Pathogenesis Of Psoriatic Arthritis Research Articles

Serum sCD40L levels are increased in patients with psoriatic arthritis and are associated with clinical response to apremilast.

The pathogenesis of psoriatic arthritis (PsA) involves several pathways, including the CD40/CD40L signaling which promotes the release of multiple cytokines. Transmembrane CD40L is also released in soluble form (sCD40L) and phosphodiesterase 4 (PDE4) seems to be involved in its cleavage. We aimed to investigate whether apremilast, a PDE4 inhibitor, could modify circulating levels of sCD40L in PsA patients, and the possible associations of these changes with clinical response. Consecutive PsA patients starting apremilast in routine clinical practice were prospectively observed. Disease Activity of Psoriatic Arthritis (DAPSA), Psoriasis Area Severity Index (PASI), Leeds Enthesitis Score (LEI) and serum samples were collected at baseline and at 6months. Samples were run in a Bio-Plex ProTM plate for sCD40L. To investigate the association of sCD40L level with DAPSA based minor response, low disease activity (LDA) and/or remission at 6months of treatment, multivariate logistic regression models with backward selection (P<0·05) were built. We studied 27patients (16 of 27 women, 59·6%) with PsA and mean age [±standard deviation (s.d.)] of 58·4±10years. A significant reduction of the mean values of DAPSA, LEI and PASI was detected at 6months. Mean serum levels of sCD40L decreased from baseline 5364±2025pg/ml to 4412±2629 at 6months (P=0·01). Baseline DAPSA [odds ratio (OR)=0·80, 95% confidence interval (CI)=0·65-0·98] and sCD40L (OR=1·001, 95% CI=1·0001-1·0027) were independently associated with DAPSA LDA/remission at 6months. In PsA patients, sCD40L levels decrease upon apremilast treatment and might predict short-term clinical response to apremilast.

Skin expression of IL-23 drives the development of psoriasis and psoriatic arthritis in mice

Psoriasis (PS) is a chronic skin inflammation. Up to 30% of the patients with PS develop psoriatic arthritis (PsA), a condition characterized by inflammatory arthritis that affects joints or entheses. Although there is mounting evidence for a critical role of interleukin-23 (IL-23) signaling in the pathogenesis of both PS and PsA, it remains unclear whether IL-23-induced skin inflammation drives joint disease. Here, we show that mice expressing increased levels of IL-23 in the skin (K23 mice) develop a PS-like disease that is characterized by acanthosis, parakeratosis, hyperkeratosis, and inflammatory infiltrates in the dermis. Skin disease preceded development of PsA, including enthesitis, dactylitis, and bone destruction. The development of enthesitis and dactylitis was not due to high circulating levels of IL-23, as transgenic animals and controls had similar levels of this cytokine in circulation. IL-22, a downstream cytokine of IL-23, was highly increased in the serum of K23 mice. Although IL-22 deficiency did not affect skin disease development, IL-22 deficiency aggravated the PsA-like disease in K23 mice. Our results demonstrate a central role for skin expressed IL-23 in the initiation of PS and on pathogenic processes leading to PsA.

Guselkumab in biologic-naive patients with active psoriatic arthritis (DISCOVER-2): a double-blind, randomised, placebo-controlled phase 3 trial

The interleukin-23 (IL-23)/T-helper 17 cell pathway is implicated in psoriatic arthritis pathogenesis. Guselkumab, an IL-23 inhibitor that specifically binds the IL-23 p19 subunit, significantly and safely improved psoriatic arthritis in a phase 2 study. DISCOVER-2 was a phase 3 trial to assess guselkumab in biologic-naive patients with psoriatic arthritis. This phase 3, double-blind, placebo-controlled study was done at 118 sites in 13 countries across Asia, Europe, and North America. We enrolled biologic-naive patients with active psoriatic arthritis (at least five swollen joints, at least five tender joints, and C-reactive protein ≥0·6 mg/dL) despite standard therapies. Patients were randomly assigned (1:1:1, computer-generated permuted blocks; stratified by baseline disease-modifying antirheumatic drug use and C-reactive protein concentration) to subcutaneous injections of guselkumab 100 mg every 4 weeks; guselkumab 100 mg at weeks 0, 4, then every 8 weeks; or placebo. The primary endpoint was American College of Rheumatology 20% improvement (ACR20) response at week 24 in all patients per assigned treatment group. Safety was assessed in all patients per treatment received. This trial is registered at ClinicalTrials.gov, NCT03158285 (active, not recruiting). From July 13, 2017, to Aug 3, 2018, 1153 patients were screened, of whom 741 were randomly assigned to receive guselkumab every 4 weeks (n=246), every 8 weeks (n=248), or placebo (n=247). One patient in the every 4 weeks group and one in the placebo group did not start treatment, and the remaining 739 patients started treatment; 716 patients continued treatment up to week 24. Significantly greater proportions of patients in the guselkumab every 4 weeks group (156 [64%] of 245 [95% CI 57-70]) and every 8 weeks group (159 [64%] of 248 [58-70]) than in the placebo group (81 [33%] of 246 [27-39]) achieved an ACR20 response at week 24 (percentage differences vs placebo 31% [95% CI 22-39] for the every 4 weeks group and 31% [23-40] for the every 8 weeks group; both p<0·0001). Up to week 24, serious adverse events occurred in eight (3%) of 245 patients receiving guselkumab every 4 weeks (three serious infections), three (1%) of 248 receiving guselkumab every 8 weeks (one serious infection), and seven (3%) of 246 receiving placebo (one serious infection). No deaths occurred. Guselkumab, a human monoclonal antibody that specifically inhibits IL-23 by binding the cytokine's p19 subunit, was efficacious and demonstrated an acceptable benefit-risk profile in patients with active psoriatic arthritis who were naive to treatment with biologics. These data support the use of selective inhibition of IL-23 to treat psoriatic arthritis. Janssen Research and Development.

Clinical, Serological and Immunological Characteristics in Greek Patients with Psoriatic Arthritis: The Role of IL-17, IL-23, and Sclerostin.

Psoriatic arthritis (PsA) is an inflammatory form of arthritis that belongs to the family of spondyloarthritis (SpA) and is related to skin psoriasis. The incidence and prevalence of the disease vary considerably between countries. PsA is classified into axial PsA and peripheral PsA, with a wide range of other extra-articular manifestations. Although the aetiology of the disease is unknown, genetic, environmental, and immunologic factors appear to affect its appearance. In recent years, the role of the immune system in the pathogenesis of PsA has been increasingly investigated. Specific cytokines such as tumour necrosis factor (TNF), interleukin (IL-) 17 and IL-23, play an essential role affecting joint structures. This observation led to the emergence of tumour necrosis factor inhibitors (TNFi) that offer considerable therapeutic benefit to PsA patients. However, chronic inflammation causes bone loss, while new bone formation may also occur in both peripheral and axial skeleton. The molecular mechanisms underlying these processes have not yet been fully understood. So far, the role of the Wnt/β-catenin pathway and its inhibitors (Dickkopf and sclerostin) has been evaluated in ankylosing spondylitis (AS), but in PsA has not been studied sufficiently. The present study aims to investigate the epidemiological characteristics and clinical features (articular and extra-articular manifestations) as well as the treatment of PsA patients in the region of northwestern (NW) Greece. It also aims to evaluate the role of specific cytokines and sclerostin in patients with PsA, giving evidence to possible future biomarkers or even therapeutic targets for the disease.

The gut microbiome in psoriasis and psoriatic arthritis.

This review summarizes existing research on the gut microbiome composition and function in psoriasis and psoriatic arthritis, exploring potential roles in disease pathogenesis, progression, and management. A strong relationship between skin, joint, and gastrointestinal inflammation exists, as demonstrated by an increased prevalence of psoriasis, psoriatic arthritis, and inflammatory bowel disease co-occurring together; however, the link between them has not been fully elucidated. Studies analyzing the gut microbiome in psoriasis and psoriatic arthritis reveal a unique pattern of dysbiosis. With regard to the gut microbiome's role in psoriasis and psoriatic arthritis pathogenesis, we discuss several theories including intestinal permeability, altered immune homeostasis, and imbalance of short- and medium-chain fatty acid-producing bacteria. We also discuss how the gut microbiome affects patient risk of psoriatic arthritis and other serious comorbidities, and how fecal microbes could be used clinically as therapeutic targets or markers of disease.

The safety and optimal dosage of an interleukin-17A inhibitor (secukinumab) in the treatment of psoriatic arthritis in a patient with concomitant hepatitis C virus infection

Psoriatic arthritis (PsA) is a chronic inflammatory disease of the group of spondylitides, which is associated with psoriasis. The decisive role is played by the activation of the interleukin (IL)-23/IL-17 axis in the pathogenesis of PsA [1]. Secukinumab (SEC) is a fully human antibody that binds to human IL-17A and neutralizes the activity of this cytokine. That the patient has concomitant diseases, chronic hepatitis B virus infection and hepatitis C viral (HCV) infection in particular, limits the use of tumor necrosis factor- α inhibitors in the treatment of PsA [2, 3]. The paper describes a clinical case that demonstrates the successful treatment with SEC in a patient with PsA and concomitant HCV infection. In addition to the safety aspects of the use of SEC to treat chronic HCV infection, the issues on optimal dosing of the drug are discussed.

Functional significance of MAIT cells in psoriatic arthritis

BackgroundMucosal-associated invariant T (MAIT) cells are gaining more relevance for autoimmune diseases because of its (i) innate and adaptive immune response (ii) tissue homing properties (iii) production of IL-17A. These cells are predominantly CD8+ cells, because of its strong association with MHC-I. Tc17 CD8+/MAIT cells likely to have a critical role in psoriatic arthritis (PsA). Herein, we have explored pathological significance of MAIT cell in PsA. MethodsPeripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMC) were collected from age/sex matched (n = 10 for each) PsA, rheumatoid arthritis (RA) and osteoarthritis patients (OA). Hi-D FACS studies were performed: (i) activated memory cells (CD3+CD45RO+) T cells were identified (ii) gating strategies were made to identity the MAIT (CD3+Vα7.2TCR+CD161hi) cells, its phenotype pattern; and functional significance in respect to IL-17A production and responsiveness to human rIL-23. Anti CD3/CD28 ab cocktail was used to activate cells along with rIL-23 to culture and enrich the MAIT cells. The percentages of each cell population and the mean fluorescence intensity (MFI) were analyzed using Flow Jo software. ResultsMAIT cells were enriched in synovial fluid of PsA (4.29 ± 0.82%) compared to PBMC (1.04 ± 0.71). With stimulation, SFMC MAIT cells produced significantly more IL-17A (32.66 ± 4.01%) compared to that of RA (23.93 ± 2.81%, p < 0.05) and OA (5.02 ± 0.16%, p < 0.05). MAIT cells were predominantly CD8+ (>80%). Significant upregulation of IL-23R was noted in synovial fluid MAIT cells of PsA (24.97 ± 2.33%, p < 0.001) and RA (21.93 ± 2.29%, p < 0.001) compared to that of OA (2.13 ± 2.29). This IL-23R was functionally active as evidenced by profound mitotic effect in presence of rIL-23. ConclusionMAIT cells are poly functional; produce multiple cytokines (IL-17A, IFN-γ, TNF-α). Here, we demonstrated synovial fluid MAIT cells as a major source of IL-17A and majority of MAIT cells were CD8+. Functionally active IL-23R on these migrated MAIT cells brings a new dimension. They may not need MR1 associated activation rather lesional IL-23 in the synovium can independently regulate these critical Tc17 CD8+ MAIT cells. Thus, these cells likely to be a part of the IL-23/IL-17A cytokine network and play a critical role in the pathogenesis of PsA.

Comprehensive analyses of long non-coding RNA expression profiles by RNA sequencing and exploration of their potency as biomarkers in psoriatic arthritis patients

BackgroundThe aim of the current study was to investigate the long non-coding RNA (lncRNA) expression profiles in psoriatic arthritis (PSA) patients by RNA sequencing, and to further explore potential biomarkers that were able to predict PSA risk and activity.MethodsLncRNA and mRNA expression profiles in peripheral blood mononuclear cells (PBMC) of 4 PSA patients and 4 normal controls (NCs) were detected by RNA sequencing, followed by comprehensive bioinformatic analyses. Subsequently, 3 top upregulated and 2 top downregulated lncRNAs were chosen for further validation in 93 PSA patients and 93 NCs by quantitative polymerase chain reaction (qPCR) assay.ResultsTotally 76 upregulated and 54 downregulated lncRNAs, as well as 231 upregulated and 102 downregulated mRNAs were discovered in PSA patients compared with NCs. Enrichment analyses revealed that they were mostly associated with nucleosome, extracellular exosome and extracellular matrix, and the top enriched pathways were systemic lupus erythematosus (SLE), alcoholism and viral carcinogenesis. qPCR assay showed that lnc-RP11-701H24.7 and lnc-RNU12 were upregulated in PSA patients compared with NCs, and they could predict PSA risk with high area under curves. Besides, lnc-RP11-701H24.7 was positively associated with ESR, SJC, TJC and pain VAS score while lnc-RNU12 was positively correlated with PASI score, CRP and PGA score, implying that both of them were positively correlated with disease activity.ConclusionOur study facilitates comprehensive understanding of lncRNA expression profiles in PSA pathogenesis, and discovers that lnc-RP11-701H24.7 and lnc-RNU12 might be served as novel biomarkers for PSA risk and activity.

Psoriatic Arthritis: What is Happening at the Joint?

Psoriatic arthritis (PsA) is a heterogeneous and inflammatory disease with diverse clinical manifestations, including psoriasis, nail psoriasis, peripheral joint disease, axial joint disease, enthesitis, and dactylitis. Typically, this varied clinical presentation complicates the clinician’s ability to distinguish PsA from other forms of arthritis. In the synovium of individuals with PsA, upregulation of the genes WNT3A, BMPR2, and TGFBR1 results in bone erosion and new bone formation, a pattern unique to the disease. Additionally, genes associated with angiogenesis and vascularization such as VEGF and TGFB1 facilitate inflammation and joint damage. Gross pathogenesis of PsA is driven by proinflammatory cytokines, and key cytokines affecting joint structures include tumor necrosis factor-α, interleukin (IL)-6, IL-17A, IL-21, IL-22, and IL-23. Early diagnosis is critical for providing treatment that prevents irreversible disease progression and function loss. This narrative review discusses differentiation of PsA from other forms of arthritis. Additionally, we detail the role of cytokines at the joint in mediating PsA pathogenesis.Funding: Novartis Pharmaceuticals Corporation.

Discovery of Autoantibodies Associated with Psoriatic Arthritis

Abstract Objective The autoimmune etiology in psoriasis is not very clear, we aim to identify autoantigens and autoantibodies in psoriasis, which may shed light on the molecular and cellular basis of the pathogenesis of psoriasis and psoriatic arthritis. Methods In this study, we developed an autoantigen array system harboring a variety of antigens including typical autoantigens in rheumatic diseases as well as skin antigens, inflammatory mediators and putative autoantigens in psoriasis. Sera from psoriasis patients (N = 73) were used to interrogate antigens on the array. Individual ELISA was also used in validation studies. Results We found several serum autoantibodies were elevated in psoriasis patients compared to healthy controls; particularly, IgG autoantibodies against two novel antigens, LL37 and ADAMTSL5, were significantly increased in the psoriasis patients compared to healthy controls. Importantly, serum levels of IgG autoantibodies against LL37 and ADAMTSL5 were correlated with Psoriasis Area and Severity Index (PASI), and reflected disease progression in longitudinally collected samples from psoriasis patients. Importantly, we found both anti-ADAMTSL5 and anti-LL-37 autoantibodies were significantly elevated in psoriatic arthritis (PsA) compared to Non-PsA, suggesting that these molecules may be involved in the pathogenesis of psoriatic arthritis. Conclusion Our findings suggest that these autoantibodies may be useful biomarkers and indicative of therapeutic targets of psoriasis and psoriatic arthritis.

Identification of Novel Autoantibodies Associated With Psoriatic Arthritis.

The autoimmune etiology in psoriasis remains to be clarified. We therefore undertook this study to identify novel pathogenic autoantigens and autoantibodies in patients with psoriasis, with the aim of shedding light on the molecular and cellular basis of the pathogenesis of psoriasis and psoriatic arthritis (PsA). In this study, we developed an autoantigen array system that harbors a variety of antigens, including typical autoantigens in rheumatic diseases as well as skin antigens, inflammatory mediators, and putative autoantigens in psoriasis. Serum samples from patients with psoriasis (n = 73) were used to interrogate the antigens on the array. In addition, enzyme-linked immunosorbent assays of individual autoantibodies were used in validation studies. Levels of several autoantibodies were found to be elevated in the serum of patients with psoriasis compared to healthy controls; in particular, IgG autoantibodies against 2 novel antigens, LL-37 and ADAMTS-L5, were significantly increased in patients with psoriasis. Importantly, serum levels of IgG autoantibodies against LL-37 and ADAMTS-L5 were correlated with the Psoriasis Area and Severity Index, and reflected disease progression in longitudinally collected serum samples from patients with psoriasis. Importantly, both anti-ADAMTS-L5 and anti-LL-37 autoantibody levels were also significantly elevated in psoriasis patients with PsA compared to those without PsA, suggesting that these molecules may be involved in the pathogenesis of PsA. Our findings indicate that these identified autoantibodies may be useful biomarkers and may serve as therapeutic targets in psoriasis and PsA.

Amplifying the concept of psoriatic arthritis: The role of autoimmunity in systemic psoriatic disease.

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis that may be present in near 30% of patients affected by psoriasis (PsO), clinically characterized by inflammation of periarticular (e.g., enthesis) and articular structures. Recently, an autoimmune footprint of PsA pathogenesis has been demonstrated with the presence of autoantigens and related autoantibodies in PsA patients' sera. In this context, histological features of PsA synovitis supports the relevance of an autoimmune pathogenesis of the disease. Since there is no currently validated test for PsA, the analysis of PsA synovial tissue revealed pathognomonic characteristics of PsA that may support the clinician in the clinical practice. PsA synovitis is characterized by a sublining infiltrate with T and B cells, vascular proliferation and a relative thin lining layer of proliferating intimal synoviocytes. PsA synovial histopathology shows that ectopic lymphoid-neogenesis with an increase of IL-23 expression. These new pathogenetics features and the systemic nature of the disease raised the concept of a Systemic Psoriatic Disease (SysPsD), characterized by multiple extra-cutaneous and -articular manifestations, highlightening the great heterogeneity of this condition. SyPsD represents a heterogeneous chronic inflammatory condition with a wide spectrum of phenotypical manifestations. The purpose of this review is to describe the new pathogenetic mechanisms and the different clinical pictures of SysPsD, with the ultimate goal of improving the knowledge of this heterogeneous chronic inflammatory condition.

Psoriatic arthritis: pathogenetic features and innovative therapies

The paper considers the modern concepts of the etiology and pathogenesis of psoriatic arthritis (PsA). The latter is currently indicated as a T-cell-mediated disease that is based on the activation of cellular immunity, followed by the hyperproduction and imbalance of key pro- and anti-inflammatory cytokines, such as tumor necrosis factor-α (TNF- α), interleukin-1β (IL-1β), IL-6, IL-12/23, and IL-17. The paper presents the basic principles of diagnosis and clinical manifestations of the disease and notes the importance of screening questionnaires, the use of which allows specialists to diagnose PsA early, by actively identifying articular complaints, the characteristic clinical and radiological signs of damage to the joint, spine, and entheses. It is pointed out that the key target of pharmacotherapy for PsA is to achieve remission or minimal activity of the main clinical manifestations of the disease, to slow down or prevent its radiographic progression, to increase the length and quality of life in patients, and to reduce the risk of comorbidities. The authors characterize the major groups of used drugs: nonsteroidal anti-inflammatory drugs, conventional and targeted synthetic disease-modifying antirheumatic drugs, and biological drugs (inhibitors of TNF-α, IL-12/23, and IL-17). The key Treat-to-target principles of patient management are considered; it is noted that strict control over disease activity and treatment results provides suppression of all major clinical manifestations of PsA. The paper also shows the basic principles of the creation and further development of the All-Russian Registry of PsA patients, which makes it possible to optimize management decision-making on the provision of high-tech medical care and drugs for this cohort of patients.

Pathogenesis of Psoriatic Arthritis

Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy involving synovial and entheseal structures, associated with psoriasis or similar conditions. The etiopathogenetic mechanisms underlying PsA remain unclarified. The most accredited hypothesis involves a complex interaction among genetic, environmental, and immunological factors. Environmental agents, particularly trauma, mechanical stress, and smoke have been cited as possible factors in triggering the disease in genetically predisposed subjects. Like other forms of spondyloarthropathies, PsA shows several genetic associations with the major histocompatibility complex (MHC) class I alleles located on chromosome 6p21.3, particularly the human leukocyte antigen (HLA)-B27 in axial phenotypes. Recent studies have demonstrated that the most common epigenetic mechanisms that regulate gene expression in PsA are represented by DNA methylation, parent of origin effect or genomic imprinting, expression or activity of epigenetic modifying enzymes, and RNA interference (RNAi) by microRNAs (miRNAs). The mechanisms underlying PsA pathogenesis activate the innate and adaptive immune system and overexpression of TNF associated with amplification of the IL-23/IL-17 axis. In recent years, more PsA susceptibility genes and epigenetic mechanisms have been identified. Advances in the knowledge of innate and adaptive immune mechanisms underlying PsA have contributed to a better understanding of the heterogeneous clinical expression of the disease and, thus, to therapy strategies. The complexity of the pathogenetic aspects involving multiple cytokines, cell lines, and molecules needs to be further investigated to advance personalized therapeutic strategies and to improve outcomes of patients affected by PsA.

Potential Role of Cytochrome c and Tryptase in Psoriasis and Psoriatic Arthritis Pathogenesis: Focus on Resistance to Apoptosis and Oxidative Stress.

Psoriasis (PsO) is an autoimmune disease characterized by keratinocyte proliferation, chronic inflammation and mast cell activation. Up to 42% of patients with PsO may present psoriatic arthritis (PsA). PsO and PsA share common pathophysiological mechanisms: keratinocytes and fibroblast-like synoviocytes are resistant to apoptosis: this is one of the mechanism facilitating their hyperplasic growth, and at joint level, the destruction of articular cartilage, and bone erosion and/or proliferation. Several clinical studies regarding diseases characterized by impairment of cell death, either due to apoptosis or necrosis, reported cytochrome c release from the mitochondria into the extracellular space and finally into the circulation. The presence of elevated cytochrome c levels in serum has been demonstrated in diseases as inflammatory arthritis, myocardial infarction and stroke, and liver diseases. Cytochrome c is a signaling molecule essential for apoptotic cell death released from mitochondria to the cytosol allowing the interaction with protease, as the apoptosis protease activation factor, which lead to the activation of factor-1 and procaspase 9. It has been demonstrated that this efflux from the mitochondria is crucial to start the intracellular signaling responsible for apoptosis, then to the activation of the inflammatory process. Another inflammatory marker, the tryptase, a trypsin-like serine protease produced by mast cells, is released during inflammation, leading to the activation of several immune cells through proteinase-activated receptor-2. In this review, we aimed at discussing the role played by cytochrome c and tryptase in PsO and PsA pathogenesis. To this purpose, we searched pathogenetic mechanisms in PUBMED database and review on oxidative stress, cytochrome c and tryptase and their potential role during inflammation in PsO and PsA. To this regard, the cytochrome c release into the extracellular space and tryptase may have a role in skin and joint inflammation.

Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active psoriatic arthritis (EQUATOR): results from a randomised, placebo-controlled, phase 2 trial

The Janus kinase 1 (JAK1) pathway has been implicated in the pathogenesis of psoriatic arthritis. We aimed to investigate the efficacy and safety of filgotinib, a selective JAK1 inhibitor, for the treatment of psoriatic arthritis. The EQUATOR trial was a randomised, double-blind, placebo-controlled phase 2 trial that enrolled adults from 25 sites in seven countries (Belgium, Bulgaria, Czech Republic, Estonia, Poland, Spain, and Ukraine). Patients (aged ≥18 years) had active moderate-to-severe psoriatic arthritis (defined as at least five swollen joints and at least five tender joints) fulfilling Classification for psoriatic arthritis (CASPAR) criteria, active or a documented history of plaque psoriasis, and an insufficient response or intolerance to at least one conventional synthetic disease-modifying anti-rheumatic drug (csDMARD). Patients continued to take csDMARDs during the study if they had received this treatment for at least 12 weeks before screening and were on a stable dose for at least 4 weeks before baseline. Using an interactive web-based system, we randomly allocated patients (1:1) to filgotinib 200 mg or placebo orally once daily for 16 weeks (stratified by current use of csDMARDs and previous use of anti-tumour necrosis factor). Patients, study team, and sponsor were masked to treatment assignment. The primary endpoint was proportion of patients achieving 20% improvement in American College of Rheumatology response criteria (ACR20) at week 16 in the full analysis set (patients who received at least one dose of study drug), which was compared between groups with the Cochran-Mantel-Haenszel test and non-responder imputation method. This trial is registered with ClincalTrials.gov, number NCT03101670. Between March 9, and Sept 27, 2017, 191 patients were screened and 131 were randomly allocated to treatment (65 to filgotinib and 66 to placebo). 60 (92%) patients in the filgotinib group and 64 (97%) patients in the placebo group completed the study; five patients (8%) in the filgotinib group and two patients (3%) in the placebo group discontinued treatment. 52 (80%) of 65 patients in the filgotinib group and 22 (33%) of 66 in the placebo group achieved ACR20 at week 16 (treatment difference 47% [95% CI 30·2-59·6], p<0·0001). 37 (57%) patients who received filgotinib and 39 (59%) patients who received placebo had at least one treatment-emergent adverse event. Six participants had an event that was grade 3 or worse. The most common events were nasopharyngitis and headache, occurring at similar proportions in each group. One serious treatment-emergent adverse event was reported in each group (pneumonia and hip fracture after a fall), one of which (pneumonia) was fatal in the filgotinib group. Filgotinib is efficacious for the treatment of active psoriatic arthritis, and no new safety signals were identified. Galapagos and Gilead Sciences.

Golimumab in the treatment of psoriatic arthritis

ABSTRACTIntroduction: Psoriatic arthritis (PsA) is an inflammatory arthritis that can be aggressive and destructive, resulting in significant morbidity. While many new agents have been approved for the treatment of PsA over the past decade, TNF inhibitors (TNFi)remain an anchor treatment, in part based on extensive clinical experience. Recently, the TNFi golimumab was approved for intravenous use in PsA.Areas covered: This expert review presents an overview of the currently available treatment options for PsA with a focus on the evidence from clinical trials supporting the use of golimumab in PsA. This information is placed in context with recent advances in the understanding of PsA pathogenesis and treatment.Expert commentary: The rapid growth of treatment options available for PsA has brought the prospect of personalized treatment selection closer to reality but improved understanding of the domains of PsA and new biomarkers may be needed before such changes reach the clinic. Until patients who are most likely to benefit from a given agent can be identified and then treated accordingly, TNFi will likely remain a central option and their further development, such as the introduction of an intravenous form of golimumab, remains an important part of treatment improvement.

Anti-LL37 Antibodies Are Present in Psoriatic Arthritis (PsA) Patients: New Biomarkers in PsA.

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis. A third of psoriatic patients develop PsA via unknown mechanisms. No reliable diagnostic markers are available for PsA, or prognostic biomarkers for PsA development in psoriasis. We previously uncovered a pro-inflammatory role for cathelicidin LL37 in lesional psoriasis skin. LL37 binds nucleic acids and stimulates plasmacytoid/myeloid dendritic cells (pDC, mDCs) to secrete type I interferon (IFN-I) and pro-inflammatory factors. LL37 becomes an autoantigen for psoriatic Th1-Th17/CD8 T cells. Anti-LL37 antibodies were detected in systemic lupus erythematosus, an autoimmune disease characterized by neutrophil-extracellular-traps release (NETosis) in target organs. LL37 can be substrate of irreversible post-translational modifications, citrullination or carbamylation, linked to neutrophil activity. Here we analyzed inflammatory factors, included LL37, in PsA and psoriasis plasma and PsA synovial fluids (SF)/biopsies. We show that LL37 (as a product of infiltrating neutrophils) and autoantibodies to LL37 are elevated in PsA, but not OA SF. Anti-LL37 antibodies correlate with clinical inflammatory markers. Anti-carbamylated/citrullinated-LL37 antibodies are present in PsA SF/plasma and, at lower extent, in psoriasis plasma, but not in controls. Plasma anti-carbamylated-LL37 antibodies correlate with PsA (DAS44) but not psoriasis (PASI) disease activity. Ectopic lymphoid structures, and deposition of immunoglobulin-(Ig)G-complexes (IC) co-localizing with infiltrating neutrophils, are observed in PsA and not OA synovial tissues (ST). Activated complement (C5a, C9), GM-CSF and IFN-I are up-regulated in PsA and not OA synovia and in PsA and psoriasis plasma but not in HD. C9 and GM-CSF levels in PsA SF correlate with clinical inflammatory markers and DAS44 (C9) and with anti-carbamylated/citrullinated-LL37 antibodies (GM-CSF and IFN-I). Thus, we uncover a role for LL37 as a novel PsA autoantibody target and correlation studies suggest participation of anti-LL37 antibodies to PsA pathogenesis. Notably, plasma antibodies to carbamylated-LL37, which correlate with DAS44, suggest their use as new disease activity markers. GM-CSF and complement C5a and C9 elevation may be responsible for autoantigens release by neutrophils and their modification, fueling inflammation and autoreactivity establishment. Finally, targeting GM-CSF, C5a, C9 can be beneficial in PsA.

The History of Psoriatic Arthritis (PsA): From Moll and Wright to Pathway-Specific Therapy.

Psoriatic arthritis is a distinct disorder, separate from rheumatoid arthritis, and first recognized in a thirteenth century Saxon skeleton. It was, however, the monumental work of Verna Wright in the 1950s that led to the acceptance by the American Rheumatism Association (now American College of Rheumatology) in 1964 as a distinct entity. Wright's work provided the framework for a better understanding of the pathogenic mechanisms operating on this condition, and eventually led to the development of targeted therapy that has proven to be more effective and safe than conventional therapy. Pathogenesis of psoriatic arthritis has been better delineated in recent years, as well as the use of biological therapy. Recent findings are discussed in detail. Historical aspects of psoriatic arthritis, recent developments in pathogenesis, and therapy are discussed, and the contributions of Verna Wright to our understanding of the disorder are presented.

Distinguishing rheumatoid arthritis from psoriatic arthritis

Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) have key differences in clinical presentation, radiographic findings, comorbidities and pathogenesis to distinguish between these common forms of chronic inflammatory arthritis. Joint involvement...