Form Of Inflammatory Arthritis Research Articles

Cytokine Secretion by Pathogen Recognition Receptor-stimulated Dendritic Cells in Rheumatoid Arthritis and Ankylosing Spondylitis

Interleukin 23 (IL-23) plays a major role in differentiation and survival of IL-17-secreting CD4+ Th17 cells. Having noted a higher frequency of Th17 cells in ankylosing spondylitis (AS) and rheumatoid arthritis (RA) than in healthy donors (HD), we investigated whether IL-23 secretion is increased in these conditions. Monocyte-derived dendritic cells (moDC) were obtained from peripheral blood of 17 HD, 16 patients with RA, and 30 patients with AS, and stimulated with ligands for several pathogen recognition receptors. Messenger RNA (mRNA) expression and cytokine secretion were analyzed by real-time polymerase chain reaction and ELISA, respectively. The combination of ligands for Toll-like receptors (TLR) 7/8 and TLR3 led to synergistic secretion of both IL-23 and IL-12p70 from all subjects; similar synergy was seen with TLR2 ligands and curdlan. However, for both combinations, moDC from patients with RA produced significantly lower amounts of IL-23 than moDC from patients with AS; in contrast, IL-12p70 secretion did not differ. Similarly, tumor necrosis factor-α, IL-6, and IL-10 were secreted at comparable levels in all subjects, whereas CXCL8 and CCL3 production was actually enhanced in moDC of patients with RA. Equivalent levels of mRNA for both IL-23p19 and IL-12p35 subunits were found in moDC from all donors, suggesting posttranscriptional regulation of IL-23 production in RA. Our observations show that IL-23 production is decreased in RA and maintained in AS. Because increased numbers of CD4+IL-17+ T cells are seen in both diseases, these observations imply that there are different mechanisms underlying chronic inflammation in these 2 forms of inflammatory arthritis.

Riesgo cardiovascular en el lupus eritematoso sistémico: factores implicados y métodos para su valoración

Cardiovascular disease has become the leading cause of mortality in patients with systemic lupus erythematosus (SLE). Accelerated atherosclerosis is considered one of the most important mechanisms implicated in the high cardiovascular (CV) mortality associated with SLE. Atherosclerosis in SLE patients arises from an interaction among classical CV risk factors, inflammatory mediators and factors specific to SLE itself. Consequently, calculating CV risk in these patients is central to decision-making on treatment to prevent CV disease. However, although Systematic COronary Risk Evaluation (SCORE) is recommended by The European League against Rheumatism (EULAR) experts and is widely used by rheumatologists for CV assessment in patients with rheumatoid arthritis and other forms of inflammatory arthritis, CV risk in SLE patients cannot be adequately evaluated with widely used charts for stratifying CV risk. Due to the lack of specific charts, assessment of traditional CV risk factors (smoking, blood pressure, diabetes, body mass index and lipid profile) and the use of validated imaging techniques to detect subclinical atherosclerosis have been proposed for the assessment of vascular disease in SLE patients. Among these techniques, calculating the intima-media thickness of the common carotid arteries measured in the far wall and the presence of plaques in the carotid system have become commonly used indicators of subclinical atherosclerosis. To a certain extent, the use of these methods allows individualized CV assessment and consequently a more useful management strategy, which can decrease CV mortality in SLE patients.

Rheumatic Manifestations of Autoimmune Thyroid Disease: The Other Autoimmune Disease

Autoimmune thyroid disease (AITD) is an inflammatory thyroiditis that in some cases is characterized by lymphocytic infiltration of the thyroid gland, also referred to as chronic lymphocytic thyroiditis or Hashimoto thyroiditis. Hashimoto thyroiditis is one of the commonest causes of hypothyroidism. Hypothyroidism has been associated with osteoarthritis (OA) and inflammatory forms of arthritis and with several well defined connective tissue diseases, which in turn can cause arthritis. The presence of arthritis in patients with AITD with normal thyroid function is now being increasingly recognized. There is also considerable evidence to suggest that AITD is highly associated with fibromyalgia syndrome. We review the current literature on the rheumatologic manifestations of AITD and describe the features in its presentation that set it apart from other forms of autoimmune arthritis.

Pathophysiology of post-traumatic arthritis

Epidemiologic studies have firmly established the association between acute joint injury and the increased risk for the subsequent development and progression of osteoarthritis (OA). All of the joint tissues are susceptible to traumatic injury, including the ligaments, menisci, articular cartilage and periarticular bone, and to some extent the natural history of the OA process is related to the magnitude, site and extent of the initial joint injury. However, independent of the specific site or target tissue affected by the injury, all of the joint tissues are eventually affected by the osteoarthritic process. Multiple mechanisms contribute to the pathogenesis of the osteoarthritic changes after a joint injury and although much of the attention has focused on the adverse effects of increased joint instability and altered joint mechanics, there is evidence that the pathogenic process in many individual is in fact attributable to the initial acute-impact injury to the articular surface and in some instances the adjacent subchondral bone. These impact injuries not only may disrupt the structural integrity of these tissues but also can induce acute as well as chronic adverse effects on the survival and functional activities of the resident cell populations. With respect to the articular cartilage these changes include de-regulation of the synthetic and reparative capacity of the chondrocytes, as well as the release of potent biological mediators such as reactive oxygen species, proteolytic enzymes and proinflammatory cytokines. In addition, although OA generally is not viewed as an inflammatory form of arthritis there is evidence that synovial inflammation not only contributes to joint symptoms but also plays a role in the structural and functional deterioration of joint tissues in both post traumatic OA and other forms of OA. De-regulated chondrocyte function and the release of biologically active chondrocyte-derived factors or products from the cartilage extracellular matrix have been implicated in the synovial inflammation, and many of the synovial derived products in turn may adversely affect the homeostasis of the adjacent articular cartilage and bone. Studies have shown that the risk factors for OA initiation and progression in patients with post traumatic OA are similar to those for idiopathic OA in that systemic host factors and local biomechanical factors interact and that obesity, female gender, and pre-existing early-stage OA contribute significantly to adverse radiographic and clinical outcomes. There remains uncertainty regarding the long-term benefit of surgical interventions with respect to prevention or slowing the development of OA, and there is a critical need for rigorous clinical and laboratory studies to define the factors that are responsible for joint deterioration in patients with traumatic joint injuries and for assessing the impact of interventions on the status of joint tissues and function.

Expression levels of interleukin-17a, interleukin-17f and their receptors in synovium of patients with rheumatoid arthritis, psoriatic arthritis and osteoarthritis: a target validation study

BackgroundAccumulating evidence suggests an important role for interleukin (IL)-17 in the pathogenesis of several inflammatory diseases, including rheumatoid arthritis (RA). IL-17A has been well studied in models of arthritis, but...

Guilty by Association: Platelet Reactivity and Inflammation in Psoriatic Arthritis

Patients with rheumatoid arthritis (RA) die prematurely from cardiovascular disease (CVD)1. The risk of adverse cardiovascular events and subsequent mortality in patients with RA is comparable to that associated with type 2 diabetes mellitus2. There is an emerging body of evidence that patients with other forms of inflammatory arthritis (IA), in particular psoriatic arthritis (PsA), are at a similarly elevated risk of CVD3. Platelets play a key role in the complex chain of events leading to the thrombotic occlusion of a coronary artery4. Antiplatelet therapy with aspirin and/or a variety of other agents is effective at reducing the mortality associated with incident CVD5 and is recommended for the primary prevention of same in patients at high risk of atherothrombotic events4. Despite the greatly increased risk of heart disease and strokes, there are currently no antiplatelet guidelines for the primary prevention of CVD in patients with IA3, and platelet function remains largely uninvestigated in this patient population. It is within this context that the recent work of Di Minno and colleagues, reported in this issue … Address correspondence to Dr. MacMullan; E-mail: pmacmullan{at}hotmail.com

Recent advances in management of gout

Incidence and prevalence of gout have markedly increased over the last few decades in keeping with the rise in prevalence of obesity and metabolic syndrome. Until recently, management of gout in patients with associated metabolic syndrome and comorbid illnesses such as renal impairment was difficult because of limited treatment options. However, significant progress has been made in the last few years, with introduction of new treatments such as interleukin-1 antagonists for management of acute gout, and febuxostat and pegloticase for chronic gout. The association of gout with alcohol, dietary purines and fructose ingestion has been confirmed in large prospective studies, thus enabling the clinician to now provide evidence-based advice to patients. Recent efficacy and safety data favour lower over higher doses of colchicine, and oral corticosteroids over non-steroidal anti-inflammatory drugs for patients with acute gout. Local ice therapy might help to differentiate gout from other forms of inflammatory arthritis, and supplementation with vitamin C help to reduce risk of gout. Several other drugs with rational mechanisms of action are in the pipeline, and likely to be introduced over the next few years. A new era has thus begun in the field of gout.

Canakinumab for the treatment of gout

Gout is the one of the most common forms of inflammatory arthritis in adults. As the incidence and prevalence of gout are increasing and many patients cannot tolerate or have contraindications to standard treatments, there is a need for new, more effective therapeutic agents. IL-1β is a proinflammatory cytokine that plays a pivotal role in the pathogenesis of gouty arthritis. Several inhibitors of IL-1 have been elaborated to date. Canakinumab is a fully human monoclonal antibody to IL-1β developed by Novartis. According to recently published results of clinical trials, canakinumab may provide a safe and effective alternative treatment option for gout flares for patients in whom standard therapies are not advised.

Effect of Genetic Polymorphisms in the Folate Pathway on Methotrexate Therapy in Rheumatic Diseases

Methotrexate (MTX) is the first-line treatment for rheumatoid arthritis and is frequently used in the management of other forms of inflammatory arthritis. It is currently challenging to predict which patients will achieve adequate disease control and which patients will develop adverse effects while taking MTX. As an analog of dihydrofolic acid, MTX enters cells through the reduced folate carrier-1 protein, and is polyglutamated. MTX polyglutamates inhibit key enzymes in the folate pathway to produce an anti-inflammatory effect. It has been suggested that genetic polymorphisms in the folate pathway may influence intracellular folate and MTX polyglutamates pools, and thus MTX response. However, studies to identify genetic predictors have yielded inconclusive results. Nonreplication across studies has been attributed to insufficient statistical power as well as pharmacological and clinical confounders. Prospective studies, standardizing the definitions of response and toxicity, and application of genome-wide approaches may advance the search for genetic predictors of MTX response.

Kardiovaskuläre Komorbidität und ihre Risikofaktoren bei rheumatoider Arthritis

Rheumatoid arthritis (RA) is still associated with an increased mortality mainly due to an increase in cardiovascular risk. This increase is not solely explained by traditional cardiovascular risk factors but also by disease characteristics, e.g. inflammation, positive rheumatoid factor and anti-citrullinated peptide antibodies (ACPA). Control of disease activity with disease-modifying drugs (DMARDs) was shown to reduce cardiovascular risk in RA patients. Use of non-steroidal antirheumatic drugs (NSAIDs) and glucocorticoids might be associated with an increased risk. The EULAR recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis have been established. These recommendations are based on national guidelines regarding control of traditional cardiovascular risk factors.

IL-17 levels in synovium of patients with rheumatoid arthritis, psoriatic arthritis and osteoarthritis: Target validation in various forms of arthritis

BackgroundAccumulating evidence suggests an important role for interleukin 17 (IL-17) in the pathogenesis of several inflammatory diseases, including rheumatoid arthritis (RA). IL-17A has been well studied in models of arthritis,...

Pain, disability and impairment associated with podiatric problems in patients with acute gout

Background Gout is on the increase worldwide and is the most common form of inflammatory arthritis affecting men. Gout is of particular significance to New Zealand, affecting approximately 15% of Maori and Pacific men in South Auckland, thus it has been dubbed the ‘gout capital of the world’. Gout most frequently affects the foot, with initial attack affecting in the first metatarsophalangeal joint (1 MPJ) in 50% of patients. Involvement of the first 1 MPJ eventually occurs in 90% of individuals with gout. Despite the predilection of gout to the foot, the impact of gout on foot function is not well understood. A recent study investigating patients with chronic gout found the foot to be a rigid, higharched with limited range of motion at the major joints of the foot. An increased threshold of pain, disability and a decrease in function was also reported. These changes associated with chronic gout may contribute to further progression of pain, disability and impairment. The impact of acute gout on musculoskeletal function has not been examined in a detailed or objective manner. The aim of the current study is to assess the impact of acute gout on foot pain, function/ impairment and disability.

Silencing the Expression of Ras Family GTPase Homologues Decreases Inflammation and Joint Destruction in Experimental Arthritis

Changes in the expression and activation status of Ras proteins are thought to contribute to the pathological phenotype of stromal fibroblast-like synoviocytes (FLS) in rheumatoid arthritis, a prototypical immune-mediated inflammatory disease. Broad inhibition of Ras and related proteins has shown protective effects in animal models of arthritis, but each of the Ras family homologues (ie, H-, K-, and N-Ras) makes distinct contributions to cellular activation. We examined the expression of each Ras protein in synovial tissue and FLS obtained from patients with rheumatoid arthritis and other forms of inflammatory arthritis. Each Ras protein was expressed in synovial tissue and cultured FLS. Each homolog was also activated following FLS stimulation with tumor necrosis factor-α or interleukin (IL)-1β. Constitutively active mutants of each Ras protein enhanced IL-1β-induced FLS matrix metalloproteinase-3 production, while only active H-Ras enhanced IL-8 production. Gene silencing demonstrated that each Ras protein contributed to IL-1β-dependent IL-6 production, while H-Ras and N-Ras supported IL-1β-dependent matrix metalloproteinase-3 and IL-8 production, respectively. The overlap in contributions of Ras homologues to FLS activation suggests that broad targeting of Ras GTPases in vivo suppresses global inflammation and joint destruction in arthritis. Consistent with this, simultaneous silencing of H-Ras, K-Ras, and N-Ras expression significantly reduces inflammation and joint destruction in murine collagen-induced arthritis, while specific targeting of N-Ras alone is less effective in providing clinical benefits.

Histone deacetylase inhibitors: a new and promising drug class for the treatment of arthritis?

Rheumatoid arthritis (RA) is the prototype of a group of disorders characterized by chronic inflammatory reaction of the joints. The persistent inflammation results from the coordinated infiltration of the synovial tissue by distinct cellular populations which are activated and release a complex network of cytokines, chemokines, and growth factors. Progress in the understanding of the pathophysiology of RA and other forms of inflammatory arthritis has led to the concept of targeting cellular activation or cytokines in an attempt to better control the inflammatory process. In this sense, biological therapies blocking TNFα, IL-1 or IL-6, or controlling costimulatory pathways or alternatively B cells have emerged. These new therapies are currently available in the treatment of patients with RA, contributing to a better management of the disease.

Genetic susceptibility factors for psoriatic arthritis

Psoriatic arthritis (PsA) has a large genetic component to its heritability, yet investigation into the genetic basis of the disease has lagged behind other rheumatic diseases mainly because of the difficulty in defining classification criteria that would accurately differentiate it from other forms of inflammatory arthritis. However, using a variety of approaches, some confirmed associations have now been identified with PsA susceptibility, making a review of these recent developments timely. Family studies continue to suggest a large genetic contribution to PsA. Using a candidate gene approach, genes robustly confirmed to be associated with psoriasis vulgaris (PsV) have also been found to be associated with PsA (HLA-Cw*0602, IL23R, IL12B). There is less overlap reported with rheumatoid arthritis (RA) than PsV susceptibility loci but one report suggests that the AFF3 locus may be associated with both RA and PsA. Large, well powered genome-wide association studies are currently underway and should provide further insights into the cause of this common arthritic disease over the next few months. The bulk of evidence so far suggests that the genetic factors underlying PsV are also associated with PsA suggesting that future studies of PsV could include patients with PsA.

A case of psoriasis vulgaris with diffuse idiopathic skeletal hyperostosis involved with ossifications of posterior and anterior longitudinal ligament

Diffuse idiopathic skeletal hyperostosis (DISH) is difficult to distinguish from various forms of inflammatory arthritis, including psoriatic arthritis (PsA), rheumatoid arthritis, and ankylosing spondylitis. A 67-year-old Japanese male had been treated for psoriasis vulgaris for 13 years. Numbness of his right arm and lower limbs and spinal stiffening had developed 7 years prior to his initial evaluation at our facility. He noticed pain mainly while exercising. There were symmetrical marginal syndesmophytes in the spine, from the thoracic vertebrae to the upper lumbar vertebrae, on radiological examinations. We therefore suspected DISH. Furthermore, ossifications of the posterior and anterior longitudinal ligaments were noted in the cervical spine. Laboratory examinations revealed a normal peripheral white blood cell count, serum C-reactive protein, and erythrocyte sedimentation rate, and he was negative for rheumatoid factor. We detected human leukocyte antigen B39 but not B27. All distal interphalangeal joints were swollen but without pain. X-ray imaging showed narrowing of the joint space, and the consolidation of the joint was recognized, but there was no new juxta-articular bone formation. Based on clinical and radiological findings, we concluded that he had DISH and not PsA. DISH was indicated by marked radiological features of the axial skeleton, particularly the thoracic spine, but may also have involved the peripheral joints. DISH is one of the entheseal disorders, and 10% of Japanese middle-aged and elderly men have DISH. Therefore, the differentiation of DISH from PsA is necessary in psoriasis patients with spinal involvement.

Inflammatory arthritis ‐ an exciting confluence of human and animal research

Inflammatory arthritis ‐ an exciting confluence of human and animal research

Mechanisms of Immune Complex–Mediated Neutrophil Recruitment and Tissue Injury

Deposition of antibody-antigen immune complexes (ICs) in tissues underlies the pathogenesis of a range of human autoimmune diseases from glomerulonephritis, systemic lupus erythematosus (SLE), arthritis, and transplantation rejection to rheumatic fever. Experimental and clinical evidence suggests that autoimmunity is a risk factor for cardiovascular disease (CVD). Here, we overview the literature that links autoimmune diseases and accelerated atherosclerosis and review our understanding of IC-induced inflammation. In particular, we discuss the contribution of the location and composition of ICs to the cellular and molecular mechanisms of disease that develop and detail the steps leading to IC-mediated leukocyte recruitment and tissue injury. The focus is on neutrophil-dependent tissue injury. Although these cells have not found a prominent place in discussions of chronic inflammatory conditions such as autoimmunity and atherosclerosis, recent literature discussed here indicates that neutrophils initiate IC-induced inflammation that in turn launches and informs the subsequent immune response. A fuller understanding of the mechanisms involved in the initiation and perpetuation of immunoglobulin G (IgG) antibody mediated inflammation may lead to the design of innovative therapeutic strategies to prevent cardiovascular complications in patients with autoimmune diseases. Well-controlled studies have demonstrated that autoimmunity is an independent risk factor for atherosclerotic lesions and premature myocardial infarction.1,2 Population-based studies in various countries have shown that CVD-associated mortality in patients with rheumatoid arthritis (RA) is 1.5 to 2.0 times higher than in control individuals.3–6 Similarly, increased rates of CVD have been reported in other forms of inflammatory arthritis, including giant cell arteritis7 and psoriatic arthritis.8 The risk for CVD and myocardial infarction is also pronounced in patients with SLE, a complex autoimmune disease affecting multiple organs. The Pittsburgh lupus cohort presented a 52-fold increase in cardiovascular events in young women with SLE.9 The Framingham Heart Study risk factors contribute to CVD …

Acute Pseudoseptic Inflammatory Local Reactions after Intra-articular Hyaluronic Acid Injections in Patients with Knee Osteoarthritis

Knee osteoarthritis is a common, but difficult problem to manage in primary care. Intra-articular hyaluronic acid injection has recently been frequently used for treating knee osteoarthritis. The adverse local reactions, except septic arthritis, following intra-articular hyaluronic acid injections are generally transient and not severe. Pseudoseptic arthritis is an extreme form of inflammatory arthr itis that is not due to bacterial infection and it is important to distinguish this from true septic arthritis. In this article, we report 2 cases of acute pseudoseptic local reactions after intra-articular hyaluronic acid injections in patients with knee osteoarthritis. (Korean J Pain 2009; 22: 191-194)

Monomeric Calgranulins Measured by SELDI-TOF Mass Spectrometry and Calprotectin Measured by ELISA as Biomarkers in Arthritis

SELDI-TOF mass spectrometry (MS) is a high-throughput proteomic approach with potential for identifying novel forms of serum biomarkers of arthritis. We used SELDI-TOF MS to analyze serum samples from patients with various forms of inflammatory arthritis. Several protein profiles were collected on different Bio-Rad Laboratories ProteinChip arrays (CM10 and IMAC-Cu(2+)) and were evaluated statistically to select potential biomarkers. SELDI-TOF MS analyses identified several calgranulin proteins [S100A8 (calgranulin A), S100A9 (calgranulin B), S100A9*, and S100A12 (calgranulin C)], serum amyloid A (SAA), SAA des-Arg (SAA-R), and SAA des-Arg/des-Ser (SAA-RS) as biomarkers and confirmed the results with other techniques, such as western blotting, immunoprecipitation, and nano-LC-MS/MS. The S100 proteins were all able to significantly differentiate samples from patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) from those of patients with inflammatory bowel diseases used as an inflammatory control (IC) group, whereas the SAA, SAA-R, and SAA-RS proteins were not, with the exception of AS. The 4 S100 proteins were coproduced in all of the pathologies and were significantly correlated with the plasma calprotectin concentration; however, these S100 proteins were correlated with the SAA peak intensities only in the RA and IC patient groups. In RA, these S100 proteins (except for S100A12) were significantly correlated with the serum concentrations of C-reactive protein, matrix metalloproteinase 3, and anti-cyclic citrullinated peptide and with the Disease Activity Score (DAS(28)). The SELDI-TOF MS technology is a powerful approach for analyzing the status of monomeric, truncated, or posttranslationally modified forms of arthritis biomarkers, such as the S100A8, S100A9, S100A12, and SAA proteins. The fact that the SELDI-TOF MS data were correlated with results obtained with the classic calprotectin ELISA test supports the reliability of this new proteomic technique.