ArticleLiterature Review
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

Rheumatoid arthritis (RA) is a systemic chronic inflammatory disease characterized by extensive synovitis resulting in erosions of articular cartilage and marginal bone with joint destruction. The lack of immunological tolerance in RA represents the first step toward the development of autoimmunity. Susceptible individuals, under the influence of environmental factors, such as tobacco smoke and silica exposure, develop autoimmune phenomena that result in the presence of autoantibodies. HLA and non-HLA haplotypes play a major role in determining the development of specific autoantibodies differentiating anti-citrullinated antibodies (ACPA) positive and negative RA patients. Rheumatoid factor (RF) and ACPA are the serological markers for RA and during the preclinical immunological phase autoantibody titres increase with a progressive spread of ACPA antigens repertoire. The presence of ACPA represents an independent risk factor for developing RA in patients with undifferentiated arthritis or arthralgia. Moreover, anti-CarP antibodies have been identified in patients with RA as well as in individuals before the onset of clinical symptoms of RA. Several autoantibodies mainly targeting post-translational modified proteins have been investigated as possible biomarkers to improve the early diagnosis, prognosis and response to therapy in RA patients. Psoriatic arthritis (PsA) is distinguished from RA by infrequent positivity for RF and ACPA, together with other distinctive clinical features. Actually, specific autoantibodies have not been described. Recently, anti-CarP antibodies have been reported in sera from PsA patients with active disease. Further investigations on autoantibodies showing high specificity and sensibility as well as relevant correlation with disease severity, progression, and response to therapy are awaited in inflammatory arthritides.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... Examples of seropositive AIRD include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), primary Sjögren's syndrome (pSS) and idiopathic inflammatory myopathies (IIM) [3]. Importantly, although RA is classified within the seropositive category, approximately 30% of patients lack the presence of the classic autoantibodies rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs) and have 'seronegative RA' [4]. ...
... In clinical practice, the monitoring of autoantibodies has proved helpful in diagnostic processes, for classification purposes and as biomarkers for disease activity, prognosis and, in the light of personalized medicine, therapeutic responses of AIRD [1,4,10]. From a pathogenesis perspective, it is relevant that autoantibodies can be detected years prior to diagnosis [10]. ...
... A selection of studies that reported presence of autoantibodies years before clinical AIRD diagnosis is highlighted in Table 1. The antigenspecific autoantibodies may show isotype-switch and a progressive accumulation before disease onset [4,5,11]. These findings raise an important question: how can these self-reactive molecules persist for years, without causing clinical signs or symptoms of autoimmunity? ...
Article
Autoimmune rheumatic diseases (AIRD) are categorized seropositive or seronegative, dependent on the presence or absence of specific autoreactive antibodies, including rheumatoid factor and anti‐citrullinated protein antibodies. Autoantibody‐based diagnostics have proven helpful in patient care, not only for diagnosis, but also for monitoring of disease activity and prediction of therapy responsiveness. Recent work demonstrates that AIRD patients develop autoantibodies beyond those contained in the original categorization. We here discuss key mechanisms that underlie autoantibody development in AIRD: defects in early B cell development, genetic variants involved in regulating B cell and T cell tolerance, environmental triggers and antigen modification. We describe how autoantibodies can directly contribute to AIRD pathogenesis through innate and adaptive immune mechanisms, eventually culminating in systemic inflammation and localized tissue damage. We conclude by discussing recent insights that suggest distinct AIRD have incorrectly been denominated seronegative.
... Artritis reumatoide y riesgo cardiovascular Claudio Karsulovic C. (1,2) , Julia Guerrero P. (2) , Annelise Goecke S. (2,3) (1) Departamento de Medicina Interna, HCUCH. (2) Cardiovascular disease (CVD) is the most frequent cause of premature death according to data from the American Heart Association and World Health Organization. ...
... Artritis reumatoide y riesgo cardiovascular Claudio Karsulovic C. (1,2) , Julia Guerrero P. (2) , Annelise Goecke S. (2,3) (1) Departamento de Medicina Interna, HCUCH. (2) Cardiovascular disease (CVD) is the most frequent cause of premature death according to data from the American Heart Association and World Health Organization. ...
... Artritis reumatoide y riesgo cardiovascular Claudio Karsulovic C. (1,2) , Julia Guerrero P. (2) , Annelise Goecke S. (2,3) (1) Departamento de Medicina Interna, HCUCH. (2) Cardiovascular disease (CVD) is the most frequent cause of premature death according to data from the American Heart Association and World Health Organization. ...
... According to a systematic 3 review of the epidemiological studies, the prevalence of PsA ranged between 6% to 4 24% in patients with psoriasis when validated criteria such as Moll and Wright, 5 Classification of Psoriatic Arthritis (CASPAR), or European Spondylarthropathy Study [3] The impact of PsA appears to be very broad and covers all 11 aspects of life. [4][5][6] 12 Psoriasis is occasionally accompanied by inflammatory conditions other than arthritis 13 such as uveitis and inflammatory bowel disease. The concept of "psoriatic disease" was 14 introduced to encompass the inflammatory involvement of several different 15 organs/systems in the same patient. ...
... HLA-B39 was related to progressive disease as 3 well.[32,33] Some HLA polymorphisms that were not associated with PsA risk 4 independently may still modify the disease course. HLA-DR7 (HLA-DRB1*07 gene 5 product), an MHC class II antigen, was found protective against disease progression and 6 HLA-DQw3 (HLA-DQB1*03 gene product) was associated with progressive disease but 7 only in the absence of HLA-DR7. ...
Article
Full-text available
Psoriatic arthritis (PsA) is an underdiagnosed entity with a broad impact on the quality of life. Although the pathogenesis is largely unknown, autoimmune footprints of the inflammation in PsA have increasingly been recognized. Most of the genetic variation predisposing to PsA is mapped to the class I major histocompatibility complex (MHC) region and shared by a variety of autoimmune diseases. Polymorphisms in the genes IL12B, IL23R, IL13, TNIP1, TRAF3IP2, TYK2 and many others explain the non-HLA genetic risk with little known functional consequences. Entheseal and synovial cellular infiltrate with oligoclonal CD8+ T cells and occasional germinal centers, loss of regulatory T cell function, and specific autoantibodies such as anti-PsA peptide, anti-LL-37, and anti-ADAMTSL5 are the immunopathological findings suggestive of autoimmunity. These were supported by clinical observations of autoimmune multimorbidity and treatment response to calcineurin/mTOR and co-stimulation inhibition.
... It is well-known that there is a close association between ACPA and bone destruction in RA (9). Previous studies support the significance of ACPA in inflammation-associated bone diseases, not confined to RA, but also in non-RA autoimmune conditions, and ACPA may be detected in psoriatic arthritis, systemic lupus erythematosus and juvenile idiopathic arthritis, as well as scleroderma and CREST syndrome, followed by Sjögren's syndrome and vasculitis (10)(11)(12)(13)(14)(15). However, the prevalence of ACPA positivity was higher in patients with RA than in those mentioned above apart from RA (11,12). ...
... Previous studies support the significance of ACPA in inflammation-associated bone diseases, not confined to RA, but also in non-RA autoimmune conditions, and ACPA may be detected in psoriatic arthritis, systemic lupus erythematosus and juvenile idiopathic arthritis, as well as scleroderma and CREST syndrome, followed by Sjögren's syndrome and vasculitis (10)(11)(12)(13)(14)(15). However, the prevalence of ACPA positivity was higher in patients with RA than in those mentioned above apart from RA (11,12). ...
Article
Idiopathic pulmonary hemosiderosis (IPH) is a rare interstitial lung disease, usually occurring in children or young adults. Although several studies reported on the coexistence of IPH and immune system diseases, the association between these conditions has not been well described. The present study reports on the case of a 21-year-old female patient who presented with bilateral lung abnormalities. The patient was admitted due to a 2-year history of progressive exertional dyspnea, as well as arthralgia and joint swelling in the recent 2 months. During the past 15 years, the patient had been diagnosed with anemia and received repeated blood transfusions. Serial chest CT scans indicated an interstitial pattern. On physical examination, the patient had pale skin with a hemoglobin level of 65 g/l and exhibited finger-clubbing. Arterial blood gas analysis revealed hypoxia. Anticyclic-citrullinated protein antibody and rheumatoid factor were highly positive. Pulmonary function tests revealed restrictive ventilation dysfunction and decreased diffusion capacity. Bronchoscopy and biopsy confirmed diffuse alveolar hemorrhage. Following assessment of the etiology, the diagnosis of IPH was made by exclusion. The patient's symptoms and laboratory findings combined also confirmed the diagnosis of rheumatoid arthritis (RA). After receiving corticosteroid treatment, the patient's condition improved, and she was discharged and followed up. Based on this patient and a review of the literature, the present study demonstrated for the first time that IPH may mediate the development of an RA pathology. Therefore, early diagnosis is important for the timely management of IPH, which may also delay or even prevent the development of immune system diseases, e.g. RA, in patients with IPH. Further attention should be paid to determine the association between IPH and immune system diseases in the clinical setting.
... While both RA and SpA feature joint inflammation, RA is an autoimmune disease with an overt humoral immune response. For instance, ACPAs are the gold-standard diagnostic tools for RA (33). There is still debate within the field as to whether SpA is an autoimmune or autoinflammatory disease (34). ...
... There is still debate within the field as to whether SpA is an autoimmune or autoinflammatory disease (34). Autoantibodies to gold-standard neoantigens in general, or ACPAs in particular, are infrequent in SpA (33). Notably, of all the axSpA samples tested in this study only three were positive for ACPAs (with 16, 19, and 45 units), confirming the reported low ACPA incidence in PsA (35). ...
Article
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.
... Rheumatoid Arthritis (RA) is a chronic autoimmune systemic inflammatory disease that may involve many organs and tissues, but principally affects the peripheral joints in a symmetrical pattern. It represents the most common inflammatory arthropathy worldwide [11]. RA is characterized by the presence of auto-Abs such as rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) [12]. ...
... RA is characterized by the presence of auto-Abs such as rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) [12]. Nevertheless, similarly to HT, RA patients may be seronegative [11] and currently available evidences would support a less severe presentation, in terms of inflammation, pain, radiographic progression and joint damage when compared to seropositive RA [13][14][15]. ...
Article
Rheumatoid arthritis (RA) and autoimmune thyroid disease (AITD) can occur in the same patient in the autoimmune polyglandular syndrome 2. The association of the two conditions has been recognized long-time ago and the prevalence of AITD in patients with RA and vice versa is well assessed. Geographical variation of AITD and related autoantibodies in RA patients is partly due to ethnic and environmental differences of the studied populations. The impacts of thyroid disorders on RA outcome and vice versa are still controversy. In both AITD and RA genetic susceptibility and environmental factors play a synergic role in the development of the diseases. In this review we aimed at investigating the association of AITD and thyroid autoantibodies with RA, the common pathogenic pathways, the correlation with RA disease activity, and influence of the treatment.
... Indeed, a higher serum and mitochondrial levels were observed compared to healthy skin; this contributes to epidermal hyperplasia (37). Concerning PsA, the result is synovial inflammation and joint destruction (38). PsA is microscopically characterized by lining layer hyperplasia, infiltration of B and T lymphocytes, and activation of the innate immune response that lead to vascular remodeling and angiogenesis into the joint (39). ...
... To date, it is well known that carbamylation happens during inflammation, after the release of MPO by neutrophils, generating a proinflammatory loop. Carbamylated proteins are recognized by circulating antibodies, the anti-carbamylated protein (anti-CarP) antibodies that have been identified in patients with RA, also before the clinical onset of the disease (38). The presence of anti-CarP antibodies in sera from PsA patients with active disease, in the absence of rheumatoid factor and/or other known autoantibodies specificities, was demonstrated (96,102). ...
Article
Full-text available
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.
... RF is a well-known negative prognostic factor as recognized by EULAR recommendations for the management of RA [26]. High RF serum levels have been associated with an aggressive articular disease, extra-articular manifestations, and a worse outcome [27]. ...
Article
Full-text available
Autoimmune diseases (AIDs) are complex diseases characterized by persistent or recurrent inflammation, alteration of immune response, and production of specific autoantibodies. It is known that different AIDs share several susceptibility genetic loci. Tumor necrosis factor alpha inducible protein 3 (TNFAIP3) encodes the ubiquitin-modifying enzyme A20, which downregulates inflammation by restricting NF- κ B, a transcription factor that regulates expression of various proinflammatory genes. Variants in TNFAIP3 gene have been described as associated with susceptibility to several AIDs. Here, we analyzed two TNFAIP3 polymorphisms in Italian patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and primary Sjogren’s syndrome (pSS), to verify if the genetic variability of TNFAIP3 gene is involved in genetic predisposition to AIDs also in the Italian population. We recruited 313 SLE patients, 256 RA patients, 195 pSS patients, and 236 healthy controls. Genotyping of rs2230926 and rs6920220 in TNFAIP3 gene was performed by an allelic discrimination assay. We carried out a case/control association study and a genotype/phenotype correlation analysis. A higher risk to develop SLE was observed for rs2230926 ( P=0.02 , OR=1.92 ). No association was observed between this SNP and the susceptibility to pSS or RA. However, the rs2230926 variant allele seems to confer a higher risk to develop lymphoma in pSS patients, while in RA patients, the presence of RF resulted significantly associated with the variant allele. Regarding the rs6920220 SNP, we observed a significant association of the variant allele with SLE ( P=0.03 , OR=1.53 ), pSS ( P=0.016 , OR=1.69 ), and RA ( P=0.0001 , OR=2.35 ) susceptibility. Furthermore, SLE patients carrying the variant allele showed a higher risk to develop pericarditis, pleurisy, and kidney complications. Our results support the importance of the TNFAIP3 gene variant role in the development of different autoimmune diseases in the Italian population and furtherly confirm a sharing of genetic predisposing factors among these three pathologies.
... Loss of B and T cell self-tolerance leads to self-reactivity, the initial step in the development of RA. However, evidence has shown that, much before the first symptoms of inflammation, antibodies against self-antigens are already present, indicating the onset of RA [8]. As the self-reaction expands, the release of cytokines and self-antibodies initiates an attack to the synovial joints. ...
Article
Rheumatoid arthritis (RA) is a classic inflammatory autoimmune disease. Local joint destruction and extra-articular manifestations of RA deeply compromise the life quality of the affected patients. RA immunopathogenesis depends on continuous immunogenic activation in which the purinergic system participates. The purinergic system comprises the signaling and metabolism of purines such as adenosine triphosphate (ATP) and adenosine. ATP signaling is involved in the activation and maintenance of the inflammatory state of RA through the activation of P2 × 7 and the production of cytokines, which orchestrate the pathogenesis of RA. The breakdown of ATP through the CD39/CD73 axis produces adenosine, which mostly inhibits the inflammatory process through activation of specific P1 receptors. Adenosine is hydrolyzed by adenosine deaminase (ADA) that interacts with other molecules playing additional roles in this disease. This review explores the release, metabolism, and the effects of binding of ATP and adenosine to their respective receptors in the context of RA, as well as their potential use as biomarkers and therapeutic targets.
... RA is a heterogeneous disease with aetiology linked to genetic, environmental and stochastic triggers, leading to the loss of the immunological tolerance to selfantigens which is the first step towards developing autoimmune phenomena [44]. ...
Conference Paper
Tumour necrosis factor (TNF) antagonists have revolutionised the management of rheumatoid arthritis (RA) and other inflammatory diseases. This success is partly tempered by substantially increased risk of granulomatous infectious diseases, particularly tuberculosis (TB). In this thesis I sought new insights into the mechanisms by which TNF blockade leads to an increased incidence of TB. In a new analysis of data collected by the British Society of Rheumatology Biologics Registry, I confirmed that anti-TNF therapy leads to reactivation of latent TB infection, rather than increasing the risk of new TB infection, consistent with published literature. I derived and validated four separate context-specific transcriptional modules representing TNF inducible gene expression in macrophages, keratinocytes and whole blood. I used these modules to quantify TNF bioactivity in clinical samples from RA patients responding to anti TNF therapies or treated with methotrexate only. As expected, anti-TNF therapy was associated with attenuated expression of the TNF modules in whole blood following ex vivo stimulation. However, anti-TNF therapy had no effect on TNF module expression and therefore TNF function, at the site of acute cell mediated immune responses in vivo, modelled by the tuberculin skin test. These data are consistent with a model in which anti-TNF therapies do not reach sufficient concentration within tissues to block TNF responses in an acute inflammatory challenge. Rather, my data suggest that anti TNF therapies mediate their therapeutic and adverse effects by regulating TNF activity at foci of chronic inflammation or by alternative non-canonical pathways. Finally I tested the hypothesis that anti-TNF therapy may inhibit cellular restriction of mycobacteria in human macrophage cultures. Using an in vitro model of human monocyte-derived macrophages, I established a new method to quantify fluorescent mycobacterial load both inside and outside cells, and showed that TNF blockade in this model did not have a significant impact on mycobacterial growth.
... A AR é uma doença inflamatória crônica que acomete essencialmente as articulações, embora outros órgãos também possam estar comprometidos 13 . Por se tratar de uma condição auto-imune, sabe-se que o sistema imunitário do organismo é direcionado contra aos seus próprios tecidos 14 . ...
Article
Full-text available
Bone remodeling is a continuous process that depends on the balanced action between osteoclasts and osteoblasts, responsible for reabsorption and bone formation, respectively. Persistent inflammatory conditions can alter this process, such as rheumatoid arthritis (RA) and periodontitis. The pathogenesis of these two diseases is associated with changes in the levels of inflammatory mediators leading to an immune imbalance associated with bone loss. Some studies have suggested that such diseases are bidirectional, where the presence of one influences the evolution of the other. This paper reviews the results of scientific research studies on the effect of non-surgical periodontal therapy (TP) on the reduction of RA severity. To do so, a search was made for scientific articles published from the year 2006, in the PubMed database, using the key words: rheumatoid arthritis, periodontitis and periodontal treatment, in the English/Portuguese languages. Nine studies with similar research methodology were selected and composed of samples from patients affected by both diseases. Parameters such as gingival bleeding index, depth of probing, bleeding at the probe or clinical level of insertion evaluated the periodontal condition of each patient, while questionnaires investigating patients' quality of life and laboratory tests related to systemic inflammatory activity were considered associated parameters To the severity of rheumatoid arthritis. In eight studies, PT significantly reduced inflammatory severity of RA. Thus, the latest scientific data indicate the benefit of TP by reducing the severity of RA, considering the ease and low cost of this type of therapy.
... Local CD4+ T-cell help to B cells is likely to be a prominent driver of humoral immunity in RA patients seropositive for ACPA (anti-citrullinated protein antibodies) and/or RF (Rheumatoid Factor). About 60-70% of RA patients present with ACPAs and 50-80% of patients are seropositive for RF (94). Already in 1992, synovial T cells from RA patients were shown to induce B cell Ig production in vitro (3). ...
Article
Full-text available
Infiltration of memory CD4+ T cells in synovial joints of Rheumatoid Arthritis (RA) patients has been reported since decades. Moreover, several genome wide association studies (GWAS) pinpointing a key genetic association between the HLA-DR locus and RA have led to the generally agreed hypothesis that CD4+ T cells are directly implicated in the disease. Still, RA is a heterogeneous disease and much effort has been made to understand its different facets. T cell differentiation is driven by mechanisms including antigen stimulation, co-stimulatory signals and cytokine milieu, all of which are abundant in the rheumatic joint, implying that any T cells migrating into the joint may be further affected locally. In parallel to the characterization and classification of T-cell subsets, the contribution of different effector T cells to RA has been investigated in numerous studies though sometimes with contradictory results. In particular, the frequency of Th1 and Th17 cells has been assessed in the synovial joints with various results that could, at least partly, be explained by the stage of the disease. For regulatory T cells, it is largely accepted that they accumulate in RA synovial fluid and that the equilibrium between regulatory T cells and effector cells is a key factor in controlling inflammation processes involved in RA. Recent phenotypic studies describe the possible implication of a novel subset of peripheral T helper cells (Tph) important for T-B cell cross talk and plasma cell differentiation in the RA joint of ACPA+ (autoantibodies against citrullinated proteins) RA patients. Finally, cytotoxic CD4+ T cells, historically described as increased in the peripheral blood of RA patients have attracted new attention in the last years. In view of the recently identified peripheral T-cell subsets, we will integrate immunological data as well as information on genetic variants and therapeutic strategy outcomes into our current understanding of the width of effector T cells. We will also integrate tissue-resident memory T cell aspects, and discuss similarities and differences with inflammatory conditions in skin (psoriasis) and mucosal organs (Crohn's disease).
... Importantly, we found both anti-ADAMTSL5 and anti-LL-37 autoantibodies were significantly elevated in PsA compared to Non-PsA, suggesting that these molecules may be involved in the pathogenesis of psoriatic arthritis. This is consistent with previous findings that autoantibodies may be associated with psoriatic arthritis (60,61). ...
Article
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. This article is protected by copyright. All rights reserved.
... Spondyloarthritis (SpA) are a heterogeneous group of inflammatory chronic diseases characterized by sharing common pathogenic, clinical and radiologic features such as the presence of inflammatory back pain, dactylitis and enthesitis, the association with the HLA-B27 and the frequent extra-articular involvement including cutaneous, ocular and intestinal manifestations. SpA affect mainly male young subjects and can lead to functional impairment and deterioration in patients' quality of life and life expectancy [1,2]. SpA include -radiographic‖ (ankylosing spondylitis, AS) and -non-radiographic‖ (nr-axSpA) forms, depending on whether definitive structural changes are evident on plain radiographs of sacroiliac joints, moreover psoriatic arthritis (PsA), reactive arthritis (ReA), acute anterior uveitis, axial SpA (axial-SpA) and SpA associated to inflammatory bowel disease (IBD; enteropathic spondyloarthritis; ESpA) are part of the SpA spectrum [3]. ...
Article
Spondyloarthritis (SpA) are a heterogeneous group of inflammatory chronic diseases characterized by sharing common pathogenic, clinical and radiologic features. The aim of this review is to support clinicians in understanding and managing this complex disease, from pathogenesis to therapeutic targets, through a systematic review of the current literature in accordance with PRISMA guidelines and checklist. HLA-B27 has been found to be associated with axial involvement either in SA and in PsA patients: it might be involved through presentation of an “arthritogenic peptide” to autoreactive CD8+ T cells or might accumulate in misfolded form and induce production pro-inflammatory cytokines by binding to several innate immune receptors. This genetic background in combination with mechanical stress leads to the activation of both innate and acquired immune responses as well as a possible role of autoimmunity in SpA pathogenesis. The release of IL-23 and IL-17 is relevant for their systemic and local effect on bone, inducing the activation of osteoclasts. Thus, the regulatory role of IL-17 on fibroblasts, osteoblasts and chondrocytes has an impact in both synovial inflammation and joint destruction. Innovative therapies targeting IL-12/23 and IL-17 and the use of small targeted synthetic molecules, as JAK-inhibitors, proved to be effective in SpA patients representing an alternative strategy to TNF-inhibitors.
... It is likely that those who are positive to these autoantibodies given definite diagnosis by this period of follow-up. 8,9 The study from Leiden cohort has given a prediction rule consisting of nine parameters to assess the risk of progression of these early undifferentiated arthritis cases to rheumatoid arthritis. 10 Our study is an analysis of the inception cohort of UDIA patients enrolled to study their natural history and treatment outcomes from Nepal. ...
Article
Full-text available
Background: Undifferentiated inflammatory arthritis is a group of inflammatory joint diseases that do not fulfil the classification criteria for any other rheumatic or connective tissue disorders. This study aims to describe the clinical, demographic and serological features of undifferentiated inflammatory arthritis cases presenting at a tertiary level rheumatology centre from Nepal. Methods: A descriptive cross-sectional study conducted at National Centre for Rheumatic Diseases, Kathmandu, Nepal which represents a midterm analysis of the undifferentiated inflammatory arthritis registry maintained at the centre. Patients more than 18 years of age, who consented for the study having least one swollen or tender joint were enrolled. Ethical approval was obtained from Nepal Health Research Council. Results: A total of 1120 patients were enrolled in the study out of which 941 (84%) were females. The mean age at diagnosis was 46.0±12.8 years and most of them were in overweight range (mean BMI: 27.0±5.8) with 818 (73%) patients having BMI more than 24.0. Patients mostly had low disease activity at presentation (DAS 28 score of 2.5±0.8). Other markers of inflammation and patient reported outcome measures (health assessment questionnaire, patient global assessment and visual analogue scale) were also in the moderate range. Seropositivity for anti-citrullinated peptides and anti-nuclear antibodies was seen in 5 (0.45%) and 43 (3.8%) patients respectively. Majority of patients were non-smokers (77%). Inflammatory arthritis on musculoskeletal ultrasonography was seen in 638 (57%). Conclusions: Undifferentiated inflammatory arthritis was more common in overweight females. Serological markers and smoking status are not common features in these patients.
... RF has moderate specificity because it can also be found in other connective tissue diseases and in some chronic infectious diseases [33]. ACPA is more specific, and the presence of ACPA is an independent risk factor for developing RA in patients with undifferentiated arthritis [34]. However, in reality, RA constitutes two clinical RA subgroups, ACPA-positive and ACPA-negative RA, that differ with respect to genetic background, predisposing environmental factors and clinical progression/remission [35]. ...
Article
Full-text available
Rheumatoid arthritis (RA) is a multifactorial, inflammatory and progressive autoimmune disease that affects approximately 1% of the population worldwide. RA primarily involves the joints and causes local inflammation and cartilage destruction. Immediate and effective therapies are crucial to control inflammation and prevent deterioration, functional disability and unfavourable progression in RA patients. Thus, early diagnosis is critical to prevent joint damage and physical disability, increasing the chance of achieving remission. A large number of biomarkers have been investigated in RA, although only a few have made it through the discovery and validation phases and reached the clinic. The single biomarker approach mostly used in clinical laboratories is not sufficiently accurate due to its low sensitivity and specificity. Multiplex immunoassays could provide a more complete picture of the disease and the pathways involved. In this review, we discuss the latest proposed protein biomarkers and the advantages of using protein panels for the clinical management of RA. Simultaneous analysis of multiple proteins could yield biomarker signatures of RA subtypes to enable patients to benefit from personalized medicine.
... Recently, antibodies directed against carbamylated antigens (anti-CarP) were identified in RA patients as well as in healthy individuals before the onset of clinical symptoms [14]. These antibodies may be helpful to predict RA mainly in ACPA-and RF-negative cases [15][16][17]. ...
... RF is thus not a specific diagnostic marker for RA. ACPA is comparatively a more specific biomarker and two-thirds of the individuals ultimately diagnosed with RA were tested positive for ACPAs 6-10 years before diagnosis [12,13]. A total of 1-3% of the healthy population may also test positive for ACPAs suggesting the decreased specificity of this biomarker [14][15][16][17]. ...
Article
Full-text available
Rheumatoid arthritis is an autoimmune disorder of complex disease etiology. Currently available serological diagnostic markers lack in terms of sensitivity and specificity and thus additional biomarkers are warranted for early disease diagnosis and management. We aimed to screen and compare serum proteome profiles of rheumatoid arthritis serotypes with healthy controls in the Pakistani population for identification of potential disease biomarkers. Serum samples from rheumatoid arthritis patients and healthy controls were enriched for low abundance proteins using ProteoMinerTM columns. Rheumatoid arthritis patients were assigned to one of the four serotypes based on anti-citrullinated peptide antibodies and rheumatoid factor. Serum protein profiles were analyzed via liquid chromatography-tandem mass spectrometry. The changes in the protein abundances were determined using label-free quantification software ProgenesisQITM followed by pathway analysis. Findings were validated in an independent cohort of patients and healthy controls using an enzyme-linked immunosorbent assay. A total of 213 proteins were identified. Comparative analysis of all groups (false discovery rate < 0.05, >2-fold change, and identified with �2 unique peptides) identified ten proteins that were differentially expressed between rheumatoid arthritis serotypes and healthy controls including pregnancy zone protein, selenoprotein P, C4b-binding protein beta chain, apolipoprotein M, N-acetylmuramoyl-L-alanine amidase, catalytic chain, oncoprotein-induced transcript 3 protein, Carboxypeptidase N subunit 2, Apolipoprotein C-I and Apolipoprotein C-III. Pathway analysis predicted inhibition of liver X receptor/retinoid X receptor activation pathway and production of nitric oxide and reactive oxygen species pathway in macrophages in all serotypes. A catalogue of potential serum biomarkers for rheumatoid arthritis were identified. These biomarkers can be further evaluated in larger cohorts from different populations for their diagnostic and prognostic potential.
... The pathogenesis of RA is complicated and not yet fully elucidated; however, both innate mechanism and highly evolved adaptive immune functions seem to operate simultaneously to create and propagate the inflammatory reactions attacking the joints [2,3]. The robust production of autoantibodies, including rheumatoid factor (RF) and anti-cyclic citrullinated peptides antibodies (ACPA), is a crucial factor in RA pathophysiology, that can lead to immune-complex deposition and the subsequent recruitment and activation of inflammatory leukocytes in the joints [4]. Usually, it is preceded by activation, somatic diversification, and affinity maturation of auto-reactive B lymphocytes, which occur in the germinal centers (GC) [5]. ...
Article
Full-text available
Background: Follicular helper T (Tfh) cells are specialized in helping B lymphocytes, which play a central role in autoimmune diseases that have a major B cell component, such as in rheumatoid arthritis (RA). Follicular regulatory T (Tfr) cells control the over-activation of Tfh and B cells in germinal centers. Dysregulation of Tfh cells and Tfr cells has been reported to be involved in the pathogenesis of some autoimmune diseases. However, the balance of Tfh and Tfr cells, and their roles in the development and progression of RA are still not clear. Methods: In this study, we enrolled 44 patients with RA (20 patients with active RA and 24 patients with inactive RA) and 20 healthy controls, and analyzed the frequencies of circulating Tfh and Tfr cells, expression of programmed death-1 (PD-1), inducible co-stimulator (ICOS), intracellular IL-21, and pSTAT3 in Tfh cells, and serum levels of IL-6. The correlation among these parameters and that of Tfh or Tfr cells with disease activity were also analyzed. Results: Patients with RA (especially active RA) had higher frequencies of Tfh cells, but lower percentages of Tfr cells, thereby resulting in elevated ratios of Tfh/Tfr. Expression levels of PD-1 and IL-21 in Tfh cells were higher in patients with RA than in healthy subjects, while no difference in ICOS expression was observed between patients and controls. Both pSTAT3 expression and serum IL-6 levels increased in patients with RA, and positive correlation between them was observed. Additionally, pSTAT3 expression was positively correlated with Tfh cell frequency. The Disease Activity Score in 28 joints based on C-reactive protein (DAS28-CRP) was negatively correlated with Tfr cell frequency, but was positively correlated with both Tfh/Tfr ratio and PD-1 expression. Conclusions: Results demonstrated that enhanced IL-6/pSTAT3 signaling may contribute to promotion of Tfh cells, consequently skewing the ratio of Tfh to Tfr cells, which may be crucial for disease progression in RA.
... Both CCP and RF are members of the autoantibodies family. CCP has high specificity but relatively low sensitivity for RA while RF is strongly sensitive but lack specificity for RA patients [5]. Therefore, there is a need for establishing new serological biomarkers to realize the early diagnosis of RA. ...
Preprint
Full-text available
Background: Erythrocytes and platelets have been demonstrated to play a critical role in inflammatory processes. However, little is known about the diagnostic value of these indices in RA patients. The aim of this study was to evaluate the clinical significance of blood counts-related parameters such as counts of red blood cells (RBCs) and platelets (PLTs), hemoglobin (Hb), red blood cells-platelet ratio (RPR) and hemoglobin-platelet ratio (HPR) in rheumatoid arthritis (RA) and their association with disease activity. Methods: Clinical and laboratory data from 178 RA patients and 164 healthy controls were collected and analyzed. RA patients were divided into inactive group and active group according to disease activity score in 28 joints based on C-reactive protein (DAS28-CRP). The relationship between blood RBC, Hb, PLT, RPR and HPR and DAS28-CRP was detected by Spearman correlation method. Receiver operating characteristic (ROC) curve was used to assess the diagnostic value of these parameters. The predictive role of these indices for RA disease activity was evaluated by logistical regression analysis. Results: Active RA patients exhibited lower levels of blood RBC counts, Hb, HCT, RPR and HPR but significantly higher level of PLT counts compared with those in inactive groups (P < 0.01). Spearman analysis showed that blood RBC counts, HCT, RPR and HPR were negatively but PLT counts were positively related with DAS28-CRP (P < 0.001) in RA. ROC curve analysis revealed that the AUC of RBC and Hb was higher than that of ESR, RF and CCP for distinguishing active RA from inactive group. Logistical regression analyses showed that PLT is an independent predictor for RA disease activity. Conclusion: Blood RBC counts, Hb, RPR and HPR were negatively but PLT counts were positively related with RA disease activity. Blood PLT may act as a novel inflammatory factor for predicting disease activity in RA.
... Patients diagnosed with RA produce a specific set of autoantibodies, typically reactive against post-translational modifications of proteins (5)(6)(7). Such autoantibodies appear decades before clinically apparent disease (8). ...
Article
Full-text available
Like other autoimmune diseases, rheumatoid arthritis (RA) develops in distinct stages, with each phase of disease linked to immune cell dysfunction. HLA class II genes confer the strongest genetic risk to develop RA. They encode for molecules essential in the activation and differentiation of T cells, placing T cells upstream in the immunopathology. In Phase 1 of the RA disease process, T cells lose a fundamental function, their ability to be self-tolerant, and provide help for autoantibody-producing B cells. Phase 2 begins many years later, when mis-differentiated T cells gain tissue-invasive effector functions, enter the joint, promote non-resolving inflammation, and give rise to clinically relevant arthritis. In Phase 3 of the RA disease process, abnormal innate immune functions are added to adaptive autoimmunity, converting synovial inflammation into a tissue-destructive process that erodes cartilage and bone. Emerging data have implicated metabolic mis-regulation as a fundamental pathogenic pathway in all phases of RA. Early in their life cycle, RA T cells fail to repair mitochondrial DNA, resulting in a malfunctioning metabolic machinery. Mitochondrial insufficiency is aggravated by the mis-trafficking of the energy sensor AMPK away from the lysosomal surface. The metabolic signature of RA T cells is characterized by the shunting of glucose toward the pentose phosphate pathway and toward biosynthetic activity. During the intermediate and terminal phase of RA-imposed tissue inflammation, tissue-residing macrophages, T cells, B cells and stromal cells are chronically activated and under high metabolic stress, creating a microenvironment poor in oxygen and glucose, but rich in metabolic intermediates, such as lactate. By sensing tissue lactate, synovial T cells lose their mobility and are trapped in the tissue niche. The linkage of defective DNA repair, misbalanced metabolic pathways, autoimmunity, and tissue inflammation in RA encourages metabolic interference as a novel treatment strategy during both the early stages of tolerance breakdown and the late stages of tissue inflammation. Defining and targeting metabolic abnormalities provides a new paradigm to treat, or even prevent, the cellular defects underlying autoimmune disease.
... Genetic susceptibilities and environmental risk factors contribute to the pathogenesis of RA (Karami et al. , 2020). Various immune cells, including macrophages, dendritic cells, and B cells, as antigen-resenting cells (APCs), process and present autoantigens such as anti-cyclic citrullinated peptide (anti-CCP) antibodies (Abs) to the T cells which triggers auto-inflammatory responses and continual inflammation (Conigliaro et al. , 2016, Scott et al. , 2010. In RA, activation of autophagy is a crucial factor for the survival of inflammatory cells, including synoviocytes and lymphocytes; also, autophagy has a significant role in citrullination and osteoclastogenesis. ...
Article
Autoimmune diseases (AD), which are classified as chronic injuries, are caused by a specific auto-reactive reaction. The etiology of most ADs is not well understood. Meanwhile, Autophagy is a protective response defining as a catabolic method by lysosomes tending to maintain homeostasis acts by recycling and discrediting cell compartments. Autophagy plays a crucial role in controlling immune homeostasis by eliminating intracellular pathogens and presenting antigens to immune cognition. MicroRNAs are commonly known as endogenous non-coding small RNAs, which span 18–25 nt and take part in the gene expression at the post-transcriptional level regulation. miRNAs play important roles in different processes like, cell differentiation, duplicating, and apoptosis. Moreover, miRNAs are the critical molecules for the regular function of the immune system by modulating immune tolerance mechanisms and autoimmunity. Recent findings support the role of dysregulated miRNAs in the pathogenesis of ADs and in the regulation of autophagy. In this review, we will focus on the role of the miRNAs in the regulation of autophagy and then will explain the role of dysregulated miRNAs in the initiation of the ADs by modulating autophagy.
... This oxidative induced post-translational modification of protein antigen produces new epitopes leading to the production of auto-antibodies when immune system recognize them as non-self and stimulate B cells against it [137]. Anti-citrullined protein antibodies and anti-carbamylated protein antibodies are two examples of auto-antibodies generated in RA patients due to the oxidative post-translational modification [139]. ...
Article
Full-text available
Autoimmune diseases (AUDs) are a multifactorial disease, among which rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis are more prevalent. Several anti-inflammatory, biologics, and AUD-modifying drugs are found effective against them, but their repeated use are associated with various adverse effects. In this review article, we have focused on the regulation of inflammatory molecules, molecular signaling pathways, immune cells, and epigenetics by natural product thymoquinone on AUDs. Studies indicate that thymoquinone can regulate inflammatory molecules including interferons, interleukins, tumor necrosis factor-α (TNF-α), oxidative stress, regulatory T cells, and various signaling pathways such as nuclear factor kappa beta (NF-κβ), janus kinase/signal transduction and activator of transcription (JAK-STAT), mitogen-activated protein kinase (MAPK) at the molecular level and epigenetic alteration. As these molecules and signaling pathways with defective immune function play an important role in AUD development, controlling these molecules and deregulated molecular mechanism is a significant feature of AUD therapeutics. Interestingly thymoquinone is reported to possess all these potential. This article reviewed the deregulated mechanism of AUDs, and the action of thymoquinone on inflammatory molecules, immune cells, signaling pathways, and epigenetic machinery. Thymoquinone can be regarded as a potential drug candidate for AUD treatment.
... Anti-CCP has high specificity but relatively low sensitivity for RA, while RF is strongly sensitive but lacks specificity for RA patients. 5 Therefore, there is a need for establishing new serological biomarkers to realize the early diagnosis of RA. ...
Article
Full-text available
Background: Platelet (PLT) and red blood cell (RBC) have been demonstrated to play a critical role in inflammatory processes. This study aimed to evaluate the association of blood PLT and RBC related parameters with the disease activity in rheumatoid arthritis (RA) patients, and also to investigate the role of these indices in differentiating among RA patients with different disease activity. Methods: Clinical data from RA patients were retrospectively analyzed. RA patients were divided into inactive group and active group according to DAS28-CRP. The relationship between blood PLT and RBC counts-related indices and DAS28-CRP was detected by Spearman correlation. ROC curve was used to assess the diagnostic value of these indices in differentiating active RA from inactive RA. Results: Active RA patients exhibited higher level of PLT counts but significantly lower levels of RBC counts, hemoglobin (Hb), red blood cells-platelet ratio (RPR) and hemoglobin-platelet ratio (HPR) compared with inactive RA. PLT counts were positively but RBC counts, Hb, RPR and HPR were negatively related with DAS28-CRP. Conclusion: Blood PLT and RBC related indices were significantly associated with RA disease activity. These indices may be used to distinguish active RA from inactive RA.
... Inflammatory arthritis (IA) refers to arthritis caused by inflammatory factors other than bone degeneration, and includes rheumatoid arthritis (RA), psoriatic arthritis, and ankylosing spondylitis 1 . RA is the most common 2 form of IA, with a prevalence rate of approximately 3% in adult 3 . The early stages of this disease are often characterized by synovial inflammation and secondary joint damage, and if not treated properly, can result in irreversible joint deformities that seriously affect a patient's work ability and quality of life 4 . ...
Article
Objective: The lymphatic system plays an important role in joint diseases. This study aimed to evaluate the effects of ginsenoside Rg1 on lymphatic drainage and accumulation of inflammatory products in the joints. Methods: Two-month-old transgenic mice that overexpress tumor necrosis factor alpha (TNF-α; TNF-Tg) were used as the animal models. Ginsenoside Rg1 was administered for 12 weeks and the lymphatic drainage in the mice was evaluated using near infrared-indocyanine green (NIR-ICG) lymphatic imaging system. The clinical symptoms of arthritis were evaluated weekly. The ankle and knee joints were harvested for hematoxylin-eosin (HE), alcian blue/orange G (ABOG), and tartrate-resistant acid phosphatase (TRAP) staining, and the foot dorsal skin was used for whole-mount immuno-staining. Simultaneously, the serum levels of IL-6 and TNF-α were detected using enzyme-linked immunosorbent assay (ELISA). Results: Ginsenoside Rg1 significantly improved the lymphatic drainage function, reduced synovial inflammation and bone erosion, decreased serum IL-6 and TNF-α concentration, and increased smooth muscle coverage on the collecting lymphatic vessels in the foot skin of the TNF-Tg mice. Furthermore, ginsenoside Rg1 treatment for 12 weeks did not cause any damage to the liver and kidney tissues. Conclusion: Ginsenoside Rg1 improves lymphatic drainage and joint inflammation in TNF-Tg mice. Therefore, ginsenoside Rg1 has the potential to be a candidate drug for the treatment of inflammatory arthritis.
... Worldwide, it represents the most common inflammatory arthropathy [2]. RA is characterized by the presence of autoantibodies such as rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) [3]. On the other hand, SpA are a heterogeneous group of inflammatory chronic diseases characterized by sharing common pathogenic, clinical and radiologic features, typically defined as "seronegative" due to the absence of RF. ...
Article
Full-text available
Importance Evidence emerged concerning how inflammatory arthritis and mood disorders can often occur in the same patient and show a similar clinical pattern. An overview of the rheumatological and psychiatric aspects of these diseases can certainly be useful for the improvement of patients' clinical and therapeutic management. Objective The aim of this narrative review was to summarize existing literature about common pathogenetic and clinical aspects as a means of improving management and therapeutic approach in patients affected by rheumatoid arthritis, psoriatic arthritis and spondyloarthritis. Outcomes such as disease activity indexes and patient reported outcomes (PROs) were considered. Findings Common pathogenetic pathways emerged between inflammatory arthritis and mood disorders. Pro-inflammatory mechanisms, such as TNFα, IL-6, IL-17 and oxidative stress factors as well as neurotransmitter alterations at the level of CNS and blood–brain barrier (BBB) cells are involved. The activation of these common pathogenetic pathways is, also, affected by the same triggers, such as smoking, stress, lifestyle, and evidence has emerged concerning the possibility of the clinical efficacy of using the same therapeutic approaches. Conclusions The main causes of the variability in clinical studies outcomes are the rheumatological diseases considered, the prevalence of depression in the general population and in patients with rheumatological diseases and the type of depressive symptom examined. Patients affected by inflammatory arthritis can present symptoms and signs in common with mood disorders, leading to possible clinical overlap. There are still few studies analyzing this concept: they are extremely heterogeneous, both in the characteristics of the population taken into consideration and in the methods used for the definition of depressive disorder, but the suggestions of the data obtained so far are promising and deserve to be pursued.
... As listed in the ACR/EULAR classification criteria, two autoantibodies namely rheumatoid factor (RF) and anticitrullinated protein antibody (ACPA) can be found in more than 60% of RA patients. [11][12][13][14] These two autoantibodies are not only hallmarks of the disease but also suggested to play important role in the pathogenesis of RA. ...
Article
Full-text available
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by joint inflammation and extra-articular manifestations. Many questions in the pathogenesis, clinical manifestation, and disease spectrum are answered after the discovery of the first autoantibody namely rheumatoid factor (RF). The finding of the second autoantibody named anti-citrullinated protein antibody (ACPA), which unearths the importance of protein citrullination process. It further provides the insight how immune cells and complement interact to perpetuate the inflammatory response. These two autoantibodies pave the way for our better understanding of RA. This review article focuses on the history, pathophysiology, and clinical association of these two autoantibodies in RA.
... В частности, в этом качестве рассматриваются с недавних пор аутоантитела к пептидам с карбамоилированными аминокислотами и аутоантитела к ферментам цитруллинирования -пептидиларгинин-дезаминазам. Они могут присутствовать у больных при отсутствии классических ревматоидных факторов и антител к цитруллинсодержащим пептидам и ассоциируются с большей тяжестью болезни [31][32]. Обсуждали и вопрос о применении биотерапии ревматоидного артрита в комплексном лечении с целью уменьшения доз лекарств (доклад К. Эдвардса, Великобритания), склеродермии (доклад Я. Леви, Израиль) и системной красной волчанке (доклад А. Дориа, Италия), равно как и особенности диагностики ювенильного ревматоидного артрита у детей -основного педиатрического ревматологического заболевания в российской практике, поражающего до 0,4% детей (доклад В. А. Черешнева и соавт., Пермь-Екатеринбург) [33][34]. ...
Article
Full-text available
The article written by the co-chairmen of the First St. Petersburg Congress on Autoimmunity "Bridge between East and West", held in St. Petersburg State University June 30-July 2, 2017 describes this event and gives an overview of the main lectures and discussions during the Congress. The latest data on the role of diet, adjuvants, vaccines, viruses and microbiome, on genetic factors, stress, smoking, lifestyle, drugs - in etiology, as well as the role of lymphocytes, macrophages, various autoantibodies, complement and cytokines - in the pathogenesis and diagnosis of autoimmune diseases were discussed. The congress discussed their comorbidity, ways of treatment and prevention, markers, methodology and contribution of serological tests in the diagnosis and classification of autoimmune diseases. Current data on physiological autoimmunity, as well as the early predictive role of autoantibodies were described. The participants performed philosophical discussions about immunological concepts, and organizational discussions of the standardization of diagnostics and the principles of working with large databases, as applied to this field. The programme included Clinical Pathophysiology все of various autoimmune rheumatologic, psycho-neurological, endocrine, cardiovascular, obstetric-gynecological and many other diseases. The authors conclude that the rapid formation of Autoimmunology as a new integral medical branch happens nowadays (9 figs, bibliography: 69 refs).
... The pro-inflammatory cytokine-interleukin 17 (IL-17) produced by CD4 + Th17 cells was shown to induce bone resorption in RA patients (9) and other Th17-produced cytokines (e.g., IL-6, IL-1b, IL-23, etc.) can also recruit neutrophils into synovial tissue to sustain chronic inflammation (10). Local CD4 + T cells have also been proposed to be a prominent driver of humoral immunity in RA patients and induced antibody against citrullinated protein and rheumatoid factor (RF), which are the two most prevalent autoantibodies in RA (11). These studies suggest that different subtype of T cells may contribute to RA progression in different ways. ...
Article
Full-text available
Fibrinogen-like protein 1 (FGL1) was recently identified as a major ligand of lymphocyte-activation gene-3 (LAG-3) on activated T cells and serves as an immune suppressive molecule for regulation of immune homeostasis. However, whether FGL1 has therapeutic potential for use in the T cell-induced the autoimmune disease, rheumatoid arthritis (RA), is still unknown. Here, we attempted to evaluate the effect of FGL1 protein on arthritis progression. We also evaluated potential adverse events in a collagen-induced arthritis (CIA) mouse model. We first confirmed that soluble Fgl1 protein could specifically bind to surface Lag-3 receptor on 3T3-Lag-3 cells and further inhibit interleukin (IL-2) and interferon gamma (IFNγ) secretion from activated primary mouse T cells by 95% and 43%, respectively. Intraperitoneal administration of Fgl1 protein significantly decreased the inflammatory cytokine level (i.e., IL-1β and IL-6) in local paw tissue, and prevented joint inflammation, cellular infiltration, bone deformation and attenuated collagen-induced arthritis progression in vivo . We further demonstrated that exogenous Fgl1 does not cause obvious adverse events during treatment by monitoring body weight and liver weight, and assessing the morphology of several organs (i.e., heart, liver, spleen, lung and kidney) by pathological studies. We expect that Fgl1 protein may be suitable to serve as a potential therapeutic agent for treatment of RA or even other types of T cell-induced autoimmune or inflammatory diseases in the future.
Article
Matrix metalloproteinase-3 or MMP3 also known as stromelysin-1 is an enzyme that is actively involved in joint destruction in rheumatoid arthritis (RA) patients. Screening the last three decades, it appears that serum levels of MMP3 reflect positively RA disease activity, joint and bone injury, and radiological erosion and predict disease outcome and drug responsiveness as summarized in several publications reporting outcomes on more than 8000 patients with RA. MMP-3 monitoring should be embedded in the routine assessment and accompany therapeutic modalities, in personalized medical RA management.
Article
Aim We conducted this retrospective study to identify objective and comprehensive diagnostic criteria for early‐stage rheumatoid arthritis (RA) that are based on ultrasound (US) and serologic findings. Method From August 2014 to May 2016, we recruited 216 consecutive patients at Hospital 1 and 223 consecutive patients at Hospital 2 who were suspected to have RA and underwent US of bilateral hands. In the US of bilateral hands from 22 sites, the findings obtained by grayscale and power Doppler (PD) assessments were each graded on a semi‐quantitative scale from 0 to 3. We also examined the assessment of the novel outcome measures in rheumatology (OMERACT)‐European League Against Rheumatism (EULAR) combined power Doppler ultrasound score (ie the cPD score) and the Global OMERACT‐EULAR Synovitis Score. We used the US findings and the combination of US and serologic findings to evaluate the diagnostic performance of these modalities. Results Seventy patients (32.4%) at Hospital 1 and 59 patients (26.5%) at Hospital 2 were diagnosed as having RA. The best‐balanced diagnostic performance at each hospital was achieved using a combination, such as (1) the presence of PD grade ≥2 articular synovitis or (2) the presence of PD grade ≥1 articular synovitis and serologic positivity, as well as by using (1) the presence of cPD grade = 3 or (2) a cPD grade ≥2 and serologic positivity. Conclusion The combination of a PD assessment or the cPD score with the measurement of autoantibodies of rheumatoid factor and/or anti‐cyclic citrullinated peptide antibodies can accurately identify patients with early‐stage RA.
Article
Autoantibodies (AAbs) are antibodies produced against our own cells or tissues either providing a first defense against infections or indicating the presence of pathological processes. They are not only able to inform on diseases evolution but also to predict some illnesses well in advance. Currently, the evaluation of the number and type of formed AAbs is employed to assess the risk, rate, severity and progression of autoimmune and cancer diseases, and to help to find therapies to prevent or mitigate these illnesses impact. Conventional methods for the determination of AAbs generally suffer from low sensitivity, time-consuming and laborious methodologies and need specialized technicians and well-equipped labs. Consequently, seeking for new methodologies for the rapid and low-cost screening of AAbs is of great interest for global health because it would shorten the delay between sample collection and diagnosis and improve the introduction of modern diagnostics into the developing world. Electrochemical biosensors are considered as a promising alternative to conventional techniques for the determination of clinical biomarkers due to their simplicity of use, low cost, high sensitivity, multiplexing abilities or compatibility with microfabrication and point of care testing. This review is focused on the critical discussion of selected electrochemical biosensors described up to date for the determination of AAbs related to autoimmune diseases and several types of cancer. An overview pointing out future directions in this field is also provided.
Article
Full-text available
Patients with rheumatoid arthritis (RA) and autoantibodies, such as rheumatoid factor and those against cyclic citrullinated peptides, are designated as seropositive and have a more severe disease with worse prognosis than seronegative RA patients. Understanding the factors that participate in systemic inflammation, in addition to articular commitment, would allow better treatment approaches for prevention of RA comorbidities and disease reactivation. We evaluated whether monocyte subsets and extracellular vesicles (EVs) could contribute to this phenomenon. Seropositive patients had higher levels of proinflammatory cytokines than those of seronegative patients and healthy controls (HCs); however, this systemic inflammatory profile was unrelated to disease activity. High frequencies of circulating EVs positive for IgG, IgM, CD41a, and citrulline, together with altered counts and receptor expression of intermediate monocytes, were associated with systemic inflammation in seropositive patients; these alterations were not observed in seronegative patients, which seem to be more similar to HCs. Additionally, the EVs from seropositive patients were able to activate mononuclear phagocytes in vitro, and induced proinflammatory cytokines that were comparable to the inflammatory response observed at the systemic level in seropositive RA patients; therefore, all of these factors may contribute to the greater disease severity that has been described in these patients.
Article
Full-text available
Anti-citrullinated protein antibodies (ACPAs) are autoantibodies commonly observed in patients with rheumatoid arthritis (RA). Currently, most of the mechanisms of ACPA formation and bone destruction are well-understood, however, some unknown mechanisms still exist. There have been many new advances in ACPA-related clinical applications and targeted therapies. However, the existence of different ACPA subtypes is a limitation of targeted therapy. Herein, we present an overview of the process of ACPA generation, the underlying pathogenesis, and relevant clinical application and prospects.
Article
Resumen La artritis psoriásica (AP) es una artritis inflamatoria crónica que pertenece a la familia de las espondiloartritis. Se estima que su prevalencia es del orden del 0,01-0,2% en la población general y podría llegar al 40% en los pacientes con psoriasis cutánea. Se trata de una enfermedad heterogénea y compleja, cuyas manifestaciones clínicas articulares y extraarticulares pueden ser extremadamente variables, lo que a menudo provoca un retraso diagnóstico y terapéutico. La afectación del aparato locomotor asocia en grados diversos manifestaciones axiales con raquialgias inflamatorias, que predominan a nivel cervicodorsal, y sacroilitis, a veces asintomática, una afectación entesítica que puede ser diseminada así como una afectación articular periférica que ataca prioritariamente a manos y pies. Además de la afectación cutánea de la psoriasis, esta artritis puede acompañarse de uveítis o también de una enfermedad inflamatoria intestinal. Reconocida actualmente como una entidad propia, la AP se ha confundido durante mucho tiempo con otras artritis, en particular con la artritis reumatoide. Su evolución puede ser grave, causando impotencia funcional y un deterioro importante de la calidad de vida; requiere un seguimiento clínico, biológico y radiológico apropiado. La reciente mejora de los conocimientos fisiopatológicos ha permitido el rápido desarrollo de biofármacos y terapias dirigidas (antifactor de necrosis tumoral alfa, antiinterleucina 12/23, antiinterleucina 17, apremilast, anticinasa Janus), eficaces contra la mayor parte de los diferentes síntomas, complementando así el arsenal terapéutico anteriormente existente (antiinflamatorios no esteroideos, inyección local de corticoides, metotrexato, leflunomida, sulfasalazina).
Article
Objectives: To evaluate long-term effects on gamma-globulins and autoantibodies of abatacept (ABA) versus tumor necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA) patients. Method: Eighteen RA patients undergoing abatacept (ABA-RA) and 18 age/sex-matched patients treated with TNFi (TNFi-RA) were compared regarding clinical data, total gamma-globulins (TGG), specific subtypes (IgG, IgM, IgA), free light chains (FLC), IgM/IgG rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP3), and anti-mutated citrullinated vimentin (anti-MCV), assessed before and every 6 months, up to 24 months. Exclusion criteria: previous abatacept/rituximab or low TGG (< 0.7 g/dL). Results: At baseline, female sex (78 vs. 78%), age (55 vs. 53 years), DAS28 (5.73 vs. 5.67), TGG (1.4 vs. 1.35 g/dL), IgG (1168 vs. 1079 mg/dL), IgM (107 vs. 113 mg/dL), IgA (333 vs. 322 mg/dL), kappa (342 vs. 249 mg/dL), lambda (170 vs. 150 mg/dL), IgM-RF (76 vs. 53 UI), IgG-RF (63 vs. 25 UI), anti-CCP3 (216 vs. 189 UI), and anti-MCV (202 vs. 102 UI) were comparable in ABA-RA and TNFi-RA (p > 0.05). Similar disease activity improvement was observed in both groups. In ABA-RA, significant decreases (p < 0.05) were observed in TGG (1.4 vs. 1.05 g/dL), IgG (1168 vs. 997), IgA (333 vs. 278 mg/dL), kappa (342 vs. 257 mg/dL), lambda (170 vs. 144 mg/dL), IgM-RF (76 vs. 37 UI), IgG-RF (65 vs. 24 UI), anti-CCP3 (216 vs. 183 UI), and anti-MCV (202 vs. 60 UI) at 6 months, without further decreases. In contrast, TNFi-RA showed no decrease in any of such parameters. ABA-RA also had more often transient IgG levels under the lower limit of normality (66.7% vs. 33.3%, p = 0.046). No severe infection occurred. DAS28, ESR, and CRP correlated significantly to gamma-globulins and FLC at baseline (p < 0.05), but these correlations were longitudinally lost in ABA-RA, but not in TNFi-RA. Conclusion: ABA, but not TNFi, induces a safe, persistent, long-term, and non-progressive reduction in gamma-globulins and autoantibodies, including anti-MCV. This pattern is dissociated from disease activity control.Key Points• ABA induces a long-term and non-progressive reduction in gamma-globulins and FLC, which occurs regardless of disease activity control.• ABA-induced reduction in gamma-globulins and FLC promotes a dissociation of such parameters and disease activity.• The same pattern of reduction is observed in autoantibodies: IgM-RF, IgG-RF, anti-CCP3, and anti-MCV.• Low transient IgG can be observed in RA patients treated with ABA, but does not correlate to infection.
Article
Introduction: Innate immune response and bone remodeling are key factors contributing to the pathogenesis of psoriatic arthritis (PsA). Moreover, the evidence of autoantibodies in patients’ sera suggests an autoimmune side in PsA. Besides the immune pathways, studies strongly support the role of genetic risk alleles in affecting the clinical heterogeneity of PsA as well as the response to therapy. A good clinical response to treatment, indeed, represents a challenge in PsA patients and the identification of patient-targeted therapies is still a critical issue. Areas covered: We performed a systematic review aiming at describing new evidence on PsA pathogenesis and treatments. Reported items for systematic reviews (PRISMA checklist) were analysed. Studies included from the PubMed database addressed the following items: innate immunity, autoimmunity, bone remodeling, and therapeutic targets in PsA; time frame of research 1970–2019. Specifically, we reviewed data on IL-17 inhibitors, abatacept, JAK inhibitors, ABT 122 and A (3) adenosine receptors agonist, CF101. Expert opinion: In PsA an intriguing pathogenetic network has been documented. Several biological and synthetic drugs are promising in terms of efficacy and safety profile.
Article
Objective To examine the expression and clinical significance of circulating CD4⁺ FoxP3– CXCR5– CXCR3⁺ PD-1hi cells in rheumatoid arthritis (RA). Methods CD4⁺ FoxP3– CXCR5– CXCR3⁺ PD-1hi cells in peripheral blood of 35 patients with active RA, 17 with RA in stable remission, and 24 healthy controls were analyzed by flow cytometry. Serum IgG and circulating plasmablast percentages were measured and correlations with CD4⁺ FoxP3– CXCR5– CXCR3⁺ PD-1hi cells were systematically analyzed. Disease Activity Scale 28 (DAS28) scores were also calculated and correlation analysis with CD4⁺ FoxP3– CXCR5– CXCR3⁺ PD-1hi cells was conducted. The levels of CD4⁺ FoxP3– CXCR5– CXCR3⁺ PD-1hi cells were compared before and after disease-modifying anti-rheumatic drug treatment. Cytokine levels in plasma and cytokine secretion in CD4 cells were measured and their correlations with CD4⁺ FoxP3– CXCR5– CXCR3⁺ PD-1hi cells were further analyzed. Results The levels of CD4⁺ FoxP3– CXCR5– CXCR3⁺ PD-1hi cells in the peripheral blood of patients with active RA were significantly increased compared with healthy controls. CD4⁺ FoxP3– CXCR5– CXCR3⁺ PD-1hi cells in patients with active RA were positively correlated with serum IgG and DAS28 scores. CD4⁺ FoxP3– CXCR5– CXCR3⁺ PD-1hi cells were significantly decreased in patients after treatment. Plasma interleukin-10 concentrations and interleukin-10-positive CD4 cell percentages were significantly positively correlated with CD4⁺ FoxP3– CXCR5– CXCR3⁺ PD-1hi cell levels. Conclusion Circulating CD4⁺ FoxP3– CXCR5– CXCR3⁺ PD-1hi cells in patients with active RA are increased and could reflect the severity of the disease, which may play a potential role in the pathogenesis of RA.
Article
Background: Rheumatoid arthritis (RA), a primary chronic articular disease with wide range of extra-articular and systemic effects. The spleen is one of the most affected organs in RA. CD4+ T cells play an important role in initiation, maintenance and control of the disease. Aim of the work: This work was designed to study the histological changes occurring in the spleen in a rat model of RA and to assess the effect of treatment with omega-3 alone, with special refer to the role of CD4+ T-cells. Materials and methods: Thirty male albino rats were divided into four groups; control group, early and progressive RA groups and omega-3 treated group. RA was induced in rats of groups II, III and IV by a single subcutaneous injection of complete Freund's adjuvant (CFA). Samples were taken after two and four weeks of the CFA injection (in early and progressive RA groups respectively). Treatment with omega-3 (300 mg/kg/day in a single, daily oral dose) started two weeks after CFA injection in rats of group IV and continued for another two weeks. Spleen specimens were collected at the appropriate times and processed to obtain paraffin blocks. Sections were then stained for histological and immunofluorescence studies. Results: Both, early and progressive RA induced noticeable structural changes in the spleen. Thickened capsule and trabeculae and marked congestion of the blood sinusoids of the red pulp were evident. Expansion of the white pulp and areas of mononuclear cellular infiltration were seen, especially in progressive RA. Affection of blood vessel walls was also noticed. Immunofluorescence study showed extensive expression of Anti-CD4 Monoclonal Antibodies especially in progressive RA. Treatment with omega-3 significantly improved the structure of the spleen as detected by both histological and immunofluorescence studies. Conclusion: Omega-3 treatment ameliorated the structural damage of the spleen caused by experimental induction of RA.
Article
This work reports the first amperometric biosensor involving the use of neutravidin-functionalized magnetic microbeads (NA-MBs) modified with a biotinylated-anti-dsDNA (b-dsDNA) as efficient magnetic microcarriers to selectively capture anti-dsDNA autoantibodies (IgG, IgA and IgM AAbs) present in the sera of patients with rheumatoid arthritis (RA). Subsequently, the attached anti-dsDNA AAbs are detected with a mixture of conventional HRP-labeled secondary antibodies (HRP-anti-human IgG/IgM/IgA mixture). The biorecognition event is monitored by amperometric transduction using the hydroquinone (HQ)/H2O2 system upon capturing the modified MBs on the surface of screen-printed carbon electrodes (SPCEs). The developed bioplatform exhibits a linear calibration plot ranging from 1 to 200 IU mL⁻¹ with a LOD of 0.3 IU mL⁻¹ for anti-dsDNA AAbs standards. In addition, the biosensor allows performing the determination of the anti-dsDNA AAbs levels directly in 100-times diluted serum samples from patients diagnosed with RA and in just 75 min. The obtained results are in agreement with those provided by an ELISA kit and allow discrimination between positive and negative samples.
Chapter
Aging implies changes in articular cartilage cells and the surrounding extracellular matrix (ECM) that are reflective of metabolic changes related to time alone. For chondrocytes, these are genomic and intracytoplasmic changes that lessen their capacity to respond and control their extracellular environment; for the matrix, these are changes that lead to decreased hydration and increased brittleness of the tissue. Clinically, this can manifest as decreased capacity to withstand mechanical forces leading to degenerative arthritis.
Article
Introduction Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects approximately 1% of the adult population. RA is multi-factorial, and as such our understanding of the molecular pathways involved in the disease is currently limited. An increasing number of studies have suggested that several molecular phenotypes (i.e. endotypes) of RA exist, and that different endotypes respond differently to various treatments. Biochemical markers may be an attractive means for achieving precision medicine, as they are objective and easily obtainable. Areas covered We searched recent publications on biochemical markers in RA as either diagnostic or prognostic markers, or as markers of disease activity. Here, we provide a narrative overview of different classes of markers, such as autoantibodies, citrulline products, markers of tissue turnover and cytokines, that have been tested in clinical cohorts or trials including RA patients. Expert opinion Although many biochemical markers have been identified and tested, few are currently being used in clinical practice. As more treatment options are becoming available, the need for precision medicine tools that can aid physicians and patients in choosing the right treatment is growing, as is the desire for more insight into the mode of action of this new drug candidate.
Article
Rheumatoid arthritis is a chronic, autoimmune connective tissue disease. In addition to joint involvement, extra-articular changes and organ complications also occur in the course of the disease. Untreated disease leads to disability and premature death. Therefore, it is very important to recognise and begin treatment early. Based on the presence of rheumatoid factor and antibodies against citrullinated peptides, we can distinguish two forms of the disease: seropositive and seronegative. Research continues to elucidate the mechanisms of the onset of the disease, as well as to uncover factors that induce and influence the activity of the disease. The presence of markers that initially appear and affect the course of the disease can potentially aid in patient treatment. In this article, we have collected biomarkers of rheumatoid arthritis that are well understood as well as those that have been recently described.
Article
Rheumatoid arthritis (RA) is a chronic incurable inflammatory autoimmune disease. T follicular helper (Tfh) cells expressing different markers play critical roles in the development of RA. However, their specific mechanisms of action and association with RA clinical parameters are not clear. We therefore performed a cohort study to investigate the effects of different Tfh cell markers on RA pathogenesis. We retrospectively reviewed clinical data from 30 patients diagnosed with RA and 30 healthy controls (HCs) who visited our hospital. Based on X-ray findings, the patients were divided into a joint bone erosion group (n = 17) and a non-erosive joint bone group (n = 13). Using flow cytometry, we determined the frequencies of five peripheral blood CD4+ Tfh cell types characterized by different markers, and examined these cell types for correlations with clinical parameters. RA patients exhibited higher frequencies of CD4+CXCR5+, CD4+CXCR5+ICOS+, CD4+CXCR5+OX40+, and CD4+CXCR5+CD40L+ Tfh cells than HCs. CD4+CXCR5+, CD4+CXCR5+CD40L+, and CD4+CXCR5+OX40+ Tfh cell frequencies positively correlated with disease activity score-28 with erythrocyte sedimentation rate (DAS28-ESR), while those of CD4+CXCR5+ and CD4+CXCR5+CD40L+ Tfh cells were related to rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibodies. In RA patients without joint bone erosion, CD4+CXCR5+CD40L+ Tfh cell frequencies were positively correlated with both RF and DAS28-ESR. Serum anti-CCP antibody levels and CD4+CXCR5+ICOS+ Tfh cell frequencies were also positively correlated. Circulating CD4+CXCR5+CD40L+ Tfh cells appear to play critical roles in RA pathogenesis, and restricting CD4+CXCR5+CD40L+ Tfh cells may be a therapeutic strategy for controlling RA.
Article
Many anti-inflammatory therapies targeting neutrophils have been developed so far. A sialic acid (SA)–modified liposomal (SAL) formulation, based on the high expression of L-selectin in peripheral blood neutrophils (PBNs) and SA as its targeting ligand, has proved to be an effective neutrophil-mediated drug delivery system targeting rheumatoid arthritis (RA). The objective of this study was to investigate the influence of particle size of drug-carrying SALs transported and delivered by neutrophils on their anti-RA effect. Dexamethasone palmitate–loaded SALs (DP-SALs) of different particle sizes (300.2 ± 5.5 nm, 150.3 ± 4.3 nm, and 75.0 ± 3.9 nm) were prepared with DP as a model drug. Our study indicated that DP-SALs could efficiently target PBNs, with larger liposomes leading to higher drug accumulation in cells. However, a high intake of large DP-SALs by PBNs inhibited their migration ability and capacity to release the payload at the target site. In contrast, small DP-SALs (75.0 ± 3.9 nm) could maintain the drug delivery potential of PBNs, leading to their efficient accumulation at the inflammatory site, where PBNs would be excessively activated to form neutrophil extracellular traps along with efficient payload release (small DP-SALs) and finally to induce excellent anti-RA effect.
Article
Serum connective tissue growth factor (CTGF) is reported to be a potential biomarker for the diagnosis of rheumatoid arthritis (RA). Our study aimed to investigate the prevalence of serum CTGF and the association with the clinical features in RA patients. Serum samples were obtained from 180 patients with RA, 168 patients with other rheumatic diseases, including 43 systemic lupus erythematosus (SLE), 34 osteoarthritis (OA), 17 primary Sjögren's syndrome (pSS), 20 ankylosing spondylitis (AS), 23 psoriatic arthritis (PsA), 6 reactive arthritis (ReA), 20 systemic sclerosis (SSc), and 5 systemic vasculitis (SV), and 64 healthy individuals. The clinical and laboratory data of patients with RA were collected. Levels of CTGF in serum were measured by enzyme linked immunosorbent assay (ELISA). Associations between CTGF and the clinical features of RA were analyzed. The positivity of serum CTGF among RA patients (33.89%) was significantly higher than those of SLE (9.3%), OA (0%), AS (0%), pSS (0%), PsA (0%), ReA (0%), SSc (5%), SV (0%), and healthy controls (4.69%) (p < 0.0001). The mean concentration of serum CTGF in RA was also significantly higher than those in other rheumatic diseases and healthy controls (p < 0.001). At the cut-off value of 263.30 pg/ml, the sensitivity, specificity, positive predictive value, and negative predictive value of serum CTGF for RA were 33.89%, 96.55%, 88.41%, and 55.45%, respectively. Anti-cyclic citrullinated peptide (anti-CCP) antibody (p < 0.001), rheumatoid factor (RF) (p < 0.001), IgG (p = 0.025), and IgM (p = 0.004) in CTGF-positive patients were higher than those in CTGF-negative patients. Besides, the positive rate of serum CTGF was significantly higher in RA patients with interstitial lung disease (ILD) (53.1%, 26/49) than RA-non-ILD patients (26.7%, 35/131, p = 0.003). Serum CTGF, as a novel biomarker, has certain diagnostic value for RA. Further studies are necessary to get more knowledge for the diagnostic performance of CTGF in RA. KEY POINTS: • Serum CTGF, as a novel biomarker, has certain diagnostic value for RA, the sensitivity, specificity, positive predictive value, and negative predictive value of which were 33.89%, 96.55%, 88.41%, and 55.45%, respectively. • Serum CTGF was more common to be positive in RA-ILD patients (53.1%, 26/49) than RA-non-ILD patients (26.7%, 35/131, p = 0.003).
Article
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.
Article
Full-text available
Purpose of review Rheumatoid arthritis–associated interstitial lung disease (RA-ILD) is one of the most serious extraarticular RA manifestations. RA-ILD is associated with worse physical function, lower quality of life, and increased mortality. RA-ILD is comprised of heterogeneous subtypes characterized by inflammation and fibrosis. Diagnosis can be difficult since the presentation of RA-ILD is characterized by non-specific symptoms and imaging findings. Management of RA-ILD is also challenging due to difficulty in precisely measuring pulmonary disease activity and response to treatment in patients who may also have articular inflammation. We provide a current overview of RA-ILD focusing on prevalence, risk factors, and treatment. Recent findings Research interest in RA-ILD has increased in recent years. Some studies suggest that RA-ILD prevalence may be increasing; this may be due to underlying biologic drivers or increases in imaging and recognition. Novel RA-ILD risk factors include the MUC5B promoter variant, articular disease activity, autoantibodies, and biomarkers of damaged pulmonary parenchyma. Treatment should focus on controlling RA disease activity, which emerging data suggest may reduce RA-ILD risk. Immunomodulatory and anti-fibrotic drugs may also treat RA-ILD. Summary RA-ILD is an underrecognized and serious manifestation of RA, but important progress is being made in identifying risk factors and treatment.
Article
Full-text available
With the emergence of biotherapies, accurate diagnosis in early arthritis is needed. At this time, there is no biological marker of psoriatic arthritis.To test whether antinuclear antibodies (ANA) can be used as a diagnostic tool in psoriatic arthritis (PsA), we evaluated the prevalence of ANA in biologic-naïve PsA patients and in healthy blood donors.232 patients from the Rheumatology department, St Marguerite's Hospital, Marseilles, who fulfilled the CASPAR criteria for PsA, underwent clinical and laboratory investigations. Antinuclear antibodies (ANA), anti-extractable nuclear antigen antibodies (ENA), rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA) were assayed. Ninety-one healthy blood donors were also tested.Detection of ANA by indirect immunofluorescence was significantly more frequent in sera from PsA patients than those from controls at serum dilution of 1:100 (57% compared with 40%, Odds Ratio (OR) 1.98 (1.2-3.4) p
Article
Full-text available
Objective: Update the 2009 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations for the spectrum of manifestations affecting patients with psoriatic arthritis (PsA). Methods: GRAPPA rheumatologists, dermatologists, and PsA patients drafted overarching principles for the management of PsA patients based on consensus at face-to-face meetings and via online surveys. We published literature reviews regarding treatment for the key domains of PsA (arthritis, spondylitis, enthesitis, dactylitis, skin, and nail disease), and convened a new group to identify pertinent comorbidities and their effect on treatment. Finally, we drafted treatment recommendations for each of the clinical manifestations and assessed the level of agreement for the overarching principles and treatment recommendations among GRAPPA members, with an online questionnaire. Results: Six overarching principles had at least 80% agreement among both health care professionals (HCPs; n=135) and patient research partners (PRPs; n=10). We developed treatment recommendations and a schema incorporating these principles for arthritis, spondylitis, enthesitis, dactylitis, skin, and nail disease, and comorbidities in the setting of PsA, using the GRADE process. Over 80% agreement was reached for approval of the individual recommendations and the overall schema. Conclusion: Herein, we present overarching principles and updated treatment recommendations for the key manifestations of PsA, including related comorbidities, based on a literature review and consensus of GRAPPA members (rheumatologists, dermatologists, other HCPs, and PRPs). Further updates are anticipated as the therapeutic landscape in PsA evolves. This article is protected by copyright. All rights reserved.
Article
Full-text available
Objectives We compared the ability of antibodies against cyclic citrullinated peptides (anti-CCP2), against mutated citrullinated vimentin (anti-MCV) and against citrullinated fibrinogen (AhFibA) to predict 1 year rapid radiographic progression (RRP; total Sharp score variation ≥5 points), in early rheumatoid arthritis (RA). Methods We analysed 566 patients from the ESPOIR cohort with early RA fulfilling the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria at year 1. We assayed the 3 anticitrullinated peptide antibodies (ACPA) tests on baseline sera. We compared the performance of these 3 ACPA tests to predict first-year RRP, by comparing areas under the receiver operating characteristic curves (ROCs). We assessed the 1 year RRP risk by ACPA titres. We used a logistic multivariate regression to analyse RRP risk in terms either of ACPA positivity or titre: high (>3 times the N cut-off) and low (1 to 3N). Results 145 patients displayed RRP. Areas under the ROCs were similar (0.60) for the 3 tests. High ACPA titres were associated with 1 year RRP, whatever the test was, and with similar ORs. Low+ anti-MCV titres were not associated with 1-year RRP, whereas low+ anti-CCP2 titres (p=0.0226) and low+ AhFibA titres (p=0.0332) were significantly associated. In multivariate analysis, 1 year RRP was associated with anti-CCP2 positivity (p<0.0001), AhFibA positivity (p<0.0001) and high anti-MCV titres (p<0.0001). Conclusions Anti-CCP2 antibodies and AhFibA were predictive of 1 year RRP in early RA whatever their titre was, whereas only high anti-MCV antibody titres were predictive, potentially making them more discriminant to predict 1 year RRP risk.
Article
Full-text available
Anti-carbamylated protein (anti-CarP) antibodies have been described in rheumatoid arthritis (RA) and arthralgia patients at risk of developing RA. To what extent these autoantibodies are specific for RA is unknown. Therefore, we investigated the diagnostic performance of the presence of anti-CarP antibodies for RA in a setting of early arthritis. Anti-CarP antibodies were detected using carbamylated fetal calf serum as substrate. Anti-CCP2 antibodies were measured using enzyme-linked immunosorbent assay and immunoglobulin M (IgM) rheumatoid factor (RF) as part of routine care. Sera were derived from patients in the Leiden Early Arthritis Clinic cohort obtained at inclusion. Test characteristics were determined using the fulfillment of the 2010 RA criteria after 1 year as outcome. In total 2086 early arthritis patients were studied regarding the presence of anti-CarP antibodies. We observed that the sensitivity and specificity of the presence of anti-CarP antibodies for RA were 44 % and 89 %, respectively. As a reference, sensitivity and specificity of the presence of anti-CCP2 antibodies were 54 % and 96 %, respectively, and of IgM-RF 59 % and 91 %. Patients harboring anti-CarP antibodies not classified as RA were mainly diagnosed with undifferentiated arthritis and less frequently reactive arthritis and psoriatic arthritis. Anti-CarP antibodies are predominantly present in RA but can also be detected in other forms of arthritis.
Article
Full-text available
Objective: To investigate the role of the periodontal pathogen Porphyromonas gingivalis in the etiology of rheumatoid arthritis (RA) by analyzing the antibody response to the P gingivalis virulence factor arginine gingipain type B (RgpB) in relation to anti-citrullinated protein antibodies (ACPAs), smoking, and HLA-DRB1 shared epitope (SE) alleles in patients with periodontitis, patients with RA, and controls. Methods: Anti-RgpB IgG was measured by enzyme-linked immunosorbent assay in 65 periodontitis patients and 59 controls without periodontitis, and in 1,974 RA patients and 377 controls without RA from the Swedish population-based case-control Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study. Autoantibody status, smoking habits, and genetic data were retrieved from the EIRA database. Differences in antibody levels were examined using the Mann-Whitney U test. Unconditional logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (95% CIs) for the association of anti-RgpB IgG with different subsets of RA patients. Results: Anti-RgpB antibody levels were significantly elevated in periodontitis patients compared to controls without periodontitis, in RA patients compared to controls without RA, and in ACPA-positive RA patients compared to ACPA-negative RA patients. There was a significant association between anti-RgpB IgG and RA (OR 2.96 [95% CI 2.00, 4.37]), which was even stronger than the association between smoking and RA (OR 1.37 [95% CI 1.07, 1.74]), and in ACPA-positive RA there were interactions between anti-RgpB antibodies and both smoking and the HLA-DRB1 SE. Conclusion: Our study suggests that the previously reported link between periodontitis and RA could be accounted for by P gingivalis infection, and we conclude that P gingivalis is a credible candidate for triggering and/or driving autoimmunity and autoimmune disease in a subset of RA patients.
Article
Full-text available
Hundreds of genomic loci have been associated with a significant number of immune-mediated diseases, and a large proportion of these associated loci are shared among traits. Both the molecular mechanisms by which these loci confer disease susceptibility and the extent to which shared loci are implicated in a common pathogenesis are unknown. We therefore sought to dissect the functional components at loci shared between two autoimmune diseases: coeliac disease (CeD) and rheumatoid arthritis (RA). We used a cohort of 12 381 CeD cases and 7827 controls, and another cohort of 13 819 RA cases and 12 897 controls, all genotyped with the Immunochip platform. In the joint analysis, we replicated 19 previously identified loci shared by CeD and RA and discovered five new non-HLA loci shared by CeD and RA. Our fine-mapping results indicate that in nine of 24 shared loci the associated variants are distinct in the two diseases. Using cell-type-specific histone markers, we observed that loci which pointed to the same variants in both diseases were enriched for marks of promoters active in CD14+ and CD34+ immune cells (P < 0.001), while loci pointing to distinct variants in one of the two diseases showed enrichment for marks of more specialized cell types, like CD4+ regulatory T cells in CeD (P < 0.0001) compared with Th17 and CD15+ in RA (P = 0.0029).
Article
Full-text available
Objectives To investigate the prevalence of anti-carbamylated protein antibodies (anti-CarP) in the Healthy first-degree relatives (HFDRs) of patients with Rheumatoid Arthritis (RA). Methods We enrolled 141 HFDRs of 63 patients with RA diagnosed accordingly to the 2010 ACR/EULAR criteria. Fifty-six normal healthy subjects (NHS), sex and age matched, served as controls. Anti-CarP IgG, anti-cyclic citrullinated peptide antibody (anti-CCP) IgG and rheumatoid factors (RF) isotypes (IgG, IgA, IgM) were assessed by solid-phase ELISA. Results Anti-CarP were detectable in 13 HFDRs (9.2%), anti-CCP in 9 (6.3%), IgG-RF in 10 (7%), IgA-RF in 17 (12%), and IgM-RF in 13 (9.2%) HFDRs. Twenty-nine (46%) RA patients were positive for anti-CarP, 31 (49.2%) for anti-CCP, and 34 (53.9%) for RF. One NHS (1.7%) resulted positive for anti-CarP, none for anti-CCP and RF. Anti-CarP showed a significantly higher prevalence in HFDRs than in NHS (p<0.0001). A significant correlation between anti-CCP and RF were found among RA patients (p=0.0002), whereas no correlations were reported between autoantibodies tested in the HFDRs. Conclusions Anti-CarP can be found in the sera of HFDRs of RA patients and their prevalence is significantly higher than in NHS. No correlation of anti-CarP with anti-CCP and RF antibodies in RA HFDRs was found. References Acknowledgements This work has been supported by Fondazione Umberto Di Mario ONLUS. We thank Giuliana Giuliani and Stefania Mieli for their technical support Disclosure of Interest None declared
Article
Full-text available
Objective: To investigate the gene-environment interaction between smoking and single nucleotide polymorphisms (SNPs), using Immunochip material, on the risk of developing either of two serologically defined subsets of RA. Methods: Interaction between smoking and 133 648 genetic markers from the Immunochip was examined for two RA subsets, defined by the presence or absence of ACPA. A total of 1590 ACPA-positive and 891 ACPA-negative cases were compared with 1856 controls in the Swedish Epidemiological Investigation of RA (EIRA) case-control study. Logistic regression models were used to determine the presence of interaction. The proportion attributable to interaction was calculated for each smoking-SNP pair. Replication was carried out in an independent dataset from northern Sweden. To further validate and extend the results, interaction analysis was also performed using genome-wide association studies data on EIRA individuals. Results: In ACPA-positive RA, 102 SNPs interacted significantly with smoking, after Bonferroni correction. All 102 SNPs were located in the HLA region, mainly within the HLA class II region, 51 of which were replicated. No additional loci outside chromosome 6 were identified in the genome-wide association studies validation. After adjusting for HLA-DRB1 shared epitope, 15 smoking-SNP pairs remained significant for ACPA-positive RA, with 8 of these replicated (loci: BTNL2, HLA-DRA, HLA-DRB5, HLA-DQA1, HLA-DOB and TAP2). For ACPA-negative RA, no smoking-SNP pairs passed the threshold for significance. Conclusion: Our study presents extended gene variation patterns involved in gene-smoking interaction in ACPA-positive, but not ACPA-negative, RA. Notably, variants in HLA-DRB1 and those in additional genes within the MHC class II region, but not in any other gene regions, showed interaction with smoking.
Article
Full-text available
Background: With the emergence of biotherapies, accurate diagnosis in early arthritis is needed. At this time, there is no biological marker of psoriatic arthritis. Objective: To test whether antinuclear antibodies (ANA) can be used as a diagnostic tool in psoriatic arthritis (PsA), we evaluated the prevalence of ANA in biologic-naïve PsA patients and in healthy blood donors. Methods: 232 patients from the Rheumatology department, St Marguerite's Hospital, Marseilles, who fulfilled the CASPAR criteria for PsA, underwent clinical and laboratory investigations. Antinuclear antibodies (ANA), anti-extractable nuclear antigen antibodies (ENA), rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA) were assayed. Ninety-one healthy blood donors were also tested. Results: Detection of ANA by indirect immunofluorescence was significantly more frequent in sera from PsA patients than those from controls at serum dilution of 1:100 (57% compared with 40%, Odds Ratio (OR) 1.98 (1.2-3.4) p<0.02) and 1:160 (52% compared with 24%, OR 3,7 (1.9-7.2) p<0.001). No patients had lupus specific autoantibodies, 15 % had RF (34/232), and 1.7 % had ACPA (4/232). Conclusions: Detection of ANA was more frequent in sera from PsA patients than in those from healthy controls. This suggests that ANA could be a diagnosis orientation tool in PsA. Nevertheless, the specificity of these antibodies still remains to be investigated.
Article
Full-text available
Psoriatic arthritis (PsA) is an inflammatory arthritis whose pathogenesis is poorly understood; it is characterized by bone erosions and new bone formation. The diagnosis of PsA is mainly clinical and diagnostic biomarkers are not yet available. The aim of this work was to clarify some aspects of the disease pathogenesis and to identify specific gene signatures in paired peripheral blood cells (PBC) and synovial biopsies of patients with PsA. Moreover, we tried to identify biomarkers that can be used in clinical practice. PBC and synovial biopsies of 10 patients with PsA were used to study gene expression using Affymetrix arrays. The expression values were validated by Q-PCR, FACS analysis and by the detection of soluble mediators. Synovial biopsies of patients showed a modulation of approximately 200 genes when compared to the biopsies of healthy donors. Among the differentially expressed genes we observed the upregulation of Th17 related genes and of type I interferon (IFN) inducible genes. FACS analysis confirmed the Th17 polarization. Moreover, the synovial trascriptome shows gene clusters (bone remodeling, angiogenesis and inflammation) involved in the pathogenesis of PsA. Interestingly 90 genes are modulated in both compartments (PBC and synovium) suggesting that signature pathways in PBC mirror those of the inflamed synovium. Finally the osteoactivin gene was upregulared in both PBC and synovial biopsies and this finding was confirmed by the detection of high levels of osteoactivin in PsA sera but not in other inflammatory arthritides. We describe the first analysis of the trancriptome in paired synovial tissue and PBC of patients with PsA. This study strengthens the hypothesis that PsA is of autoimmune origin since the coactivity of IFN and Th17 pathways is typical of autoimmunity. Finally these findings have allowed the identification of a possible disease biomarker, osteoactivin, easily detectable in PsA serum.
Article
Full-text available
This review focuses on the genetic features of psoriatic arthritis (PsA) and their relationship to phenotypic heterogeneity in the disease, and addresses three questions: what do the recent studies on human leukocyte antigen (HLA) tell us about the genetic relationship between cutaneous psoriasis (PsO) and PsA – that is, is PsO a unitary phenotype; is PsA a genetically heterogeneous or homogeneous entity; and do the genetic factors implicated in determining susceptibility to PsA predict clinical phenotype? We first discuss the results from comparing the HLA typing of two PsO cohorts: one cohort providing the dermatologic perspective, consisting of patients with PsO without evidence of arthritic disease; and the second cohort providing the rheumatologic perspective, consisting of patients with PsA. We show that these two cohorts differ considerably in their predominant HLA alleles, indicating the heterogeneity of the overall PsO phenotype. Moreover, the genotype of patients in the PsA cohort was shown to be heterogeneous with significant elevations in the frequency of haplotypes containing HLA-B*08, HLA-C*06:02, HLA-B*27, HLA-B*38 and HLA-B*39. Because different genetic susceptibility genes imply different disease mechanisms, and possibly different clinical courses and therapeutic responses, we then review the evidence for a phenotypic difference among patients with PsA who have inherited different HLA alleles. We provide evidence that different alleles and, more importantly, different haplotypes implicated in determining PsA susceptibility are associated with different phenotypic characteristics that appear to be subphenotypes. The implication of these findings for the overall pathophysiologic mechanisms involved in PsA is discussed with specific reference to their bearing on the discussion of whether PsA is conceptualised as an autoimmune process or one that is based on entheseal responses.
Article
Full-text available
Although susceptibility genes for anti-citrullinated peptide/protein antibodies (ACPA)-positive rheumatoid arthritis (RA) have been successfully discovered by genome-wide association studies (GWAS), little is known about the genetic background of ACPA-negative RA. We intended to elucidate genetic background of ACPA-negative RA. We performed a meta-analysis of GWAS comprising 670 ACPA-negative RA and 16,891 controls for 1,948,138 markers, followed by a replication study of the top 35 single nucleotide polymorphisms (SNPs) using 916 cases and 3,764 controls. Inverse-variance method was applied to assess overall effects. To assess overlap of susceptibility loci between ACPA-positive and -negative RA, odds ratios (ORs) of the 21 susceptibility markers to RA in Japanese were compared between the two subsets. In addition, SNPs were stratified by the p-values in GWAS meta-analysis for either ACPA-positive RA or ACPA-negative RA to address the question whether weakly-associated genes were also shared. The correlations between ACPA-positive RA and the subpopulations of ACPA-negative RA (rheumatoid factor (RF)-positive and RF-negative subsets) were also addressed. Rs6904716 in LEMD2 of the human leukocyte antigen (HLA) locus showed a borderline association with ACPA-negative RA (overall p = 5.7 × 10(-8)), followed by rs6986423 in CSMD1 (p = 2.4 × 10(-6)) and rs17727339 in FCRL3 (p = 1.4 × 10(-5)). ACPA-negative RA showed significant correlations of ORs with ACPA-positive RA for the 21 susceptibility SNPs and non-HLA SNPs with p-values far from significance. These significant correlations with ACPA-positive RA were true for ACPA-negative RF-positive and ACPA-negative RF-negative RA. On the contrary, positive correlations were not observed between the ACPA-negative two subpopulations. Many of the susceptibility loci were shared between ACPA-positive and -negative RA.
Article
Full-text available
Objectives To investigate the possible link between Porphyromonas gingivalis (P. gingivalis) infection and RA, according to antibody profile, genetic and environmental factors, and RA severity. Patients and Methods For assessing P. gingivalis infection, serum levels of antibodies directed against P. gingivalis LPS were measured in 694 early-RA patients not exposed to steroid or DMARD. Anti-P. gingivalis antibodies titers were compared between early-RA patients and various control groups, and according to various patients characteristics. Results The titre of anti-P. gingivalis antibodies did not significantly differ between RA and controls. Anti-P. gingivalis antibody titres did not significantly differ with ACPA, RF, or HLA-shared epitope status. Anti-P. gingivalis antibody titres were significantly higher among never smoker patients compared to ever-smoker (p= 0.0049). Among non-smokers, high anti-P. gingivalis antibody levels were associated with an higher prevalence of erosive change (mSHS erosion subscale ≥1: 47.5 vs. 33.3%, p=0.0135). Conclusion In this large early-RA cohort, we did not detect any association of anti-P. gingivalis antibodies with RA or with ACPA status. These results suggest that the association of periodontitis and RA could be linked to other bacterial species than P. gingivalis or to another mechanism than citrullination. Nevertheless we found higher anti-P. gingivalis antibody titres in non-smokers. In addition, in this population of non-smokers, high anti-P. gingivalis antibody titres were associated with a more severe disease. We hypothesize that the role of tobacco in RA pathogenesis is so high that the effect of P. gingivalis could be revealed only in a population not exposed to tobacco. This article is protected by copyright. All rights reserved. © 2015 American College of Rheumatology.
Article
Full-text available
The presence of a new autoantibody system, anti-carbamylated protein (anti-CarP) antibodies, has been identified in rheumatoid arthritis (RA). The presence of anti-CarP antibodies was evaluated in samples taken from individuals who subsequently developed RA before and after onset of symptoms and related to previously analysed antibodies against citrullinated peptides (ACPA specificities) and anti-CCP2. A total of 252 individuals, with 423 samples from before onset of symptoms of RA, and 197 population controls were identified as donors to the Medical Biobank of Northern Sweden; 192 of them were also sampled at the time of diagnosis. All samples were analysed for anti-CarP IgG and anti-CCP2 antibodies using ELISAs. Ten different antibody reactivities against citrullinated antigens (ACPA specificities) were analysed using a custom-made microarray based on the ImmunoCAP ISAC system (Phadia). The concentration of anti-CarP antibodies was significantly increased in the pre-symptomatic individuals compared with controls (P <0.001) and also increased significantly after disease onset (P <0.001). The sensitivity for anti-CarP antibodies in the pre-symptomatic individuals was 13.9% (95% CI: 11 to 17.6) and 42.2% (95% CI: 35.4 to 49.3) following development of RA. Anti-CarP antibody positivity was found in 5.1% to 13.3% of individuals negative for anti-CCP2 or ACPA specificities. Presence of anti-CarP antibodies was significantly related to radiological destruction at baseline, at 24 months and also to radiological change (P <0.05, all). The results indicate that anti-CarP antibodies are associated with disease development, even after adjusting for the presence of different ACPA fine specificities, and in anti-CCP2 negative individuals and contribute to the identification of a subset of patients with worse radiological progression of the disease independent of ACPA.
Article
Full-text available
Anti-carbamylated protein (anti-CarP) antibodies could further elucidate early rheumatoid arthritis (RA) pathogenesis and predict clinical disease. We compared the diagnostic accuracy of anti-CarP antibodies for future RA to other RA-related antibodies in military personnel. Stored pre-RA diagnosis serum samples from 76 RA cases were tested for anti-CarP fetal calf serum (FCS), anti-CarP fibrinogen (Fib), anticyclic citrullinated peptide antibodies version 2 (anti-CCP2), rheumatoid factor-nephelometry (RF-Neph), and RF isotypes [immunoglobulin M (IgM), IgG, and IgA]. Positivity for all antibodies was determined as ≥ 2 SD of log-transformed means from controls. Relationships between autoantibodies and future RA were assessed in prediagnosis serum for all RA cases compared to controls using sensitivity, specificity, and logistic regression. Differences in diagnostic accuracy between antibody combinations were assessed using comparisons of area under the curves (AUC). Anti-CarP-FCS was 26% sensitive and 95% specific for future RA, whereas anti-CarP-Fib was 16% sensitive and 95% specific for future RA. Anti-CarP-FCS positivity was associated with future RA, while anti-CarP-Fib trended toward association. The antibody combination of anti-CCP2 and/or ≥ 2 RF (RF-Neph and/or RF-isotypes) resulted in an AUC of 0.72 for future RA, where the AUC was 0.71 with the addition of anti-CarP-FCS to this prior combination. Adding anti-CarP-FCS to antibody combinations did not improve AUC. However, anti-CarP-FCS was associated with future onset of RA, and was present in prediagnosis serum in ~10% of RA cases negative for anti-CCP2 but positive for RF.
Article
Full-text available
Objective: to define the clinical value of rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (anti-CCP) in early psori- atic arthritis (PA). Subjects and methods. Fifty-six patients (32 females and 24 males) with early PA with a mean duration of 12±6.7 months were studied. The examinees' age ranged from 18 to 76 years (mean age 44±15.5 years). Mean psoriasis duration was 12.5±2.2 years. RF IgM was determined using a high-sensitive nephelometric method on a BN Pro-Spec analyzer (Siemens, Germany) and serum anti-CCP concentra- tions were measured by immunochemiluminescence on a COBAS e411 analyzer (Roche, Switzerland). Group 1 included 10 patients with anti-CCP and/or RF (a study group); Group 2 comprised 46 patients without anti-CCP and RF (a control group). Results. There was anti-CCP in 7 (12.5%) of the patients with early PA, RF in 8 (14.3%), both of them in 5 (9%). The study group had a severer course of PA accompanied by polyarthritis, inflamed distal interphalangeal joints, axial arthritis, dactylitis, enthesitis, and, in some cases spondylitis and sacroiliitis. In groups 1 and 2, the number of tender joints was 17.6±4 and 10±1.5, respectively (p = 0.04); that of swollen ones, 12.6±1.5 and 7.0±1.1 (p = 0.02); DAS28 index, 5.9±1.7 and 4.5±1.5 (p = 0.02); ESR, 34.5±5.9 and 22±2.3 (p = 0.04), high-sensitive C reactive protein, 70±25.3 and 24.9±5.0 (p = 0.06); and Sharp ratio, 68.7±14.3 and 21.3±3.8 (p < 0.004). Conclusion. In patients with early PA, anti-CCP and RF were encountered with an approximately equal frequency; at the same time, they were associated with polyarthritis, high disease activity, and an erosive process.
Article
Full-text available
Psoriatic arthritis (PsA) is a chronic inflammatory disease of unknown origin, characterized by erosions and new bone formation. Diagnosis of PsA is mainly clinical and there are no biomarkers available. Moreover in PsA autoantibodies have not been described so far. Indeed an autoimmune origin has been suggested but never proven. Aim of the study was to investigate the possible presence of autoantibodies typically associated with PsA. We used pooled IgG immunoglobulins derived from 30 patients with PsA to screen a random peptide library in order to identify disease relevant autoantigen peptides. Among the selected peptides, one was recognised by nearly all the patients' sera. The identified peptide (PsA peptide: TNRRGRGSPGAL) shows sequence similarities with skin autoantigens, such as fibrillin 3, a constituent of actin microfibrils, desmocollin 3, a constituent of the desmosomes and keratin 78, a component of epithelial cytoskeleton. Interestingly the PsA peptide shares homology with the nebulin-related anchoring protein (N-RAP), a protein localized in the enthesis (point of insertion of a tendon or ligament to the bone), which represents the first affected site during early PsA. Antibodies affinity purified against the PsA peptide recognize fibrillin, desmocollin, keratin and N-RAP. Moreover antibodies directed against the PsA peptide are detectable in 85% of PsA patients. Such antibodies are not present in healthy donors and are present in 13/100 patients with seroposive rheumatoid arthritis (RA). In seronegative RA these antibodies are detectable only in 3/100 patients. Our results indicate that PsA is characterized by the presence of serum autoantibodies crossreacting with an epitope shared by skin and joint antigens.
Article
Full-text available
IntroductionTo investigate rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) status and levels as predictors of mortality in two large cohorts of patients with early inflammatory arthritis (EIA).Methods Data from the Norfolk Arthritis Register (NOAR) and Leiden Early Arthritis Clinic (EAC) cohorts were used. At baseline, patients had demographic data and smoking status recorded; RF, ACPA and inflammatory markers were measured in the local laboratories. Patients were flagged with national death registers until death or censor date. Antibody status was stratified as negative, low or high positive by RF and ACPA levels individually. In addition, patients were grouped as seronegative, RF positive, ACPA positive or double antibody (RF and ACPA) positive. Cox regression models explored associations between antibody status and mortality adjusting for age, sex, smoking status, inflammatory markers and year of enrolment.Results4962 (NOAR:3053, EAC:1909) patients were included, 64% were female. Median age at onset was 56 (NOAR) and 54 (EAC) years. 35% and 42% of patients were ACPA/RF positive in NOAR and EAC respectively. When antibody status was stratified as negative, low or high positive, there were no consistent findings between the two cohorts. Double antibody positivity was associated with excess mortality in both cohorts compared to seronegative patients: NOAR and EAC respective adjusted HR (95% CI): 1.35 (1.09-1.68) and 1.58 (1.16-2.15).Conclusions Patients with EIA who are seropositive for both RF and ACPA have increased mortality compared to those who are single positive or seronegative. Antibody level in seropositive patients was not consistently associated with excess mortality.
Article
Full-text available
Objective The immune response to post-translationally modified antigens is a key characteristic of rheumatoid arthritis. Carbamylation is such a posttranslational modification. Recently, we demonstrated that autoantibodies recognizing carbamylated proteins are present in sera of rheumatoid arthritis. The molecular mechanisms underlying the break of tolerance and hence the induction of anti-CarP antibody responses are unknown as well as their appearance in mouse models for systemic arthritis. Therefore we analyzed their appearance in the mouse collagen-induced arthritis model. Methods collagen induced arthritis was induced by immunization with type II collagen in complete Freund's adjuvant. Arthritis severity was monitored by clinical scoring and anti-CarP antibody levels were determined by ELISA. Results Anti-CarP antibodies were detectable in mice with collagen induced arthritis. We did not detect ACPA in mice with collagen induced arthritis. The specificity of the antibodies for carbamylated proteins was confirmed by inhibition assays and immunoblotting. Injection with complete Freund's adjuvant without type II collagen could also induce anti-CarP antibodies, however, in mice with arthritis, the anti-CarP antibody response was stronger and developed more rapidly. The onset of collagen induced arthritis was preceded by an increase of anti-CarP IgG2a levels in the serum. Conclusion In mice with collagen induced arthritis we did not observe an immune response against citrullinated antigens, but we did observe an immune response against carbamylated antigens. This anti-CarP response already appeared before disease onset, indicating that collagen induced arthritis can be used as an in vivo model to study anti-CarP antibodies. Our data also indicate that the tolerance to carbamylated proteins, in contrast to the response to citrullinated proteins, is easily broken and that arthritis boosts the immune response against these proteins. The anti-CarP response in mice with CIA can be used as a model for immune responses to post-translationally modified proteins.
Article
Full-text available
In rheumatoid arthritis (RA), several genetic risk factors and smoking are strongly associated with the presence of anticitrullinated protein antibodies (ACPA), while much less is known about risk factors for ACPA-negative RA. Antibodies against carbamylated proteins (anti-CarP) have been described in both ACPA-positive and ACPA-negative RA patients. In this study, we have analysed the relationships among anti-CarP antibodies, ACPA, genetic risk factors (HLA-DRB1 alleles and PTPN22) and smoking in RA. Presence of antibodies to carbamylated fetal calf serum (CarP-FCS) and fibrinogen (CarP-Fib) was determined by inhouse ELISAs among RA cases in the Leiden Early Arthritis Clinic (n=846) and in the Swedish Epidemiological Investigation of Rheumatoid Arthritis (n=1985) cohorts. ORs for associations with different HLA-DRB1 alleles, PTPN22 genotypes and smoking were calculated separately for each cohort as well as in meta-analysis in RA subsets defined by the presence/absence of anti-CarP and anticyclic citrullinated peptide (anti-CCP) antibodies. In both cohorts, anti-CarP antibody positivity was mainly detected in the anti-CCP-positive population (49%-73%), but also in the anti-CCP-negative population (8%-14%). No associations between anti-CarP antibodies and HLA-DRB1 shared epitope alleles could be identified, while there were data to support an association between anti-CarP-FCS and HLA-DRB1*03. Further analyses did not reveal any specific associations of anti-CarP antibodies with other HLA-DRB1 alleles, PTPN22 genotypes or smoking. Anti-CarP antibodies were present in both ACPA-positive and ACPA-negative RA. There were no significant associations among anti-CarP antibodies and HLA-DRB1 alleles, PTPN22 or smoking. These data suggest that different biological mechanisms may underlie anti-CarP versus anti-CCP antibody formation.
Article
Full-text available
Rheumatoid arthritis (RA) patients can be classified based on presence or absence of anticitrullinated peptide antibodies (ACPA) in their serum. This heterogeneity among patients may reflect important biological differences underlying the disease process. To date, the majority of genetic studies have focused on the ACPA-positive group. Therefore, our goal was to analyse the genetic risk factors that contribute to ACPA-negative RA. We performed a large-scale genome-wide association study (GWAS) in three Caucasian European cohorts comprising 1148 ACPA-negative RA patients and 6008 controls. All patients were screened using the Illumina Human Cyto-12 chip, and controls were genotyped using different genome-wide platforms. Population-independent analyses were carried out by means of logistic regression. Meta-analysis with previously published data was performed as follow-up for selected signals (reaching a total of 1922 ACPA-negative RA patients and 7087 controls). Imputation of classical HLA alleles, amino acid residues and single nucleotide polymorphisms was undertaken. The combined analysis of the studied cohorts resulted in identification of a peak of association in the HLA-region and several suggestive non-HLA associations. Meta-analysis with previous reports confirmed the association of the HLA region with this subset and an observed association in the CLYBL locus remained suggestive. The imputation and deep interrogation of the HLA region led to identification of a two amino acid model (HLA-B at position 9 and HLA-DRB1 at position 11) that accounted for the observed genome-wide associations in this region. Our study shed light on the influence of the HLA region in ACPA-negative RA and identified a suggestive risk locus for this condition.
Article
Purpose Anti-citrullinated protein antibodies (ACPA) are probably involved in the pathogenesis of rheumatoid arthritis. During the course of disease epitope spreading might occur. In this study, the ACPA repertoire of arthralgia patients and the association with arthritis development were studied. Methods 244 arthralgia patients positive for anti-cyclic citrullinated peptide antibodies (aCCP) and/or IgM rheumatoid factor, without clinical symptoms of arthritis were included. Arthritis was defi ned as the presence of one or more swollen joints at clinical examination during twice-yearly follow-up. Sera were tested at baseline for reactivity to fi ve citrullinated peptides derived from fi brinogen (three), vimentin (one) and α-enolase (one) and the fi ve corresponding arginine peptides in an ELISA. Results 65 patients (27%) developed arthritis in a median of two joints after a median follow-up of 10 (IQR: 4–18) months. Reactivity to each peptide was signifi cantly associated with arthritis development (p<0.01). The peptide reactivity pattern did not differ between patients who did or did not develop arthritis. Within aCCP positive patients, patients who recognised two or more additional citrullinated peptides developed arthritis more often (p=0.05). The number of recognised peptides was positively associated with the aCCP level (p<0.001). Cross-reactivity between different peptides was minimal. Conclusion The ACPA repertoire in arthralgia patients can already be expanded. High aCCP levels are associated with a qualitatively broad ACPA response. Patients with a broader ACPA response have higher risk of developing arthritis. This indicates that epitope spreading occurs in arthralgia patients and might be initiated before onset of joint complaints.
Article
Objective Human leucocyte antigen (HLA)-DRB1∗13 alleles are associated with protection from anticitrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA). It is, however, unknown at which phase of disease development (seroconversion, ACPA maturation, disease onset or outcome) these alleles are most important. We therefore examined the effect of HLA-DRB1∗13 on: ACPA presence (systemic autoimmunity associated with RA) in individuals with and without RA, on ACPA characteristics and on clinical outcome measures. Methods The effect of HLA-DRB1∗13 on ACPA presence in subjects with or without RA (non-RA) was assessed in the Swedish twin registry (n=10 748). ACPA characteristics were studied in patients with ACPApositive RA from the Swedish Epidemiological Investigation of RA (EIRA, n=1224) and the Dutch Leiden Early Arthritis Clinic (EAC, n=441). Disease activity at inclusion and disease outcome (diseasemodifying antirheumatic drugs (DMARD)-free sustained remission and radiographic progression) was assessed in patients with RA from the EAC. Results HLA-DRB1∗13 is associated with protection from ACPA-positive RA ( prevalence 16% vs 28% in ACPA-negative non-RA), but not with significant protection from ACPA in individuals without RA (prevalence: 22%, p value 0.09). HLA-DRB1∗13 is associated with lower ACPA-levels (EIRA: 447 U/ml versus 691 U/ml, p value= 0.0002) and decreased citrullinated epitope recognition (EIRA: p<0.0001). No association between HLA-DRB1∗13 and disease activity or outcome was found. Conclusions These data indicate that HLA-DRB1∗13 mainly affects the onset of ACPA-positive RA in ACPApositive non-RA individuals. In RA, HLA-DRB1∗13 influences ACPA characteristics but not the disease course. This implies that therapeutic strategies aimed at emulating the HLA-DBR1∗13 protective effect may be most effective in ACPA-positive healthy individuals at risk for RA.
Article
Background/Objective Recently, we discovered a new auto- antibody system in rheumatoid arthritis (RA): anti carbamylated protein antibodies (anti-CarP). These antibodies have additional prognostic value in predicting joint destruction when compared to anti-citrullinated protein antibodies (ACPA). However, it is not yet known whether anti-CarP antibodies are present before the diagnosis of RA and whether they have predictive value for the development of RA. Therefore we studied whether anti-CarP antibodies are present in arthralgia patients and whether their presence associates with the development of RA. Methods Sera of 340 arthralgia patients without clinical signs of arthritis and 32 healthy controls were measured for the presence of anti-CarP IgG antibodies. One hundred eleven arthralgia patients (33%) were IgM-rheumatoid factor (IgM-RF) positive/anti-cyclic citrullinated peptide 2 (aCCP2) negative and 229 (67%) were aCCP2 positive. Patients were followed for the development of RA (2010 criteria). The median follow up time was 36 months. Cox regression analysis was performed to compare the risk of developing RA between Anti-CarP positive and negative arthralgia patients in follow up time. Results The arthralgia cohort consisted of 340 IgM-RF and/or aCCP positive patients. Anti-CarP antibodies were present in sera of 113 (39%) of the tested patients. A total of 120 patients developed RA after a median (IQR) of 12 (6–24) months. The presence of anti-CarP antibodies was associated with the development of RA in the whole arthralgia cohort even after correction for RF and aCCP2 status (HR: 1.56; 95%CI: 1.06–2.29; p = 0.023), as well as in the aCCP2 positive subgroup (OR: 2.231; 95%CI: 1.31–3.79; p = 0.003). Conclusions Anti-CarP antibodies were present in arthralgia patients and their presence predicted the development of RA independent of aCCP2 antibodies. Disclosure These studies were financially supported by Janssen Biologics BV, (Johnson & Johnson).
Conference Paper
A new type of servo-variable pump and variable pump controlled system are developed in order to solve the problems of big throttling loss and low efficiency of energy in the valve controlled electro-hydraulic servo system. The pump displacement servo control is realized by using a small power servo motor to drive the pump swash plate variable mechanism of axial plunger variable pump. The close variable pump controlled system and its mathematical model are established. The feed forward-feedback iterative learning control method is applied to tackle the position servo control of variable pump controlled system. The simulation model is structured on the platform of Simulink. The convergence and tracking characteristics of feed forward-feedback iterative learning control are researched by simulations. The results show that the proposed method possesses good convergence characteristics, and the smaller tracking errors and hysteresis can be achieved compared with the traditional PID controller for the variable pump controlled system by three to four iterative learning.