Response to anti-IL17 therapy in inflammatory disease is not strongly impacted by genetic background.

Response to the anti-IL17 monoclonal antibody secukinumab is heterogeneous, and not all participants respond to treatment. Understanding whether this heterogeneity is driven by genetic variation is a key aim of pharmacogenetics and could influence precision medicine approaches in inflammatory diseases. Using changes in disease activity scores across 5,218 genotyped individuals from 19 clinical trials across four indications (psoriatic arthritis, psoriasis, ankylosing spondylitis, and rheumatoid arthritis), we tested whether genetics predicted response to secukinumab. We did not find any evidence of association between treatment response and common variants, imputed HLA alleles, polygenic risk scores of disease susceptibility, or cross-disease components of shared genetic risk. This suggests that anti-IL17 therapy is equally effective regardless of an individual's genetic background, a finding that has important implications for future genetic studies of biological therapy response in inflammatory diseases.

Advanced genomics and clinical phenotypes in psoriatic arthritis.

Psoriatic Arthritis (PsA) is a complex polygenic inflammatory disease showing a variable musculoskeletal involvement in patients with skin psoriasis. PsA coexist in 25-40 % of patients with the dermatological manifestations, but PsA may also predate the appearance of psoriasis. Nonetheless, the immunopathogenesis of psoriasis and PsA manifest significant similarities, with a major role of the individual susceptibility in both cases. Genome wide association studies (GWAS) identified several genes/loci associated with the risk to develop PsA, both dependent and independent of psoriasis. The major challenge is thus represented by the need to translate the identification of functional polymorphisms and other genetics findings into biological mechanisms along with the identification of novel putative drug targets. A functional genomics approach aims to increase GWAS power and recent evidence supports the use of a multilayer process, including eQTL, methylome, chromatin conformation analysis and genome editing to discover novel genes that can be affected by disease-associated variants, such as PsA. The available data have considered PsA as a unique homogeneous clinical entity while the clinical experience supports a wide variability of skin and joint manifestations coexisting in diverse patients with different mechanisms underlying the musculoskeletal and dermatological domains. A better discrimination of the patient features is encouraged by the limited data on functional genomics. We provide herein a review of the latest findings on PsA functional genomics highlighting the exciting developments in the field and how these might lead to a better understanding of gene regulation underpinning disease mechanisms and ultimately refine clinical phenotyping.

Exploring the causal relationship between inflammatory cytokines and inflammatory arthritis: A Mendelian randomization study.

OBJECTIVES: Previous studies have reported an association between inflammatory cytokines and inflammatory arthritis, including Ankylosing spondylitis (AS), rheumatoid arthritis (RA), and psoriatic arthritis (PsA). This study aims to explore the causal relationship between inflammatory cytokines and AS, RA, and PsA using Mendelian randomization (MR). METHODS: We conducted a bidirectional two-sample MR analysis using genetic summary data from a publicly available genome-wide association study (GWAS) that included 41 genetic variations of inflammatory cytokines, as well as genetic variant data for AS, RA, and PsA from the FinnGen consortium. The main analysis method used was Inverse variance weighted (IVW) to investigate the causal relationship between exposure and outcome. Additionally, other methods such as MR Egger, weighted median (WM), simple mode, and weighted mode were employed to strengthen the final results. Sensitivity analysis was also performed to ensure the reliability of the findings. RESULTS: The results showed that macrophage colony-stimulating factor (MCSF) was associated with an increased risk of AS (OR = 1.163, 95 % CI = 1.016-1.33, p = 0.028). Conversely, high levels of TRAIL and beta nerve growth factor (ß-NGF) were associated with a decreased risk of AS (OR = 0.892, 95 % CI = 0.81-0.982, p = 0.002; OR = 0.829, 95 % CI = 0.696-0.988, p = 0.036). Four inflammatory cytokines were found to be associated with an increased risk of PsA: vascular endothelial growth factor (VEGF) (OR = 1.161, 95 % CI = 1.057-1.275, p = 0.002); Interleukin 12p70 (IL12p70) (OR = 1.189, 95 % CI = 1.049-1.346, p = 0.007); IL10 (OR = 1.216, 95 % CI = 1.024-1.444, p = 0.026); IL13 (OR = 1.159, 95 % CI = 1.05-1.28, p = 0.004). Interleukin 1 receptor antagonist (IL-1rα) was associated with an increased risk of seropositive RA (OR = 1.181, 95 % CI = 1.044-1.336, p = 0.008). Similarly, genetic susceptibility to inflammatory arthritis was found to be causally associated with multiple inflammatory cytokines. Lastly, the sensitivity analysis supported the robustness of these findings. CONCLUSIONS: This study provides additional insights into the relationship between inflammatory cytokines and inflammatory arthritis, and may offer new clues for the etiology, diagnosis, and treatment of inflammatory arthritis.

Genetically proxied PCSK9 inhibition is associated with reduced psoriatic arthritis risk.

BACKGROUND: Lipid pathways play a crucial role in psoriatic arthritis development, and some lipid-lowering drugs are believed to have therapeutic benefits due to their anti-inflammatory properties. Traditional observational studies face issues with confounding factors, complicating the interpretation of causality. This study seeks to determine the genetic link between these medications and the risk of psoriatic arthritis. METHODS: This drug target study utilized the Mendelian randomization strategy. We harnessed high-quality data from population-level genome-wide association studies sourced from the UK Biobank and FinnGen databases. The inverse variance-weighted method, complemented by robust pleiotropy methods, was employed. We examined the causal relationships between three lipid-lowering agents and psoriatic arthritis to unveil the underlying mechanisms. RESULTS: A significant association was observed between genetically represented proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition and a decreased risk of psoriatic arthritis (odds ratio [OR]: 0.51; 95% CI 0.14-0.88; P < 0.01). This association was further corroborated in an independent dataset (OR 0.60; 95% CI 0.25-0.94; P = 0.03). Sensitivity analyses affirmed the absence of statistical evidence for pleiotropic or genetic confounding biases. However, no substantial associations were identified for either 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors or Niemann-Pick C1-like 1 inhibitors. CONCLUSIONS: This Mendelian randomization analysis underscores the pivotal role of PCSK9 in the etiology of psoriatic arthritis. Inhibition of PCSK9 is associated with reduced psoriatic arthritis risk, highlighting the potential therapeutic benefits of existing PCSK9 inhibitors.

Circulating tRNA-derived fragments are decreased in patients with rheumatoid arthritis and increased in patients with psoriatic arthritis.

INTRODUCTION: tRNA-derived fragments (tRFs) play an important role in immune responses. To clarify the role of tRFs in autoimmunity we studied circulating tRF-levels in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA), and in a murine model for arthritis. MATERIAL AND METHODS: Circulating tRF-levels were quantified by miR-Q RT-qPCR. tRNA processing and modification enzyme expression was analysed by RT-qPCR and public transcriptomics data. RESULTS: Significant reduction (up to 3-fold on average) of tRF-levels derived from tRNA-Gly-GCC,CCC, tRNA-Glu-CTC and tRNA-Val-CAC,AAC was observed in RA patients, whereas tRNA-Glu-CTC and tRNA-Val-CAC,AAC tRFs were found at significantly higher levels (up to 3-fold on average) in PsA patients, compared to healthy controls. Also in arthritic IL1Ra-KO mice reduced levels of tRNA-Glu-CTC fragments were seen. The expression of NSUN2, a methyltransferase catalysing tRNA methylation, was increased in RA-peripheral blood mononuclear cells (PBMCs) compared to PsA, but this is not consistently supported by public transcriptomics data. DISCUSSION: The observed changes of specific tRF-levels may be involved in the immune responses in RA and PsA and may be applicable as new biomarkers. CONCLUSION: Circulating tRF-levels are decreased in RA and increased in PsA and this may, at least in part, be mediated by methylation changes.

The association between endoplasmic reticulum aminopeptidase 2 gene single nucleotide polymorphisms and the risk of psoriasis and psoriatic arthritis in Egyptians.

BACKGROUND: Psoriasis (Ps) is a disorder attributed to the immune system that involves inflammation of the skin and joints. Psoriasis is a multifactorial disorder in which genetic factors represent about 70% of the disease risk. This study aims to establish the correlation between the ERAP2 gene's single nucleotide polymorphisms (SNPs) rs2910686 and rs2248374 with the susceptibility to Ps and/or psoriatic arthritis (PsA) among the Egyptian population. METHODS AND RESULTS: Genotyping of ERAP2 gene SNPs (rs2910686 and rs2248374) in 120 psoriatic patients with and without arthritis and 100 controls was done using real-time PCR. The genotype frequency and distribution of the ERAP2 SNP (rs2910686 and rs2248374) were in Hardy-Weinberg equilibrium (HWE). For rs2910686, the TC and CC genotypes and C allele frequency were significant risk factors for PsA compared to the controls (OR = 5.708, OR = 10.165, and OR = 4.282, respectively). They also were significant risk factors for Ps compared to the controls (OR = 5.165, OR = 5.040, and OR = 3.258, respectively). For rs2248374, the AG genotype significantly increased the risk of PsA (OR = 2.605) and Ps (OR = 3.768) compared to controls. The AG genotype was significantly related to the risk of Ps (OR = 3.369) G allele with PsA (OR = 1.608) and Ps (OR = 1.965) compared to controls. CONCLUSION: In Egyptian individuals, the ERAP2 gene polymorphisms (rs2248374 and rs2910686) may contribute genetically to the pathophysiology of psoriasis and PsA.

Mendelian randomization analysis of psoriasis and psoriatic arthritis associated with risks of ulcerative colitis.

OBJECTIVE: This study is designed to explore the potential causal relationship between psoriasis and psoriatic arthritis (PsA) while investigating the genetic basis shared by these inflammatory diseases. METHODS: Significant single nucleotide polymorphisms (SNPs) associated with UC, psoriasis, and PsA were selected as genetic instrumental variables using Genome-Wide Association Study (GWAS) datasets. Additionally, Mendelian randomization (MR) methods, including inverse-variance weighting (IVW), MR-Egger regression, and Weighted Median (WME), were utilized to evaluate the causal relationships between these diseases. Moreover, sensitivity analysis and heterogeneity testing were conducted to validate the stability of the results. RESULTS: A total of 123 significant SNPs associated with psoriasis, PsA, and UC were identified as genetic instrumental variables based on GWAS datasets. The analysis revealed a 36% increased risk of UC with psoriasis (odds ratio [OR] = 1.350, 95% confidence interval [CI] = 1.065-1.729, P = 0.012) and a 32.9% increased risk of UC with PsA (OR = 1.329, 95% CI = 1.176-1.592, P < 0.001). Further analysis showed a 43.5% increased risk of psoriasis with UC (OR = 1.435, 95% CI = 1.274-1.831, P < 0.001) and a 45.8% increased risk of PsA with UC (OR = 1.458, 95% CI = 1.166-1.822, P = 0.0013). In addition, sensitivity analysis and heterogeneity testing demonstrated the high stability of these results. Particularly, neither MR-Egger regression analysis nor leave-one-out analysis revealed significant heterogeneity or pleiotropy bias, indicating the reliability of these causal estimates. Moreover, the use of the MR-PRESSO further confirmed the positive correlation between psoriasis and UC, and the corrected estimates remained consistent with IVW analysis results after excluding potential outlier SNPs, enhancing the credibility of the analysis. CONCLUSIONS: This study strengthens the understanding of the genetic and causal relationships among UC, psoriasis, and PsA through GWAS and MR methods, revealing the genetic basis they may share. These findings not only provide a novel perspective on the comorbidity mechanisms of these diseases but also offer a valuable reference for the development of future treatment strategies and intervention measures.

A bidirectional two-sample Mendelian randomization study to evaluate the relationship between psoriasis and interstitial lung diseases.

BACKGROUND: Prior observational studies have suggested a potential direct link between psoriasis (PSO) and interstitial lung disease (ILD). Consequently, we applied Mendelian randomization (MR) to further evaluate the bidirectional causal relationships between PSO and its different phenotypes [psoriatic arthritis (PSA)/psoriasis vulgaris (PSV)] and ILD. METHODS: Data regarding PSO/PSA/PSV and ILD were sourced from publicly accessible genome-wide association studies (GWAS) databases, focusing on European populations. We used five algorithms- MR Egger, weighted median, inverse-variance weighted (IVW), simple mode, and weighted mode- to evaluate the causal relationships between PSO/PSA/PSV and ILD, with a primary emphasis on the IVW method. RESULTS: The analysis indicated a potential association between PSA and an elevated risk of ILD [IVW odds ratio (OR): 1.035 (95% CI 1.008, 1.064; P = 0.012)], with no evidence of a direct relationship between total PSO and PSV with ILD. Conversely, no substantial evidence emerged from the reverse MR analysis to suggest that ILD significantly affects total PSO or the specific PSA/PSV phenotypes. CONCLUSION: Our findings provide genetic evidence supporting the notion that PSA may be a contributory risk factor for ILD. Further investigations are warranted to explore the underlying mechanisms of this potential causal relationship between PSA and ILD.

Exploring the causal association between frailty index with the common types of arthritis: a Mendelian randomization analysis.

BACKGROUND: Previous observational studies indicated a complex association between frailty and arthritis. AIMS: To investigate the genetic causal relationship between the frailty index and the risk of common arthritis. METHODS: We performed a large-scale Mendelian randomization (MR) analysis to assess frailty index associations with the risk of common arthritis in the UK Biobank (UKB), and the FinnGen Biobank. Summary genome-wide association statistics for frailty, as defined by the frailty index, and common arthritis including rheumatoid arthritis (RA), osteoarthritis (OA), psoriatic arthritis (PSA), and ankylosing spondylitis (AS). The inverse-variance weight (IVW) method served as the primary MR analysis. Heterogeneity testing and sensitivity analysis were also conducted. RESULTS: Our results denoted a genetic association between the frailty index with an increased risk of OA, the odds ratio (OR)IVW in the UKB was 1.03 (95% confidence interval [CI]: 1.01-1.05; P = 0.007), and ORIVW was 1.55 (95% CI: 1.16-2.07; P = 0.003) in the FinnGen. For RA, the ORIVW from UKB and FinnGen were 1.03 (1.01-1.05, P = 0.006) and 4.57 (1.35-96.49; P = 0.025) respectively. For PSA, the frailty index was associated with PSA (ORIVW = 4.22 (1.21-14.67), P = 0.023) in FinnGen, not in UKB (P > 0.05). However, no association was found between frailty index and AS (P > 0.05). These results remained consistent across sensitivity assessments. CONCLUSION: This study demonstrated a potential causal relationship that genetic predisposition to frailty index was associated with the risk of arthritis, especially RA, OA, and PSA, not but AS. Our findings enrich the existing body of knowledge on the subject matter.

PIM Kinases as Potential Biomarkers and Therapeutic Targets in Inflammatory Arthritides.

The Proviral Integration site for the Moloney murine leukemia virus (PIM)-1 kinase and its family members (PIM-2 and PIM-3) regulate several cellular functions including survival, proliferation, and apoptosis. Recent studies showed their involvement in the pathogenesis of rheumatoid arthritis RA, while no studies are available on psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). The main objective of this study is to assess the expression of PIM kinases in inflammatory arthritides, their correlation with proinflammatory cytokines, and their variation after treatment with biologic disease-modifying anti-rheumatic drugs or JAK inhibitors. We evaluated PIM-1, -2, and -3 expression at the gene and protein level, respectively, in the peripheral blood mononuclear cells and serum of patients with RA, PsA, axSpA, and healthy individuals (CTR). All the samples showed expression of PIM-1, -2, and -3 kinases both at the gene and protein level. PIM-1 was the most expressed protein, PIM-3 the least. PIM kinase levels differed between controls and disease groups, with reduced PIM-1 protein and increased PIM-3 protein in all disease samples compared to controls. No difference was found in the expression of these molecules between the three different pathologies. PIM levels were not modified after 6 months of therapy. In conclusion, our preliminary data suggest a deregulation of the PIM pathway in inflammatory arthritides. In-depth studies on the role of PIM kinases in this field are warranted.

The Association between Genetics and Response to Treatment with Biologics in Patients with Psoriasis, Psoriatic Arthritis, Rheumatoid Arthritis, and Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis.

Genetic biomarkers could potentially lower the risk of treatment failure in chronic inflammatory diseases (CID) like psoriasis, psoriatic arthritis (PsA), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD). We performed a systematic review and meta-analysis assessing the association between single nucleotide polymorphisms (SNPs) and response to biologics. Odds ratio (OR) with 95% confidence interval (CI) meta-analyses were performed. In total, 185 studies examining 62,774 individuals were included. For the diseases combined, the minor allele of MYD88 (rs7744) was associated with good response to TNFi (OR: 1.24 [1.02-1.51], 6 studies, 3158 patients with psoriasis or RA) and the minor alleles of NLRP3 (rs4612666) (OR: 0.71 [0.58-0.87], 5 studies, 3819 patients with RA or IBD), TNF-308 (rs1800629) (OR: 0.71 [0.55-0.92], 25 studies, 4341 patients with psoriasis, RA, or IBD), FCGR3A (rs396991) (OR: 0.77 [0.65-0.93], 18 studies, 2562 patients with psoriasis, PsA, RA, or IBD), and TNF-238 (rs361525) (OR: 0.57 [0.34-0.96]), 7 studies, 818 patients with psoriasis, RA, or IBD) were associated with poor response to TNFi together or infliximab alone. Genetic variants in TNFα, NLRP3, MYD88, and FcRγ genes are associated with response to TNFi across several inflammatory diseases. Most other genetic variants associated with response were observed in a few studies, and further validation is needed.

Psoriasis and Psoriatic Arthritis-Associated Genes, Cytokines, and Human Leukocyte Antigens.

In recent years, research has intensified in exploring the genetic basis of psoriasis (PsO) and psoriatic arthritis (PsA). Genome-wide association studies (GWASs), including tools like ImmunoChip, have significantly deepened our understanding of disease mechanisms by pinpointing risk-associated genetic loci. These efforts have elucidated biological pathways involved in PsO pathogenesis, particularly those related to the innate immune system, antigen presentation, and adaptive immune responses. Specific genetic loci, such as TRAF3IP2, REL, and FBXL19, have been identified as having a significant impact on disease development. Interestingly, different genetic variants at the same locus can predispose individuals to either PsO or PsA (e.g., IL23R and deletion of LCE3B and LCE3C), with some variants being uniquely linked to PsA (like HLA B27 on chromosome 6). This article aims to summarize known and new data on the genetics of PsO and PsA, their associated genes, and the involvement of the HLA system and cytokines.

Do genetics contribute to TNF inhibitor response prediction in Psoriatic Arthritis?

Psoriatic arthritis (PsA) is a heterogeneous chronic musculoskeletal disease, affecting up to 30% of people with psoriasis. Research into PsA pathogenesis has led to the development of targeted therapies, including Tumor Necrosis Factor inhibitors (TNF-i). Good response is only achieved by ~60% of patients leading to 'trial and error' drug management approaches, adverse reactions and increasing healthcare costs. Robust and well-validated biomarker identification, and subsequent development of sensitive and specific assays, would facilitate the implementation of a stratified approach into clinical care. This review will summarise potential genetic biomarkers for TNF-i (adalimumab, etanercept and infliximab) response that have been reported to date. It will also comment upon the importance of managing clinical confounders when understanding drug response prediction. Variants in multiple gene regions including TNF-A, FCGR2A, TNFAIP3, TNFR1/TNFR1A/TNFRSF1A, TRAIL-R1/TNFRSF10A, FCGR3A have been reported to correlate with TNF-i response at various levels of statistical significance in patients with PsA. However, results were often from heterogenous and underpowered cohorts and none are currently implemented into clinical practice. External validation of genetic biomarkers in large, well-documented cohorts is required, and assessment of the predictive value of combining multiple genetic biomarkers with clinical measures is essential to clinically embed pharmacogenomics into PsA drug management.

Challenges and opportunities in animal models of psoriatic arthritis.

OBJECTIVE: To review the preparation, characteristics and research progress of different PsA animal models. METHODS: Computerized searches were conducted in CNKI, PubMed and other databases to classify and discuss the relevant studies on PsA animal models. The search keywords were "PsA and animal model(s), PsA and animal(s), PsA and mouse, PsA and mice, PsA and rat(s), PsA and rabbit(s), PsA and dog(s)" RESULTS: The experimental animals currently used to study PsA are mainly rodents, including mice and rats. According to the different methods of preparing the models, the retrieved animal models were classified into spontaneous or genetic mutation, transgenic and induced animal models. These PsA animal models involve multiple pathogenesis, some experimental animals' lesions appear in a short and comprehensive cycle, some have a high success rate in molding, and some are complex and less reproducibility. This article summarizes the preparation methods, advantages and disadvantages of different models. CONCLUSIONS: The animal models of PsA aim to mimic the clinicopathological alterations of PsA patients through gene mutation, transgenesis or targeted proinflammatory factor and to reveal new pathogenic pathways and therapeutic targets by exploring the pathological features and clinical manifestations of the disease. This work will have very far-reaching implications for the in-depth understanding of PsA and the development of new drugs.

Associations between family history of psoriatic disease and clinical characteristics on patients with psoriatic arthritis: a nationwide study from the Chinese Registry of Psoriatic Arthritis (CREPAR II).

OBJECTIVES: The study aimed to identify clinical characteristics in Chinese patients with psoriatic arthritis (PsA) with or without a family history of psoriasis and/or PsA. METHODS: Patients with PsA were recruited based on Chinese REgistry of Psoriatic ARthritis (CREPAR) between December 2018 and June 2021. The demographics, clinical information relating to PsA, laboratory variables and comorbidities were collected. The association between family history of psoriatic disease and clinical characteristics on PsA was analysed using logistic regression analysis. RESULTS: Among 1074 eligible patients with PsA, 313 (29.1%) had a family history of psoriasis and/or PsA. Compared with patients without a family history, notably, patients with a family history of psoriasis and/or PsA had an earlier age of onset of psoriasis and PsA, higher proportions of enthesitis and nail involvement, a higher prevalence of positive human leukocyte antigen-B27 (HLA-B27), lower disease activity score 28-erythrocyte sedimentation rate, higher proportions of hyperlipidaemia, lower proportions of hypertension and diabetes. Furthermore, after adjusting for confounding factors, logistic regression analysis demonstrated that a positive family history of psoriasis and/or PsA was associated with more females (OR 1.514, 95% CI 1.088-2.108, p=0.014), earlier age at psoriasis onset (OR 0.971, 95%CI 0.955-0.988, p=0.001), a higher prevalence of HLA-B27 (OR 1.625 95%CI 1.089-2.426, p=0.018), more presence of nail involvement (OR 1.424, 95%CI 1.007-2.013, p=0.046) and enthesitis (OR 1.393, 95%CI 1.005-1.930, p=0.046), a higher proportion of hyperlipidaemia (OR 2.550, 95%CI 1.506-4.317, p=0.001) in PsA patients. CONCLUSIONS: This was first nationwide study to characterize patients with and without a family history of psoriatic disease in China. The findings from the present study revealed that family history of psoriasis and/or PsA had greater effects on disease phenotypes of PsA, especially nail disease and enthesitis.

HLA-Cw6 allele and biologic therapy are protective factors against liver fibrosis in psoriatic arthritis patients.

OBJECTIVES: To evaluate the association between liver fibrosis and the HLACw6 allele in psoriatic arthritis (PsA) patients. METHODS: A retrospective longitudinal study involving PsA patients with determination of the HLA-Cw6 allele was performed. Liver fibrosis was estimated by using the FIB-4 (fibrosis-4) score. A multivariate logistic model was undertaken to assess the odds ratio (OR), with its 95% confidence interval, of liver fibrosis after adjustment for potential confounding factors. RESULTS: A total of 209 PsA patients were included: 25.3% HLA-Cw6 were positive, 59.8% were receiving biological disease-modifying anti-rheumatic drugs (bDMARDs), 29.6% had arterial hypertension (AHT), 24% dyslipidaemia, and 4.2% acute myocardial infarction (AMI). The HLA-Cw6 allele was more frequent in PsA patients with normal FIB-4 values (p=0.024), as opposed to AHT (p=0.002), AMI (p=0.023) and dyslipidaemia (p=0.030), which were found more frequently in subjects with altered FIB-4 values. The presence HLA-Cw6 and the use of bDMARDs were confirmed as protective factors against liver fibrosis (OR 0.210, 0.062-0.707, p=0.012 and OR 0.397, 0.166-0.949, p=0.038, respectively). Conversely, AHT emerged as a risk factor (OR 2.973, 1.125-7.858, p=0.028). CONCLUSIONS: In PsA, the HLA-Cw6 allele and bDMARDs behave as protective factors for liver fibrosis, while AHT is an independent risk factor.

Synovial monocytes from psoriatic and rheumatoid arthritis patients are modulated differently by TNF inhibitors and glucocorticoids: an ex-vivo study.

OBJECTIVES: Synovial monocytes (expressing CD14+CD16+) affect pro-inflammatory responses in the synovium microenvironment of psoriatic arthritis (PsA) and rheumatoid arthritis (RA). The effect of various drugs on those cells was evaluated. METHODS: Synovial fluid mononuclear cells (SFMCs) from PsA (n=29) and RA (n=11) patients were cultured with biologics or glucocorticoids (GCs). CD14+CD16+ cells were analysed by flow cytometry. TNF secretion was assessed by ELISA and changes in cytokine and matrix metalloproteinase-9 (MMP-9) mRNA by qPCR. RESULTS: TNF inhibitors (i) [adalimumab (ADA) and infliximab (IFX)] significantly reduced the %CD14+CD16+ cells (p<0.04 and p<0.02, respectively) compared to IL-17Ai, IL-12/23i, and GCs in PsA patients' SFMCs. Similarly, those TNFi reduced the %CD14+CD16+ cells (p<0.05 and p<0.02, respectively) compared to IL-6Ri, CD20i and GCs in RA patients' SFMCs. TNFi (ADA p<0.01, IFX p=0.0003), and GCs (p<0.05) reduced TNF levels in PsA patients SFMCs supernatants. IFX down-regulated IL-1ß mRNA (p<0.005) while GCs betamethasone (BET) (p<0.01) and methylprednisolone acetate (MPA) (p<0.005) led to IL-1ß up-regulation. IFX down-regulated IL-8 and MMP-9 (p<0.01) and up-regulated IL-10 (p<0.005), and GCs did so to a greater extent (for IL-8, BET p<0.0001 and MPA p<0.005, for MMP-9, BET and MPA p<0.0001 and for IL-10, BET and MPA p<0.0001). CONCLUSIONS: TNFi but not GCs reduced the inflammatory monocytes. Both TNFi and GCs inhibited TNF secretion but differently modulated IL-1ß, IL-8, MMP-9 and IL-10 gene expression. Our data point to TNFi as a modulator of synovial monocytes.

The IFIH1/MDA5 rs1990760 Gene Variant (946Thr) Differentiates Early- vs. Late-Onset Skin Disease and Increases the Risk of Arthritis in a Spanish Cohort of Psoriasis.

The melanoma differentiation-associated protein 5 (MDA5; encoded by the IFIH1 gene) mediates the activation of the interferon pathway in response to a viral infection. This protein is also upregulated in autoimmune diseases and psoriasis skin lesions. IFIH1 gene variants that increase MDA5 activity have been associated with an increased risk for immune-mediated diseases, including psoriasis. Our aim is to determine the association between three IFIH1 variants (rs35337543 G/C, intron8 + 1; rs35744605 C/A, Glu627Stop; and rs1990760 C/T, Ala946Thr) and the main clinical findings in a cohort of Spanish patients with psoriasis (N = 572; 77% early-onset). Early-onset psoriasis patients (EOPs) had a significantly higher frequency of severe disease and the Cw6*0602 allele. Carriers of rs1990760 T (946Thr) were more common in the EOPs (p < 0.001), and the effect was more pronounced among Cw6*0602-negatives. This variant was also associated with an increased risk of psoriatic arthritis (PsA) independent from other factors (OR = 1.62, 95%CI = 1.11-2.37). The rs3533754 and rs35744605 polymorphisms did not show significant differences between the two onset age or PsA groups. Compared to the controls, the 946Thr variant was more common in the EOPs (nonsignificant difference) and significantly less common in patients aged >40 years (p = 0.005). In conclusion, the common IFIH1 rs1990760 T allele was significantly more frequent in early-onset compared to late-onset patients. This variant was also an independent risk factor for PsA in our cohort. Our study reinforces the widely reported role of the IFIH1 gene variants on psoriatic disease.

Beyond plaque psoriasis - pathogenesis and treatment of other psoriasis phenotypes.

PURPOSE OF REVIEW: Psoriasis vulgaris is the commonest presentation of psoriatic disease, but morphologic variants such as pustular psoriasis (PP) and a closely related disease, pityriasis rubra pilaris (PRP), have been known for a long time, have been associated with rheumatologic manifestations indistinguishable from psoriatic arthritis (PsA) that may go unrecognized, and often represent a therapeutic conundrum. There is recent evidence that underlying genetic and pathogenetic differences may provide the basis for newer therapeutic approaches. RECENT FINDINGS: This narrative review highlights the clinical, genetic and pathogenetic characteristics of PP and PRP, their association with PsA and recent developments in their treatment, especially with biologic agents targeting IL-36 and other cytokines of pathogenic relevance. SUMMARY: The clinical manifestations of PP and PRP are less well known to rheumatologists than those of psoriasis, and recent advances in our insight on their pathogenesis may eventually overcome the therapeutic difficulties faced by dermatologists and rheumatologists in the management of these diseases and their rheumatologic manifestations.

Defining imaging sub-phenotypes of psoriatic arthritis: integrative analysis of imaging data and gene expression in a PsA patient cohort.

OBJECTIVES: To define imaging sub-phenotypes in patients with PsA; determine their association with whole blood gene expression and identify biological pathways characterizing the sub-phenotypes. METHODS: Fifty-five patients with PsA ready to initiate treatment for active disease were prospectively recruited. We performed musculoskeletal ultrasound assessment of the extent of inflammation in the following domains: synovitis, peritenonitis, tenosynovitis and enthesitis. Peripheral whole blood was profiled with RNAseq, and gene expression data were obtained. First, unsupervised cluster analysis was performed to define imaging sub-phenotypes that reflected the predominant tissue involved. Subsequently, principal component analysis was used to determine the association between imaging-defined sub-phenotypes and peripheral blood gene expression profile. Pathway enrichment analysis was performed to identify underlying mechanisms that characterize individual sub-phenotypes. RESULTS: Cluster analysis revealed three imaging sub-phenotypes: (i) synovitis predominant [n = 31 (56%)]; (ii) enthesitis predominant [n = 13 (24%)]; (iii) peritenonitis predominant [n = 11 (20%)]. The peritenonitis-predominant sub-phenotype had the most severe clinical joint involvement, whereas the enthesitis-predominant sub-phenotype had the highest tender entheseal count. Unsupervised clustering of gene expression data identified three sub-phenotypes that partially overlapped with the imaging sub-phenotypes suggesting biological and clinical relevance of these sub-phenotypes. We therefore characterized enriched differential pathways, which included: immune system (innate system, B cells and neutrophil degranulation), complement system, platelet activation and coagulation function. CONCLUSIONS: We identified three sub-phenotypes based on the predominant tissue involved in patients with active PsA. Distinct biological pathways may underlie these imaging sub-phenotypes seen in PsA, suggesting their biological and clinical importance.