The genes mgtE and spoVG are involved in zinc tolerance of Staphylococcus aureus.

Metals are essential for all living organisms, but the type of metal and its concentration determines its action. Even low concentrations of metals may have toxic effects on organisms and therefore exhibit antimicrobial activities. In this study, we investigate the evolutionary adaptation processes of Staphylococcus aureus to metals and common genes for metal tolerance. Laboratory and clinical isolates were treated with manganese, cobalt, zinc, or nickel metal salts to generate growth-adapted mutants. After growth in medium supplemented with zinc, whole-genome sequencing identified, among others, two genes, mgtE (SAUSA300_0910), a putative magnesium transporter and spoVG (SAUSA300_0475), a global transcriptional regulator, as hot spots for stress-induced single-nucleotide polymorphisms (SNPs). SNPs in mgtE were also detected in mutants treated with high levels of cobalt or nickel salts. To investigate the effect of these genes on metal tolerance, deletion mutants and complementation strains in an S. aureus USA300 LAC* laboratory strain were generated. Both, the mgtE and spoVG deletion strains were more tolerant to cobalt, manganese, and zinc. The mgtE mutant was also more tolerant to nickel exposure. Inductively coupled plasma mass spectrometry analysis demonstrated that the mgtE deletion mutant accumulated less intracellular zinc than the wild type, explaining increased tolerance. From these results, we conclude that mgtE gene inactivation increases zinc tolerance presumably due to reduced uptake of zinc. For the SpoVG mutant, no direct effect on the intracellular zinc concentration was detected, indicating toward different pathways to increase tolerance. Importantly, inactivation of these genes offers a growth advantage in environments containing certain metals, pointing toward a common tolerance mechanism. IMPORTANCE: Staphylococcus aureus is an opportunistic pathogen causing tremendous public health burden and high mortality in invasive infections. Treatment is becoming increasingly difficult due to antimicrobial resistances. The use of metals in animal husbandry and aquaculture to reduce bacterial growth and subsequent acquisition of metal resistances has been shown to co-select for antimicrobial resistance. Therefore, understanding adaptive mechanisms that help S. aureus to survive metal exposure is essential. Using a screening approach, we were able to identify two genes encoding the transporter MgtE and the transcriptional regulator SpoVG, which conferred increased tolerance to specific metals such as zinc when inactivated. Further testing showed that the deletion of mgtE leads to reduced intracellular zinc levels, suggesting a role in zinc uptake. The accumulation of mutations in these genes when exposed to other metals suggests that inactivation of these genes could be a common mechanism for intrinsic tolerance to certain metals.

Association of disease duration and PASI response rates at week 12 in patients with moderate-to-severe plaque psoriasis receiving biologics in the real-world psoriasis study of health outcomes (PSoHO).

PURPOSE: Currently, in the treatment of moderate-to-severe psoriasis (PsO) there is a lack of evidence demonstrating optimal biologic treatment response with respect to disease duration. The aim of this post-hoc analysis, using real world data from the Psoriasis Study of Health Outcomes (PSoHO), is to provide evidence if early intervention with biologics is associated with better treatment outcomes and if there is any difference among drug classes or individual biologics. MATERIALS AND METHODS: For this post-hoc analysis patients were categorised into two subgroups according to shorter (≤2 years) or longer (>2 years) disease duration. Analysis was performed on anti-interleukin (IL)-17A cohort vs other biologics cohort, anti-IL-17A vs other drug classes, and pairwise comparisons of ixekizumab vs individual biologics, provided that the statistical models converged. Analysis investigated the association of disease duration with the proportion of patients achieving 100% improvement in Psoriasis Area Severity Index score (PASI 100) at week 12. Adjusted comparative analyses, reported as odds ratio (OR), were performed using Frequentist Model Averaging (FMA) for each cohort or treatments within each subcategory of the subgroups. RESULTS: At week 12, anti-IL-17A and other biologics cohorts displayed minimal differences in numerical response rate for PASI 100 with respect to disease duration. The anti-IL-17A cohort showed a higher numerical PASI 100 response rate compared to the other biologic cohort irrespective of disease duration (≤2 years: 36.7% vs 21.8%; >2 years: 35.8% vs 21.9%). CONCLUSION: Overall, the results do not clearly indicate that treating patients early is critical in achieving optimal patient outcomes. Furthermore, patients treated with ixekizumab show numerically higher response rates relative to other individual biologics irrespective of disease duration.

Baseline Characteristics and mNAPSI Change from Baseline Scores Through Month 12 for Patients with Moderate-to-Severe Plaque Psoriasis and Concomitant Nail Psoriasis Treated with Biologics from PSoHO.

INTRODUCTION: Nail psoriasis is highly prevalent among patients with psoriasis yet remains one of the most challenging areas to treat. To better understand the treatment landscape for psoriatic nail disease, more studies are needed that compare the effectiveness of different biologics for patients with nail psoriasis. This study contributes to this objective by directly comparing the effectiveness of approved biologics in improving nail psoriasis for patients up to month 12 in a real-world setting. METHODS: Psoriasis Study of Health Outcomes (PSoHO) is an ongoing 3-year, prospective, non-interventional cohort study of adults with chronic moderate-to-severe plaque psoriasis initiating or switching to a new biologic. This study assessed the change in modified Nail Psoriasis Severity Index (mNAPSI) score from baseline to months 3, 6 and 12 for 763 patients and compared the effectiveness of anti-interleukin (IL)-17A biologics versus other approved biologics, as well as ixekizumab versus secukinumab, guselkumab, risankizumab and adalimumab. Comparative adjusted analyses used frequentist model averaging (FMA). Least square mean difference (LSMD) in mNAPSI scores are presented as observed. RESULTS: Irrespective of the severity of nail psoriasis at baseline, the anti-IL-17A cohort had greater mean mNAPSI reductions from baseline compared to the other biologics cohort through month 12, reaching significance at months 3 and 6 in the adjusted analysis. For patients with moderate-to-severe nail psoriasis, ixekizumab showed numerically higher mean reductions in mNAPSI scores compared to all other studied biologics, reaching significance versus guselkumab at all timepoints and risankizumab at month 6. CONCLUSION: This real-world study showed that patients with moderate-to-severe psoriasis and any severity of concomitant nail involvement had significantly faster and more substantial improvements in nail psoriasis up to month 6 in the anti-IL-17A cohort compared to the other biologics cohort. Of the individual biologics studied, ixekizumab showed the highest numerical improvements in nail psoriasis at month 12. TRIAL REGISTRATION: EUPAS24207.

Histidine transport is essential for the growth of Staphylococcus aureus at low pH.

Staphylococcus aureus is an opportunistic pathogen capable of causing many different human diseases. During colonization and infection, S. aureus will encounter a range of hostile environments, including acidic conditions such as those found on the skin and within macrophages. However, little is known about the mechanisms that S. aureus uses to detect and respond to low pH. Here, we employed a transposon sequencing approach to determine on a genome-wide level the genes required or detrimental for growth at low pH. We identified 31 genes that were essential for the growth of S. aureus at pH 4.5 and confirmed the importance of many of them through follow up experiments using mutant strains inactivated for individual genes. Most of the genes identified code for proteins with functions in cell wall assembly and maintenance. These data suggest that the cell wall has a more important role than previously appreciated in promoting bacterial survival when under acid stress. We also identified several novel processes previously not linked to the acid stress response in S. aureus. These include aerobic respiration and histidine transport, the latter by showing that one of the most important genes, SAUSA300_0846, codes for a previously uncharacterized histidine transporter. We further show that under acid stress, the expression of the histidine transporter gene is increased in WT S. aureus. In a S. aureus SAUSA300_0846 mutant strain expression of the histidine biosynthesis genes is induced under acid stress conditions allowing the bacteria to maintain cytosolic histidine levels. This strain is, however, unable to maintain its cytosolic pH to the same extent as a WT strain, revealing an important function specifically for histidine transport in the acid stress response of S. aureus.

Effectiveness of Biologics, Patient-Reported Outcomes, and Clinical Photography in a Subset of Patients with Moderate-to-Severe Psoriasis: Week 12 Results from the Psoriasis Study of Health Outcomes (PSoHO).

Purpose: Since skin is highly accessible, clinical photography is a useful tool to visually substantiate the real-world effectiveness outcomes of biologic-treated adults with moderate-to-severe psoriasis (PsO). We report the effectiveness and patient-reported outcomes at Week 12 between anti-interleukin (IL)-17A biologics and other biologics as well as ixekizumab and guselkumab in patients with available clinical photography at baseline and Week 12. Patients and Methods: The Psoriasis Study of Health Outcomes (PSoHO) is an international, non-interventional, cohort study investigating the effectiveness of biologics in adults with moderate-to-severe psoriasis at Week 12. Outcomes included the proportion of patients who achieved 90% improvement in Psoriasis Area and Severity Index (PASI90) and/or static Physician Global Assessment (sPGA) 0/1 (primary endpoint), PASI100, PASI90, Dermatology Life Quality Index (DLQI), and Itch Numeric Rating Scale (NRS) (secondary endpoints) at Week 12. Data are reported descriptively. Results: This analysis included 59 biologic-treated (23 anti-IL-17A; 36 other biologics) patients with available clinical photographs from the overall PSoHO study (n=1981). At baseline, the mean (standard deviation [SD]) age was 45.7 (11.1) years, 71.2% were male, 52.5% were bio-experienced and the median (interquartile range) duration of disease was 10.5 (12.4) years. Mean (SD) PASI was 16.9 (9.3) and sPGA was 3.5 (0.8). At Week 12, 65.2%/47.2% of the anti-IL-17A/other biologics cohort achieved the primary outcome. Response rates for PASI90/100 were numerically higher with anti-IL-17A than with other biologics. Patients receiving anti-IL-17A had numerically better outcomes for DLQI 0/1 and Itch NRS than those receiving other biologics at Week 12. Clinical photographs confirmed skin improvements in ixekizumab- and guselkumab-treated patients. Conclusion: This subgroup analysis showed that anti-IL-17A biologics are effective at rapidly improving signs and symptoms of PsO and improving quality of life. Additionally, serial photography provided visual evidence of biologic treatment response over time.

Network meta-analyses comparing the efficacy of biologic treatments for achieving complete resolution of nail psoriasis at 24-28 and 48-52 weeks.

BACKGROUND: Available network meta-analyses (NMAs) comparing the efficacy of biologics in nail psoriasis (NP) have not included recently approved biologics such as bimekizumab nor have they provided comparisons up to 1 year. OBJECTIVE: We conducted two NMAs that update and extend results from a previous NMA comparing biologics for achieving complete resolution of NP. METHODS: Bayesian NMAs were performed using a generalized linear model with a logit link to model the binary outcome of nail clearance at weeks 24-28 and 48-52. RESULTS: For the NMA at weeks 24-28, which included seven biologics and placebo, the absolute probability of achieving complete resolution of NP was highest for ixekizumab (46.4%; 95% credibility interval [CrI] 35.2-58.0), followed by brodalumab (37.1%; 95% CrI 17.1-62.2) and bimekizumab (30.3%; 95% CrI 12.7-53.9). For the NMA at weeks 48-52, which included six biologics, the absolute probability was highest for ixekizumab (77.2%; 95% CrI 51.1-93.4), followed by adalimumab (75.6%; 95% CrI 61.5-87.3) and brodalumab (71.9%; 95% CrI 38.4-93.2). CONCLUSION: Among biologics included in these two NMAs, ixekizumab has the highest absolute probability of achieving complete resolution of NP. Results may help to inform treatment decisions for patients with NP.

Diastereoselective Reductive Etherification Via High-Throughput Experimentation: Access to Pharmaceutically Relevant Alkyl Ethers.

This manuscript describes the development of the first diastereoselective intermolecular synthesis of alkyl ethers via reductive etherification of diverse ketones or aldehydes with alcohols. Key to this development was the use of low-temperature high-throughput experimentation (HTE) technologies that enabled rapid reaction optimizations and parallel synthesis. A broad scope of pharmaceutically relevant substrates was surveyed, which formed alkyl ethers effectively. In addition, we demonstrated that the diastereoselectivity of this transformation can be readily modulated by prudent selection of the reductant.

Comparative effectiveness of biologics for patients with moderate-to-severe psoriasis and special area involvement: week 12 results from the observational Psoriasis Study of Health Outcomes (PSoHO).

Introduction: Psoriasis localized at the scalp, face, nails, genitalia, palms, and soles can exacerbate the disease burden. Real-world studies comparing the effectiveness of treatments for these special areas are limited. Methods: Psoriasis Study of Health Outcomes (PSoHO) is an international, prospective, non-interventional, study comparing the effectiveness of anti-interleukin (IL)-17A biologics (ixekizumab and secukinumab) compared to other approved biologics and the pairwise comparative effectiveness of ixekizumab relative to five other individual biologics for patients with moderate-to-severe psoriasis. To determine special area involvement, physicians answered binary questions at baseline and week 12. The proportion of patients who achieved special area clearance at week 12 was assessed. Missing outcome data were imputed as non-response. Comparative treatment analyses were conducted using frequentist model averaging. Results: Of the 1,978 patients included, 83.4% had at least one special area involved at baseline with the scalp (66.7%) as the most frequently affected part, followed by nails (37.9%), face/neck (36.9%), genitalia (25.6%), and palms and/or soles (22.2%). Patients with scalp, nail, or genital, but not palmoplantar or face/neck psoriasis, had significantly higher odds of achieving clearance at week 12 in the anti-IL-17A cohort compared to the other biologics cohort. Patients with scalp psoriasis had a 10-20% higher response rate and significantly greater odds (1.8-2.3) of achieving clearance at week 12 with ixekizumab compared to included biologics. Conclusion: Biologics demonstrate a high level of clearance of special areas at week 12 in a real-world setting. Patients with scalp, nail, or genital involvement have significantly higher odds of clearance at week 12 with anti-IL-17A biologics compared to other biologics.

A Comprehensive Review of Ixekizumab Efficacy in Nail Psoriasis from Clinical Trials for Moderate-to-Severe Psoriasis and Psoriatic Arthritis.

Nail psoriasis is a difficult-to-treat manifestation of psoriatic disease affecting up to 80% of patients with psoriatic arthritis (PsA) and 40-60% of patients with plaque psoriasis (PsO). Ixekizumab (IXE), a high-affinity monoclonal antibody that selectively targets interleukin-17A, is approved for the treatment of patients with PsA and patients with moderate-to-severe PsO. This narrative review aims to summarize nail psoriasis data generated from IXE clinical trials in patients with PsA (SPIRIT-P1, SPIRIT-P2, and SPIRIT-H2H) and/or moderate-to-severe PsO (UNCOVER-1, -2, -3, IXORA-R, IXORA-S, and IXORA-PEDS) with an emphasis on head-to-head clinical trial data. Across numerous trials explored, IXE treatment was associated with greater improvement in resolution of nail disease versus comparators at week 24, results which were maintained up to and beyond week 52. Additionally, patients experienced higher rates of resolution of nail disease versus comparators at week 24 and maintained high levels of resolution up to week 52 and beyond. In both PsA and PsO, IXE demonstrated efficacy in treating nail psoriasis, and therefore may be an effective therapy option. Trial Registration: ClinicalTrials.gov identifier UNCOVER-1 (NCT01474512), UNCOVER-2 (NCT01597245), UNCOVER-3 (NCT01646177), IXORA-PEDS (NCT03073200), IXORA-S (NCT02561806), IXORA-R (NCT03573323), SPIRIT-P1 (NCT01695239), SPIRIT-P2 (NCT02349295), SPIRIT-H2H (NCT03151551).

Baseline Body Surface Area and Itch Severity Define Response to Baricitinib in Patients with Moderate-to-Severe Atopic Dermatitis at Week 16.

INTRODUCTION: Atopic dermatitis (AD) is a chronic, inflammatory skin disease characterized by heterogeneous clinical phenotypes and high symptom burden, especially through itch. Baricitinib (BARI), an oral Janus Kinase 1/2 inhibitor, is approved in Europe, Japan, and other countries, for treatment of adults with moderate-to-severe AD who are candidates for systemic therapy. This post hoc analysis of a Phase 3 topical corticosteroid (TCS) combination therapy trial (BREEZE-AD7) aims to characterize patients who might benefit most from BARI. METHOD: Classification and regression tree (CART) analysis was used to identify baseline predictors for patients treated with BARI 4-mg, who achieved ≥ 75% improvement in Eczema Area and Severity Index (EASI75), or EASI75 or Itch Numerical Rating Scale (NRS) ≥ 4-point improvement at week 16 (responders), versus non-responders. Subgroup efficacy analyses were performed based on identified predictor variables, combined with Itch NRS < 7/ ≥ 7. Missing data were imputed as non-responder. RESULTS: Baseline body surface area (BSA) was identified by CART as strongest variable predicting response to BARI at week 16, with a cut-off around 40% (BSA ≤ 40%). When combining BSA with itch severity, highest response rates were achieved by BARI patients with BSA ≤ 40%/Itch NRS ≥ 7 at baseline. In this subgroup, 69% and 58% of patients treated with BARI 4-mg achieved EASI75 and Itch NRS ≥ 4-point response at week 16, respectively. While these response rates were 65% and 50% for BARI 4-mg patients with baseline BSA ≤ 40%/Itch NRS < 7, they were 33% and 11% in BSA > 40%/Itch NRS < 7, and 32% and 49% in BSA > 40%/Itch NRS ≥ 7 subgroups, respectively. CONCLUSION: Using a machine learning approach, patients with moderate-to-severe AD and a BSA affecting 10-40% and Itch NRS ≥ 7 were characterized as likely to benefit most from BARI 4-mg TCS combination therapy. This was confirmed by subgroup analyses, which showed that these patients are most likely to show favorable response rates in improving AD signs and symptoms, specifically itch, after 16 weeks of treatment.

Allelic-Exchange Procedure in Staphylococcus aureus.

This protocol continues a series of methods for the construction of an in-frame gene deletion in Staphylococcus aureus strain RN4220. To this end, we describe in this protocol an allelic-exchange procedure for S. aureus We have previously described how an allelic-exchange plasmid containing a desired gene deletion (in this case, pIMAY*-ΔtagO) can be constructed and isolated from Escherichia coli, then introduced into electrocompetent S. aureus cells by electroporation. This plasmid contains a temperature-sensitive origin of replication, a counterselectable marker (pheS* gene) and confers chloramphenicol resistance to S. aureus As a specific example, we present the construction of strain RN4220*ΔtagO from strain RN4220 carrying the pIMAY*-ΔtagO plasmid. The protocol can be easily adapted for the construction of other gene deletions and/or allelic-exchange plasmids.

Preparation of Electrocompetent Staphylococcus aureus Cells and Plasmid Transformation.

This protocol is part of a series of methodologies for the construction of an in-frame gene deletion in Staphylococcus aureus strain RN4220. Having previously described how an allelic-exchange plasmid containing a desired gene deletion (in this case, pIMAY*-ΔtagO) can be constructed and isolated from Escherichia coli, we now present details of the next steps in this method-the preparation of electrocompetent S. aureus cells and introduction of the tagO mutant plasmid DNA into the S. aureus cells by electroporation. Colonies containing the plasmid can then be selected on chloramphenicol plates at a low temperature permissive for plasmid replication.

Staphylococcus aureus Colony Polymerase Chain Reaction.

Here, we describe a protocol for a colony polymerase chain reaction (PCR) method for Staphylococcus aureus The methodology involves the preparation of small S. aureus lysates by using the enzyme lysostaphin to degrade the peptidoglycan layer. These lysates are prepared using a small patch of bacteria grown on LB agar plates, and the lysates can subsequently be used for PCR analyses.

Construction of a Staphylococcus aureus Gene-Deletion Allelic-Exchange Plasmid by Gibson Assembly and Recovery in Escherichia coli.

We present a protocol for the generation of a gene-deletion allelic-exchange plasmid and its recovery in Escherichia coli for the purpose of constructing an in-frame gene deletion in Staphylococcus aureus Here, we present detailed methodologies for (i) the primer design (using the S. aureus tagO gene as our specific example); (ii) PCR amplification of the required gene fragments; (iii) preparation of the cloning vector (using the S. aureus allelic-exchange vector pIMAY* as an example); (iv) the Gibson assembly cloning method; (v) introduction of the plasmid into E. coli; (vi) confirmation of the plasmid insert in E. coli by colony PCR; and, finally, (vii) confirmation of the insert by sequencing. We also consider the long-term storage of the E. coli strains containing the desired plasmid.

Allelic Exchange: Construction of an Unmarked In-Frame Deletion in Staphylococcus aureus.

Here we describe an allelic-exchange procedure for the construction of an unmarked gene deletion in the bacterium Staphylococcus aureus As a practical example, we outline the construction of a tagO gene deletion in S. aureus using the allelic-exchange plasmid pIMAY*. We first present the general principles of the allelic-exchange method, along with information on counterselectable markers. Furthermore, we summarize relevant cloning procedures, such as the splicing by overhang extension (SOE) polymerase chain reaction (PCR) and Gibson assembly methods, and we conclude by giving some general consideration to performing genetic modifications in S. aureus.

Corrigendum: Efficacy of ixekizumab in patients with moderate-to-severe plaque psoriasis and prediabetes or type 2 diabetes.

[This corrects the article DOI: 10.3389/fmed.2022.1092688.].

Methods used for indirect comparisons of systemic treatments for psoriasis. A systematic review.

Background: Indirect comparisons (including network meta-analyses [NMAs]) allow us to compare benefits and risks of multiple interventions for the same clinical condition when head-to-head comparisons are not feasible. Objective: To provide guidance to the clinical community on better understanding indirect comparison methods to help them to interpret their results by applying two quality standards to published indirect comparisons of systemic biologics for moderate to severe psoriasis. Methods: A systematic literature review (SLR) of published indirect comparisons of biologics for the treatment of moderate to severe psoriasis in adults was conducted. Data extraction was performed using a predefined subset of NICE TSD7 (National Institute for Health and Care Excellence Technical Support Document 7) checklist questions and methods used to perform each analysis were descriptively compared. Methodological quality of the SLR underlying each indirect comparison was assessed using AMSTAR 2 (A MeaSurement Tool to Assess systematic Reviews version 2). Results: Twenty-two NMAs and four adjusted indirect comparisons (AICs) were identified. Although there were some similarities, for example, application of Bayesian random-effects models, several important methodological aspects varied considerably across NMAs identified, for example, classes of drugs, number of treatments and studies included, reporting and handling of different doses, and reporting of both checks for and investigations of inconsistency. Methodological comparisons across AICs were limited by the small number. The quality of most underlying SLRs described, assessed as overall level of confidence in the results, was 'critically low'. Conclusions: Understanding that there are different methodologies employed to answer differing research questions is key to helping clinicians to interpret the indirect evidence currently available in psoriasis.

Real-world evidence for ixekizumab in the treatment of psoriasis and psoriatic arthritis: literature review 2016-2021.

OBJECTIVES: To describe the results of a structured literature review of real-world outcomes with ixekizumab in patients with psoriasis (PsO) and/or psoriatic arthritis (PsA). METHODS: Literature databases, conference proceedings and additional sources were searched for relevant publications. Real-world studies of ≥25 ixekizumab-treated patients with PsO and/or PsA were included. Data on clinical effectiveness, treatment persistence/patterns, economic outcomes, patient-reported outcomes (PROs) and safety were extracted. RESULTS: Fifty-one publications were included. Most studies focused on patients with PsO, and the number of publications with a focus on PROs was low. Studies of treatment patterns found that in general, ixekizumab had similar or better persistence versus other biologics, and rates or risk of switching similar to or less than comparator drugs. Adherence to ixekizumab was high, and patients were less likely to discontinue ixekizumab than other biologics. Ixekizumab was effective in the real world, with a safety profile consistent with that reported in clinical trials. CONCLUSIONS: Real-world use of ixekizumab in PsO and PsA is effective and safe, with generally high treatment persistence and adherence. Further work is required to determine the impact of ixekizumab on PROs in PsO, and to gather more data on real-world use of ixekizumab in PsA.

Comparative Effectiveness of Biologics Across Subgroups of Patients with Moderate-to-Severe Plaque Psoriasis: Results at Week 12 from the PSoHO Study in a Real-World Setting.

INTRODUCTION: In routine clinical care, important treatment outcomes among patients with moderate-to-severe plaque psoriasis (PsO) have been shown to vary according to patient demographics and disease characteristics. This study aimed to provide direct comparative effectiveness data at week 12 between anti-interleukin (IL)-17A biologics relative to other approved biologics for the treatment of PsO across seven clinically relevant patient subgroups in the real-world setting. METHODS: From the international, non-interventional Psoriasis Study of Health Outcomes (PSoHO), 1981 patients with moderate-to-severe PsO were grouped a priori according to seven clinically relevant demographic and disease variables with binary categories, which were sex (male or female), age (< 65 or ≥ 65 years), body mass index (≤ 30 or > 30 kg/m2), race (White or Asian), PsO disease duration (< 15 or ≥ 15 years), psoriatic arthritis (PsA) comorbidity (present or absent), and prior biologic use (never or ≥ 1). Across these subgroups, effectiveness was compared between the anti-IL-17A cohort (ixekizumab, secukinumab) versus all other approved biologics and ixekizumab versus five individual biologics. The proportion of patients in each subgroup who achieved 90% improvement in Psoriasis Area and Severity Index (PASI90) and/or static Physician Global Assessment (sPGA) 0/1, PASI100, or PASI90 at week 12 were assessed. Comparative analyses were conducted using frequentist model averaging (FMA). Missing data were imputed using non-responder imputation. RESULTS: Patients in each of the seven subgroups achieved similar response rates to those of the overall treatment cohort, apart from patients with PsA treated with other biologics who had 7-10% lower response rates. Consequently, patients with comorbid PsA had significantly higher odds of achieving skin clearance at week 12 with anti-IL-17A biologics compared to other biologics. Patients in all subgroups had significantly higher odds of achieving PASI90 and/or sPGA (0,1), PASI100, and PASI90 in the anti-IL-17A cohort relative to the other biologics cohort, except for the Asian subgroup. No sex- or age-specific differences in treatment effectiveness after 12 weeks were identified, neither between the treatment cohorts nor between the individual treatment comparisons. CONCLUSIONS: Despite relative consistency of comparative treatment effectiveness across subgroups, the presence of comorbid PsA may affect a patient's clinical response to some treatments.