Impact of serum interleukin-22 as a biomarker for the differential use of molecular targeted drugs in psoriatic arthritis: a retrospective study.

BACKGROUND: We explored whether serum cytokines could be used as biomarkers for optimal use of tumor necrosis factor inhibitors (TNF-i) and interleukin (IL)-17 inhibitors (IL-17-i) in patients with psoriatic arthritis (PsA). METHODS: In cohort 1 (47 patients treated with IL-17-i [n=23] or TNF-i [n=24] for ≥1 year), we identified serum cytokines that predicted the achievement of Disease Activity in Psoriatic Arthritis-remission (DAPSA-REM), Psoriasis Area and Severity Index (PASI) 90, and Minimal Disease Activity after 1 year of TNF-i or IL-17-i therapy. Subsequently, we developed treatment strategies based on the identified cytokines; initiation of IL-17-i therapy in patients with low IL-22 concentrations (IL-22 <0.61376 pg/ml) and TNF-i therapy in patients with high IL-22 concentrations (0.61376< IL-22 pg/ml). In cohort 2 (34 patients), treatment responses were compared between the strategic treatment group (n=17), which was treated based on the treatment strategies, and the mismatched treatment group (n=17) to verify the validity of the treatment strategies developed using serum cytokines as biomarkers. RESULTS: In cohort 1, serum IL-22 concentration was identified as a predictor of DAPSA-remission after 1 year of IL-17-i therapy. Regarding treatment strategies, we selected TNF-i for patients with high IL-22 concentrations and IL-17-i for those with low IL-22 concentrations. There were no significant differences in the baseline characteristics between the strategic and mismatched treatment groups. Regarding treatment effects, activity significantly improved at 1 year in both groups. Upon comparison of the treatment effects, the rate of achieving DAPSA-REM and Minimal Disease Activity at month 12 was significantly higher in the strategic treatment group. CONCLUSIONS: The results of this pilot study suggest that IL-22 may be a biomarker of treatment response to TNF-i and IL-17-i in patients with PsA. Further large-scale studies in independent, prospectively collected datasets are required to verify that IL-22 is indeed a biomarker of treatment response in these patients.

Identification and Evaluation of Serum Protein Biomarkers That Differentiate Psoriatic Arthritis From Rheumatoid Arthritis.

OBJECTIVE: To identify serum protein biomarkers that might distinguish patients with early inflammatory arthritis (IA) with psoriatic arthritis (PsA) from those with rheumatoid arthritis (RA) and may be used to support appropriate early intervention. METHODS: The serum proteome of patients with PsA and patients with RA was interrogated using nano-liquid chromatography mass spectrometry (nano-LC-MS/MS) (n = 64 patients), an aptamer-based assay (SomaScan) targeting 1,129 proteins (n = 36 patients), and a multiplexed antibody assay (Luminex) for 48 proteins (n = 64 patients). Multiple reaction monitoring (MRM) assays were developed to evaluate the performance of putative markers using the discovery cohort (n = 60 patients) and subsequently an independent cohort of PsA and RA patients (n = 167). RESULTS: Multivariate machine learning analysis of the protein discovery data from the 3 platforms revealed that it was possible to differentiate PsA patients from RA patients with an area under the curve (AUC) of 0.94 for nano-LC-MS/MS, 0.69 for bead-based immunoassay measurements, and 0.73 for aptamer-based analysis. Subsequently, in the separate verification and evaluation studies, random forest models revealed that a subset of proteins measured by MRM could differentiate PsA and RA patients with AUCs of 0.79 and 0.85, respectively. CONCLUSION: We present a serum protein biomarker panel that can separate patients with early-onset IA with PsA from those with RA. With continued evaluation and refinement using additional and larger patient cohorts, including those with other arthropathies, we suggest that the panel identified here could contribute to improved clinical decision making.

Circulating Mir-140 and leptin improve the accuracy of the differential diagnosis between psoriatic arthritis and rheumatoid arthritis: a case-control study.

The differential diagnosis of psoriatic arthritis (PsA) and rheumatoid arthritis (RA) is difficult because of the lack of diagnostic clinical signs and reliable biomarkers. This study investigated microRNAs (miRNA) and adipokines as potential additional markers to discriminate PsA from RA. The expression profile of miRNA (miR-21, miR-140, miR-146a, miR-155, miR-181b, miR-223, miR-let-7e) and inflammatory cytokines (IL-1ß, IL-6, IL-17a, IL-23a, TNF-α) from peripheral blood mononuclear cells of PsA and RA patients compared to healthy controls (HC) were evaluated by real-time PCR, and serum adipokines (adiponectin, chemerin, leptin, resistin, visfatin) and cytokines by ELISA assay. Univariable binary logistic regression was used to find the association between PsA and potential predictors. The gene expression of miRNA and cytokines and the serum levels of adipokines were found significantly different in PsA and RA patients compared to HC, as well as in PsA versus RA. MiR-140 gene expression resulted up-regulated in PsA patients and reduced in RA in comparison to HC, and, for the first time, significantly higher in PsA compared with RA. Serum levels of IL-23a and leptin were significantly increased in PsA and RA populations than in HC, as well as in PsA versus RA. Furthermore, circulating TNF-α was up-regulated in PsA and RA in comparison to controls, while resulted higher in RA than in PsA. Univariable binary logistic regression analysis found the above-mentioned markers associated to PsA versus RA. Our results first demonstrated an increased expression of circulating miR-140 and serum leptin in PsA patients compared to RA, which were identified as potential additional biomarkers to discriminate PsA from RA. Since the differential diagnosis of PsA and RA poses challenges in clinical practice, our data may help to enhance the diagnostic performance of PsA in daily practice.

Perceptions of Rheumatologists on Diagnosis of Psoriatic Arthritis in China.

Objective: High prevalence of undiagnosed psoriatic arthritis (PsA) and prolonged diagnostic delay are key troubles in the appropriate management of PsA. To analyze the possible causes for this phenomenon, a web-based nationwide survey was conducted to investigate rheumatologists' perceptions on PsA diagnosis in China. Methods: The electronic questionnaire consisting of 38 questions were designed by an expert panel and distributed with the online survey tool Sojump, which is a professional online survey platform. The completed questionnaires by real-name rheumatologists were collected. Results: A total of 1594 valid questionnaires were included. More than half of Chinese rheumatologists reported it was challenging to make a diagnosis of PsA. The four major challenges were "Difficulties in identification of atypical or hidden psoriasis", "Absence of diagnostic biomarkers", "No active self-report of history or family history of psoriasis" and "Various musculoskeletal manifestations". In diagnosing PsA, minor participants had incorrect knowledge of inflammatory arthropathy (13.7%), acute phase reactant (23.8%), and rheumatoid factor (28.7%). There were no significant differences in the knowledge of PsA and practice habits in diagnosing PsA between modern western medicine (WM)- and traditional Chinese medicine (TCM)-rheumatologists. The part-time rheumatologists were not as good as full-time rheumatologists in diagnosing PsA. Conclusions: About three quarters of Chinese rheumatologists are familiar with the elements in PsA diagnosis and have good practice habits in diagnosing PsA. Four main challenges in making PsA diagnosis are revealed. There was no significant difference in the knowledge of PsA between WM- and TCM-rheumatologists.

Disease Differentiation and Monitoring of Anti-TNF Treatment in Rheumatoid Arthritis and Spondyloarthropathies.

Rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) are comprehensive immunological disorders. The treatment of these disorders is limited to ameliorating the symptoms and improving the quality of life of patients. In this study, serum samples from RA, AS, and PsA patients were analyzed with metabolomic tools employing the 1H NMR method in combination with univariate and multivariate analyses. The results obtained in this study showed that the changes in metabolites were the highest for AS > RA > PsA. The study demonstrated that the time until remission or until low disease activity is achieved is shortest (approximately three months) for AS, longer for RA and longest for PsA. The statistically common metabolite that was found to be negatively correlated with the healing processes of these disorders is ethanol, which may indicate the involvement of the gut microflora and/or the breakdown of malondialdehyde as a cell membrane lipid peroxide product.

Psoriatic disease is associated with systemic inflammation, endothelial activation, and altered haemostatic function.

Psoriasis is a chronic, immune-mediated inflammatory skin disease, affecting approximately 2% of the general population, which can be accompanied by psoriatic arthritis (PsA). The condition has been associated with an increased cardiovascular burden. Hypercoagulability is a potential underlying mechanism that may contribute to the increased risk of major cardiovascular events in psoriatic individuals. Whole blood samples were collected from 20 PsA patients and 20 healthy individuals. The concentrations of inflammatory molecules (C-reactive protein, serum amyloid A, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, and soluble P-selectin) were determined by enzyme-linked immunosorbent assays. In addition, clotting efficiency was evaluated by thromboelastography. The fibrin network architecture was also assessed by scanning electron microscopy. Elevated levels of circulating inflammatory molecules were significantly associated with the presence of psoriatic disease. Furthermore, an increased tendency towards thrombus formation was significantly predictive of disease presence. Scanning electron microscopy revealed that fibrin clots were denser in psoriatic individuals, compared to healthy controls, with an increased fibrin fibre diameter associated with psoriatic disease. Our results add to the accumulating evidence of the systemic nature of psoriasis and the subsequent risk of cardiovascular comorbidities, potentially due to an acquired hypercoagulability. We suggest that haemostatic function should be monitored carefully in psoriatic patients that present with severe disease, due to the pre-eminent risk of developing thrombotic complications.

Targeting the CCR6/CCL20 Axis in Entheseal and Cutaneous Inflammation.

OBJECTIVE: To assess the involvement of the CCR6/CCL20 axis in psoriatic arthritis (PsA) and psoriasis (PsO) and to evaluate its potential as a therapeutic target. METHODS: First, we quantified CCL20 levels in peripheral blood and synovial fluid from PsA patients and examined the presence of CCR6+ cells in synovial and tendon tissue. Utilizing an interleukin-23 minicircle DNA (IL-23 MC) mouse model exhibiting key features of both PsO and PsA, we investigated CCR6 and CCL20 expression as well as the preventive and therapeutic effect of CCL20 blockade. Healthy tendon stromal cells were stimulated in vitro with IL-1ß to assess the production of CCL20 by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. The effect of conditioned media from stimulated tenocytes in inducing T cell migration was interrogated using a Transwell system. RESULTS: We observed an up-regulation of both CCR6 and CCL20 in the enthesis of IL-23 MC-treated mice, which was confirmed in human biopsy specimens. Specific targeting of the CCR6/CCL20 axis with a CCL20 locked dimer (CCL20LD) blocked entheseal inflammation, leading to profound reductions in clinical and proinflammatory markers in the joints and skin of IL-23 MC-treated mice. The stromal compartment in the tendon was the main source of CCL20 in this model and, accordingly, in vitro activated human tendon cells were able to produce this chemokine and to induce CCR6+ T cell migration, the latter of which could be blocked by CCL20LD. CONCLUSION: Our study highlights the pathogenic role of the CCR6/CCL20 axis in enthesitis and introduces the prospect of a novel therapeutic approach for treating patients with PsO and PsA.

Effect of interleukin-17A inhibitor in Japanese patients with psoriatic arthritis compared with tumor necrosis factor-alpha inhibitor.

OBJECTIVES: The patient of severe psoriatic arthritis (PsA) is mainly treated with oral methotrexate, ciclosporin, and anti-tumor necrosis factor-alpha inhibitors (TNFi). Recently, anti-interleukin-17A inhibitors (IL-17Ai) have been used in the treatment of PsA. This study aimed to evaluate the efficacy and safety of IL-17Ai in Japanese patients with PsA compared with those of TNFi. METHODS: This was a longitudinal and retrospective study. The study population included 31 Japanese patients with PsA. All enrolled patients fulfilled the Classification Criteria for Psoriatic Arthritis. All patients were treated with TNFi or IL-17Ai. The assessed clinical manifestations were C-reactive protein (CRP)-based Disease Activity Score in 28 Joints (DAS28-CRP), disease activity in psoriatic arthritis (DAPSA), 20% achievement of American College of Rheumatology core set, swollen joint count (SJC), tender joint count (TJC), and visual analog scale (VAS). Functional ability of patients with PsA was analyzed using the modified health assessment questionnaire (mHAQ) score. We evaluated the parameters at baseline and weeks 12, 24, and 52. RESULTS: The change in SJC, TJC, VAS, mHAQ, and DAPSA had no significant difference at weeks 12, 24, and 52. The improvements of CRP and DAS28-CRP were significantly higher in TNFi group only at week 12. The biologics retention rate was significantly higher in TNFi group by the log-rank test. No critical adverse events occurred. CONCLUSIONS: Our study presented that IL-17Ai had treatment effects comparable to TNFi. IL-17Ai might have the potential to become an alternative to the previous drug, but more large-scale studies are expected.

Clonal expansion of large granular lymphocytes in patients with spondyloarthritis and psoriatic arthritis treated with TNFα inhibitors.

To determine the prevalence of clonal T-large granular lymphocyte (T-LGL) cells in patients with spondyloarthritis (SpA) and psoriatic arthritis (PsA) and to define possible risk factors for this condition. We present a cross-sectional analysis with retrospective and prospective aspects. 115 SpA patients, 48 PsA patients and 51 controls were recruited between December 28, 2017 and January 23, 2019. Flow cytometry (FACS) was performed to screen for aberrant T-LGL cells. Molecular analysis was then employed to confirm the diagnosis in patients with suggestive FACS findings. Patients with clonal T-LGL populations were followed prospectively by FACS analysis. Electronic patient files were retrospectively analyzed to determine risk factors. Median age was 49 years for SpA, 55.5 years for PsA, and 54 years for controls. Median disease duration of SpA and PsA was 15 years and 11 years, respectively. 79.8% of patients had received biologics at some point, 75.5% had ever received tumor necrosis factor (TNF) inhibitors. 59.5% were treated with TNF inhibitors at the time of study inclusion. We identified clonal T-LGL expansions in 13 individuals equaling a prevalence of 6% (13/214). T-LGL patients were taking TNF inhibitors more frequently at the time of study inclusion (p = 0.022) and were more likely to have ever been treated with TNF inhibition (p = 0.046). Clonal T-LGL expansions can be detected in patients with SpA, PsA and also in healthy controls. Confirming earlier results, exposure to TNFα-blocking agents appears to increase the risk of developing clonal expansions of T-LGL cells.

Large-scale plasma-metabolome analysis identifies potential biomarkers of psoriasis and its clinical subtypes.

BACKGROUND: Psoriasis is an immune-mediated skin disease for which the crosstalk between genetic and environmental factors is responsible. To date, no definitive diagnostic criteria for psoriasis yet, and specific biomarkers are required. OBJECTIVE: We performed metabolome analysis to identify metabolite biomarkers of psoriasis and its subtypes such as psoriatic arthritis (PsA) and cutaneous psoriasis (PsC). METHODS: We constructed metabolomics profiling of 130 plasma samples (42 PsA patients, 50 PsC patients, and 38 healthy controls) using a nontargeted metabolomics approach. RESULTS: Psoriasis-control association tests showed that one metabolite (ethanolamine phosphate) was significantly increased in psoriasis samples than in the controls, whereas three metabolites decreased (false discovery rate [FDR] < 0.05; XA0019, nicotinic acid, and 20α-hydroxyprogesterone). In the association test between PsA and PsC, tyramine significantly increased in PsA than in PsC, whereas mucic acid decreased (FDR < 0.05). Molecular pathway analysis of the PsA-PsC association test identified enrichment of vitamin digestion and absorption pathway in PsC (P = 1.3 × 10-4). Correlation network analyses elucidated that a subnetwork centered on aspartate was constructed among the psoriasis-associated metabolites; meanwhile, the major subnetwork among metabolites with differences between PsA and PsC was primarily formed from saturated fatty acids. CONCLUSION: Our large-scale metabolome analysis highlights novel characteristics of plasma metabolites in psoriasis and the differences between PsA and PsC, which could be used as potential biomarkers of psoriasis and its clinical subtypes. These findings contribute to our understanding of psoriasis pathophysiology.

Broad proteomic screen reveals shared serum proteomic signature in patients with psoriatic arthritis and psoriasis without arthritis.

OBJECTIVE: To identify novel serum proteins involved in the pathogenesis of PsA as compared with healthy controls, psoriasis (Pso) and AS, and to explore which proteins best correlated to major clinical features of the disease. METHODS: A high-throughput serum biomarker platform (Olink) was used to assess the level of 951 unique proteins in serum of patients with PsA (n = 20), Pso (n = 18) and AS (n = 19), as well as healthy controls (HC, n = 20). Pso and PsA were matched for Psoriasis Area and Severity Index (PASI) and other clinical parameters. RESULTS: We found 68 differentially expressed proteins (DEPs) in PsA as compared with HC. Of those DEPs, 48 proteins (71%) were also dysregulated in Pso and/or AS. Strikingly, there were no DEPs when comparing PsA with Pso directly. On the contrary, hierarchical cluster analysis and multidimensional scaling revealed that HC clustered distinctly from all patients, and that PsA and Pso grouped together. The number of swollen joints had the strongest positive correlation to ICAM-1 (r = 0.81, P < 0.001) and CCL18 (0.76, P < 0.001). PASI score was best correlated to PI3 (r = 0.54, P < 0.001) and IL-17 receptor A (r = -0.51, P < 0.01). There were more proteins correlated to PASI score when analysing Pso and PsA patients separately, as compared with analysing Pso and PsA patients pooled together. CONCLUSION: PsA and Pso patients share a serum proteomic signature, which supports the concept of a single psoriatic spectrum of disease. Future studies should target skin and synovial tissues to uncover differences in local factors driving arthritis development in Pso.

Increased levels of plasma nucleotides in patients with rheumatoid arthritis.

Novel biomarkers of rheumatoid arthritis (RA), in addition to antibodies against cyclic citrullinated peptides, are required. Metabolome analysis is a promising approach to identify metabolite biomarkers for clinical diagnosis. We adopted a comprehensive non-targeted metabolomics approach combining capillary electrophoresis time-of-flight mass spectrometry (TOFMS) and liquid chromatography TOFMS. We constructed metabolomics profiling of 286 plasma samples of a Japanese population [92 RA patients, 13 systemic lupus erythematosus (SLE) patients and 181 healthy controls). RA case-control association tests showed that seven metabolites exhibited significantly increased levels in RA samples compared with controls (P < 1.0 × 10-4; UTP, ethanolamine phosphate, ATP, GDP, ADP, 6-aminohexanoic acid and taurine), whereas one exhibited a decreased level (xanthine). The plasma levels of these eight metabolites were not significantly different between seropositive and seronegative RA patients (P > 0.05; n = 68 and 24, respectively). The four nucleotide levels (UTP, ATP, GDP and ADP) were significantly higher in the non-treatment patients in comparison between patients with and without treatment (P < 0.014; n = 57 and 35, respectively). Furthermore, we found that none of the four nucleotide levels showed significant differences in SLE case-control association tests (P > 0.2; 13 patients with SLE and the 181 shared controls) and psoriatic arthritis (PsA) case-control association tests (P > 0.11; 42 patients with PsA and 38 healthy controls), indicating disease specificity in RA. In conclusion, our large-scale metabolome analysis demonstrated the increased plasma nucleotide levels in RA patients, which could be used as potential clinical biomarkers of RA, especially for seronegative RA.

Visceral adiposity in patients with psoriatic arthritis and psoriasis alone and its relationship with metabolic and cardiovascular risk.

BACKGROUND: Fat mass distribution, especially in the abdominal visceral region, has been rarely evaluated in patients with PsA or psoriasis (PsO). METHODS: Patients with PsA and patients with PsO alone were evaluated and compared with control subjects (1:1 ratio in each patient group) matched for age, sex and BMI category. Body composition and fat distribution (android and visceral fat) were evaluated by DXA. Anthropometric measurements, disease activity and the systematic coronary risk evaluation (SCORE) cardiovascular risk were assessed. Metabolic parameters (insulin, homeostasis model assessment for insulin resistance), serum adipokines [total and high-molecular-weight adiponectin, leptin, resistin and retinol-binding protein-4 (RBP4)] were measured. RESULTS: Data for 52 patients with PsA and 52 patients with PsO and their respective paired controls were analysed. Android fat and visceral fat were found to be significantly higher in patients with PsO compared with their controls, while these measurements did not differ between patients with PsA and their controls. By multivariate analysis, after adjusting for age, sex and BMI, visceral fat was higher in PsO patients compared with PsA patients (P = 0.0004) and the whole group of controls (P = 0.0013). Insulin levels and HOMA-IR were increased in both PsA and PsO groups. High-molecular-weight/total adiponectin ratio was decreased in patients with PsO. RBP4 was significantly higher in both PsA and PsO patients. In patients with PsO, visceral fat strongly correlated with SCORE (r = 0.61). CONCLUSION: Visceral fat accumulates more in PsO alone than in PsA. Visceral adiposity may be a more pressing concern in PsO relative to PsA. TRIAL REGISTRATION: The ADIPSO study (Évaluation du tissu ADIpeux et des adipokines dans le PSOriasis et le rhumatisme psoriasique et analyse de ses relations avec le risque cardiovasculaire) is a case-control study conducted in Besançon, France, and is registered on ClinicalTrials.gov under the number NCT02849795.

Análise do perfil clínico e epidemiológico de pacientes com artrite psoriásica em ambulatório de reumatologia na Região Amazônica / Clinical and epidemiological profile analysis of patients with psoriatic arthritis in a rheumatology clinic in the Amazon Region

Objetivo: Conhecer o perfil clínico e epidemiológico de pacien- tes portadores de artrite psoriásica de uma região brasileira. Método: Pesquisa observacional, transversal, epidemiológica e documental, baseada na coleta de dados obtidos a partir da análise de 53 prontuários de pacientes cadastrados do Ambu- latório de Reumatologia da Universidade do Estado do Pará, na Região Amazônica. Resultados: Houve predominância do padrão do tipo poliartrite simétrica, sem distinção entre os sexos, com a presença de manifestações extra-articulares, pso- ríase em placas, em uso de metotrexato em doses médias. Con- clusão: Apesar da etiopatogenia da doença ser dependente de fatores genéticos, ambientais e imunológicos e da população amazônica ser muito particular, de uma miscigenação entre eu- ropeus, ameríndios e negros, o perfil clínico e epidemiológicos dos pacientes do Ambulatório de Reumatologia da Universidade do Estado do Pará é semelhante ao das literaturas nacional e internacional.

Objective: To know the clinical and epidemiologic profile of pso- riatic arthritis patients of a Brazilian region. Method: This is an observational, cross-sectional, epidemiological, and documental study, based on the data obtained from the analysis of the medi- cal records of 53 patients registered on the Rheumatology Cli- nic of the Universidade do Estado do Pará, in the Amazon area. Results: There was a predominance of the symmetrical polyar- ticular pattern, with no sexual distinction, extra articular invol- vement, plaque psoriasis, and treatment withn methotrexate, in medium doses. Conclusion: Despite the etiopathogenesis being dependent on genetic, environmental, and immunological fac- tors, and the population of the Amazon being a mix of Europeans, Amerindians, and black people, the clinical and epidemiological profile of the patients of the Rheumatology clinic of the Univer- sidade do Estado do Pará is similar to the ones described on the national and international literature.

Treatment of psoriatic arthritis complicated by systemic lupus erythematosus with the IL-17 blocker secukinumab and an analysis of the serum cytokine profile.

Psoriasis is a chronic disease of the skin that often affects the joints (psoriatic arthritis, PsA). Biologic agents such as TNF-α, IL-23 and IL-17 blockers have been proven to be quite effective against psoriasis and PsA, indicating the importance of those cytokines in the pathogenesis of the diseases. The importance of the IL-23/IL-17 axis has also been reported in systemic lupus erythematosus (SLE), but the safety and effectiveness of IL-17 blockers in SLE remain largely unknown. We encountered a patient with PsA and SLE. We treated him with an IL-17 blocker, secukinumab, and quantified the serum levels of various cytokines before and after the initiation of secukinumab therapy. As expected, the treatment was effective against the symptoms of PsA. No serious adverse events were observed in terms of SLE. Interestingly, serum IL-6 was substantially decreased after the initiation of therapy, whereas serum IL-17 was under the detection limit. These data indicate that IL-17 is produced locally, upstream of IL-6 production.

Single-cell sequencing reveals clonal expansions of pro-inflammatory synovial CD8 T cells expressing tissue-homing receptors in psoriatic arthritis.

Psoriatic arthritis (PsA) is a debilitating immune-mediated inflammatory arthritis of unknown pathogenesis commonly affecting patients with skin psoriasis. Here we use complementary single-cell approaches to study leukocytes from PsA joints. Mass cytometry demonstrates a 3-fold expansion of memory CD8 T cells in the joints of PsA patients compared to peripheral blood. Meanwhile, droplet-based and plate-based single-cell RNA sequencing of paired T cell receptor alpha and beta chain sequences show pronounced CD8 T cell clonal expansions within the joints. Transcriptome analyses find these expanded synovial CD8 T cells to express cycling, activation, tissue-homing and tissue residency markers. T cell receptor sequence comparison between patients identifies clonal convergence. Finally, chemokine receptor CXCR3 is upregulated in the expanded synovial CD8 T cells, while two CXCR3 ligands, CXCL9 and CXCL10, are elevated in PsA synovial fluid. Our data thus provide a quantitative molecular insight into the cellular immune landscape of psoriatic arthritis.

A novel biomarker of MMP-cleaved prolargin is elevated in patients with psoriatic arthritis.

Psoriatic arthritis (PsA) is a chronic musculoskeletal inflammatory disease found in up to 30% of psoriasis patients. Prolargin-an extracellular matrix (ECM) protein present in cartilage and tendon-has been previously shown elevated in serum of patients with psoriasis. ECM protein fragments can reflect tissue turnover and pathological changes; thus, this study aimed to develop, validate and characterize a novel biomarker PROM targeting a matrix metalloproteinase (MMP)-cleaved prolargin neo-epitope, and to evaluate it as a biomarker for PsA. A competitive ELISA was developed with a monoclonal mouse antibody; dilution- and spiking-recovery, inter- and intra-variation, and accuracy were evaluated. Serum levels were evaluated in 55 healthy individuals and 111 patients diagnosed with PsA by the CASPAR criteria. Results indicated that the PROM assay was specific for the neo-epitope. Inter- and intra- assay variations were 11% and 4%, respectively. PROM was elevated (p = 0.0003) in patients with PsA (median: 0.24, IQR: 0.19-0.31) compared to healthy controls (0.18; 0.14-0.23) at baseline. AUROC for separation of healthy controls from PsA patients was 0.674 (95% CI 0.597-0.744, P < 0.001). In conclusion, MMP-cleaved prolargin can be quantified in serum by the PROM assay and has the potential to separate patients with PsA from healthy controls.

Achieving sustained minimal disease activity with methotrexate in early interleukin 23-driven early psoriatic arthritis.

OBJECTIVES: Methotrexate (MTX) is currently the recommended first-line therapy for treating psoriatic arthritis (PsA), despite lacking clear evidence. No estimates of efficacy of MTX in usual care and no clear MTX responsive clinical or laboratory variables are currently available. This study describes the response to MTX monotherapy in newly diagnosed patients with PsA in usual care. Second, we compared clinical variables and cytokine profiles in patients responding and not responding to MTX monotherapy. METHODS: We used data collected in the Dutch southwest Early Psoriatic Arthritis cohoRt study to select patients with PsA with oligoarthritis or polyarthritis, and at least 1 year follow-up. We analysed disease activity at 6 months of patients who started MTX monotherapy and still used MTX monotherapy 1 year after diagnosis. Cytokine profiles were determined at baseline and after 3 and 6 months with a bead-based multi-immunoassay. RESULTS: We identified 219 patients of which 183 (84%) patients started MTX monotherapy within 6 months after diagnosis. 90 patients used MTX monotherapy throughout the first year of which 44 patients (24%) reached minimal disease activity(MDA) at 6 months, decreasing to 33 patients (18%) after 1 year. Non-responders had significantly higher concentrations of interleukin (IL) 23 and IL-10 before and during MTX therapy. CONCLUSIONS: Our results showed that only 18% of patients with PsA are in sustained MDA after 1 year of MTX monotherapy and non-responders more often had IL-23-driven disease. Our results indicate the need for more treat-to-target and personalised therapy strategies in PsA.

Immunoglobulin A antibodies to oxidized collagen type II as a potential biomarker for the stratification of spondyloarthritis from rheumatoid arthritis.

OBJECTIVES: The discovery of diseased tissue-specific neoantigens offers the opportunity to develop important disease tissue-specific biomarkers that can help in the prediction, diagnosis, and stratification of diseases. This opportunity is specifically significant for autoimmune diseases where diagnostic biomarkers are not available. Inflammatory autoimmune diseases are commonly associated with local generation of large amounts of reactive oxidants. We have previously identified oxidative post-translationally modified (oxPTM) tissue-specific neoantigens in rheumatoid arthritis (RA) and type 1 diabetes that elicit an immune response. In the current study, we studied the presence and clinical significance of antibodies to oxPTM collagen type II (CII) in patients with spondyloarthritis (SpA). METHOD: Levels of antibodies specific to native CII and oxPTM-CII were assessed by enzyme-linked immunosorbent assay. RESULTS: Immunoglobulin G (IgG) binding to oxPTM-CII was observed in 52%, 83%, and 28% of serum samples from patients with axial spondyloarthritis (axSpA), RA, and psoriatic arthritis (PsA), respectively. Importantly, while strong IgA anti-oxPTM-CII responses were detected in axSpA and PsA patients, with 47% and 84% respective binders, no IgA anti-oxPTM-CII was detected in RA patients. IgA anti-oxPTM-CII reactivity in axSpA patients treated with biologics was higher and more frequent, with 85% binders compared to 9% binders in patients treated with synthetic disease-modifying anti-rheumatic drugs. CONCLUSION: Our data imply that SpA and PsA are associated with the presence of antibodies to oxPTM-CII, suggesting that there may be a humoral component that may distinguish patients with SpA from RA. Our approach could be adapted to other diseases, particularly to inflammatory autoimmune diseases.

Real life experience of apremilast in psoriasis and arthritis psoriatic patients: Preliminary results on metabolic biomarkers.

Psoriasis is a common inflammatory skin condition, affecting 2-4% of the worldwide population. Psoriasis remains an important public health challenge because there are many clinical forms of psoriasis in particular sites, probably related to the dysregulation of different cytokines. Therefore, there is a continuous need to improve treatment options with mechanisms of action different from those of the currently known therapies. Advances in knowledge of the molecular bases of pathogenesis lead to a better understanding of the disease, thus influencing the development and management of effective treatments. Moreover, data from recent published work indicate that psoriasis coexists with cardiovascular diseases, metabolic syndrome, diabetes mellitus and psychiatric disorders. We present results from our 52-week open-label trial in a cohort of psoriatic and psoriatic arthritis patients treated with daily p.o. doses of apremilast 60 mg. We confirmed the efficacy and safety of the drug in favoring the improvement of skin and joint disease as well as the modulation of metabolic biomarkers in diabetic and non-diabetic psoriatic patients. Apremilast could be used successfully in psoriatic patients affected by cardiometabolic comorbidities, ensuring an improvement in both diseases.