing interests: KE reports grants and personal fees from Janssen during the conduct of the study, grants from AbbVie, LEO Pharma, UCB and Novartis, and personal fees from AbbVie, Almirall, BMS, LEO Pharma, Lilly, Sanofi, UCB, Galderma and Novartis outside the submitted work; PW reports receiving honoraria as consultant or speaker from the following companies involved in the development or distribution of drugs for psoriasis: AbbVie, Almirall, Biogen, Celgene, Eli Lilly, Janssen, LEO Pharma, Medac and Novartis, and honoraria received by his institution for active participation in clinical studies sponsored by Janssen, AbbVie and Eli Lilly; AP has no conflicts of interest to report; KS reports conducting clinical studies during the past 36 months with the following companies: AbbVie, Almirall, Boehringer, Celgene, Chugai, Galapagos, Galderma, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme Corp., Novartis Regeneron and UCB Pharma; KA reports honoraria for participation in advisory boards, consultation, clinical trials or as speaker from AbbVie, Almirall, Antabio, Bayer, BMS, Euroimmune, Emphasis, Emeritipharma, Galderma, Janssen, La Roche-Posay, LEO Pharma, L’Oréal, Novartis, Parexel International, Pierre Fabre, Roxall, RG, Sanofi Genzyme, TFS Trial Form Support and UCB; SW is a full-time employee of Janssen-Cilag Germany; EJM-E is a full-time employee of Johnson & Johnson, and is listed as an inventor on a patent application related to uses of guselkumab to treat psoriasis, pending; HB reports personal fees from Janssen-Cilag Germany during the conduct of the study, and personal fees from Janssen-Cilag Germany outside the submitted work; FJHT reports personal fees from Janssen-Cilag, Germany during the conduct of the study and personal fees from Janssen-Cilag, Germany outside the submitted work; KR reports grants and personal fees from Janssen during the conduct of the study, grants from AbbVie, Lilly, LEO Pharma, UCB, Pfizer, Affibody, Biogen-Idec, Boehringer Ingelheim Pharma, BMS, Celgene, Covagen, Forward Pharma, Fresenius Medical Care, Galapagos, Kyowa Kirin, Medac, Merck Sharp & Dohme, Milteny, Novartis, Ocean Pharma, Sandoz, Sanofi, Sun Pharma, Takeda and XBiotech; personal fees from AbbVie, Lilly, LEO Pharma, UCB, Pfizer, Amgen, Affibody, Biogen-Idec, Boehringer Ingelheim Pharma, BMS, Celgene, Covagen, Forward Pharma, GSK, Kyowa Kirin, Medac, Merck Sharp & Dohme Corp, Novartis, Ocean Pharma, Samsung Bioepis, Sandoz, Sanofi, Takeda, Valeant and Xenoport outside the submitted work., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Over the past two decades, significant progress has been achieved in the treatment of psoriasis by targeting the human cytokine network. At present, 11 biologicals - antibodies, and a soluble receptor - are used to neutralize key inflammatory cytokines. Based on their targets, they can be grouped into the following four classes: TNF-α-, IL-12/23-, IL-17- and IL-23-inhibitors. The range of available substances, as well as their different modes of action can be challenging when selecting the right drug for an individual patient. In this article, we provide an overview of the approved biologicals for the treatment of psoriasis, including their advantages and limitations, and summarize criteria for therapy selection.

The idea of the local drug delivery system is getting popular nowadays to treat gingivitis and periodontitis. The method of delivering the drug locally is quite easy and requires minimal intervention. This delivery system not only treats the periodontal diseases effectively but also prevents the side effects linked with the use of the drugs which are used orally for longer periods to cure these diseases. Chlorhexidine (CHX) is being widely used to treat these conditions because of its broad spectrum anti-bacterial effect and is found to be more effective in lowering plaque formation. The aim of this study was to appraise the effect of the local drug delivery system by using 1% CHX gel in patients with periodontal diseases. 1% CHX gel was prepared and its physicochemical characteristics were then assessed. Clinical parameters and inflammatory salivary biomarkers were evaluated in two groups of patients. Group I: standard treatment group. Group II: gel treatment group. These parameters were evaluated before treatment and after 4 weeks of treatment. 1% CHX gel was highly effective in reducing gingivitis and periodontitis by using the local drug delivery system which allowed the drug to retain into the periodontal pocket for prolong period of time.

The gold standard therapy for treating the periodontal infections is the removal of bacterial plaque and deposits of calculus from tooth surfaces by scaling and root planning. In order to eliminate these bacterial reservoirs, beside conventional treatment, chemo therapeutic agents are commonly prescribed by periodontologists. To avoid the systemic side effects and development of antibiotics resistance, local drug delivery methods has gained the attention of dentists to treat periodontal infections, along with scaling and root planning. The aim of this study was to evaluate the effectiveness of local drug delivery system in combination with scaling and root planning, by using 1% metronidazole gel and mouthwash. The patients were divided into 3 groups. Group I: conventional treatment group. Group II: patients received treatment with gel. Group III: patients received treatment with mouthwash. All groups received treatment for 30 days. Clinical parameters and salivary concentration of TNF-α, PGE2 and nitric oxide were measured before and after treatment in both groups. All clinical parameters and inflammatory biomarkers significantly reduced in gel and mouthwash group patients (p≤0.001) as compared to patients received conventional treatment. The gel is found to be more efficacious than mouthwash especially in reducing clinical attachment loss (p< 0.05) and in reducing inflammatory biomarkers (p≤0.001). We strongly suggest the use of metronidazole via local drug delivery system combined with scaling and root planning to treat periodontal diseases.

Various immune cells and their messenger substances influence the development of psoriasis. Cytokines of the IL-17 family are of particular importance. In addition to IL-17A, which plays a central role in the pathogenesis of psoriasis, other subtypes of the IL-17 family also have a proinflammatory effect. This review provides an up-to-date overview of the immunopathogenesis of psoriasis with regard to the six IL-17 subtypes, in particular their physiological and pathogenic properties, as well as their significance for psoriasis therapy., (© 2020 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Simvastatin is an anti-hyperlipidemic drug which reduces the cholesterol synthesis and also has anti-inflammatory, immunomodulatory and anti-microbial action against the bacteria. This develops the interest of periodontologist to use it in combination with conventional treatment to treat periodontal diseases. The objective of the study was to develop the gel and mouthwash of simvastatin and use it locally to treat gingivitis and periodontitis as an adjunct to scaling and root planning. The patients were randomly allocated into three groups that were standard treatment group, gel treatment group and mouthwash treatment group. Results indicated that simvastatin gel and mouthwash in 1% preparation showed favorable results by significantly reducing periodontal parameters and inflammatory biomarkers (p<0.001) as compared to standard treatment. Thus, we strongly suggest the use of simvastatin by local drug delivery system as an adjunct treatment of scaling and root planning.

Inflammation and its mediators have an important role in gingivitis and periodontitis. Prostaglandin is one of the eicosanoid involved in many chronic inflammatory diseases, including periodontal diseases. Aspirin irreversibly acetylates cyclooxygenase and inactivate this enzyme responsible for the production of PGE 2 that mediates pain and inflammation. The aim of the study was to prepare aspirin gel and mouthwash in 1% concentration and use it in patients with periodontal diseases during the non-surgical periodontal treatment and to assess its anti-inflammatory effects on salivary biomarkers PGE 2 , TNF-α, and nitric oxide. Thirty patients were divided into three treatment groups, standard treatment group, second received scaling and root planning with gel application of 1% aspirin, third received scaling and root planning followed by rinsing with 1% aspirin mouthwash. Results indicated that the levels of PGE 2 , TNF-α and nitric oxide in the groups of patients received gel treatment and mouthwash treatment was decreased to significant levels (p<0.001) as compared to the group of standard treatment. Aspirin gel was found to be more effective in reducing inflammatory biomarkers in contrast to aspirin mouthwash (p<0.001). We concluded from our study, that low concentration of aspirin oral preparations are highly active in reducing the inflammatory biomarkers associated with periodontal diseases.

Amitriptyline, an agent universally used to treat depression, has an anti-inflammatory activity and a potential for lowering inflammatory mediators. Periodontal diseases like gingivitis and periodontitis if untreated contributes to gingival tissue destruction and bone resorption. These diseases are commonly treated with conventional non-steroidal anti-inflammatory agents and antibiotics along with standard periodontal treatment. The aim of this experimental, observational and randomized clinical control trial was to evaluate the anti-inflammatory effects of amitriptyline on clinical parameters and on inflammatory biomarkers in patients of periodontal diseases by developing 1% oral gel and mouthwash formulations. 30 patients participated in the study were grouped in three categories, patients received standard conventional treatment, patients received gel treatment for four weeks after standard treatment, patients received mouthwash for four weeks after standard periodontal treatment. Results showed that amitriptyline gel and mouthwash in 1% formulation showed promising results by significantly reducing periodontal parameters and inflammatory biomarkers (p<0.001) as compared to standard treatment. Thus, we suggest that gel and mouthwash formulation of amitriptyline is highly efficacious in treating the periodontal diseases.

Fumarates (fumaric acid esters, FAEs) are orally administered systemic agents used for the treatment of psoriasis and multiple sclerosis. In 1994, a proprietary combination of FAEs was licensed for psoriasis by the German Drug Administration for use within Germany. Since then, fumarates have been established as one of the most commonly used treatments for moderate-to-severe psoriasis in Germany and other countries. The licensed FAE formulation contains dimethyl fumarate (DMF), as well as calcium, zinc, and magnesium salts of monoethyl fumarate (MEF). While the clinical efficacy of this FAE mixture is well established, the combination of esters on which it is based, and its dosing regimen, was determined empirically. Since the mid-1990s, the modes of action and contribution of the different FAEs to their overall therapeutic effect in psoriasis, as well as their adverse event profile, have been investigated in more detail. In this article, the available clinical data for DMF are reviewed and compared with data for the other FAEs. The current evidence substantiates that DMF is the main active compound, via its metabolic transformation to monomethyl fumarate (MMF). A recent phase III randomized and placebo-controlled trial including more than 700 patients demonstrated therapeutic equivalence when comparing the licensed FAE combination with DMF alone, in terms of psoriasis clearance according to the Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA). Thus, DMF as monotherapy for the treatment of psoriasis is as efficacious as in combination with MEF, making the addition of such fumarate derivatives unnecessary.

Biomarkers are of increasingly high importance in medicine, particularly in the realm of 'personalized medicine'. They are valuable for predicting prognosis and dose selection. Moreover, they may be helpful in detecting therapeutic and adverse responses and in patient stratification based on efficacy or safety prediction. Thus, biomarkers are essential tools for the selection of appropriate patients for treatment with certain drugs to and enable personalized medicine, that is 'providing the right treatment to the right patient, at the right dose at the right time'. Currently, there are six drugs approved for dermatological indications with recommended or mandatory biomarker testing. Most of them are used to treat melanoma and human immunodeficiency virus infection. In contrast to the few fully validated biomarkers, many exploratory biomarkers and biomarker candidates have potential applications. Prognostic biomarkers are of particular significance for malignant conditions. Similarly, diagnostic biomarkers are important in autoimmune diseases. Disease severity biomarkers are helpful tools in the treatment for inflammatory skin diseases. Identification, qualification and implementation of the different kinds of biomarkers are challenging and frequently necessitate collaborative efforts. This is particularly true for stratification biomarkers that require a companion diagnostic marker that is co-developed with a certain drug. In this article general definitions and requirements for biomarkers as well as for the impact of biomarkers in dermatology are reviewed and opportunities and challenges are discussed., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Several types of collaboration are being pursued to identify, validate and apply new biomarkers. Here, we highlight examples of such initiatives and discuss the challenges, approaches to address these challenges and key factors for success.