In clinical practice, interruption of treatment may not result in immediate cessation of disease control, and some patients even experience sustained treatment response following treatment ...interruption. This post hoc analysis of UNCOVER-1 and -2 Phase 3 clinical trials characterized the time to loss of treatment response in patients with psoriasis who responded to ixekizumab through a 12-week treatment period, and who were then re-randomized to placebo for the following 48 weeks. For those with static Physician Global Assessment sPGA0/1 and Psoriasis Area and Severity Index PASI90 at Week 12, the median time to loss of PASI90 was 16.1 weeks (95% confidence interval 12.7-16.4). For those with PASI100 at Week 12, the median time to loss of PASI100 was 12.1 weeks (95% confidence interval 9.0-13.0). A small subset of patients maintained high levels of disease control through Week 60. This study adds to the growing body of evidence on sustained treatment response following treatment interruption.
Fluorescence based primer extension (FPE) is a molecular method to determine transcriptional starting points or processing sites of RNA molecules. This is achieved by reverse transcription of the RNA ...of interest using specific fluorescently labeled primers and subsequent analysis of the resulting cDNA fragments by denaturing polyacrylamide gel electrophoresis. Simultaneously, a traditional Sanger sequencing reaction is run on the gel to map the ends of the cDNA fragments to their exact corresponding bases. In contrast to 5'-RACE (Rapid Amplification of cDNA Ends), where the product must be cloned and multiple candidates sequenced, the bulk of cDNA fragments generated by primer extension can be simultaneously detected in one gel run. In addition, the whole procedure (from reverse transcription to final analysis of the results) can be completed in one working day. By using fluorescently labeled primers, the use of hazardous radioactive isotope labeled reagents can be avoided and processing times are reduced as products can be detected during the electrophoresis procedure. In the following protocol, we describe an in vivo fluorescent primer extension method to reliably and rapidly detect the 5' ends of RNAs to deduce transcriptional starting points and RNA processing sites (e.g., by toxin-antitoxin system components) in S. aureus, E. coli and other bacteria.
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.
It is challenging to select the most appropriate biologic treatment for patients with moderate-to-severe plaque psoriasis.
To compare speed of onset and level of skin improvement between the ...interleukin (IL)-17A antagonist ixekizumab and the IL-23 p19 inhibitors guselkumab, tildrakizumab, and risankizumab in patients with moderate-to-severe plaque psoriasis.
Using data from controlled clinical trials, both adjusted indirect comparisons (AICs) and matching adjusted indirect comparisons (MAICs) were performed to determine the risk difference (RD) between ixekizumab and each IL-23 p19 inhibitor for the proportion of patients with ≥75%/90%/100% improvement compared with baseline in Psoriasis Area and Severity Index (PASI 75/90/100) up to week 12. Placebo, etanercept, or ustekinumab were used as the comparator bridge.
In all (M)AICs, RDs generally significantly favored ixekizumab over guselkumab (placebo bridge), tildrakizumab (placebo or etanercept bridge), and risankizumab (placebo or ustekinumab bridge) from the earliest assessment time (≥ week 2) to week 12 when considering PASI 75/90/100 responses.
Ixekizumab provides a faster onset of effect and earlier clinical benefits than guselkumab, tildrakizumab, or risankizumab in patients with moderate-to-severe psoriasis, as reflected by higher levels of skin improvement than with these IL-23 p19 inhibitors up to week 12.
In
, resistance to β-lactamase stable β-lactam antibiotics is mediated by the penicillinbinding protein 2a, encoded by
or by its homologues
or
. However, a substantial number of meticillin-resistant ...isolates lack known
genes and, thus, are called meticillin resistant lacking
(MRLM). This study aims to identify the genetic mechanisms underlying the MRLM phenotype. A total of 141 MRLM isolates and 142 meticillin-susceptible controls were included in this study. Oxacillin and cefoxitin minimum inhibitory concentrations were determined by broth microdilution and the presence of
genes was excluded by PCR. Comparative genomics and a genome-wide association study (GWAS) approach were applied to identify genetic polymorphisms associated with the MRLM phenotype. The potential impact of such mutations on the expression of PBP4, as well as on cell morphology and biofilm formation, was investigated. GWAS revealed that mutations in
were significantly associated with the MRLM phenotype. GdpP is a phosphodiesterase enzyme involved in the degradation of the second messenger cyclic-di-AMP in
. A total of 131 MRLM isolates carried truncations, insertions or deletions as well as amino acid substitutions, mainly located in the functional DHH-domain of GdpP. We experimentally verified the contribution of these
mutations to the MRLM phenotype by heterologous complementation experiments. The mutations in
had no effect on transcription levels of
; however, cell sizes of MRLM strains were reduced. The impact on biofilm formation was highly strain dependent. We report mutations in
as a clinically relevant mechanism for β-lactam resistance in MRLM isolates. This observation is of particular clinical relevance, since MRLM are easily misclassified as MSSA (meticillin-susceptible
), which may lead to unnoticed spread of β-lactam-resistant isolates and subsequent treatment failure.
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.
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.
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.
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.
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.
Patients with psoriasis have an increased prevalence of type 2 diabetes when compared to the general population. Research suggests that type 2 diabetes (T2D) as well as obesity may have an impact on ...patients' response to treatment. This post-hoc analysis reports the efficacy of ixekizumab in treating moderate-to-severe psoriasis in patients with prediabetes or T2D.
UNCOVER-1, UNCOVER-2, and UNCOVER-3 were three Phase 3, multicenter, randomized, double-blind, placebo-controlled trials that evaluated the efficacy and safety of ixekizumab in adult patients with moderate-to-severe psoriasis. Patients were aged ≥18 years with chronic moderate-to-severe psoriasis (defined as ≥10% body surface area affected, static Physician Global Assessment ≥3, and Psoriasis Area and Severity Index PASI ≥12 at screening and baseline) who were candidates for phototherapy or systemic therapy. UNCOVER-1, UNCOVER-2, and UNCOVER-3 participants received ixekizumab as per label (that is, an initial dose of two subcutaneous injections 160 mg in total at Week 0, followed by 80 mg every 2 weeks through Week 12 and 80 mg every 4 weeks thereafter through Week 60).
The proportions of patients with prediabetes, T2D and normoglycemia that achieved PASI75, PASI90, and PASI100 at Week 60 were similar. Results suggest that patients with T2D were slower to achieve PASI100 than patients with prediabetes or those with normoglycemia. Ixekizumab had no effect on any metabolic markers in patients receiving the treatment.
Despite the higher rate of obesity and extreme obesity in patients with prediabetes and T2D, ixekizumab was an efficacious treatment in treating patients with psoriasis.
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