Serum-based soluble markers differentiate psoriatic arthritis from osteoarthritis.

OBJECTIVES: We aimed to identify soluble biomarkers that differentiate psoriatic arthritis (PsA) from osteoarthritis (OA). METHODS: Markers of cartilage metabolism (cartilage oligomeric matrix protein [COMP], hyaluronan), metabolic syndrome (adiponectin, adipsin, resistin, hepatocyte growth factor [HGF], insulin, leptin) and inflammation (C-reactive protein [CRP], interleukin-1ß [IL-1ß], IL-6, IL-8, tumour necrosis factor alpha [TNFα], monocyte chemoattractant protein-1 [MCP-1], nerve growth factor [NGF]) were compared in serum samples from 201 patients with OA, 77 patients with PsA and 76 controls. Levels across the groups were compared using the Kruskal-Wallis test. Pairwise comparisons were made with Wilcoxon rank-sum test. Multivariate logistic regression analyses were performed to identify markers that differentiate PsA from OA. Receiver operating characteristic (ROC) curves were constructed based on multivariate models. The final model was further validated in an independent set of 73 PsA and 75 OA samples using predicted probabilities calculated with coefficients of age, sex and biomarkers. RESULTS: Levels of the following markers were significantly different across the three groups (p<0.001)-COMP, hyaluronan, resistin, HGF, insulin, leptin, CRP, IL-6, IL-8, TNFα, MCP-1, NGF. In multivariate analysis, COMP (OR 1.24, 95% CI 1.06 to 1.46), resistin (OR 1.26, 95% CI 1.07 to 1.48), MCP-1 (OR 1.10, 95% CI 0.07 to 1.48) and NGF (OR<0.001, 95% CI <0.001 to 0.25) were found to be independently associated with PsA versus OA. The area under the ROC curve (AUROC) for this model was 0.99 compared with model with only age and sex (AUROC 0.87, p<0.001). Similar results were obtained using the validation sample. CONCLUSION: A panel of four biomarkers may distinguish PsA from OA. These results need further validation in prospective studies.

Th17 gene expression in psoriatic arthritis synovial fluid and peripheral blood compared to osteoarthritis and cutaneous psoriasis.

OBJECTIVES: The IL-23/IL-17 axis is central to the pathogenesis of psoriatic arthritis (PsA). We aimed to identify Th17 signalling genes that are dysregulated in synovial fluid of PsA compared to osteoarthritis (OA) patients and to determine if differences in peripheral blood can distinguish PsA from psoriasis patients and controls. METHODS: Synovial fluid cells (SFCs) from 14 PsA and 9 OA patients were obtained and stored in TRIzol reagent. RNA was isolated by phenol-chloroform extraction and purified with RNeasy miniprep kits. Total RNA was extracted from PAXgene whole blood from 20 PsA, 20 psoriasis without arthritis (PsC) and 11 controls. Quantitative RT-PCR arrays were used to profile expression of 84 genes related to the Th17 regulatory network. Fold change differences were compared by Mann-Whitney U-test with false discovery rate (FDR) correction (FDR<0.05). RESULTS: In PsA compared to OA SFCs, a total of 33 genes were up-regulated and 27 genes were down-regulated. Signalling molecules (such as STAT3, FOXP3) were highly expressed in PsA SFCs, while cytokines (such as IL17F, IL6) were more predominant in OA SFCs after non-supervised hierarchal clustering. Nine genes (MMP3, CCL1, IL17C, CCL20, IL17F, IL3, CXCL5, IL6 and CX3CL1) had concordant expression in SFCs and in peripheral blood cells (PBCs) of PsA compared to PsC and/or controls. CONCLUSIONS: We identified expression differences in Th17 signalling genes in PsA compared to OA SFCs, with an elevation of signalling molecules and attenuation of cytokine expression in PsA. A subset of genes was concordant in PBCs; these may thus be potential biomarkers of PsA.

Epigenetics of psoriatic disease: A systematic review and critical appraisal.

Psoriasis is an inflammatory disease of the skin that is sometimes accompanied by an auto-inflammatory arthritis called psoriatic arthritis (PsA). Psoriasis and PsA are multifactorial diseases that result from complex interactions of environmental and genetic risk factors. Epigenetic marks, which are labile chemical marks with diverse functions, form a layer of biological information that sits at the interface of genetics and the environment. Aberrant epigenetic regulation has been previously implicated in other rheumatological disorders. The purpose of this review is to summarize and critically evaluate the nascent literature on epigenetics in psoriasis and PsA. A systematic review yielded 52 primary articles after applying inclusion and exclusion criteria. Data were extracted using a standardized template and study quality assessed using a methodological quality checklist. Studies reflect a broad range of epigenetic sub-disciplines, the most common being DNA methylation, followed by the parent of origin effect or genomic imprinting, expression or activity of epigenetic modifying enzymes, and histone modifications. Epidemiological studies demonstrating excessive paternal transmission provided the earliest evidence of epigenetic deregulation in psoriatic disease, however few studies have examined its molecular mechanisms. Methylation studies evolved rapidly from low resolution global to targeted analyses of known psoriatic disease susceptibility loci such as HLA-C*0602. The recent explosion of epigenome-wide association studies has provided us with novel insights into psoriasis pathogenesis, and the mechanism of action of UVB, methotrexate, and anti-TNF therapies, as well as molecular signatures of psoriasis that may have clinical relevance. Finally, recent studies of pharmacological inhibitors of epigenetic modifier enzymes demonstrate their potential applicability as novel treatment modalities for psoriasis. Challenges of epigenetics research in psoriasis and PsA were identified and future perspectives are discussed herein.

Corrigendum: Proteinase-Mediated Macrophage Signaling in Psoriatic Arthritis.

[This corrects the article DOI: 10.3389/fimmu.2020.629726.].

The association between synovial fluid serine proteinase activity and response to intra-articular corticosteroid injection in psoriatic arthritis.

INTRODUCTION/OBJECTIVES: Intra-articular corticosteroid (IAS) injections are often used for the immediate relief of pain and inflammation in the joint of psoriatic arthritis (PsA) patients. However, studies identifying factors that predict response to the IAS injections are lacking. We aimed to assess the usefulness of serine proteinase activity measurements in PsA synovial fluid (SF) samples obtained at the time of injection in predicting clinical response. METHODS: The PsA patients with available SF samples from the knee joint were identified from the University of Toronto PsA cohort. Clinical response was defined as an absence of tenderness or swelling in the injected joint at the first post-injection visit, at either 3 or 6 months. SF proteinase activity was determined by measuring cleavage of fluorogenic tri-peptide substrates for trypsin-like (VPR-AMC and VLK-AMC) and chymotrypsin-like (AAPF-AMC) serine proteinases. Generalized estimating equation (GEE) models were used to investigate factors associated with response. RESULTS: A total of 32 patients with 60 injected joints and data available for follow-up at 3 or 6 months were included in the analysis, with 25 (41.7%) injected joints resulting in clinical response. Age, sex, active joint count, systemic medications and SF serine proteinase activity at the time of injection were included as covariates. Only treatment with biologics was significantly associated with response at 3 or 6 months in the multivariate reduced model (OR 3.02, p = 0.027). CONCLUSIONS: We could not demonstrate an association between SF serine proteinase activity and response to IAS injection. Biologic agents significantly improve the likelihood of achieving clinical response.

Proteinase-Mediated Macrophage Signaling in Psoriatic Arthritis.

Objective: Multiple proteinases are present in the synovial fluid (SF) of an arthritic joint. We aimed to identify inflammatory cell populations present in psoriatic arthritis (PsA) SF compared to osteoarthritis (OA) and rheumatoid arthritis (RA), identify their proteinase-activated receptor 2 (PAR2) signaling function and characterize potentially active SF serine proteinases that may be PAR2 activators. Methods: Flow cytometry was used to characterize SF cells from PsA, RA, OA patients; PsA SF cells were further characterized by single cell 3'-RNA-sequencing. Active serine proteinases were identified through cleavage of fluorogenic trypsin- and chymotrypsin-like substrates, activity-based probe analysis and proteomics. Fluo-4 AM was used to monitor intracellular calcium cell signaling. Cytokine expression was evaluated using a multiplex Luminex panel. Results: PsA SF cells were dominated by monocytes/macrophages, which consisted of three populations representing classical, non-classical and intermediate cells. The classical monocytes/macrophages were reduced in PsA compared to OA/RA, whilst the intermediate population was increased. PAR2 was elevated in OA vs. PsA/RA SF monocytes/macrophages, particularly in the intermediate population. PAR2 expression and signaling in primary PsA monocytes/macrophages significantly impacted the production of monocyte chemoattractant protein-1 (MCP-1). Trypsin-like serine proteinase activity was elevated in PsA and RA SF compared to OA, while chymotrypsin-like activity was elevated in RA compared to PsA. Tryptase-6 was identified as an active serine proteinase in SF that could trigger calcium signaling partially via PAR2. Conclusion: PAR2 and its activating proteinases, including tryptase-6, can be important mediators of inflammation in PsA. Components within this proteinase-receptor axis may represent novel therapeutic targets.

The Association Between HLA Genetic Susceptibility Markers and Sonographic Enthesitis in Psoriatic Arthritis.

OBJECTIVE: Enthesitis is an important pathophysiologic component of psoriatic arthritis (PsA). HLA genes are implicated in the pathogenesis of PsA. Little is known about the relationship between HLA genetic susceptibility markers and enthesitis in PsA patients. Our aim was to examine the association between HLA genetic susceptibility markers and sonographic enthesitis in PsA. METHODS: A cross-sectional analysis was conducted in patients with PsA. Sonographic enthesitis was assessed according to the Madrid Sonography Enthesitis Index scoring system. HLA genotyping was performed using sequence-specific oligonucleotide probes. The association between 6 HLA susceptibility markers of PsA and the severity of sonographic enthesitis was assessed using multivariate regression models adjusted for age, sex, body mass index, and disease duration. RESULTS: Two hundred twenty-five patients were included, 57.8% of whom were men. The mean ± SD age was 56.1 ± 12.7 years, and the mean ± SD PsA duration was 16.9 ± 12.3 years. In the multivariate regression model, HLA-B*27 was associated with a higher enthesitis score (ß = 4.24 [95% confidence interval {95% CI} 0.02, 8.46]), and the interaction between HLA-B*27 and PsA duration was statistically significant, showing an increasing effect of HLA-B*27 with longer PsA duration (ß = 4.62 [95% CI 1.38, 7.86]). CONCLUSION: HLA-B*27 is associated with more severe sonographic enthesitis in PsA, particularly in patients with longer disease duration. This finding highlights the possible role of genetic variants in predisposing to PsA subphenotypes.

The Association Between Obesity and Clinical Features of Psoriatic Arthritis: A Case-control Study.

OBJECTIVE: To assess whether obesity is associated with distinct psoriatic arthritis (PsA) features and whether it interacts with PsA HLA susceptibility alleles. METHODS: Patients with early PsA were compared with patients with psoriasis without arthritis (PsC). The primary predictor was the body mass index (BMI) at the first visit to the clinic. The clinical features across 3 BMI groups were compared by linear trend test and Cochrane-Armitage trend test. The interaction between BMI and HLA risk alleles for psoriatic disease (HLA-B*27, B*3901, B*3801, B*0801, B*4402, B*4403, and C*0602) were assessed using logistic regression analysis. RESULTS: There were 314 patients with early PsA, and 498 patients with PsC were analyzed. Obesity was more frequent in patients with PsA compared with PsC (OR 1.77; p = 0.002). Higher BMI was associated with older age at onset of PsA (p < 0.0001) and psoriasis (p = 0.009). The frequency of HLA-B*27 was higher in patients with normal weight compared with those with higher BMI (p = 0.002). A significant interaction was found for the combined effect of HLA-B*27 and obesity in logistic regression analysis (p = 0.036). In patients who were HLA-B*27-negative, the association between obesity and PsA was statistically significant (OR 2.39; p < 0.001), but obesity was less frequent in patients with PsA who were HLA-B*27-positive. CONCLUSION: Obesity is linked with late-onset psoriasis and PsA, while normal weight is associated with the presence of the HLA-B*27 allele and an earlier onset of the disease. These results highlight the differential risk factors that may drive the inflammatory process in psoriatic disease.

Brief Report: CXCL10 Is a Possible Biomarker for the Development of Psoriatic Arthritis Among Patients With Psoriasis.

OBJECTIVE: Biomarkers that can predict the development of psoriatic arthritis (PsA) in patients with psoriasis would be useful in clinical practice. The aim of this study was to assess whether CXCL10 could be a predictive biomarker of PsA prior to its onset. METHODS: Psoriasis patients without arthritis were followed up prospectively and assessed annually for development of PsA by a rheumatologist. Patients in whom PsA developed were designated as converters, while those in whom PsA did not develop were termed nonconverters. Baseline serum concentrations of CXCL10 were measured by Luminex assay in 46 converters and 45 nonconverters. RESULTS: The level of CXCL10 was significantly higher in converters (median 493 pg/ml [interquartile range (IQR) 356-984]) than in nonconverters (median 371 pg/ml [IQR 263-578]; P = 0.005). In contrast, C-reactive protein (CRP) levels were not significantly different between converters and nonconverters at baseline. CXCL10 was associated with conversion status after adjustment for age, sex, duration of psoriasis, and duration of follow-up (odds ratio 1.3, 95% confidence interval 1.1-1.5, P = 0.004). In a subset of converters, the CXCL10 level was significantly higher at baseline (median 927.4 pg/ml [IQR 547.6-1,243]) than after PsA diagnosis (491.5 pg/ml [IQR 323.2-607]; P < 0.0001), while CRP levels were lower at baseline (26.6 µg/ml [IQR 16.37-62.75]) than after PsA diagnosis (36.1 µg/ml [IQR 14.74-101.7]; P = 0.003). CXCL10 gene expression was increased 17.3-fold in synovial fluid (SF) compared with blood from PsA patients (P = 0.01) and 44.3-fold in the SF of PsA patients compared with the SF of patients with gout (P = 0.001). CONCLUSION: CXCL10 may be involved in PsA pathogenesis and is a candidate predictive biomarker for PsA in patients with psoriasis.

Differential gene and protein expression of chemokines and cytokines in synovial fluid of patients with arthritis.

BACKGROUND: Psoriatic arthritis (PsA), an inflammatory musculoskeletal disease, develops in approximately 30% of patients with psoriasis. Previously, chemokine (C-X-C motif) ligand 10 (CXCL10) was identified as a predictive biomarker of PsA in patients with psoriasis and was reduced after development of PsA. The purpose of the present study was to explore messenger RNA (mRNA) and protein expression of CXCL10 and its receptor, chemokine (C-X-C motif) receptor 3 (CXCR3), in the joints of patients with PsA to gain insight into their role in the pathogenesis of the disease. METHODS: Sera from 47 patients with PsA and 33 healthy control subjects were compared for expression of CXCL10 by Luminex assay. Synovial fluid (SF) was obtained from patients with PsA (n = 40), osteoarthritis (OA; n = 14), gout (n = 8), and rheumatoid arthritis (RA; n = 11) during clinical care. SF mRNA and protein expression of CXCL10, interleukin-17A (IL-17A), CXCR3, TBX21, RORC and/or interferon γ (IFNγ) were compared among the above-mentioned disease groups, as well as in paired SF and serum samples from patients with PsA using real-time polymerase chain reaction and Luminex assays, respectively. RESULTS: Serum CXCL10 was significantly higher in patients with PsA than in control subjects (p = 0.0007). CXCL10, IL-17A, and TBX21 expression were elevated in SF cells of patients with PsA compared with those of patients with OA and gout, but not those of patients with RA. CXCR3 and RORC were elevated in PsA SF cells compared with all other patient groups. Concordant results were obtained for CXCL10 and IL-17A protein expression. IFNγ was elevated in PsA SF compared with OA SF (p = 0.015). CXCL10 protein expression was substantially increased in SF (median 7283.9 pg/ml, interquartile range [IQR] 1330-10,362 pg/ml) compared with paired serum samples (median 282.06, IQR 180.7-395.8 pg/ml; p = 0.001), whereas IFNγ was significantly reduced (SF median 6.03 pg/ml, IQR 4.47-8.94 pg/ml; versus serum median 23.70 pg/ml, IQR 3.2-104.6 pg/ml; p = 0.001). CONCLUSIONS: CXCL10 may have an important etiological role in PsA that is analogous to that in RA, and it is a candidate biomarker to distinguish PsA from healthy individuals and from patients with OA and gout.

The Association of HLA-class I Genes and the Extent of Atherosclerotic Plaques in Patients with Psoriatic Disease.

OBJECTIVE: To investigate the association between HLA susceptibility and disease severity markers and the extent of atherosclerosis in patients with psoriatic disease. METHODS: White patients with psoriatic arthritis (PsA) and psoriasis without PsA (PsC) were recruited. An ultrasound of the carotid arteries was performed and the size of each atherosclerotic plaque was measured. The resulting score, the total plaque area (TPA), represented the extent of atherosclerosis. HLA genotyping was performed using sequence-specific oligonucleotide probes. The association between 10 HLA susceptibility and severity markers of PsC and PsA and the severity of atherosclerosis was assessed by ordinal logistic regression models adjusted for age, sex, and cardiovascular (CV) risk factors. RESULTS: The study involved 411 patients (273 PsA, 138 PsC). Of them, 61.8% had at least 1 atherosclerotic plaque. HLA-B*13:02 and HLA-C*06:02 were associated with more severe atherosclerosis (age- and sex-adjusted OR 2.31, 95% CI 1.23-4.32 and OR 1.68, 95% CI 1.12-2.52, respectively). HLA-B*38:01 was associated with less severe atherosclerosis (OR 0.49, 95% CI 0.28-0.86). These associations remained statistically significant after adjusting for CV risk factors. Higher levels of erythrocyte sedimentation rate (ESR) were associated with more severe atherosclerosis (age- and sex-adjusted OR 1.33, p = 0.02). HLA-B*13:02-positive (p = 0.01) as well as HLA-C*06:02-positive (p = 0.008) patients had higher levels of ESR over time. CONCLUSION: HLA-C*06:02 and B*13:02 alleles are associated with a higher burden of atherosclerosis in patients with psoriatic disease. This association may be mediated by a higher level of systemic inflammation.

Immunoglobulin G subclass analysis in psoriatic arthritis.

OBJECTIVE: The occurrence of monoclonal gammopathy of undetermined significance (MGUS) is common in chronic immune mediated disorders. This increased monoclonal antibody production could result from chronic stimulation of lymphocytes, with the immunoglobulin G (IgG) subtype accounting for the majority of cases in psoriatic arthritis (PsA). We aimed to identify IgG subclass profiles in patients with PsA and to determine association with specific disease characteristics. METHODS: Serum samples from 221 patients with PsA from a single cohort were analyzed for their serum IgG subclass levels. All patients fulfilled the ClASsification for Psoriatic ARthritis (CASPAR) criteria and were followed at 6-month to 12-month intervals according to a standard protocol. MGUS was defined as the occurrence of a discrete band in the gammaglobulin region on at least 2 separate serum protein electrophoresis tests performed 6 months apart. Patients with high abnormal IgG subclass levels were compared to patients with normal levels using descriptive tests. RESULTS: Elevations of IgG1-4 were common in PsA, with ∼20%-49% of patients having elevations of each subclass, IgG2 being the most common subclass abnormality. However, no clinical-serological correlation was found in the group with abnormal IgG2 levels. Of the 38 patients with MGUS, elevations in IgG1 were most common. Patients with an abnormal IgG1 subclass level were more likely to have a discrete band in the gammaglobulin region, higher prevalence of MGUS, and abnormal erythrocyte sedimentation rate or C-reactive protein levels. CONCLUSION: Determination of the IgG subclass concentration in PsA did not seem to add any significant value in identifying specific disease manifestations. However, this study provides insight into the pathological process leading to MGUS in PsA.