Comparative efficacy and safety of bimekizumab in psoriatic arthritis: a systematic literature review and network meta-analysis.

OBJECTIVES: To understand the relative efficacy and safety of bimekizumab, a selective inhibitor of IL-17F in addition to IL-17A, vs other biologic and targeted synthetic DMARDs (b/tsDMARDs) for PsA using network meta-analysis (NMA). METHODS: A systematic literature review (most recent update conducted on 1 January 2023) identified randomized controlled trials (RCTs) of b/tsDMARDs in PsA. Bayesian NMAs were conducted for efficacy outcomes at Weeks 12-24 for b/tsDMARD-naïve and TNF inhibitor (TNFi)-experienced patients. Safety at Weeks 12-24 was analysed in a mixed population. Odds ratios (ORs) and differences of mean change with the associated 95% credible interval (CrI) were calculated for the best-fitting models, and the surface under the cumulative ranking curve (SUCRA) values were calculated to determine relative rank. RESULTS: The NMA included 41 RCTs for 22 b/tsDMARDs. For minimal disease activity (MDA), bimekizumab ranked 1st in b/tsDMARD-naïve patients and 2nd in TNFi-experienced patients. In b/tsDMARD-naïve patients, bimekizumab ranked 6th, 5th and 3rd for ACR response ACR20/50/70, respectively. In TNFi-experienced patients, bimekizumab ranked 1st, 2nd and 1st for ACR20/50/70, respectively. For Psoriasis Area and Severity Index 90/100, bimekizumab ranked 2nd and 1st in b/tsDMARD-naïve patients, respectively, and 1st and 2nd in TNFi-experienced patients, respectively. Bimekizumab was comparable to b/tsDMARDs for serious adverse events. CONCLUSION: Bimekizumab ranked favourably among b/tsDMARDs for efficacy on joint, skin and MDA outcomes, and showed comparable safety, suggesting it may be a beneficial treatment option for patients with PsA.

Importance of quick attainment of minimal disease activity for a positive impact on lives of patients with psoriatic arthritis.

OBJECTIVE: To compare patient-reported outcomes (PROs) from the first year to the third year between patients with psoriatic arthritis (PsA) who achieved minimal disease activity (MDA) in the first year after diagnosis and those who did not. METHODS: Consecutive, newly diagnosed, patients with DMARD naïve PsA with oligoarthritis or polyarthritis were selected from the Dutch southwest Early PsA cohoRt. Patients were categorised in three groups: (1) Patients who were in MDA at both 9 months and 12 months after diagnosis (sustained MDA); (2) Patients who achieved MDA in the first year but in whom it was not sustained at both 9 months and 12 months (non-sustained MDA); (3) Patients who did not achieve MDA in the first year (no MDA). PROs were compared between groups from the first year to the third year after diagnosis using a linear mixed model. RESULTS: 240 patients were selected; 104 (43%) were classified as sustained MDA, 60 (25%) as non-sustained MDA and 76 (32%) as no MDA. Patients who did not achieve MDA in the first year experienced remarkably lower PROs during follow-up, compared with the sustained MDA group: health status (European Quality of life 5-Dimensions 5-Levels) was 0.23 units lower (95% CI -0.28 to -0.18), functional impairment (Health Assessment Questionnaire-Disability Index) was 0.81 units higher (95% CI 0.70 to 0.92), pain (Visual Analogue Scale) was 35.38 mm higher (95% CI 30.57 to 40.18), fatigue (Bristol Rheumatoid Arthritis Fatigue-Multidimensional Questionnaire) was 17.88 units higher (95% CI 14.60 to 21.16), and anxiety and depression (Hospital Anxiety and Depression Scale) were, respectively, 3.26 units (95% CI 2.25 to 4.27) and 4.04 units higher (95% CI 3.10 to 4.99). CONCLUSION: Failure to achieve MDA in the first year after PsA diagnosis was associated with worse PROs that persisted over the years.

Imprinted Gene Expression and Function of the Dopa Decarboxylase Gene in the Developing Heart.

Dopa decarboxylase (DDC) synthesizes serotonin in the developing mouse heart where it is encoded by Ddc_exon1a, a tissue-specific paternally expressed imprinted gene. Ddc_exon1a shares an imprinting control region (ICR) with the imprinted, maternally expressed (outside of the central nervous system) Grb10 gene on mouse chromosome 11, but little else is known about the tissue-specific imprinted expression of Ddc_exon1a. Fluorescent immunostaining localizes DDC to the developing myocardium in the pre-natal mouse heart, in a region susceptible to abnormal development and implicated in congenital heart defects in human. Ddc_exon1a and Grb10 are not co-expressed in heart nor in brain where Grb10 is also paternally expressed, despite sharing an ICR, indicating they are mechanistically linked by their shared ICR but not by Grb10 gene expression. Evidence from a Ddc_exon1a gene knockout mouse model suggests that it mediates the growth of the developing myocardium and a thinning of the myocardium is observed in a small number of mutant mice examined, with changes in gene expression detected by microarray analysis. Comparative studies in the human developing heart reveal a paternal expression bias with polymorphic imprinting patterns between individual human hearts at DDC_EXON1a, a finding consistent with other imprinted genes in human.

The role of CCCTC-binding factor (CTCF) in genomic imprinting, development, and reproduction.

CCCTC-binding factor (CTCF) is the major protein involved in insulator activity in vertebrates, with widespread DNA binding sites in the genome. CTCF participates in many processes related to global chromatin organization and remodeling, contributing to the repression or activation of gene transcription. It is also involved in epigenetic reprogramming and is essential during gametogenesis and embryo development. Abnormal DNA methylation patterns at CTCF motifs may impair CTCF binding to DNA, and are related to fertility disorders in mammals. Therefore, CTCF and its binding sites are important candidate regions to be investigated as molecular markers for gamete and embryo quality. This article reviews the role of CTCF in genomic imprinting, gametogenesis, and early embryo development and, moreover, highlights potential opportunities for environmental influences associated with assisted reproductive techniques (ARTs) to affect CTCF-mediated processes. We discuss the potential use of CTCF as a molecular marker for assessing gamete and embryo quality in the context of improving the efficiency and safety of ARTs.

Genome-wide and parental allele-specific analysis of CTCF and cohesin DNA binding in mouse brain reveals a tissue-specific binding pattern and an association with imprinted differentially methylated regions.

DNA binding factors are essential for regulating gene expression. CTCF and cohesin are DNA binding factors with central roles in chromatin organization and gene expression. We determined the sites of CTCF and cohesin binding to DNA in mouse brain, genome wide and in an allele-specific manner with high read-depth ChIP-seq. By comparing our results with existing data for mouse liver and embryonic stem (ES) cells, we investigated the tissue specificity of CTCF binding sites. ES cells have fewer unique CTCF binding sites occupied than liver and brain, consistent with a ground-state pattern of CTCF binding that is elaborated during differentiation. CTCF binding sites without the canonical consensus motif were highly tissue specific. In brain, a third of CTCF and cohesin binding sites coincide, consistent with the potential for many interactions between cohesin and CTCF but also many instances of independent action. In the context of genomic imprinting, CTCF and/or cohesin bind to a majority but not all differentially methylated regions, with preferential binding to the unmethylated parental allele. Whether the parental allele-specific methylation was established in the parental germlines or post-fertilization in the embryo is not a determinant in CTCF or cohesin binding. These findings link CTCF and cohesin with the control regions of a subset of imprinted genes, supporting the notion that imprinting control is mechanistically diverse.

A survey of tissue-specific genomic imprinting in mammals.

In mammals, most somatic cells contain two copies of each autosomal gene, one inherited from each parent. When a gene is expressed, both parental alleles are usually transcribed. However, a subset of genes is subject to the epigenetic silencing of one of the parental copies by genomic imprinting. In this review, we explore the evidence for variability in genomic imprinting between different tissue and cell types. We also consider why the imprinting of particular genes may be restricted to, or lost in, specific tissues and discuss the potential for high-throughput sequencing technologies in facilitating the characterisation of tissue-specific imprinting and assaying the potentially functional variations in epigenetic marks.