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Background: Secukinumab is effective against a range of psoriatic manifestations. Investigating psoriasis (PsO) relapse following secukinumab discontinuation could provide insights into long-term PsO remission., Objectives: To examine PsO relapse rates on treatment discontinuation following 1 year of secukinumab treatment., Methods: This study (clinical trial number: NCT01544595) is an extension of the phase III ERASURE/FIXTURE studies in patients with moderate-to-severe plaque PsO. After 1 year of secukinumab 300 mg or 150 mg treatment, participants who had responded to treatment with a ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75) at week 52 were randomly assigned to receive placebo (n = 120 and n = 100, respectively). On relapse, patients receiving placebo were switched to their previous secukinumab dose. The study primary outcome was the nonrelapse rate after secukinumab withdrawal., Results: Following the last dose of secukinumab 300 mg, 20.8% (25/120) and 10.0% (12/120) of patients who switched to placebo did not relapse at 1 and 2 years after discontinuation, respectively. Patients who received secukinumab 150 mg for 1 year showed a lower proportion of nonrelapse following treatment discontinuation [14% (14/100) and 6% (6/100)] at 1 and 2 years, respectively. Patients who did not relapse maintained low mean PASI (2.8) at 1 year drug free vs. baseline (20.9); 1.7 at 2 years drug free vs. baseline (19.2), following an initial 52-week treatment with secukinumab 300 mg. Disease duration (P = 0.02) and severity (P = 0.02) were significantly associated with time to relapse in patients initially treated with secukinumab 300 mg; patients with shorter disease duration and lower baseline PASI remained relapse-free for longer., Conclusions: Following discontinuation of secukinumab, a proportion of patients stayed relapse-free. Further, patients with shorter disease duration remained relapse-free for longer, suggesting that earlier treatment with secukinumab may result in long-term clinical control of moderate-to-severe PsO., Competing Interests: Conflicts of interest M.L. has received grants from AbbVie, Amgen, Arcutis, Avotres, Boehringer Ingelheim, Cara therapeutics, Dermavant Sciences, Eli Lilly, Incyte, Inozyme, Janssen Research & Development, LLC, Ortho Dermatologics, Sanofi-Regeneron and UCB, and has received consulting fees from Almirall, AltruBio Inc., AnaptysBio, Arcutis, Inc., AstraZeneca, Avotres Therapeutics, Brickell Biotech, Boehringer Ingelheim, Bristol-Myers Squibb, Castle Biosciences, Celltrion, Corevitas, Dermavant Sciences, EPI, Evommune, Inc., Facilitation of International Dermatology Education, Forte Biosciences, Foundation for Research and Education in Dermatology, Galderma, Genentech, Incyte, LEO Pharma, Meiji Seika Pharma, Mindera, Pfizer, Seanergy, Strata, Trevi and Verrica. L.I. has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by: AbbVie, Almirall, Amgen, Astra Zeneca, BMS, Boehringer Ingelheim, Celgene, Centocor, Eli Lilly, Janssen Cilag, Kyowa, Leo Pharma, MSD, Novartis, Pfizer, Regranion, Samsung and Union Therapeutics UCB. He is also an employee at MC2 Therapeutics A/S. L.E. has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by AbbVie, Novartis, Janssen, Leo Pharma and ITN. J.G.K. received grants from Novartis, Pfizer, Amgen, Lilly, Boehringer, Innovaderm, Bristol Myer Squibb, Janssen, AbbVie, Paraxel, Leo Pharma, Vitae, Akros, Regeneron, Allergan, Novan, Biogen MA, Sienna, UCB, Celgene, Botanix, Incyte, Avillion and Exicure, and has received honoraria from Novartis, Pfizer, Amgen, Lilly, Boehringer, BiogenIdec, AbbVie, Leo Pharma, Escalier, Valeant, Aurigne, Allergan, Asana, UCB, Sienna, Celgene, Nimbus, Menlo, Aristea, Sanofi, Sun Pharma, Almirall, Arena, BMS, Ventyx, Aclaris and Galapagos NV. M.S.-F. and L.T. have been supported by Novartis through an institutional research grant. F.K. and M.M. are employed by Novartis Pharma AG (Basel, Switzerland). R.Y. is employed by China Novartis Institutes for BioMedical Research (Shanghai, China)., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)

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: Clinical trials have shown promising results for interleukin-23 inhibitors in the treatment of psoriasis. The drugs have been used in clinical practice since 2017., Objective: To investigate the drug survival and effectiveness of interleukin-23 inhibitors in the treatment of psoriasis and psoriatic arthritis (PsA) in a real-world setting., Methods: The study was a retrospective analysis of patients treated with either guselkumab, tildrakizumab, or risankizumab at the Department of Dermatology, Aarhus University Hospital, during the period from June 11 2018, to July 14 2021., Results: A total of 80 patients were included. During the study, 19 patients discontinued treatment with an interleukin-23 inhibitor, and mean treatment duration (SD) was 61.4 weeks (43.7). Seventy-six patients (95%) had previous use of ≥1 biologic. One-year drug survival was 81.0%. Among patients, 64.3% achieved a Psoriasis Area and Severity Index (PASI) ≤ 2 at weeks 12-17; 61.3%, at weeks 40-60. There was no statistically significant difference between the drugs regarding the chance of achieving PASI ≤ 2 ( p >.05). Twenty-two patients (27.5%) had PsA. Among these, 40.9% and 36.4% achieved complete remission and partial remission, respectively., Conclusions: Interleukin-23 inhibitors appear to have high and similar drug survival and effectiveness in patients with difficult-to-treat psoriasis and PsA.

Hidradenitis suppurativa is a chronic inflammatory skin disease with limited treatment options. The poorly understood pathogenesis hinders the development of effective treatments; therefore, a pressing need exists to further elucidate the molecular mechanisms in hidradenitis suppurativa. This study investigated the underlying inflammatory pathways and cell types in hidradenitis suppurativa using transcriptomic approaches with RNA sequencing of lesional and non-lesional skin biopsies from hidradenitis suppurativa, which was jointly analyzed with previously published transcriptomic data from atopic dermatitis and psoriasis patients. The differential expression and pathway enrichment analyses demonstrated the activation of multiple inflammatory processes, including the innate and adaptive immune systems, implicated in the hidradenitis suppurativa pathogenesis. In agreement, hidradenitis suppurativa exhibited a unique and heterogeneous cell type signature involving lymphoid and myeloid cells such as B cells and macrophages. Furthermore, hidradenitis suppurativa displayed increased expression of T H 1/2/17 signatures with no predominant T H signatures unlike psoriasis (T H 1/17) and atopic dermatitis (T H 2). In summary, our study provides molecular insights into the pathomechanisms in hidradenitis suppurativa, revealing a strong and widespread immune activation, which may benefit from treatment strategies offering a broad immunomodulation of various key inflammatory pathways. Our data not only corroborate previously reported findings but also enhance our understanding of the immune dysregulation in hidradenitis suppurativa, uncovering novel and potential therapeutic targets.

Enhanced treatment options for psoriasis and growing use of guidelines increased the potential to better quality of psoriasis care in Europe. The aim of the PsoBarrier EU study is to compare the quality and processes of psoriasis care in four European countries with different healthcare systems, based on validated quality indicators. This cross-sectional survey was conducted in dermatology centres in Denmark, Germany, Poland and Spain on 1,304 patients, using standardized patient and physician questionnaires. Measured by quality of psoriasis care indicators, patients in Poland had the most critical outcomes, such as the highest disease severity (Psoriasis Area and Severity Index; PASI) and lowest health-related quality of life (Dermatology Life Quality Index; DLQI). This indicates differences in psoriasis care, with Polish participants experiencing more severe psoriasis and its consequences. Differences in the healthcare systems, which create barriers to accessing treatments, could explain variations in quality of care.

Background: Clinical trials have established the efficacy of brodalumab in treatment of psoriasis and psoriatic arthritis. Real-world evidence is needed to fully evaluate the drug., Objective: Here we investigate drug survival and clinical effectiveness of brodalumab in patients with psoriasis and psoriatic arthritis in a real-world setting., Methods: This was a retrospective single-centre study enrolling patients receiving brodalumab for psoriasis at the Department of Dermatology, Aarhus University Hospital, Denmark. The primary endpoints were drug survival, reasons for discontinuation, percentage of patients achieving a Psoriasis Area and Severity Index (PASI) ≤ 2 and clinical effectiveness against psoriatic arthritis., Results: Eighty-three patients were included (mean age 49.2 ± 17.4 years, 59.0% male, 9.6% bio-naïve, mean baseline PASI 10.9 ± 6.9). Twenty-seven patients discontinued treatment primarily due to ineffectiveness and adverse events (AEs). Kaplan-Meier-estimated 1-year drug survival was 65.7%. An absolute Psoriasis Area and Severity Index (PASI) ≤ 2 was achieved by 68.2% of patients at end of follow-up, by 70.0% at weeks 12-17 and by 76.2% after 40-60 weeks of treatment. Neither drug survival nor PASI ≤ 2 was associated with baseline PASI ≥ 10, body mass index ≥ 30, previous treatment with > 2 biologics or other IL-17 inhibitors in particular (P > 0.05). Psoriatic arthritis remission or partial remission was achieved by 10 out of 18 patients with psoriatic arthritis; treatment failure was reported in 5 patients., Conclusions: Brodalumab was effective against psoriasis and psoriatic arthritis in a real-world setting. The drug survival was lower than reported in other real-world settings., (© 2023. The Author(s).)

Background: Biologic treatments have been studied mainly in patients with a long-term history of psoriasis and previous treatment failures., Objectives: The purpose of this primary analysis of the STEPIn study is to determine whether early intervention with secukinumab in patients with new-onset moderate to severe plaque psoriasis is superior to standard of care treatment with narrow band ultraviolet B (nb-UVB) phototherapy., Methods: The STEPIn study is a randomized, open-label, multicentre study to investigate early intervention with 52 weeks of secukinumab 300 mg administered subcutaneously versus standard treatment with nb-UVB phototherapy in patients with new-onset (≤12 months) moderate to severe plaque psoriasis (NCT03020199). The primary and additional secondary endpoints were ≥90% improvement in Psoriasis Area and Severity Index (PASI 90) at Week 52 and Investigator's Global Assessment (IGA mod 2011) 0/1 response at Week 52, respectively., Results: In the secukinumab and nb-UVB study arms, 77/80 and 76/80 randomized patients received at least one dose of study treatment, respectively. The primary endpoint was achieved: 91.1% (70/77) of patients achieved a PASI 90 response at Week 52 in the secukinumab arm versus 42.3% (32/76) in the nb-UVB arm (p < 0.0001, odds ratio [OR] estimate [95% confidence intervals, CI] = 16.3 [5.6, 46.9]). The additional secondary endpoint was also achieved: 85.7% of patients achieved an IGA 0/1 response at Week 52 in the secukinumab arm versus 36.8% in the nb-UVB arm (p < 0.0001). The safety data were consistent with the safety profiles of secukinumab and nb-UVB with no new or unexpected safety signals., Conclusions: Secukinumab was superior to nb-UVB in treating patients with new-onset moderate to severe plaque psoriasis. The high and sustained skin clearance observed indicates that biologic treatment for psoriasis may be more effective if used early in the disease course., (© 2023 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.)

Introduction: Chronic inflammatory skin diseases may have a profound negative impact on the quality of life. Current treatment options may be inadequate, offering an unsatisfactory response or side effects. Therefore, ongoing efforts exist to identify novel effective and safe treatments. Heat shock protein (HSP) 90 is a chaperone that promotes the activity of a wide range of client proteins including key proinflammatory molecules involved in aberrant inflammation. Recently, a proof-of-concept clinical trial of 13 patients suggested that RGRN-305 (an HSP90 inhibitor) may be an oral treatment for psoriasis. However, HSP90 inhibition may be a novel therapeutic approach extending beyond psoriasis to include multiple immune-mediated inflammatory skin diseases., Methods: This study aimed to investigate ( i ) the anti-inflammatory effects and mechanisms of HSP90 inhibition and ( ii ) the feasibility of topical RGRN-305 administration (new route of administration) in models of inflammation elicited by 12-O-tetradecanoylphorbol-13-acetate (TPA) in primary human keratinocytes and mice (irritative dermatitis murine model)., Results/discussion: In primary human keratinocytes stimulated with TPA, a Nanostring® nCounter gene expression assay demonstrated that HSP90 inhibition with RGRN-305 suppressed many proinflammatory genes. Furthermore, when measured by quantitative real-time polymerase chain reaction (RT-qPCR), RGRN-305 significantly reduced the gene expression of TNF, IL1B, IL6 and CXCL8 . We next demonstrated that topical RGRN-305 application significantly ameliorated TPA-induced skin inflammation in mice. The increase in ear thickness (a marker of inflammation) was significantly reduced (up to 89% inhibition). In accordance, RT-qPCR of the ear tissue demonstrated that RGRN-305 robustly reduced the gene expression of proinflammatory markers ( Tnf, Il1b, Il6, Il17A and Defb4 ). Moreover, RNA sequencing revealed that RGRN-305 mitigated TPA-induced alterations in gene expression and suppressed genes implicated in inflammation. Lastly, we discovered that the anti-inflammatory effects were mediated, at least partly, by suppressing the activity of NF-κB, ERK1/2, p38 MAPK and c-Jun signaling pathways, which are consistent with previous findings in other experimental models beyond skin inflammation. In summary, HSP90 inhibition robustly suppressed TPA-induced inflammation by targeting key proinflammatory cytokines and signaling pathways. Our findings suggest that HSP90 inhibition may be a novel mechanism of action for treating immune-mediated skin disease beyond psoriasis, and it may be a topical treatment option., Competing Interests: LI has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by: AbbVie, Almirall, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Centocor, Eli Lilly, Janssen Cilag, Kyowa, Leo Pharma, MSD, Novartis, Pfizer, Regranion, Samsung, Union Therapeutics UCB. GG is the CEO of Regranion, which owns the rights to RGRN-305. CJ has served as a consultant and/or paid speaker for Eli Lilly, Abbvie, Leo Pharma and L’Oréal. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ben Abdallah, Seeler, Bregnhøj, Ghatnekar, Kristensen, Iversen and Johansen.)

Background: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis that occurs in a large proportion of patients with psoriasis causing pain and impaired quality of life. Early recognition and treatment are important as PsA may result in structural joint damage with a risk of reduced physical function., Objectives: The aim of this study was to determine the proportion of psoriasis patients with suspicion of PsA who are diagnosed with PsA or other rheumatologic conditions following referral from a dermatology department. Furthermore, the study aimed to identify clinical and patient-reported variables identifying patients with psoriasis in whom joint discomfort is an expression of PsA., Methods: This single-center retrospective study included all patients with psoriasis who had been referred for rheumatological evaluation on suspicion of PsA in the period from 2014 to 2018., Results: A total of 364 patient records were reviewed. This identified 106 patients with psoriasis who had been referred for rheumatologic evaluation on suspicion of PsA. Patients with a previous diagnosis of PsA were excluded from the analysis. Among the referred patients, 23.6% were diagnosed with either peripheral or axial PsA or both. A total of 23.6% were diagnosed with osteoarthritis and an additional 14.2% were diagnosed with inactive PsA. For patient-reported swollen joints and dermatologist-assessed swollen joints at referral, the positive predictive values/negative predictive values for a PsA diagnosis were 40%/100% and 50%/92%, respectively., Conclusion: In this study, 23.6% of patients with psoriasis symptoms suggestive of PsA were diagnosed with axial and/or peripheral arthritis following rheumatologic evaluation. Patient-reported swollen joints and dermatologist-assessed swollen joints indicated a high likelihood of peripheral PsA. Additionally, the absence of patient-reported swollen joints indicated a very low probability of establishing a diagnosis of peripheral PsA., (© 2023 S. Karger AG, Basel.)

Psoriasis is a common chronic inflammatory skin disease accompanied by heterogenous clinical and histological features, including a characteristic keratinocyte hyperproliferation and dermal immunogenic profile. In addition, psoriasis is associated with widespread transcriptomic alterations including changes in microRNA (miRNA) and circular RNA (circRNA) abundance, which constitute non-coding RNA (ncRNA) classes with specific regulatory capacities in diverse physiological and pathological processes. However, the knowledge about the expression dynamics of ncRNA during psoriasis treatment is sparse. To elucidate the dynamics of miRNA and circRNA abundance during secukinumab (anti-IL-17A) treatment, we studied their expression patterns in skin biopsies from 14 patients with severe plaque-type psoriasis before and during an 84-day secukinumab therapy at day 0, 4, 14, 42, and 84 using NanoString nCounter technology. We found a comprehensive downregulation of the majority of investigated circRNAs and specific alterations in the miRNA profile, including an upregulation of miR-203a-3p, miR-93-5p, and miR-378i in lesional compared to non-lesional skin before treatment. During treatment, the circRNAs progressively returned to the expression levels observed in non-lesional skin and already four days after treatment initiation most circRNAs were significantly upregulated. In comparison, for miRNAs, the normalization to baseline during treatment was delayed and limited to a subset of miRNAs. Moreover, we observed a strong correlation between multiple circRNAs, including ciRS-7 and circPTPRA, and the psoriasis area and severity index (PASI). Similar pronounced correlations could, however, not be found for miRNAs. Finally, we did not observe any significant changes in circRNA expression in peripheral blood mononuclear cells during treatment. In conclusion, we uncovered a rapid shift in global circRNA abundance upon anti-IL-17A treatment, which predated clinical and histological improvements, and a strong correlation with PASI, indicating a biomarker potential of individual circRNAs., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: L.I. served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by AbbVie, Almirall, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Centocor, Eli Lilly, Janssen Cilag, Kyowa, Leo Pharma, MSD, Novartis, Pfizer, Samsung, and UCB. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Climatotherapy is a well-described treatment of psoriasis. Dead Sea climatotherapy (DSC) in Israel consists of intensive sun and Dead Sea bathing and is very effective in improving clinical and patient-reported outcomes. However, the effect of DSC has not been widely studied. We aimed to investigate the effect of DSC on psoriasis skin using quantitative immunohistochemistry techniques and analysis of blood samples. Skin punch biopsies from 18 psoriasis patients from a previous cohort study were used. Biopsies were obtained from non-lesional skin and from a psoriasis target lesion at baseline. A biopsy was acquired from the target lesion after DSC. Among patients who achieved complete visual clearance, a biopsy was also obtained at relapse. Blood samples were obtained at the same time points. We performed haematoxylin and eosin staining and quantitative immunohistochemical analysis of CD3, CD4, CD8, CD11c, CD103, CD163, CD207, forkhead box P3, Ki67 and myeloperoxidase. We performed blood tests of cholesterol, c-reactive protein, glucose, haemoglobin A1c and triglycerides. All skin biomarkers except for CD207 were decreased after DSC. At relapse, none of the biomarkers were significantly different from the baseline lesional measurements. Total CD207 staining correlated with psoriasis area and severity index at baseline while CD163 staining correlated with psoriasis area and severity index at EOT. No changes were observed in selected blood tests during the study. Consistent with clinical results, DSC is highly effective in the short term almost normalising all investigated biomarkers. However, at relapse, biomarkers were upregulated to the baseline level., (© 2022 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.)

Importance: Given the possible treatment modalities in psoriasis management, little is known about whether drug monitoring is associated with response rate., Objective: To determine whether drug monitoring is associated with response to brodalumab therapy., Design: A multicenter case series study of patients with psoriasis treated with brodalumab whose treatment with previous IL-17A inhibitor therapy failed. Patients were recruited from the Departments of Dermatology at Gentofte and Aarhus University Hospitals, Denmark, between 2018 and 2020. Patient visits were conducted after 4 and 12 weeks of therapy. Patients not achieving Psoriasis Area and Severity Index 75% improvement from baseline (PASI 75) after 12 weeks were discontinued and considered nonresponders. Patients maintaining PASI 75 response were followed up for up to 52 weeks., Exposure: Treatment with brodalumab, 210 mg, at weeks 0, 1, 2, then every 2 weeks., Main Outcomes and Measures: Outcome measures were PASI reductions vs brodalumab levels and antibrodalumab antibodies., Results: Twenty patients with psoriasis (13 [65%] were male; median age, 50 years [range, 19-66 years]) were included. After 12 weeks of therapy, patients with quantifiable levels of brodalumab (≥0.05 μg/mL) experienced significantly higher PASI reductions than those without (median, 93%; range, 61%-100% vs median, -3; range, -49% to 94%, respectively; P = .006). After 12 weeks of therapy, 4 of 5 patients (80%) not achieving PASI 75 had subquantifiable drug levels (<0.05 μg/mL), although this finding was seen for only 3 of 14 PASI 75 responders (21%). None of 7 patients (35%) with subquantifiable drug levels after 12 weeks of therapy maintained response. No antibrodalumab antibodies were detected in any of the tested samples., Conclusions and Relevance: Results of this case series study suggest that circulating brodalumab level is a factor associated with clinical treatment response. Monitoring patient levels of circulating brodalumab may aid clinical decision-making and help prevent ineffective therapy.

Importance: A clear dosing regimen for methotrexate in psoriasis is lacking, and this might lead to a suboptimal treatment. Because methotrexate is affordable and globally available, a uniform dosing regimen could potentially optimize the treatment of patients with psoriasis worldwide., Objective: To reach international consensus among psoriasis experts on a uniform dosing regimen for treatment with methotrexate in adult and pediatric patients with psoriasis and identify potential future research topics., Design, Setting, and Participants: Between September 2020 and March 2021, a survey study with a modified eDelphi procedure that was developed and distributed by the Amsterdam University Medical Center and completed by 180 participants worldwide (55 [30.6%] resided in non-Western countries) was conducted in 3 rounds. The proposals on which no consensus was reached were discussed in a conference meeting (June 2021). Participants voted on 21 proposals with a 9-point scale (1-3 disagree, 4-6 neither agree nor disagree, 7-9 agree) and were recruited through the Skin Inflammation and Psoriasis International Network and European Academy of Dermatology and Venereology in June 2020. Apart from being a dermatologist/dermatology resident, there were no specific criteria for participation in the survey. The participants worked mainly at a university hospital (97 [53.9%]) and were experienced in treating patients with psoriasis with methotrexate (163 [91.6%] had more than 10 years of experience)., Main Outcomes and Measures: In a survey with eDelphi procedure, we tried to reach consensus on 21 proposals. Consensus was defined as less than 15% voting disagree (1-3). For the consensus meeting, consensus was defined as less than 30% voting disagree., Results: Of 251 participants, 180 (71.7%) completed all 3 survey rounds, and 58 participants (23.1%) joined the conference meeting. Consensus was achieved on 11 proposals in round 1, 3 proposals in round 2, and 2 proposals in round 3. In the consensus meeting, consensus was achieved on 4 proposals. More research is needed, especially for the proposals on folic acid and the dosing of methotrexate for treating subpopulations such as children and vulnerable patients., Conclusions and Relevance: In this eDelphi consensus study, consensus was reached on 20 of 21 proposals involving methotrexate dosing in patients with psoriasis. This consensus may potentially be used to harmonize the treatment with methotrexate in patients with psoriasis.

Studies on switch between interleukin (IL)-17 inhibitors are scarce. We assessed the effectiveness of brodalumab in patients with previous treatment failure of IL-17A inhibitor(s). Patients with psoriasis and previous treatment failure of an IL-17A inhibitor were treated with brodalumab at standard dose. Effectiveness was assessed after 12, 26, and 52 weeks of treatment. The primary outcome was the proportion of patients that had achieved an absolute psoriasis area and severity index (PASI) ≤2 and/or a relative reduction of PASI of 75% (PASI75) at week 12. Plasma cytokine levels were measured at baseline and after 12 weeks of treatment. In total, 20 patients were included, seven (35%) were female, the median age was 50 years, and the median baseline PASI was 13.5. Analyzing the data using nonresponder imputation, 14 (70%) patients had achieved either PASI75 and/or PASI ≤2, 8 (40%) had achieved PASI90, and three (15%) had achieved PASI100 at week 12. In total, nine patients (45%) completed the 52-weeks trial and seven patients (35%) still had PASI75 throughout 52 weeks. Seventeen out of 20 patients experienced any adverse events (AEs) during 52 weeks with no serious AEs or deaths. Patients responding to treatment had lower levels of tumor necrosis factor (TNF)-α and IL-6 at baseline compared with those who did not respond to treatment (TNF-α, p = 0.041, IL-6, p = 0.0054). In conclusion, treatment with brodalumab despite previous treatment failure with an IL-17A inhibitor can be effective and well-tolerated., (© 2021 Wiley Periodicals LLC.)

Objectives: The genetic contribution to psoriatic disease is substantial with a dominating influence of the HLA region. The profile of HLA class I genotypes likely contributes to shaping clinical phenotypes. Herein we aimed to explore such genotypes in cohorts of closely characterised subsets of psoriatic disease with special focus on psoriatic arthritis mutilans (PAM), a severe and rare form of psoriatic arthritis (PsA)., Methods: Cohorts of patients with the diagnosis of psoriasis vulgaris with or without arthritis (n=1217), psoriasis without arthritis (n=534), psoriatic arthritis without mutilating disease (n=337) and psoriatic arthritis mutilans (n=63) were collected and genotyped for HLA class I and II genes, with standardised methodologies. Cases were compared with a healthy control population (n=2468). Case-only and case-control association tests were performed to address the hypothesis of genetic contribution to clinical phenotypes., Results: The presence of HLA-B*27 was strikingly increased in PAM (45%) compared with PsA without mutilating disease (13%) and with healthy controls (13%). However, within the PAM population, HLA-B*27 did not correlate with clinical markers such as number of mutilating joints, radiographic scoring, disease duration and age of disease onset., Conclusions: HLA-B*27 emerges as an important genotype marker for PAM.

Keratinocytes are the key cellular target for IL-17A-mediated effects in psoriasis and HSP90 is important for IL-17A-mediated signalling. RGRN-305 is a novel HSP90 inhibitor reported to reduce psoriatic phenotypes in preclinical animal models. The aim of this study was to investigate the effect of RGRN-305 on a psoriasis-like inflammatory response in human keratinocytes in vitro. Using RT-qPCR, we demonstrated a significantly increased expression of the HSP90 isoforms HSP90AB1, HSP90B1 and TRAP1 in lesional compared with non-lesional psoriatic skin. In a psoriasis-like setting where keratinocytes were stimulated with TNFα and/or IL-17A, we analysed the mRNA expression using the NanoString nCounter technology and demonstrated that the HSP90 inhibitor RGRN-305 significantly reduced the IL-17A- and TNFα-induced gene expression of a number of proinflammatory genes, including the psoriasis-associated genes CCL20, NFKBIZ, IL36G and IL23A. In agreement with the mRNA data, the protein level of CCL20, IκBζ and IL-36γ were inhibited by RGRN-305 as demonstrated by western blotting and ELISA. Interestingly, when keratinocytes were stimulated with a TLR3 agonist, RGRN-305 also demonstrated potent immunomodulatory effects, significantly inhibiting poly(I:C)-induced expression of the proinflammatory genes TNFα, IL1B, IL6 and IL23A. Taken together, our data support a role for HSP90 not only in the pathogenesis of psoriasis, but also in broader immune responses. Therefore, HSP90 provides an attractive target for the treatment of psoriasis and other diseases where the innate immune system plays an important role., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Importance: The efficacy of adalimumab biosimilars is similar to that of brand-name adalimumab (Humira, hereinafter originator) in clinical trials. However, limited knowledge about real-world data exists for adalimumab biosimilars., Objective: To assess the outcomes following a mandatory nonmedical switch from adalimumab originator to adalimumab biosimilars in patients with psoriasis., Design, Setting, and Participants: This cohort study assesses the outcomes following a switch from adalimumab originator to an adalimumab biosimilar. Patients in the Biological Treatment in Danish Dermatology (DERMBIO) registry, a Danish nationwide registry of all patients treated with biologics (including biosimilars) for psoriasis since 2007, were assessed for eligibility. All patients who switched from adalimumab originator to an adalimumab biosimilar between November 1, 2018, and May 1, 2019, were included in the adalimumab biosimilar cohort. All patients with a visit between May 1, 2017, and November 1, 2017, treated with adalimumab originator were included in the adalimumab originator cohort. Data were analyzed from June 1, 2020, to October 10, 2021., Exposure: Switch from adalimumab originator to an adalimumab biosimilar., Main Outcomes and Measures: The primary outcome was 1-year drug retention in patients switching to adalimumab biosimilars compared with patients treated with adalimumab originator. Crude and adjusted retention rates for the adalimumab biosimilar cohort were compared with the adalimumab originator cohort with Cox proportional hazards regression using robust variance., Results: A total of 348 patients were included in the adalimumab biosimilar cohort (mean [SD] age, 52.2 [13.6] years; 251 [72.1%] male) and 378 patients in the adalimumab originator cohort (mean [SD] age, 51.1 [14.1] years; 272 [72.0%] male). The 1-year drug retention rates were 92.0% (95% CI, 89.0%-94.9%) for the adalimumab biosimilar cohort and 92.1% (95% CI, 89.4%-94.8%) for the adalimumab originator cohort. Similar hazard ratios were observed between the 2 cohorts. The crude hazard ratios were 1.02 (95% CI, 0.61-1.70; P = .94) for all causes of drug discontinuation, 0.82 (95% CI, 0.39-1.73; P = .60) for insufficient effect, and 1.41 (95% CI, 0.52-3.77; P = .50) for adverse events for the adalimumab biosimilar cohort when compared with the adalimumab originator cohort., Conclusions and Relevance: In this cohort study from Denmark, a nonmedical switch from adalimumab originator to adalimumab biosimilars was not associated with drug retention.

Objective: We describe patient-reported outcomes and quality of life through 5 years of treatment in patients with moderate-to-severe plaque psoriasis in the UNCOVER-1 and -2 studies., Methods: This analysis included patients who were randomized to ixekizumab every 2 weeks then received ixekizumab every 4 weeks during the maintenance period, and who achieved static physician global assessment (0,1) at week 12, completed week 60, and entered the long-term extension period (weeks 60&ndash;264). Outcomes measures included responses in itch numeric rating scale (NRS), skin pain visual analog scale (VAS), and dermatology life quality index (DLQI) (0,1), and mean change from baseline in short form health survey (SF-36) mental (MCS) and physical component summaries (PCS), psoriasis skin appearance bothersomeness (PSAB), and work productivity activity impairment (WPAI)., Results: At week 264 in UNCOVER-1 and -2, the observed itch NRS &ge;4 responses were 82.4% and 93.1%, respectively, the itch NRS=0 responses were 51.7% and 58.5%, respectively, the skin pain VAS=0 responses were 59.3% and 63.1%, respectively, and the DLQI (0,1) responses were 75.0% and 88.1%, respectively. The observed mean changes from baseline at week 264 in UNCOVER-1 and UNCOVER-2 were 3.4 and 6.5, respectively, for SF-36 MCS, 4.4 and 4.8, respectively, for SF-36 PCS, and -21.3 and -22.0, respectively, for PSAB. WPAI psoriasis item scores improved from baseline in both UNCOVER-1 and -2., Conclusion: Ixekizumab provided clinically meaningful and sustained improvements in itch, skin pain, DLQI, PSAB, SF-36 PCS, SF-36 MCS, and WPAI through 5 years of treatment in patients with moderate-to-severe plaque psoriasis. J Drugs Dermatol. 20(4):394-401. doi:10.36849/JDD.5821Visit the JDD Psoriasis Resource Center for more.

The interleukin (IL)-36 cytokine family plays an essential role in inflammatory processes in the skin and is implicated in the pathogenesis of psoriasis. This study explored the role of IL-36 in psoriasis and investigated the molecular mechanism involved in tumour necrosis factor-α (TNFα)/IL-17A-mediated IL-36 induction. In human keratinocytes IL-36 expression was strongly upregulated by combined TNFα and IL-17A stimulation. Moreover, IκBζ, encoded by NFKBIZ, was identified as a key regulator required for TNFα/IL-17A-induced IL-36γ expression. TNFα/IL-17A-induced IL-36γ expression also involved the nuclear factor κB (NF-κB), p38 mitogen-activated protein kinase and ERK1/2 signalling pathways. Furthermore, a specific NF-κB DNA-binding site in the promoter region of IL36G responsible for the TNFα/IL-17A-induced IL36G gene expression was identified. Finally, in a cohort of patients with psoriasis receiving anti-IL-17A treatment, a positive correlation was found between the expression of NFKBIZ and IL36G. In conclusion, these data reveal a novel crucial regulatory mechanism by which TNFα and IL-17A regulate IL-36γ expression.

Axial spondyloarthritis (axSpA), psoriatic arthritis (PsA), psoriasis, inflammatory bowel disease (IBD), and noninfectious uveitis form a distinct group among the immune mediated inflammatory diseases. Thus, many patients suffer from more than one of these disease manifestations. Here, we will use the term spondylitis-psoriasis-enthesitis-enterocolitis-dactylitis-uveitis-peripheral synovitis (SPEED-UP) spectrum disease. The aim is to review the new targeted pharmacological treatment options for all these diseases. All biological or targeted synthetic drugs with U.S. Food and Drug Administration (FDA) or European Medicines Agency (EMA) approval for any of the diagnoses axSpA, PsA, psoriasis, IBD, or non-infectious uveitis were included. Some of the drugs have documented efficacy in more than one of the diseases, e.g. tumor necrosis factor (TNF) inhibitors. However, other drugs are particularly effective for a specific inflamed tissue and approved in only one or two of the disease entities, e.g. abatacept for peripheral arthritis and vedolizumab for inflammatory bowel disease. This contributes with bedside to bench understanding of the immunology underlying this disease spectrum and provides clinicians with an overview that can assist stratified treatment decisions. We hope that this review will help guide clinicians to speed up treatment of patients with this disease spectrum., (Copyright © 2020. Published by Elsevier B.V.)

Early response to treatment with biologics might be important for the stability of psoriasis and long-term outcome. The aim of this study was therefore to assess whether risk of flares and drug survival are associated with disease activity in the first 6 months of treatment of psoriasis with biologics. Biologic-naïve patients from the Danish nationwide registry, DERMBIO, were grouped based on absolute Psoriasis Area and Severity Index (PASI) during the first 6 months of treatment, as: PASI = 0, PASI > 0-≤2, PASI > 2-≤ 4, and PASI > 4. Among 1,684 patients, 746 achieved PASI= 0, 485 PASI > 0-≤2, 246 PASI > 2-≤4, and 207 PASI > 4. Longer flare-free period and drug survival were observed for patients with lower PASI in the first 6 months of treatment (adjusted hazard ratios for flares (95% confidence interval) with PASI=  0 as reference: PASI > 0-≤2 (1.35 (1.11-1.72]), PASI > 2-≤ 4 (2.32 [1.80-2.99]), and PASI > 4 (2.38 [1.80-3.15])). In conclusion, a low PASI in the first 6 months of treatment with biologics in biologic-naïve patients with psoriasis was associated with a more stable disease course, lower risk of flares, and longer drug survival.

Introduction: Anti-tumor necrosis factor agents are key treatment options in moderate-severe psoriasis. The advent of multiple biosimilars of these drugs provides a major opportunity to address this particular factor by helping to reduce costs. Reduced cost can help improve undertreatment, which is one of the challenges in treating moderate-severe psoriasis. There is now a wealth of real-world evidence demonstrating that patients with psoriasis can be initiated on - or transitioned to - an anti-TNF biosimilar without detrimental effects on overall safety and efficacy. Furthermore, recent results suggest that patients can be switched between different biosimilar versions of the same anti-TNF agent without any compromise in outcomes., Areas Covered: In this review, we summarized the role of anti-TNFs in psoriasis, health economic aspects of anti-TNF biosimilars, and their real-world data in clinical practice and registries., Expert Opinion: The introduction and competition of anti-TNF biosimilars reduced the cost of biologics and accumulated real-world data support efficacy and safety of anti-TNF biosimilars for psoriasis treatment. Although IL-17 and IL-23 inhibitors show better efficacy in psoriasis patients, long-term efficacy and safety data of anti-TNF and cost-effectiveness of anti-TNF biosimilars may play an important role to increase patient access to biologics through greater adoption of biosimilars.

IL-37 broadly suppresses inflammation in various disease models. However, studies of the regulation and role of IL-37 in psoriasis are limited and contradictive. Using transcriptome analysis, PCR, protein determination, and immunofluorescence, we demonstrated marked downregulation of IL-37 in biopsies from human lesional psoriasis skin compared with paired samples of nonlesional skin. Immunofluorescence analysis showed that IL-37 was localized to stratum granulosum of the epidermis. TNF-α stimulation of normal human epidermal keratinocytes led to increased IL37 expression through a p38 MAPK-mediated mechanism, whereas IL-17A, IL-17C, IL-17F, and IL-22 acted suppressively. Intradermal injection with recombinant human IL-37 into imiquimod-induced psoriasis skin of C57BL/6J mice demonstrated a trend toward a protective effect, however NS. Altogether, these results demonstrate that IL-37 is downregulated in human lesional psoriasis skin. This may be a consequence of the loss of stratum granulosum, but key cytokines in the development of psoriasis also seem to contribute to this downregulation., (Copyright © 2020 The Authors.)

Background: IκBζ plays a key role in psoriasis by mediating IL-17A-driven effects, but the molecular mechanism by which IL-17A regulates IκBζ expression is not clarified., Objective: We sought to explore the molecular transformation in patients with psoriasis during anti-IL-17A (secukinumab) treatment with a focus on IκBζ., Methods: The study was an open-label, single-arm, single-center secukinumab treatment study that included 14 patients with plaque psoriasis. Skin biopsy specimens and blood samples were collected on days 0, 4, 14, 42, and 84 and processed for microarray gene expression analysis. Furthermore, in vitro experiments with human keratinocytes and synovial fibroblasts were conducted., Results: Secukinumab improved clinical scores and histologic psoriasis features. Moreover, secukinumab altered the skin transcriptome. The major transcriptional shift appeared between day 14 and day 42 after treatment initiation, although 80 genes were differentially expressed already at day 4. Expression of nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor (IκB) ζ (NFKBIZ, the gene encoding IκBζ) was reduced already after 4 days of treatment in the skin. NFKBIZ expression correlated to Psoriasis Area and Severity Index score, and NFKBIZ mRNA levels in the skin decreased during anti-IL-17A treatment. Moreover, specific NFKBIZ signature genes were significantly altered during anti-IL-17A treatment. Finally, we identified NF-κB activator 1 (Act1), p38 mitogen-activated protein kinase (MAPK), Jun NH2-terminal kinase (JNK), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) as key signaling pathways in NFKBIZ/IκBζ regulation., Conclusion: Our results define a crucial role for IκBζ in the antipsoriatic effect of secukinumab. Because IκBζ signature genes were regulated already after 4 days of treatment, this strongly indicates that IκBζ plays a crucial role in the antipsoriatic effects mediated by anti-IL-17A treatment., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The initiation and evaluation of treatment with biologics for psoriasis is based on the Psoriasis Area Severity Index (PASI) and/or Dermatological Life Quality Index (DLQI). However, these indices do not always correlate well, and changes in the DLQI do not always follow changes in the PASI. Based on data from the Danish national registry (DERMBIO), this study investigated the correlation between changes in PASI and DLQI in a cohort of patients with moderate-to-severe psoriasis treated with biologics or apremilast using Spearman's rank correlation analyses. The correlation analysis of 1,677 patients, of whom 276 had available data after 5 years, showed weak-to-moderate correlation between PASI and DLQI during a 5-year period and between changes in PASI and DLQI: 0.58 (p < 0.0001) for baseline to 3 months and 0.42 (p < 0.0001) for 3 to 12 months. The first question on "Symptoms and feelings" made up the largest proportion of the overall DLQI. The correlation between PASI and DLQI is weak-to-moderate and varies over time. Changes in PASI correlate weak-to-moderately with changes in DLQI during the first 12 months of treatment, with symptoms being the most important factor contributing to impaired quality of life.

Background: Psoriasis is a chronic inflammatory skin disease characterized by hyperproliferation and abnormal differentiation of keratinocytes. It is one of the most prevalent chronic inflammatory skin conditions in adults worldwide, with a considerable negative impact on quality of life. Circular RNAs (circRNAs) are a recently identified type of non-coding RNA with diverse cellular functions related to their exceptional stability. In particular, some circRNAs can bind and regulate microRNAs (miRNAs), a group of RNAs that play a role in the pathogenesis of psoriasis. The aim of this study was to characterize the circRNAome in psoriasis and to assess potential correlations to miRNA expression patterns., Methods: We used high-throughput RNA-sequencing (RNA-seq), NanoString nCounter technology and RNA chromogenic in situ hybridization (CISH) to profile the circRNA expression in paired lesional and non-lesional psoriatic skin from patients with psoriasis vulgaris. In addition, 799 miRNAs were profiled using NanoString nCounter technology and laser capture microdissection was used to study the dermis and epidermis separately., Results: We found a substantial down-regulation of circRNA expression in lesional skin compared to non-lesional skin. We observed that this mainly applies to the epidermis by analyzing laser capture microdissected tissues. We also found that the majority of the circRNAs were downregulated independently of their corresponding linear host genes. The observed downregulation of circRNAs in psoriasis was neither due to altered expression levels of factors known to affect circRNA biogenesis, nor because lesional skin contained an increased number of inflammatory cells such as lymphocytes. Finally, we observed that the overall differences in available miRNA binding sites on the circRNAs between lesional and non-lesional skin did not correlate with differences in miRNA expression patterns., Conclusions: We have performed the first genome-wide circRNA profiling of paired lesional and non-lesional skin from patients with psoriasis and revealed that circRNAs are much less abundant in the lesional samples. Whether this is a cause or a consequence of the disease remains to be revealed, however, we found no evidence that the loss of miRNA binding sites on the circRNAs could explain differences in miRNA expression between lesional and non-lesional skin.

Psoriasis (skin psoriasis, PsO) is a chronic inflammatory condition. In about one-third of cases, the joints are affected (psoriatic arthritis, PsA). Both conditions, especially PsA, profoundly impact patients' health-related quality of life (HRQoL). To describe the impact of psoriasis on HRQoL and patients' contact with the healthcare system in Sweden, Denmark, and Norway, the NORdic PAtient survey of Psoriasis and Psoriatic arthritis (NORPAPP) asked 22,050 adults randomly selected in Sweden, Denmark and Norway if they had psoriasis. 1264 individuals who reported physician-diagnosed PsO/PsA were invited to the full survey; 1221 responded (74.6% diagnosed with PsO alone; 25.4% with PsA ± PsO). Respondents with PsA most frequently consulted a rheumatologist; however, 14.3% had never seen a rheumatologist. Respondents with PsO alone most frequently consulted a general practitioner and 10.7% had never seen a dermatologist (although those with severe symptoms visited dermatologists more often). Negative impacts on HRQoL were reported by 38.1% of respondents with PsO [mostly limitations on clothing (22.6%), sleep disorders (16%), and depression/anxiety (16%)] and by 73% of respondents with PsA [mostly limitations on clothing (41.8%), sports/leisure (44.0%), or daily routine (45.1%) and sleeping disorders]. Absence from work/education was more common with PsA ± PsO (51.9%) than PsO alone (15.1%). In this survey in Sweden, Denmark, and Norway, the impact of psoriasis on the respondents' HRQoL was profound and was greater for PsA than for PsO, as was sickness absence. Sleeping disorders and depression were common and should not be overlooked.

Optimal clinical management of psoriasis and psoriatic arthritis (PsA) Optimal clinical management of psoriasis and psoriatic arthritis (PsA) requires understanding of the impact on patients. The NORdic PAtient survey of Psoriasis and PsA (NORPAPP) aimed to obtain current data on disease prevalence and patient perceptions in Sweden, Denmark and Norway. Among 22,050 individuals questioned, the reported prevalence of psoriasis and/or PsA was 9.7% (5.7% physician-diagnosed plus 4.0% self-diagnosed only); prevalence was similar in Sweden (9.4%) and Denmark (9.2%) but significantly higher in Norway (11.9%). Of those reporting a physician's diagnosis, 74.6% reported psoriasis alone, 10.3% PsA alone and 15.1% both. Patients with PsA perceived their disease to be more severe than those with psoriasis; patients with PsA and psoriasis reported greater disease severity than those with each condition alone. Patient's perceptions of psoriasis severity correlated weakly (Spearman's rho 0.42) with clinical severity; both patient perceptions and clinical measures are important in the assessment and management of psoriasis.

Antagonists of IL-17A and its receptor have proven to be highly effective in the treatment of psoriasis. However, many of the underlying molecular mechanisms involved in the pathogenesis of psoriasis are still to be determined. IκBζ (encoded by the NFKBIZ gene) plays a key role in the development of psoriasis by mediating IL-17A- and IL-17F-driven effects. Both IL-17A and IL-17F expression are increased in lesional psoriatic skin. IL-17A/A and IL-17F/F homodimers as well as the IL-17A/F heterodimer signal through the same receptors. The aim of this study was to characterize the role of the IL-17A/F heterodimer in the regulation of NFKBIZ expression and in the regulation of selected psoriasis-associated genes. We demonstrated that IL-17A/F stimulation of human keratinocytes significantly induced NFKBIZ expression. Moreover, silencing IκBζ by siRNA revealed that IκBζ is a key regulator of IL-17A/F-inducible psoriasis-associated genes, including CCL20, DEFB4, IL-8, CHI3L1 and S100A7. In addition, IL-17A/F-induced NFKBIZ expression was mediated by a mechanism involving the p38 MAPK and NF-κB signalling pathways. In conclusion, we present IκBζ as a novel key regulator of IL-17A/F-driven effects in psoriasis. Thus, antagonists to IL-17A/F or IκBζ may present a targeted approach for treating psoriasis., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The spleen is thought to play a role in atherosclerosis-associated immunity and cardiovascular research has indicated the existence of a cardio-splenic axis. The aim of this study was to assess splenic 18F-fluorodeoxyglucose uptake as a measure of systemic inflammation in patients with untreated psoriasis compared with historical controls assessed by positron emission tomography-computed tomography. Patients with moderate-to-severe psoriasis (n = 12, age 61.4 ± 4.1 years, 83% men, mean  Psoriasis Area Severity Index score of 14.5) and controls (n = 23, age 60.4 ± 4.5 years, 87% men) were included in the study. Splenic inflammation was measured using the background-corrected spleen-liver-ratio (SLR) based on mean standardized uptake values. Mean ± SD SLR was increased in patients with psoriasis compared with controls (0.94 ± 0.11 vs. 0.82 ± 0.08; p = 0.001). SLR was significantly associated with aortic inflammation. These results support the existence of systemic inflammation in patients with psoriasis, and provide the rationale for a mechanistic link between psoriasis-driven inflammation and cardiovascular comorbidity through a spleen-atherosclerotic axis.

Biological therapy became available for psoriasis with the introduction of alefacept at the beginning of this century. Up to then, systemic treatment options comprised small molecule drugs, targeting the immune system in a non-specific manner. The first biologics targeted T-cell activation and migration and served as an alternative to small molecules. However, significant improvement in outcome was first accomplished with the introduction of tumor necrosis factor-α inhibitors that were already approved for other inflammatory disorders, including rheumatic diseases. Along with the progress in understanding psoriasis pathogenesis, highly targeted and effective therapies have since developed with the perspective not only to improve but to clear psoriasis. These accomplishments enable future achievement of advanced goals to individualize treatment best suited for each patient. Mechanistic studies with patients treated with the new highly targeted biologics may guide us towards these goals. This review offers an overview of biologics developed for psoriasis and illustrate a historical progress in the treatment of this common chronic inflammatory skin condition., Competing Interests: The authors declare no conflict of interest. Lars Iversen has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by: AbbVie, Admiral, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Centocor, Eli Lilly, Janssen Cilag, Leo Pharma, MSD, Novartis, Pfizer and UCB.

Background: Ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin 17A, is efficacious in treating moderate-to-severe plaque psoriasis through 60 weeks., Objective: To evaluate the efficacy and safety of ixekizumab through 108 weeks of treatment in UNCOVER-3., Methods: Patients (N = 1346) were randomized 2:2:2:1 to 80 mg ixekizumab every 2 or 4 weeks, 50 mg etanercept twice weekly, or placebo. At week 12, patients switched to ixekizumab every 4 weeks during a long-term extension (LTE) period. Efficacy data were summarized using as-observed, multiple imputation (MI), and modified MI (mMI) methods., Results: For patients (N = 385) receiving the recommended dose (ixekizumab every 2 weeks on weeks 0-12 and every 4 weeks during LTE), the 108-week as-observed, MI, and mMI response rates were 93.4%, 88.3%, and 83.6%, respectively, for patients achieving ≥75% improvement from baseline in the Psoriasis Area and Severity Index, and the 108-week as-observed, MI, and mMI response rates were 82.6%, 78.3%, and 74.1%, respectively, for patients with a static Physician's Global Assessment score of 0 or 1. During LTE, 1077 (84.5%) patients reported ≥1 treatment-emergent adverse event, and 85% were mild or moderate in severity. Discontinuation because of adverse events occurred in 6.4% of patients., Limitations: There was no comparison treatment group after week 12., Conclusion: Ixekizumab is well tolerated and demonstrates persistent efficacy through 108 weeks., (Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

TNFα-, IL-23- and IL-17-targeting drugs are highly effective in the treatment of psoriasis. However, the precise molecular mechanism remains unknown. In psoriatic skin, the presence of Langerhans cells (LCs) is reduced, but the role of LC is poorly understood. The purpose of this study was to investigate the impact of TNFα and IL-23/IL-17 on the presence of LC in the skin during treatment. Therefore, psoriatic skin was investigated before and after 4 days of adalimumab or ustekinumab treatment. Furthermore, TNFα and IL-17A stimulation was investigated in an ex vivo model of epidermis and dermis from healthy normal skin kept in cultures at an air-liquid interphase for 4 days. In a gene array analysis, we found that the two LC markers, CD1a and CD207, were among the most up- or downregulated genes in psoriatic skin after anti-TNFα therapy. Validation showed that both mRNA expression and protein level followed the same pattern and became significantly upregulated after 4 days of treatment. No changes were seen after ustekinumab treatment. In the ex vivo skin model, a decrease in the CD1a level was seen after TNFα stimulation and it was caused by LC migration from epidermis. No response in LC migration was seen after IL-17A stimulation. Taken together, we demonstrated that changes in the LC level in epidermis precede the histological and clinical changes during adalimumab treatment in psoriatic skin. Furthermore, TNFα plays a prominent role in orchestrating LC migration in the skin. This seems not to be the true for the IL-23/IL-17A pathway., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Tripartite motif-containing protein 21 (TRIM21) regulates pro-inflammatory cytokines and type I interferons and acts as an autoantigen in certain autoimmune diseases, but TRIM21 has not been investigated in psoriasis. It has been suggested that TRIM21 may have a dual function; in the early phase of inflammation, it may function as a stimulator; but upon immune stimulation, its ubiquitinating mode of action may shift from stabilization to degradation of IRF3 causing inhibition of the immune responses. The imiquimod (IMQ)-induced psoriasis-like mouse model displays features similar to those of human psoriasis. However, chronicity is lacking in this model. We investigated whether the role of TRIM21 in psoriasis was pro-inflammatory or anti-inflammatory. We hypothesized that a shift of the TRIM21-ubiquitinating mode of action may explain the lack of chronicity in the IMQ-induced psoriasis-like mouse model. We showed that TRIM21 expression is increased in lesional psoriatic skin and in the early phase of IMQ-induced inflammation both in vitro and in vivo. Surprisingly, inflammation was significantly less pronounced in TRIM21 knockout mice than in wild-type mice as shown by ear thickness measured at days 8, 9 and 10 after treatment start, by spleen weight as a marker of systemic effect of IMQ at 10 days after treatment start and by expression of IL-12p40 at days 3 and 10 after treatment start and IL-17A at day 3 after treatment start. Therefore, induction of TRIM21 expression cannot explain the lack of chronicity in the IMQ-induced psoriasis-like skin inflammation mouse model., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The JAK/STAT signaling pathway is suggested to play an important role in the pathogenesis of psoriasis, and recently JAK/STAT inhibitors have shown promising results in psoriasis treatment. The present study aimed to characterize the role of STAT2 in psoriasis. We demonstrated an increased expression of STAT2 and an increased level of phosphorylated/activated STAT2 in lesional compared with nonlesional psoriatic skin. Gene silencing of STAT2 by siRNA in human keratinocytes revealed that upon IFNα stimulation CXCL11 and CCL5 were the only two cytokines, among 102 analyzed, found to be regulated through a STAT2-dependent mechanism. Moreover, the regulation of CXCL11 and CCL5 depended on IRF9, but not on STAT1 and STAT6. The CXCL11 and CCL5 expression was increased in lesional compared with nonlesional psoriatic skin, and analysis demonstrated positive correlation between the expression of CXCL11 and IFNγ and between the expression of CCL5 and IFNγ in lesional psoriatic skin. In contrast, no correlation between the expression of CXCL11 and IL-17A and the expression of CCL5 and IL-17A in lesional psoriatic skin was found. Our data suggest that STAT2 plays a role in the psoriasis pathogenesis by regulating the expression of CXCL11 and CCL5, and thereby attracting IFNγ-producing immune cells to the skin.

Methotrexate (MTX) has been used in the treatment of psoriasis and other dermatological diseases for more than 50 years. However, there is limited evidence regarding its effect, dose and monitoring, and a lack of consensus regarding how the drug should be used in daily practice. Although the use of MTX is governed by guidelines, such as the European S3-Guidelines and the National Institute for Health and Care Excellence (NICE) guideline, it is important to discuss and adjust these guidelines to national standards. An expert meeting was held in Denmark at the end of 2014, in order to reach consensus regarding the use of MTX in dermatological practice in Denmark. Participants included dermatologists, hepatologists, paediatricians, clinical biochemists and a rheumatologist. Topics discussed were: liver disease monitoring, teratogenic effects of MTX, risk of cancer, and use of MTX in children. We report here the conclusions of this expert meeting regarding use of MTX in dermatological practice.

Leptin is an adipocyte-derived cytokine secreted mostly by adipose tissue. Serum leptin levels are elevated in obese individuals and correlate positively with body mass index (BMI). Interestingly, serum leptin levels are also elevated in patients with psoriasis and correlate positively with disease severity. Psoriasis is associated with obesity; patients with psoriasis have a higher incidence of obesity, and obese individuals have a higher risk of developing psoriasis. Additionally, obese patients with psoriasis experience a more severe degree of psoriasis. In this study, we hypothesised that leptin may link psoriasis and obesity and plays an aggravating role in psoriasis. To investigate leptin's role in psoriasis, we applied the widely accepted imiquimod (IMQ)-induced psoriasis-like skin inflammation mouse model on leptin-deficient (ob/ob) mice and evaluated psoriasis severity. Moreover, we stimulated human keratinocytes with leptin and investigated the effect on proliferation and expression of pro-inflammatory proteins. In ob/ob mice, clinical signs of erythema, infiltration and scales in dorsal skin and inflammation in ear skin, as measured by ear thickness, were attenuated and compared with wt mice. Moreover, IL-17A and IL-22 mRNA expression levels, as well as increased epidermal thickness, were significantly less induced. In vitro, the effect of leptin stimulation on human keratinocytes demonstrated increased proliferation and induced secretion of several pro-inflammatory proteins; two hallmarks of psoriasis. In conclusion, leptin deficiency attenuated IMQ-induced psoriasis-like skin inflammation in a mouse model, and leptin stimulation induced a pro-inflammatory phenotype in human keratinocytes, thus, supporting an aggravating role of leptin in psoriasis., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Psoriasis is a common chronic inflammatory and immune-mediated skin disease. Antagonists of TNF-α and, recently, IL-17 have proven to be highly effective in the treatment for psoriasis; however, the molecular mechanisms involved in the pathogenesis of psoriasis are poorly understood. Recently, we presented evidence that IκBζ is a key regulator in the development of psoriasis through its role in mediating IL-17A-driven effects. Like IL-17A, IL-17F is produced by a variety of immune cells, and the expression of IL-17F is increased in psoriatic skin. The purpose of this study was to characterize the role of IL-17F in the regulation of IκBζ expression and to investigate whether IL-17F regulates psoriasis-associated genes in human keratinocytes through IκBζ. Here, we demonstrate that IL-17F stimulation induces IκBζ expression at both the mRNA and the protein levels in normal human keratinocytes. Moreover, silencing IκBζ by siRNA revealed that IκBζ is a key regulator of specific IL-17F-inducible psoriasis-associated genes and proteins, including DEFB4/hBD2, S100A7, CCL20, IL-8 and CHI3L1. In addition, IL-17F-induced IκBζ expression is mediated by a mechanism involving the p38 MAPK and NF-κB signalling pathways, as shown by the clear reduction in IL-17F-mediated expression of IκBζ during chemical inhibition of these two signalling pathways. In summary, we present IκBζ as a novel key regulator of IL-17F-driven effects in psoriasis. Thus, antagonists to IκBζ could potentially provide a more targeted approach for treating psoriasis as well as for treating the other inflammatory and immune-mediated diseases for which IL-17-targeting drugs have recently been approved., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Psoriasis is a chronic cutaneous inflammatory disease. The immunopathogenesis is a complex interplay between T cells, dendritic cells and the epidermis in which T cells and dendritic cells maintain skin inflammation. Anti-tumour necrosis factor (anti-TNF)-α agents have been approved for therapeutic use across a range of inflammatory disorders including psoriasis, but the anti-inflammatory mechanisms of anti-TNF-α in lesional psoriatic skin are not fully understood. We investigated early events in skin from psoriasis patients after treatment with anti-TNF-α antibodies by use of bioinformatics tools. We used the Human Gene 1.0 ST Array to analyse gene expression in punch biopsies taken from psoriatic patients before and also 4 and 14 days after initiation of treatment with the anti-TNF-α agent adalimumab. The gene expression was analysed by gene set enrichment analysis using the Functional Annotation Tool from DAVID Bioinformatics Resources. The most enriched pathway was visualised by the Pathview Package on Kyoto Encyclopedia of Genes and Genomes (KEGG) graphs. The analysis revealed new very early events in psoriasis after adalimumab treatment. Some of these events have been described after longer periods of anti-TNF-α treatment when clinical and histological changes appear, suggesting that effects of anti-TNF-α treatment on gene expression appear very early before clinical and histological changes. Combining microarray data on biopsies from psoriasis patients with pathway analysis allowed us to integrate in vitro findings into the identification of mechanisms that may be important in vivo. Furthermore, these results may reflect primary effect of anti-TNF-α treatment in contrast to studies of gene expression changes following clinical and histological changes, which may reflect secondary changes correlated to the healing of the skin., Competing Interests: The authors have declared that no competing interests exist.

Background: Most psoriasis patients have mild to moderate disease, commonly treated topically. Current topical agents have limited efficacy and undesirable side effects associated with long-term use. Tofacitinib is a small molecule Janus kinase inhibitor investigated for the topical treatment of psoriasis., Methods: This was a 12-week, randomized, double-blind, parallel-group, vehicle-controlled Phase 2b study of tofacitinib ointment (2 % and 1 %) applied once (QD) or twice (BID) daily in adults with mild to moderate plaque psoriasis. Primary endpoint: proportion of patients with Calculated Physician's Global Assessment (PGA-C) clear or almost clear and ≥2 grade improvement from baseline at Weeks 8 and 12. Secondary endpoints: proportion of patients with PGA-C clear or almost clear; proportion achieving Psoriasis Area and Severity Index 75 (PASI75) response; percent change from baseline in PASI and body surface area; change from baseline in Itch Severity Item (ISI). Adverse events (AEs) were monitored and clinical laboratory parameters measured., Results: Overall, 435 patients were randomized and 430 patients received treatment. The proportion of patients with PGA-C clear or almost clear and ≥2 grade improvement from baseline at Week 8 was 18.6 % for 2 % tofacitinib QD (80 % confidence interval [CI] for difference from vehicle: 3.8, 18.2 %) and 22.5 % for 2 % tofacitinib BID (80 % CI: 3.1, 18.5 %); this was significantly higher vs vehicle for both dosage regimens. No significant difference vs vehicle was seen at Week 12. Significantly more patients achieved PGA-C clear or almost clear with 2 % tofacitinib QD and BID and 1 % tofacitinib QD (not BID) at Week 8, and with 2 % tofacitinib BID at Week 12. Pruritus was significantly reduced vs vehicle with 2 % and 1 % tofacitinib BID (starting Day 2), and 2 % tofacitinib QD (starting Day 3). Overall, 44.2 % of patients experienced AEs, 8.1 % experienced application site AEs, and 2.3 % experienced serious AEs. The highest incidence of AEs (including application site AEs) was in the vehicle QD group., Conclusions: In adults with mild to moderate plaque psoriasis, 2 % tofacitinib ointment QD and BID showed greater efficacy than vehicle at Week 8, but not Week 12, with an acceptable safety and local tolerability profile., Trial Registration: NCT01831466 registered March 28, 2013.

Importance: Inflammatory pathways of psoriasis share similarities with the mechanisms identified in atherosclerosis, and the association between psoriasis and cardiovascular disease due to accelerated coronary artery disease is well established. The effect of anti-inflammatory drugs on the development of coronary atherosclerosis remains essentially unknown., Objective: To investigate the association of biological therapy with changes in coronary artery disease progression, measured by repeated coronary computed tomography (CT)., Design, Setting, and Participants: This single-center prospective, controlled, observer-blinded clinical study at a tertiary dermatology university hospital clinic enrolled patients with severe psoriasis initiating biological therapy and matched controls not receiving systemic therapy from April 11, 2011, through June 30, 2014., Interventions: Biological therapy approved for psoriasis (adalimumab, etanercept, infliximab, ustekinumab) with the possibility to switch between treatments to ensure tight control of inflammation., Main Outcomes and Measures: Patients underwent noncontrast coronary artery calcium (CAC) CT and contrast-enhanced coronary CT angiography at baseline and after 13 months of follow-up. Changes in CAC score, number of coronary plaques, severity of narrowing, composition, and vessel wall volume were measured., Results: There were 28 treated patients (mean [SD] age, 49.2 [10.2] years; 71% men; mean [SD] Psoriasis Area Severity Index [PASI], 15.4 [4.3]) and 28 controls (mean [SD] age, 52.8 [10.6] years; 71% men; mean [SD] PASI, 12.4 [3.9]). The CAC scores remained stable in the intervention group (mean [SD] yearly CAC change, -16 [56]; P = .15) and progressed in the control group (14 [29]; P = .02) (intervention vs controls: P = .02). The number of segments with luminal abnormalities remained unchanged in both groups. The severity of luminal narrowing in the diseased segments was unchanged in the intervention group (Wilcoxon W = 76, n = 483, P = .39) but increased at follow-up in the control group (Wilcoxon W = 281, n = 414, P = .02). Automated vessel wall volume index remained unchanged from baseline to follow-up in the intervention group (mean [SD] baseline, 7.1 [1.5], follow-up, 7.1 [1.7]; P = .91), while controls demonstrated statistically nonsignificant progression (baseline, 8.3 [1.6], follow-up, 8.9 [2.2]; P = .06)., Conclusions and Relevance: Clinically effective treatment with biologic agents was associated with reduced coronary artery disease progression in patients with severe psoriasis. These findings support a beneficial effect of biologic anti-inflammatory agents in preventing cardiovascular disease progression in addition to disease control in inflammatory diseases.

Background: Psoriasis and atopic dermatitis (AD) are immuno-inflammatory diseases that can result in lifelong systemic inflammation. Unlike AD, psoriasis has been associated with cardiovascular disease. The aim of this study was to examine the prevalence, severity, and subtype of coronary artery disease (CAD) in psoriasis and AD patients without known cardiovascular disease., Methods: Consecutively enrolled patients (psoriasis n = 58, AD n = 31) and retrospectively matched controls (n = 33) were examined using cardiac computed tomography angiography (CCTA) and assessed using an 18-segment model of the coronary tree., Results: The prevalence of a coronary artery calcium score >0 was 29.8% in psoriasis and 45.2% in AD, vs 15.2% in controls (P = .09 and P = .01, respectively). More patients with psoriasis had a coronary artery calcium score ≥100 (psoriasis 19.3%, controls 2.9%; P = .02). CCTA showed the presence of plaques in 38.2% of psoriasis patients and 48.1% of AD patients, vs 21.2% of controls (P = .08 and P = .03, respectively). Psoriasis was associated with an increased prevalence of significant coronary stenosis (stenosis >70%) (psoriasis 14.6%, controls 0%; P = .02) and 3-vessel coronary affection or left main artery disease (psoriasis 20%, controls 3%; P = .02), whereas AD was associated with mild (AD 40.7%, controls 9.1%; P = .005) single-vessel affection., Conclusions: These findings suggest that psoriasis and AD are associated with an increased prevalence of CAD. Patients with psoriasis have an increased prevalence of severe CAD., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Psoriasis is a common immune-mediated, chronic, inflammatory skin disease characterized by hyperproliferation and abnormal differentiation of keratinocytes and infiltration of inflammatory cells. Although TNFα- and IL-17A-targeting drugs have recently proven to be highly effective, the molecular mechanism underlying the pathogenesis of psoriasis remains poorly understood. We found that expression of the atypical IκB member IκB (inhibitor of NF-κB) ζ, a selective coactivator of particular NF-κB target genes, was strongly increased in skin of patients with psoriasis. Moreover, in human keratinocytes IκBζ was identified as a direct transcriptional activator of TNFα/IL-17A-inducible psoriasis-associated proteins. Using genetically modified mice, we found that imiquimod-induced psoriasis-like skin inflammation was completely absent in IκBζ-deficient mice, whereas skin inflammation was still inducible in IL-17A- and TNFα-deficient mice. IκBζ deficiency also conferred resistance against IL-23-induced psoriasis. In addition, local abrogation of IκBζ function by intradermal injection of IκBζ siRNA abolished psoriasis-like skin inflammation. Taken together, we identify IκBζ as a hitherto unknown key regulator of IL-17A-driven effects in psoriasis. Thus, targeting IκBζ could be a future strategy for treatment of psoriasis, and other inflammatory diseases for which IL-17 antagonists are currently tested in clinical trials.