Pathogenesis Of Psoriatic Arthritis Research Articles

Long Non-Coding RNAs Play a Role in the Pathogenesis of Psoriatic Arthritis by Regulating MicroRNAs and Genes Involved in Inflammation and Metabolic Syndrome.

Psoriatic arthritis (PsA) is an inflammatory arthritis, characterized by inflammation of entheses and synovium, leading to joint erosions and new bone formation. It affects 10–30% of patients with psoriasis, and has an estimated prevalence of approximately 1%. PsA is considered to be primarily an autoimmune disease, driven by autoreactive T cells directed against autoantigens present in the skin and in the joints. However, an autoinflammatory origin has recently been proposed. Long noncoding RNAs (lncRNAs) are RNAs more than 200 nucleotides in length that do not encode proteins. LncRNAs play important roles in several biological processes, including chromatin remodeling, transcription control, and post-transcriptional processing. Several studies have shown that lncRNAs are expressed in a stage-specific or lineage-specific manner in immune cells that have a role in the development, activation, and effector functions of immune cells. LncRNAs are thought to play a role in several diseases, including autoimmune disorders. Indeed, a few lncRNAs have been identified in systemic lupus erythematosus, rheumatoid arthritis, and psoriasis. Although several high-throughput studies have been performed to identify lncRNAs, their biological and pathological relevance are still unknown, and most transcriptome studies in autoimmune diseases have only assessed protein-coding transcripts. No data are currently available on lncRNAs in PsA. Therefore, by microarray analysis, we have investigated the expression profiles of more than 50,000 human lncRNAs in blood samples from PsA patients and healthy controls using Human Clariom D Affymetrix chips, suitable to detect rare and low-expressing transcripts otherwise unnoticed by common sequencing methodologies. Network analysis identified lncRNAs targeting highly connected genes in the PsA transcriptome. Such genes are involved in molecular pathways crucial for PsA pathogenesis, including immune response, glycolipid metabolism, bone remodeling, type 1 interferon, wingless related integration site, and tumor necrosis factor signaling. Selected lncRNAs were validated by RT-PCR in an expanded cohort of patients. Moreover, modulated genes belonging to meaningful pathways were validated by RT-PCR in PsA PBMCs and/or by ELISA in PsA sera. The findings indicate that lncRNAs are involved in PsA pathogenesis by regulating both microRNAs and genes and open new avenues for the identification of new biomarkers and therapeutical targets.

Novel molecular mechanisms in the pathophysiology of psoriatic arthritis

The complex pathogenesis of psoriatic arthritis (PsA) is still only partially understood; however, recently a greatly improved understanding of this disease has been achieved, especially with respect to the inflammatory processes of the entheses. Thus, the clinical aspects of enthesitis increasingly differentiate PsA from other autoimmune diseases and sharpen the unique pathological clinical picture of PsA. Better pathophysiological understanding and the development of different biomarker approaches will bolster early detection of PsA. Therefore, the successful early recognition of PsA and more reliable identification of psoriasis patients at risk might be possible in the near future.

Ustekinumab for the treatment of psoriasis and psoriatic arthritis: a drug evaluation and literature review

ABSTRACTIntroduction: Psoriasis (PsO) is an inflammatory disorder characterized by proliferation of keratinocytes, and it may be associated with a systemic inflammatory articular disorder, psoriatic arthritis (PsA). The presentations of PsO and PsA are heterogeneous, and our understanding of pathogenesis has led to a better understanding of the role of the interleukin (IL)-23/T-helper 17 (Th17) axis.Areas covered: Ustekinumab is a monoclonal antibody against IL-12 and IL-23. The pathogenesis of PsO and PsA is a multifactorial process involving genetic, environmental, and lifestyle factors. IL-23 signaling and activation of Th17 cells leads to a self-perpetuating inflammatory loop resulting in continuous keratinocyte proliferation and synovitis. Treatment options are varied, ranging from topical therapy to injection of targeted biologic disease-modifying antirheumatic drugs (bDMARDs). Evidence on the use of ustekinumab in the management of PsO is strong, but it is not as impressive in management of PsA.Expert opinion: IL-12/23 inhibition appears to be a good first-line option for plaque PsO, but efficacy in PsA does not compare favorably to IL-17 inhibition. In general, poorer responses to therapy with any bDMARD in PsA cohorts highlight psoriatic disease heterogeneity. Until new knowledge can remedy the failure of monotherapy, synergistic methods may have to be explored, including combination biologic therapy.

The association between occupational-related mechanical stress and radiographic damage in psoriatic arthritis

ObjectiveTo assess the association between occupational-related mechanical factors and the severity of radiographic peripheral and axial joint damage in patients with longstanding Psoriatic Arthritis (PsA). MethodsPatients with longstanding PsA (disease duration≥10 years) were identified from a prospective longitudinal cohort. Using an occupation history questionnaire, patients were asked to report all paid employments since the age of 18. The key predictor variables included various occupational-related mechanical exposures. A job classification database was used to rate the level of exposure to various occupational physical activities. The outcomes were the extent of radiographic damage in the peripheral and axial joints, as measured by the modified Steinbrocker score (mSS), and the modified Stokes Ankylosing Spondylitis Spine Score (mSASSS). The association between the predictors and outcome variables was assessed by negative binomial regression models after adjusting for potential confounding variables. ResultsA total of 307 eligible patients were analyzed. In the multivariable analysis, exposure to prolonged repetitive hand movements (exp(β) 1.17 (95% 1.07, 1.28)) and occupations that required higher level of finger dexterity (exp(β) 1.27 (95% 1.09, 1.47)) were associated with a higher mSS. With regards to axial damage, none of the occupational exposures or workers abilities was associated with mSASSS. ConclusionHigh level of occupation-related mechanical stress is associated with increased radiographic peripheral joint damage among patients with longstanding PsA. This finding supports the potential role of micro-trauma in the pathogenesis of PsA.

Ustekinumab in psoriatic arthritis and related phenotypes.

Psoriatic arthritis (PsA) is an inflammatory arthritis that commonly occurs with psoriasis and is attributed to genetic, immunologic and environmental factors. The T-helper (Th)-17 pathway and the interleukin (IL)-23/IL-17 axis have become prominent players in PsA and considerably increased our understanding of disease pathogenesis. In this review article, we will focus on the emerging role of IL-12/23 and its blockade, in the pathogenesis and management of PsA as well as of psoriasis and inflammatory bowel disease. Ustekinumab, is a fully human monoclonal immunoglobulin (Ig)G1 antibody that binds specifically to the p40 subunit of IL-12 and IL-23, primarily inhibiting downstream Th-17 signalling pathways. Ustekinumab produced consistent and sustained clinical efficacy in two phase III clinical trials in PsA, PSUMMIT-1 and PSUMMIT-2, with data out to 52 weeks, and no new safety signals. PSUMMIT-1 included patients with active PsA despite conventional therapy who were all naïve to anti-tumour necrosis factor (TNF) agents, whereas PSUMMIT-2 also included anti-TNF experienced patients. Similarly, ustekinumab produced consistent clinical efficacy in two phase III clinical trials in psoriasis, PHOENIX-1 and PHOENIX-2, and in both induction and maintenance of moderate-to-severe Crohn's disease, UNITI-1, UNITI-2 and IM-UNITI, without an increased safety signal. Currently, ustekinumab is used in the treatment of PsA following the failure of nonsteroidal anti-inflammatory drugs (NSAIDs) and conventional disease-modifying antirheumatic drugs (DMARDs), and as an alternative to, or after failure of an anti-TNF agent.

Current treatment options for psoriatic arthritis: spotlight on abatacept.

Psoriatic arthritis (PsA) is a chronic inflammatory disease of joints, tendon sheaths, and entheses affecting patients with established skin psoriasis, or, less frequently, patients without a personal history of psoriasis with a positive familial history. Many treatment options are now available to deal with the different aspects of the disease, including traditional and biological disease-modifying antirheumatic drugs and the recently released targeted synthetic disease-modifying antirheumatic drugs. However, ~40% of patients still fail to achieve a meaningful clinical response to first-line biologic therapy advocating the development of novel medications. It is now well accepted that T-cells participate in the immunopathogenesis of several autoimmune diseases. For this reason, the potential intervention on T-cells represented an attractive therapeutic target for a long time, becoming a clinical reality with the development of abatacept. Abatacept is a biologic agent selectively targeting the T-cell costimulatory signal delivered through the CD80/86-CD28 pathway and was approved in December 2005 by the US Food and Drug Administration and in May 2007 by European Medicines Agency for the treatment of patients with rheumatoid arthritis in combination with methotrexate. Based on the relevant role of T-cells in PsA pathogenesis and following the positive results obtained in a phase III clinical trial, abatacept recently received approval for treatment of patients with PsA. In this review, we will focus on the current knowledge about the emerging role of abatacept in treatment of PsA.

Augmented Th17 Differentiation Leads to Cutaneous and Synovio-Entheseal Inflammation in a Novel Model of Psoriatic Arthritis.

To introduce a novel preclinical animal model of psoriatic arthritis (PsA) in R26Stat3Cstopfl/fl CD4Cre mice, and to investigate the role of Th17 cytokines in the disease pathogenesis. We characterized a novel murine model of Th17-driven cutaneous and synovio-entheseal disease directed by T cell-specific expression of a hyperactive Stat3 allele. By crossing R26Stat3Cstopfl/fl CD4Cre mice onto an interleukin-22 (IL-22)-knockout background or treating the mice with a neutralizing antibody against IL-17, we interrogated how these Th17 cytokines could contribute to the pathogenesis of PsA. R26Stat3Cstopfl/fl CD4Cre mice developed acanthosis, hyperkeratosis, and parakeratosis of the skin, as well as enthesitis/tendinitis and periarticular bone erosion in different joints, accompanied by osteopenia. T cell-specific expression of a hyperactive Stat3C allele was found to drive the augmented Th17 response in these animals. Careful characterization of the mouse bone marrow revealed an increase in osteoclast progenitor (OCP) and RANKL-producing cells, which contributed to the osteopenia phenotype observed in the mutant animals. Abrogation of the Th17 cytokines IL-17 or IL-22 improved both the skin and bone phenotype in R26Stat3Cstopfl/fl CD4Cre mice, revealing a central role of Th17 cells in the regulation of OCP and RANKL expression on stromal cells. Perturbation of the IL-23/Th17 axis instigates Th17-mediated inflammation in R26Stat3Cstopfl/fl CD4Cre mice, leading to cutaneous and synovio-entheseal inflammation and bone pathologic features highly reminiscent of human PsA. Both IL-17A and IL-22 produced by Th17 cells appear to play critical roles in promoting the cutaneous and musculoskeletal inflammation that characterizes PsA.

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

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. 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. 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 (β = 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 (β = 4.62 [95% CI 1.38, 7.86]). 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.

MiR-146a G/C rs2910164 variation in South African Indian and Caucasian patients with psoriatic arthritis

BackgroundPsoriasis and psoriatic arthritis (PsA) are inflammatory associated autoimmune disorders. MicroRNA (miR)-146a plays a crucial role in regulating inflammation. A single nucleotide polymorphism in the miR-146a gene (rs2910164), aberrantly alters its gene expression and linked with the pathogenesis of several disorders, including psoriasis and PsA. In South Africa, psoriasis and PsA are extremely rare in the indigenous African population and most common in both the Indian and Caucasian population. The aim of this study was to investigate whether the miR-146a rs2910164 contributes towards psoriasis and PsA development in South African Indian and Caucasian patients.MethodsSouth African Indian (n = 84) and Caucasian (n = 32) PsA patients (total n = 116) and healthy control subjects (Indian: n = 62 and Caucasian: n = 38; total n = 100) were recruited in the study. DNA was extracted from whole blood taken from all subjects, and genotyped for the miR-146a rs2910164 using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Data for laboratory parameters were obtained from pathology reports. The consulting rheumatologist collected all other clinical data.ResultsUnstratified data (Caucasians + Indians): A significant decrease in C-reactive protein (CRP) levels in PsA patients was observed (CRP monitored at inclusion vs. after 6 months of treatment) (18.95 ± 2.81 mg/L vs. 9.68 ± 1.32 mg/L, p = 0.0011). The miR-146a rs2910164 variant C-allele frequency in PsA patients was significantly higher vs. healthy controls (35.78% vs. 26% respectively, p = 0.0295, OR = 1.59 95% CI 1.05–2.40). Stratified data (Indians): The variant C-allele frequency in Indian PsA patients was significantly higher vs. healthy Indian controls (35.71% vs. 22.58%, p = 0.0200, OR = 1.91 95% CI 1.13–3.22). Stratified data (Caucasians): The variant C-allele frequency distribution between Caucasian PsA patients and healthy Caucasian controls was similar.ConclusionThe rs2910164 variant C-allele may play a role in the progression of PsA in the South African Indian population. The main limitation in this study was the small sample size in the case-control cohorts, with a low overall statistical power (post-hoc power analysis = 19%).

Genetics of Psoriatic Arthritis – an update

Psoriatic arthritis (PsA) is an inflammatory arthritis that commonly occurs with psoriasis and is attributed to genetic, immunologic and environmental factors. It shares skin involvement with psoriasis, articular involvement particularly with spondyloarthritis, bowel involvement with Crohn’s disease and eye involvement with uveitis, suggesting the existence of some common pathways. The Th-17 pathway and the IL-23/IL-17 axis have become prominent players in PsA and have considerably increased our understanding of disease pathogenesis. In this review article, we will focus on the genetic, epigenetic, and pharmacogenetic information with respect to PsA. Prominent genes identified in PsA via GWAS include HLA-A, HLA-B, HLA-C, IL-12B, IL-23R, IL-23A, TNIP1, TRAF3IP2, CSF2/P4HA2, FBXL19, REL, TYK2, NOS2, PTPN22, TNFAIP3, IFNLR1, IFIH1, and NFKBIA. These genetic markers have also illuminated key signaling pathways involved in PsA pathogenesis which can be broadly classified into those involved in epidermal differentiation, innate immunity, antigen presentation and processing, and acquired/adaptive immunity. With respect to PsA pathogenesis, the most consistent and predominant genetic effect is located on chromosome 6p21.3 within the major histocompatibility complex (MHC) region. The most significant association for increased PsA risk was with asparagine or serine residue at amino acid position 97 of HLA-B, where asparagine at position 97 of HLA-B represents the HLA-B*27 allele. Moreover, specific HLA alleles have been associated with disease susceptibility, expression and progression in PsA. The prominent emerging role of the Th-17 signaling pathway in PsA pathogenesis will be highlighted. The lack of identified PsA genetic susceptibility loci is largely attributed to the much smaller number of patients, classification criteria used, and the greater clinical heterogeneity of PsA compared with psoriasis.

Psoriatic arthritis: tissue-directed inflammation?

The clinical picture of psoriatic arthritis (PsA) is heterogeneous, potentially involving numerous organs and tissues, such as skin and joint. From a clinical point of view, discrete tissue PsA features develop and respond to treatments apparently independently. The pathogenic events occurring in the various tissues are only partially understood. Although the vast majority of known genetic predisposing factors are shared between patients with skin psoriasis (PSO) and those affected by PsA, some tissue-specific variants have been identified. Furthermore, current data suggest that the TNF pathway and IL-23/Th17 pathways may be differentially activated in distinct tissue sites. In this review, we briefly describe current knowledge on the pathogenesis of PsA in terms of genetic predisposition, environmental factors and immunology, advancing our hypothesis to explain why a common immunologic process can express itself with significant differences in various tissues.

Enthesitis: A hallmark of psoriatic arthritis

To describe the growing importance of enthesitis in patients with psoriatic arthritis (PsA) and discuss the advantages and disadvantages of clinical and imaging methods currently used to assess enthesitis. PubMed literature searches were conducted using the terms psoriatic arthritis, entheses, enthesitis, pathology, imaging, ultrasound, magnetic resonance imaging, clinical, and indices. Articles were deemed relevant if they provided insight into the pathology, monitoring, and/or diagnosis of enthesitis in PsA, or if they discussed clinical or imaging indices used to assess enthesitis. Enthesitis is an early manifestation of PsA that is associated with increased disease activity and reduced quality of life. A variety of clinical indices exist to assess enthesitis in PsA; however, the Leeds Enthesitis Index and Maastricht Ankylosing Spondylitis Enthesitis Score index have been the most frequently used indices in recent clinical trials. Limitations of these indices include an inability to discern structural involvement, risk of missing subclinical enthesitis, and lack of sensitivity in detecting enthesitis, especially in patients with central sensitization and/or pain amplification. Such limitations have led to the emergent importance of imaging techniques in the assessment of enthesitis. Although there have been recent advances in magnetic resonance imaging, ultrasound (US) appears to be the preferred method for detecting enthesitis because it allows for accurate assessment of the soft-tissue components of entheses and also for new bone formation. Hypoechogenicity, increased thickness of tendon insertion, calcifications, enthesophytes, erosions, and Doppler activity have been identified as important US characteristics of enthesitis. Enthesitis is thought to be integrally involved in the pathogenesis of PsA and is associated with worse prognostic outcomes in patients with PsA. A validated US index with entheses that are less confounded by mechanical factors and obesity would be the most effective measure of enthesitis in PsA. As imaging techniques continue to advance, our understanding of enthesitis and its involvement in PsA will also improve.

Targeting IL-17 in psoriatic arthritis.

Psoriatic arthritis (PsA) is a chronic and progressive inflammatory arthritis intimately associated with psoriasis, and can be an impairing disease that leads to reduced quality of life and significant morbidity. Treatment often requires TNF antagonists, yet many patients with PsA are not responsive to the standard anti-TNF therapies. The interleukin-17 (IL-17)/IL-17 receptor (IL-17R) family has recently been implicated in the pathogenesis of PsA and psoriasis. Much enthusiasm has been generated for the development of biologics that target the IL-17 signaling pathway directly or indirectly, many of which have produced striking results in the setting of psoriasis and PsA. Herein, we review the role of IL-17 and the IL-17 receptor (IL-17R) in the pathogenesis of PsA, as well as the clinical evidence for IL-17 and IL-17R targeted therapeutics.

Ixekizumab: an anti- IL-17A monoclonal antibody for the treatment of psoriatic arthritis

ABSTRACTIntroduction: Psoriatic arthritis (PsA) is an inflammatory rheumatic disease that manifests itself with synovitis, dactylitis, enthesitis and also axial involvement. Interleukin-17A has been identified as a master cytokine in the inflammatory response and pathogenesis of PsA and spondyloarthritis in general. Ixekizumab is a new humanized monoclonal antibody that blocks the biological activity of IL-17A. This biological agent has previously demonstrated a high level of efficacy in psoriasis.Areas covered: This review discusses the basic immunology of the IL-17 cytokine family, the contribution of IL-17A to the immunopathogenesis of PsA, the clinical trials that evaluated ixekizumab in patients with PsA (SPIRIT program) and the safety of this agent.Expert opinion: Ixekizumab demonstrated its efficacy in different aspects of PsA including peripheral joint involvement, dactylitis, skin symptoms and patient reported outcomes in the 2 phase III trials from the SPIRIT program. Its safety profile was consistent with previous observations in patients with psoriasis. The role of IL-17A in the management of patients with PsA needs further clarification. According to EULAR recommendations for the management of PsA, IL-17A inhibitors may be used as second line biological DMARDs after TNF inhibitors.

The LIM-Only Protein Four and a Half LIM Domain Protein 2 Attenuates Development of Psoriatic Arthritis by Blocking Adam17-Mediated Tumor Necrosis Factor Release

Four and a half LIM domain protein 2 (Fhl2) is an intracellular adaptor molecule with a high protein-protein interaction capacity. It acts as a modulator of several signaling molecules in the cytosol and as a cofactor of transcription in the nucleus. Recent studies suggest the role of Fhl2 in tissue repair and the anti-inflammatory response. Herein, we show that Fhl2-deficient mice develop a more severe psoriatic arthritis disease under induction of the inducible human tumor necrosis factor (hTNF) transgene than wild-type mice. The disease was accompanied by increased infiltration of activated macrophages and T regulatory cells in skin and digit joints as well as by increased expression of matrix metalloproteases and bone-specific proteases. The more severe pathogenesis of psoriatic arthritis in Fhl2 knockout mice coincided with enhanced levels of soluble hTNF cytokine, but surprisingly not with transcription of the hTNF transgene. Studying the shedding of cell membrane-bound hTNF by Adam17, a known Fhl2 interacting protein, revealed an enhanced release of TNF in the absence of Fhl2. In summary, our results show that Fhl2 anticipates the emerging inflammation and specifically the development of psoriatic arthritis by impeding the Adam17-mediated release of TNF.

Signs of innate immune activation and premature immunosenescence in psoriasis patients

Psoriasis is a chronic inflammatory disease that affects skin and is associated with systemic inflammation and many serious comorbidities ranging from metabolic syndrome to cancer. Important discoveries about psoriasis pathogenesis have enabled the development of effective biological treatments blocking the T helper 17 pathway. However, it has not been settled whether psoriasis is a T cell-mediated autoimmune disease or an autoinflammatory disorder that is driven by exaggerated innate immune signalling. Our comparative gene expression and hierarchical cluster analysis reveal important gene circuits involving innate receptors. Innate immune activation is indicated by increased absent in melanoma 2 (AIM2) inflammasome gene expression and active caspase 1 staining in psoriatic lesional skin. Increased eomesodermin (EOMES) expression in lesional and non-lesional skin is suggestive of innate-like virtual memory CD8+ T cell infiltration. We found that signs of systemic inflammation were present in most of the patients, correlated with the severity of the disease, and pointed to IL-6 involvement in the pathogenesis of psoriatic arthritis. Among the circulating T cell subpopulations, we identified a higher proportion of terminally differentiated or senescent CD8+ T cells, especially in patients with long disease duration, suggesting premature immunosenescence and its possible implications for psoriasis co-morbidities.

Psoriatic cutaneous inflammation promotes human monocyte differentiation into active osteoclasts, facilitating bone damage.

Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy that can be associated with focal bone erosions. Psoriasis usually precedes the psoriatic arthritis onset by an average of 10 years, but this relation is not yet fully elucidated. Pro-inflammatory cytokines, such as IL-33, OPN, IL-17, and TNF-α are involved in both psoriasis and PsA pathogenesis as well as in bone homeostasis. In this study, we have demonstrated that IL-33, OPN, IL-17, and TNF-α induced the release of a wide range of pro-osteoclastogenic factors from the skin, such as RANKL, that promote monocyte differentiation in osteoclasts. The addition of osteoprotegerin, a RANKL inhibitor, to monocyte cultures treated with supernatant from stimulated skin did not completely deplete osteoclast formation, suggesting that skin produced several additional pro-osteoclastogenic mediators, which could act in a RANKL-independent manner. Moreover, we have found that RANKL serum levels as well as osteoclast number and activity in psoriatic patients with and without arthritis, was influenced by severity of cutaneous disease. Our data demonstrate that psoriatic cutaneous inflammation contributes to bone damage.

Use of the interleukin-17A inhibitor secukinumab in psoriatic arthritis: a subanalysis of the Russian population in the international randomized clinical trials FUTURE 1 and FUTURE 2

The investigators carried out an analysis of the efficacy and safety of secukinumab (SEC) in the randomized placebocontrolled trials (RPCTs) FUTURE 1 and FUTURE 2, as well as a subanalysis of the data obtained in the Russian population of patients with active psoriatic arthritis (PsA). The FUTURE 1 and FUTURE 2 trials enrolled a total of 1003 patients with active PsA. They received SEC (n = 703) or placebo (PL) (n = 300). The use of SEC 300 or 150 mg without previous intravenous (IV) loading dose or either 150 or 75 mg with the IV loading dose led to a significant improvement in patients with PsA. The positive changes in the main clinical manifestations of PsA at 24 weeks persisted until 52 weeks of therapy. SEC was effective in both the patients who had not previously received tumor necrosis factor-α inhibitors and those who had previously taken these drugs, and the result of therapy did not depend on concomitant methotrexate use.The incidence of cancer was low and comparable in the SEC and PL groups. Analysis of the combined data on the safety of the two RPCTs showed that the treatment duration-adjusted incidence of malignant neoplasms was 0.5 per 100 patient-years in the SEC groups and 0.9 in the PL groups. The safety profile of SEC in these RPCTs corresponds to that in the previous studies of the drug.The data from the pooled analysis of the Russian subpopulation of patients with PsA fully agree with the results obtained in the evaluation of all the patients included in FUTURE 1 and FUTURE 2 and confirm the most important role of IL-17А in the pathogenesis of PsA.

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

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. 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. 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). CXCL10 may be involved in PsA pathogenesis and is a candidate predictive biomarker for PsA in patients with psoriasis.

Interleukin (IL)-9/IL-9R axis drives γδ T cells activation in psoriatic arthritis patients.

Cytokines such as tumour necrosis factor (TNF)-α, interleukin (IL)-12, interferon (IFN)-γ, IL-23 and, more recently, IL-9, have been implicated in the initiation/maintenance of inflammation in psoriasis and psoriatic arthritis (PsA). In the present study we aimed to characterize the role of γδ T cells in peripheral blood and synovial fluid of PsA patients and to investigate their response to in-vitro stimulation with antigen or cytokines (IL-9 and IL-23). γδ T cells isolated from peripheral blood mononuclear cells and synovial fluid were analysed by flow cytometry to evaluate the phenotype and cytokine production. IL-23R and IL-9R gene expression were also evaluated by reverse transcription-polymerase chain reaction (RT-PCR). Peripheral blood mononuclear cells (PBMC), sorted γδ T cells and γδ cell lines were also stimulated in vitro with isopentenyl pyrophosphate (IPP), recombinant IL-9 or recombinant IL-23. Our results show an expansion of γδ T cells with a predominant effector memory phenotype in peripheral blood and synovium of untreated PsA patients, which reverses significantly after treatment with anti-TNF-α or anti-IL-12/IL-23R monoclonal antibodies (mAbs). Moreover, in PsA patients γδ T cells activation is driven prevalently by IL-9/IL-9R interaction, and not only by IL-23/IL-23R. Together these findings indicate γδ T cells and IL-9 as new players in the pathogenesis of PsA.