Biomarkers In Psoriatic Arthritis Research Articles

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.

Exploring the Psoriatic Arthritis Proteome in Search of Novel Biomarkers.

Psoriatic arthritis (PsA) is an inflammatory arthritis which develops in up to one-third of patients suffering from the cutaneous disorder, psoriasis. The complex and heterogeneous nature of PsA renders it difficult to diagnose, leading to poor outcomes and, therefore, warrants an examination into soluble biomarkers, which may facilitate early detection of the disease. Protein biomarkers are a dynamic resource of pathophysiological information able to provide an immediate reflection of pathological changes caused by disease. Investigations of the serum and synovial fluid of PsA patients has provided new insights into the molecular basis of this disease and led to the identification of sensitive diagnostic and prognostic biomarkers. The collection of novel PsA biomarkers identified through proteomic studies has been reviewed below.

Clinical Features of Psoriatic Arthritis: a Comprehensive Review of Unmet Clinical Needs

Psoriatic arthritis (PsA) is a form of inflammatory arthritis (IA) affecting approximately 0.25% of the population. It is a heterogeneous disorder associated with joint damage, disability, disfiguring skin disease and in severe cases, premature mortality. Inherently irreversible and frequently progressive, the process of joint damage begins at, or before, the clinical onset of disease. Early recognition and intervention is thus crucial to patient outcome. At disease onset, however, PsA often resembles other forms of arthritis-especially rheumatoid arthritis (RA). Despite the similarities between PsA and RA, their distinctive pathologies require different treatments. For example, drugs that are effective in RA may not be effective in PsA and can even cause adverse effects. Since there is no currently validated test for PsA, the diagnosis is often missed or delayed and this has functional consequences for the patient. In the context of PsA and RA, making an accurate diagnosis is not the only challenge faced by rheumatologists. Choosing an effective and safe medication to manage the disease is another significant challenge and currently approximately 40% achieve meaningful responses such as minimal disease activity status. For the patient, several months may be lost as a result of trial and error testing-meanwhile, irreversible joint damage may occur. Clearly, more effective clinical tests are urgently needed to improve personalised patient care in PsA. Specifically, there is need to develop minimally invasive tests predictive of diagnosis, response to treatment and radiographic progression. In this review, we examined the biomarker development process, highlighted the importance of qualifying unmet clinical needs and emphasised the challenges that impede biomarker studies. We have compiled a comprehensive list of potentially clinically relevant biomarkers in PsA and provided a summary of proteomic technologies that might usefully support additional biomarker research in 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.

Emerging biomarkers in psoriatic arthritis.

Psoriasis is an immune-mediated skin disease which affects 2-4% of the worldwide population. Approximately 20-30% of patients with psoriasis develop psoriatic arthritis (PsA), a frequently destructive and disabling condition. As skin manifestations precede joint symptoms in nearly all patients with PsA, identification of biomarkers for early prediction of joint damage is an important clinical need. Because not all patients with PsA respond to treatment in the same fashion, identification of biomarkers capable of predicting therapeutic response is also imperative. Here, we review existing literature and discuss current investigations to identify potential biomarkers for PsA disease activity, with particular emphasis on microRNAs as novel markers of interest. Serum (soluble) biomarkers, peripheral osteoclast precursor as cellular biomarkers, and genetic loci associated with skin and joint disease are also reviewed.

An Integrative Approach to Biomarker Development in Psoriatic Arthritis

The recent discovery that the interleukin 23/Th17 pathway is pivotal in the pathogenesis of psoriatic arthritis (PsA) creates new opportunities for the development of mechanistic biomarkers that will assist in the diagnosis and management of this disorder. While biomarkers are still in the discovery phase, new approaches including multiplex panels, fine sequencing of epigenetic and genetic data in non-coding regions of the human genome, and improved imaging modalities will likely foster the development of actionable biomarkers in PsA. In this report, I review the field of biomarkers, underscore the importance of an integrative approach that incorporates both descriptive and mechanistic biomarkers, and discuss the status of biomarker discovery in PsA.

Quantitative tandem mass-spectrometry of skin tissue reveals putative psoriatic arthritis biomarkers.

BackgroundPsoriatic arthritis (PsA) is a distinct inflammatory arthritis occurring in 30% of psoriasis patients. There is a high prevalence of undiagnosed PsA in psoriasis patients; therefore, identifying soluble biomarkers for PsA could help in screening psoriasis patients for appropriate referral to a rheumatologist. Potential PsA biomarkers likely originate in sites of inflammation, such as the skin, and subsequently enter systemic circulation. Our goal was to identify candidate PsA biomarkers by comparing the proteome of skin biopsies obtained from patients with PsA to that from patients with psoriasis without PsA.MethodsSkin biopsies were obtained from involved and uninvolved skin of 10 PsA and 10 age/gender-matched psoriasis patients without PsA (PsC). Using strong cation exchange chromatography, followed by label-free quantitative tandem mass spectrometry, we characterized the proteomes of pooled skin samples. Extracted ion current intensities were used to calculate protein abundance ratios, and these were utilized to identify differentially regulated proteins.ResultsForty-seven proteins were elevated in PsA-derived skin compared to PsC-derived skin. Selected reaction monitoring assays were developed to quantify these potential PsA markers in individual skin samples, and 8 markers were confirmed in an independent sample set. ITGB5 and POSTN were measured in serum samples from 33 PsA and 15 PsC patients, using enzyme-linked immunosorbent assays. ITGB5 was significantly elevated in PsA serum (P < 0.01), and POSTN showed a trend. ITGB5 and POSTN correlated significantly in both patient groups (r = 0.472, P < 0.001).ConclusionProteomic analysis of PsA and PsC skin identified eight new candidate biomarkers. These markers need to be validated with a larger and independent cohort, in order to delineate their clinical utility in PsA patients. These proteins may also uncover unknown aspects of PsA pathobiology.Electronic supplementary materialThe online version of this article (doi:10.1186/1559-0275-12-1) contains supplementary material, which is available to authorized users.

Biomarkers in psoriatic arthritis: recent progress.

Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis. About a quarter of patients with psoriasis of the skin will develop PsA, although it is currently challenging-if not impossible-to determine a priori which individuals will progress. Identification of biomarkers for screening, disease activity, joint damage, treatment response and comorbidities are therefore perceived as important clinical needs in the field. Over the last few years, several lines of investigation have advanced our knowledge of new markers for PsA and its outcomes, including genomic, proteomic, cellular and tissue studies. Imaging studies utilizing ultrasonography have been applied to better understand the natural history of the disease. Novel biomarkers, such as soluble proteins and microbiomics, are also being described. Although no biomarker has yet been validated for use in clinical practice, discovery studies are in progress and validation cohorts are being designed. In this report, we review the latest progress in biomarker research in PsA and its potential implications in pathogenesis, diagnosis and therapy.

Biomarkers: Project Update from the GRAPPA 2012 Annual Meeting

For members of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), an important goal has been the identification of soluble biomarkers in psoriatic arthritis that might predict the development of radiographic progression. Work over the past year has resulted in approval of a draft protocol, and an announcement is forthcoming of the outcome of an assessment process for centers that applied to manage the project. GRAPPA is now ready to commence formal negotiations with potential funding partners and intends to initiate this project in the near future.

AB0518 Synovial biomarkers in peripheral spondyloarthritis.

ObjectivesTo analyse a panel of synovial fluid (SF) and synovial tissue (ST) biological markers expression at single joint level to find candidate biomarkers in resistant peripheral spondyloarthritis (SpA).MethodsTwenty seven resistant...

Serum kallikrein-8 correlates with skin activity, but not psoriatic arthritis, in patients with psoriatic disease

About 30% of cutaneous psoriasis (PsC) patients develop psoriatic arthritis (PsA) in the joint, which is under-recognized by dermatologists. Biomarkers for PsA are needed so that early referral to a rheumatologist is made. Kallikreins (KLKs) are secreted serine proteases implicated in skin desquamation and inflammation. This study examined KLK potential as serum biomarkers of PsA in cutaneous psoriasis patients. KLKs were measured by ELISAs in synovial fluids of three PsA patients and three control early osteoarthritis (OA) patients, as well as in a cohort of 152 serum samples collected from age- and sex-matched PsC patients, with (n=76) or without PsA (n=76). KLK expression in psoriatic plaques was examined by immunohistochemistry. Univariate and multivariate logistic regression analyses were conducted to analyze the association between serum KLK levels and disease class (PsC, PsA). Serum KLKs that associated with PsA were correlated with clinical parameters of skin and joint activity. Among the seven KLKs tested, KLK6 and KLK8 were elevated in both PsA synovial fluids and psoriatic plaques, but only serum KLK8 levels were associated with psoriatic disease (odds ratio=2.56, p=0.03). Although significantly elevated in PsC and PsA sera compared to healthy controls, KLK8 did not discriminate PsA from PsC patients. KLK8 correlated positively with the psoriasis area and severity index (PASI) (r=0.43, p=0.001) independent of age, sex and psoriasis duration ( β=1.153, p=0.0003) and exhibited no correlations with tender or swollen joint counts. Increased KLK8 serum level in PsA patients reflects disease activity in the skin but not in the joints. Serum KLK levels are not useful for screening psoriasis patients for PsA.

Update on Biomarkers in Psoriatic Arthritis: A Report from the GRAPPA 2010 Annual Meeting: Table 1.

Biomarkers may be used to screen patients with psoriasis for psoriatic arthritis (PsA) and to assess disease activity and severity. Candidate biomarkers should fulfil the key features of the OMERACT (Outcome Measures in Rheumatology) filter, that is, truth, discrimination, and feasibility. A number of biomarkers are currently being investigated in psoriatic disease for important clinical outcomes. Serum high sensitivity C-reactive protein, cartilage oligomeric matrix protein, interleukin 6 (IL-6), osteoprotegerin, matrix metalloprotease-3 (MMP-3), and the ratio of C-propeptide of type II collagen (CPII) to collagen fragment neoepitopes Col2-3/4 (long mono) (C2C) show promise as serum biomarkers that distinguish subjects with PsA from those with psoriasis alone. Serum MMP-3 and melanoma inhibitory activity, synovial fluid IL-1, IL-1 receptor-α, IL-6, IL-8, and chemokine CCL3 and synovial tissue CD3-positive T cells may prove useful as biomarkers of PsA activity. Circulating osteoclast precursors, Dickkopf-1, macrophage colony stimulating factor, receptor activator of nuclear factor-κB ligand, and bone alkaline phosphatase are strong candidates as biomarkers of radiographic change. Prospective studies to identify biomarkers for psoriatic disease are high on the research agenda of the Group for Research and Assessment of Psoriasis and PsA.

Update on Biomarkers in Psoriatic Arthritis

Biomarkers in psoriatic arthritis (PsA) may serve as surrogate end points for disease outcome and can provide insights into disease susceptibility and natural history. Biomarkers could relate to diagnosis, pathogenesis, prognosis, therapeutic response, and comorbidities. The "felt need" is, however, in the development of biomarkers for the presence of PsA in patients with psoriasis, as well as that for joint damage. During the past few years, many studies related to PsA biomarkers have been conducted. These studies are reviewed here. C-reactive protein, matrix metalloproteinase-3, and circulating osteoclast precursors show promise. An international goal-directed study to determine biomarkers for joint damage in PsA is now under way through a collaborative effort of GRAPPA (the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis) and OMERACT (Outcome Measures for Rheumatology Clinical Trials).

Biomarkers in Psoriasis and Psoriatic Arthritis: GRAPPA 2008

Biomarkers can provide valuable insights into disease susceptibility and natural history and may serve as surrogate endpoints for a variety of different outcomes. At the 2008 annual meeting of GRAPPA (Group for Research and Assessment of Psoriasis and Psoriatic Arthritis), members were updated on the development of biomarkers in psoriatic arthritis (PsA). Plenary presentations included a translational approach to biomarker development (Christopher Ritchlin, University of Rochester, NY, USA), biomarkers for psoriasis (Abrar Qureshi, Harvard Medical School, MA, USA), new data on biomarkers for damage in PsA (Kurt de Vlam, University Hospitals Leuven, Belgium), and design considerations for a longitudinal study of joint damage being undertaken under the OMERACT umbrella with colleagues working on rheumatoid arthritis and ankylosing spondylitis (Costantino Pitzalis, Barts and the London School of Medicine, London, UK; Oliver FitzGerald, St. Vincent's Hospital, Dublin, Ireland). At the conclusion of this session, the meeting attendees discussed specific design issues of the proposed longitudinal study, including study duration, disease process core domains, and the instruments to be used in recording enthesitis, dactylitis, nail involvement, quality of life and structural damage. The appearance of new therapeutic options in PsA raises the need for sensitive biomarkers for both disease activity and outcome.

Synovial effusion and synovial fluid biomarkers in psoriatic arthritis to assess intraarticular tumor necrosis factor-α blockade in the knee joint

IntroductionThe purpose of this study was theevaluation of synovial effusion (SE), synovial fluid (SF) and synovial tissue (ST) biomarkers in relation to disease activity indexes to assess the response to intraarticular (IA) tumor necrosis factor (TNF)-α blockers in psoriatic arthritis (PsA).MethodsSystemic and local disease activity indexes (disease activity score (DAS); the Ritchie articular index (mRAI), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP); Thompson articular (THOMP) and joint articular (KJAI)-Index ) and ST samples were assessed at baseline, throughout treatment, and during the follow-up in 14 patients affected with PsA who underwent IA injections (0.5 ml to 12.5 mg) in the knee joint of etanercept (E) or placebo (P) once every two weeks for a 10-week period. Total SF white blood cell (WBC) counts (WBC/μl) and SF cytokine/chemokine (CK/CCK) levels were measured before IA-E at baseline, after IA-E, and as long as there were adequate amounts of SF for knee aspiration (post). Characterization of synovial mononuclear cell infiltration and synovial vessels was carried out in 8 out of 14 knees by staining serial sections of synovial tissue biopsies for CD45, CD3, CD68, CD31 and CD105.ResultsAt baseline, CRP and/or ESR were significantly correlated with SF-CK (interleukin- (IL-)1β, IL-1Ra, IL-6, IL-8) and CCK (CCL3). Post-IA injections, there was a decrease in SE in the knees in which aspiration following IA-E injection was possible as well as a significant reduction in SF WBC/μl and in SF-CK (IL-1β, IL-1Ra, IL-6 and IL-22). Pre- and post-IA-E injections, there were significant correlations between ST markers and SF-CK (IL-1β with CD45; IL-1β and IL-6 with CD31) and between SF-CCK (CCL4 and CCL3 with CD3). At the end of the study, there was a significant reduction in disease activity indexes (CRP, DAS, RAI, THOMP, KJAI) as well as in the ST markers (CD45; CD3).ConclusionsSynovial effusion regression is a reliable indicator of the response to IA TNF-α blockers in PsA patients as it is confirmed by the correlation between SF biomarkers to disease activity and synovial tissue inflammation.

The effect of etanercept on osteoclast precursor frequency and enhancing bone marrow oedema in patients with psoriatic arthritis

Objective:The frequency of osteoclast precursors (OCPF) and the presence of bone marrow oedema (BMO) are potential response biomarkers in psoriatic arthritis (PsA). Previous studies suggest a central role for tumour...