Characteristic Feature Of Rheumatoid Arthritis Research Articles

Role of melatonin in rheumatoid arthritis: a narrative review

Melatonin, also known as methoxytryptamine-5-acetyl-N, is the main hormone secreted by the pineal gland. It shows that exogenous melatonin as a supplement can help improve sleep quality and act as an anti-inflammatory factor. Melatonin, in multiple ways, controls the immune system, including regulating inflammatory pathways, apoptosis signaling pathways, and regulating the circadian clock. CD4+ T helper (Th1), Th17, and regulatory T cells, which are the important cells in the immune system, are affected by melatonin. Studies did not demonstrate serious complications following the consumption of melatonin. Rheumatoid Arthritis (RA) is an autoimmune disease that causes a chronic inflammatory situation. RA is a systematic disease that affects multi-organ. The characteristic feature of RA is targeting symmetrically small joints. RA has an unknown etiology, and numerous immune cells, cytokines, interleukins, and inflammatory factors participate in the etiology of RA. In addition, oxidative stress and the relation of oxidative stress with clinical presentation and RA disease activity. Due to the following information, melatonin might be a possible supplementary treatment for RA. Some studies demonstrated that melatonin supplements have advantages in some autoimmune and inflammatory diseases. Studies suggest pro-inflammatory factors reduction and increase in anti-inflammatory agents with melatonin supplementation, while other studies have reported no considerable effects, and the results are controversial. Some clinical studies evaluate the impact of melatonin on RA disease clinical signs and symptoms, but they did not report any clinical improvements. Considering the lack of a definite conclusion due to the limited available evidence, future studies are suggested.

HEMATOLOGICAL CHANGES AND NUTRITIONAL CHANGES IN RHEUMATOID ARTHRITIS AND OSTEOARTHRITIS PATIENT AS COMPARED TO CONTROL

Background: Rheumatoid Arthritis is a chronic multisystem disease of unknown etiology. The characteristic feature of Rheumatoid arthritis is persistent inflammatory synovitis, usually involving peripheral joints in a symmetric distribution. Hematologic disorders including anemia, white blood cells abnormalities, platelet abnormalities, coagulopathy and hematological malignancies can be manifested in many autoimmune rheumatic diseases Objective: The objective of this study to calculate the energy intake and check the hematological changes in study group and compared with control. Material and Methods: The study was undertaken in the Department of Biochemistry, S.R.N. Hospital and Medical College Allahabad. In this study 300 samples collected of the age 20-70 year. In which 100 normal individuals they are free from any disease and 100 OA and RA patient collected. Conclusion: On the basis of data we have conclude that arthritis patients have lower level of hemoglobin, higher levels of hemolysis and ESR as compared to control. Lower level of Hb, Iron and increased levels of TIBC is a marker of IDA and ACD which plays a significant role in the etiopathogenesis in Anemia in Rheumatoid arthritis and Osteoarthritis.

α-bisabolol Exerts Anti-inflammatory Action and Ameliorates Collagen-induced Arthritis in Rats

Background: Development of synovial hypertrophy, articular tissue inflammation and tenderness in joints is the characteristic feature of rheumatoid arthritis. Drugs that are derived from natural sources which target inflammation with reduced side-effects receive much attention. Hence, the present study was designed to investigate the anti-arthritic effects of α-bisabolol, a natural chamomile essential oil and also an anti-inflammatory molecule on the rat model of collagen-induced arthritis (CIA). Methods: Animal model of CIA was established and orally administered with α-bisabolol (100 mg/kg) or vehicle and the pathological and inflammatory parameters were evaluated. Result: The results of the present findings indicate that α-bisabolol treatment ameliorates CIA-induced inflammation via inhibiting the proteases and inflammatory mediators suggesting that α-bisabolol may be a potential candidate against arthritis inflammations.

The sonographic identification of cortical bone interruptions in rheumatoid arthritis: a morphological approach.

Bone erosions are the hallmark of structural damage in rheumatoid arthritis (RA). Among imaging techniques, ultrasonography (US) has emerged as an accurate, reliable, repeatable, low-cost and non-invasive imaging modality to detect erosive changes in RA. However, small interruptions of the cortical bone detectable by last generation US equipment do not necessarily represent bone erosions. According to the available data, in addition to cortical bone interruption itself, only a few morphological US findings have been proposed to define RA bone erosions. However, other additional features may be considered to facilitate the interpretation of US cortical bone interruptions in RA. These could be summarised using the following four domains: size, site, shape and scenery. This hypothesis article provides a critical literature review of US features characteristic of RA bone erosions and pictorial evidence supporting the potential role of a morphological analysis in the US identification of bone erosions in RA patients.Plain language summary The ultrasonographic morphology of cortical interruptions is helpful for the identification of bone erosions in rheumatoid arthritis: the “four Ss” approach Bone erosions are characteristic features of rheumatoid arthritis. They are associated with a more aggressive disease and with irreversible physical disability. In recent years, ultrasonography has emerged as an accurate and reliable technique for the detection of bone erosions, that appear as interruptions of the cortical bone with variable size. However, cortical bone interruptions do not necessarily represent bone erosions. Since bone erosions represent the earliest evidence of the destructive behaviour of RA, their identification is crucial.Besides the cortical interruption itself, only a few morphological ultrasonographic features were proposed to characterise bone erosions in rheumatoid arthritis.We believe that a morphological approach, including size, site, shape and scenery, may be considered to facilitate the interpretation of ultrasonographic cortical bone interruptions in rheumatoid arthritis.In this hypothesis article we carried out a critical review of the scientific literature and provided extensive pictorial evidence of the ultrasonographic spectrum of cortical interruptions supporting the potential role of considering the “four Ss” for the ultrasonographic identification of bone erosions in rheumatoid arthritis.

An Update on Imaging in Rheumatoid Arthritis

Modern imaging modalities allow accurate detection of both inflammation and damage in rheumatoid arthritis (RA) joints. This narrative review aims to summarize the recent literature relating to magnetic resonance imaging (MRI), musculoskeletal ultrasound (MSUS) and high-resolution peripheral quantitative computerized tomography (HR-pQCT). Imaging has aided understanding of the pathogenesis of RA: HR-pQCT studies suggest that cortical micro-channels may facilitate erosive changes in the setting of synovitis. Both MRI and MSUS studies have aimed to quantify the degree of changes seen in asymptomatic people where age-related changes are common, highlighting the importance of understanding the thresholds of ‘normality’. Whilst synovitis has been considered the characteristic feature of RA, there is growing evidence that imaging-detected tenosynovitis may be of importance in predicting the development of RA, diagnosing RA and predicting flare in stable RA. Much focus has been placed on recent MRI and MSUS studies demonstrating that systematic repeated imaging of RA treated with tight control strategies does not improve outcomes at the group level; however these studies did not explore pre-test probability issues at the individual patient level. The literature is somewhat mixed on whether MRI and MSUS may provide useful guidance on which patients in remission can safely have therapy de-escalated. Recent work has also continued to validate and refine pathology definitions and semi-quantitative scoring for these tools as outcome measures in clinical trials. A review of recently published literature allowed the identification of several themes: understanding pathogenesis, attempts to define ‘normal’ joints on imaging, the utility of imaging in the diagnosis of RA, predicting the development of RA in at risk populations and the relevance to Ra clinical practice and trials.

Rheumatoid Arthritis of Knee Joints: MRI-Pathological Correlation.

To evaluate the correlation between features of knee joint rheumatoid arthritis (RA) identified on MRI and histological examination as a means of elucidating the pathogenesis of joint destruction in RA. This is a prospective analysis of 26 knee joints of 22 patients who underwent total knee arthroplasty (TKA) for the treatment of RA. Based on the degree of destruction of articular cartilage and the menisci, the occurrence of bone marrow edema and bone erosion, and synovial thickening, the stage of the knee joints were classified using MRI by two radiologists. Differences in the severity of destruction of the articular cartilage of the medial and lateral femoral condyles and medial and lateral tibial plateaus, the medial and lateral menisci, and bone were compared using analysis of variance with a post-hoc test, and the Mann-Whitney U-test. Samples of cartilage, subchondral bone, menisci, and synovium were obtained from the resected knee specimens during TKA and analyzed semiquantitatively using microscopy and immunohistochemistry. Histological differences between areas of bone erosion and bone marrow edema were evaluated using a Mann-Whitney U-test. The extent of articular destruction was classified as grade 4 for the medial and lateral femoral condyles and the medial and lateral tibial plateaus for most patients, with an average destruction grade of 3.6 (F = 5.455, P = 0.002), with the least amount of destruction identified on the lateral femoral condyle. The majority of knee joints in the RA patients were at stage 3 (21/26, 80.8%), followed by stage 4 (4/26, 15.4%). Fibrosis, thinning and destruction, and hyperplasia were the most severe pathological changes in cartilage. In a total of 26 specimens, 36 areas of bone marrow edema and 68 areas of bone erosion were identified, with fibrosis, a mosaic structure of bone, and lymphocyte infiltration being the most severe changes in these areas. The degree of meniscus destruction was classified as grade 4 in the majority patients for both the medial and lateral meniscus, with an average degree of meniscal destruction over all specimens of 3.85, and greater destruction of the medial meniscus than of the lateral meniscus (Z = 2.062, P = 0.039). Fibrosis and engulfing calcified debris were the most severe pathological manifestations. Synovitis was also identified in all 26 specimens, with hyperplasia of intima cells and lymphocyte and plasma cell infiltration being the most severe pathological manifestations. Severe destruction of the articular cartilage and menisci is a characteristic feature of RA. Bone marrow edema and bone erosion can both also be found, but are less characteristic. Synovial infiltration may be the triggering mechanism of the destruction of the cartilage, menisci, and bone marrow. However, the origin of bone marrow edema requires further investigation.

The use of synthetic peptides for detection of anti-citrullinated protein antibodies in rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology. A characteristic feature of RA is the presence of anti-citrullinated protein antibodies (ACPA). Since ACPAs are highly specific for RA and are often present before the onset of RA symptoms, they have become valuable diagnostic and prognostic. As a result, several assays for detection of ACPAs exist, which vary in sensitivity and specificity. In this study, we analyzed the reactivity of RA sera to selected peptides by solid-phase immunoassays in order to develop an ACPA assay with improved sensitivity and specificity. ACPA levels were determined with respect to sensitivity and specificity in 332 serum samples using the newly developed peptide panel, which was compared to the commercial assays CCPlus (Eurodiagnostica) and CCP3.1 (Inova Diagnostics).A primary panel (peptides 814, 33062 and 33156) was identified, which obtained a sensitivity of 71%, while the complete peptide panel reacted with 79% of RA sera screened. Total specificities of 89% and 80% were obtained for the primary peptide panel and the complete peptide panel. Sensitivities for the commercial assays ranged between 71% and 76% and specificities between 88% and 90%. These findings indicate that the generated peptide panel is optimal for ACPA detection and able to compete with commercial available assays. Collectively, this study may contribute to characterize autoimmunity towards citrullinated proteins and to the development of new and improved diagnostic assays for detection of ACPA and determination of RA.

Clinical Cases: Valvular heart disease142A sub-aortic valve mass in a rheumatoid arthritis patient: an unconventional mechanism of aortic regurgitation143Symptomatic severe aortic regurgitation with coronary obstruction due to chronic type a dissection144Mitral valve prolapse and ventricular tachycardia: a long-lasting love story

Clinical Cases: Valvular heart disease142A sub-aortic valve mass in a rheumatoid arthritis patient: an unconventional mechanism of aortic regurgitation143Symptomatic severe aortic regurgitation with coronary obstruction due to chronic type a dissection144Mitral valve prolapse and ventricular tachycardia: a long-lasting love story

Severity and Diurnal Improvement of Morning Stiffness Independently Associate with Tenosynovitis in Patients with Rheumatoid Arthritis.

Background and objectivesAlthough morning stiffness has long been recognized as a characteristic feature of rheumatoid arthritis (RA), it is no more included in the 2010 ACR/EULAR Classification Criteria or in the current major instruments for evaluating disease activity of RA. In this cross-sectional study, we aimed to determine the independent value and the optimal measurement of morning stiffness by clarifying the associations between morning stiffness and synovial inflammation.Patients and methodsWe enrolled 76 consecutive RA patients who underwent musculoskeletal ultrasound examination and agreed to participate in the study. In addition to asking the duration of morning stiffness, we asked patients to complete a diagram which represents the time course of their morning stiffness in the dominant hand. Based on this diagram, we calculated the severity and the diurnal improvement of morning stiffness. We also determined the activity of intra-articular synovitis in 11 joints and tenosynovitis in 8 tendons/tendon compartments in the same hand by using power Doppler (PD) ultrasound with a semiquantitative score (0–3).ResultsFor intra-articular synovitis, swollen/tender joint counts more strongly correlated with total PD scores (ρ = 0.379–0.561, p ≤ 0.001) than did any parameters of morning stiffness (ρ = 0.217–0.314, p = 0.006–0.021). For tenosynovitis, however, the severity on awakening and the improvement of morning stiffness more strongly correlated with total PD scores (ρ = 0.503–0.561, p < 0.001) than did swollen/tender joint counts (ρ = 0.276–0.388, p = 0.001–0.016). Multivariate analyses identified the severity on awakening and the improvement but not the duration of morning stiffness as factors that independently associate with the total tenosynovial PD score.ConclusionsOur data demonstrate a pathophysiological link between morning stiffness and tenosynovitis and also give an insight into the optimal measurement of morning stiffness. Our data support an independent value of evaluating morning stiffness in the management of RA.

Chronotherapy for rheumatoid arthritis: current perspectives

Chronotherapy for rheumatoid arthritis: current perspectives Hideto To Department of Medical Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama, Japan Abstract: Rheumatoid arthritis (RA) is an autoimmune disorder of unknown etiology. Morning stiffness, a characteristic feature of RA, shows a 24-hour rhythm. Cytokines, which are considered to play an important role in the pathogenesis of RA, also exhibit a 24-hour rhythm, with a peak in the early morning. These rhythms have been attributed to the endogenous hormone balance and changes in expression levels of clock-related genes. Chronotherapy based on the 24-hour rhythm of RA has been performed using glucocorticoids and disease-modifying antirheumatic drugs. In a previous study, it was reported that modified-release prednisone tablets were administered to patients with RA at night, which demonstrated that the severity of morning stiffness was markedly less than that in patients receiving the standard treatment. Methotrexate (MTX) is the most frequently used RA drug worldwide. In a basic study, cytokines and inflammatory responses in RA model animals showed 24-hour rhythms, based on which MTX was administered and exerted dosing time-dependent antirheumatic effects. Plasma C-reactive protein and cytokine levels also exhibit 24-hour rhythms in patients with RA, with peaks occurring in the early morning. MTX has been shown to markedly inhibit the exacerbation of arthritis in patients with RA when it is administered as inflammatory responses and tumor necrosis factor-α levels begin to increase. Tacrolimus (TAC) is an immunosuppressive agent that is administered to patients who undergo organ transplants. Since one of the mechanisms of action of TAC is the inhibition of inflammatory cytokine production, it is used as an RA therapeutic drug. When TAC was previously administered in the early light or early dark phase to RA model animals, the group treated in the early light phase had notably inhibited increase in arthritis scores compared with that in the early dark phase. The selection of an optimal dosing time associated with 24-hour rhythms in RA symptoms may lead to more effective and safer treatments for RA using glucocorticoids and disease-modifying antirheumatic drugs. Keywords: methotrexate, steroid, circadian rhythm, cytokines

DPP-4 Inhibition in Diabetic Rheumatoid Arthritis Patients

Abs tract Rheumatoid arthritis (RA) is a common disorder that affects the synovium with an autoimmune reaction. Additionally, the prevalence of diabetes mellitus (DM) in RA patients is higher compared with normal population. Chronic systemic inflammation is a characteristic feature of RA and also has been associated with both insulin resistance and type 2 DM. A recent research by Ospelt et al. showed that inhibition of fibroblast activation protein and dipeptidylpeptidase increases cartilage invasion by rheumatoid arthritis synovial fibroblasts. Furthermore, Jacobs et al. has suggested in a recent publication that the use of a dipeptidylpeptidase inhibitor in the setting of RA is a precious contribution in a determination of the role of RASFs in disease progression. The recent guidelines for the treatment and management of diabetes from the American Diabetes Asoociation, American Association of Clinical Endocrinologists and the National Institute for Health and Clinical Excellenge include DPP-4 inhibitors, a new therapeutic option. However, the available data on the inhibition of dipeptidyl peptidase in RA suggest that we should be careful in terms of the use of DPP-4 inhibitors in the treatment of diabetic patients with RA. Turk Jem 2013; 17: 81-2

Cross‐reactivity of a human IgG1 anticitrullinated fibrinogen monoclonal antibody to a citrullinated profilaggrin peptide

Rheumatoid arthritis (RA) is the most common autoimmune rheumatic disease. It is characterized by persistent joint inflammation, resulting in loss of joint function, morbidity and premature mortality. The presence of antibodies against citrullinated proteins is a characteristic feature of RA and up to 70% of RA patients are anticitrullinated protein antibody (ACPA) positive. ACPA responses have been widely studied and are suggested to be heterogeneous, favoring antibody cross-reactivity to citrullinated proteins. In this study, we examined factors that may influence cross-reactivity between a commercial human anticitrullinated fibrinogen monoclonal antibody and a citrullinated peptide. Using a citrullinated profilaggrin sequence (HQCHQEST- Cit-GRSRGRCGRSGS) as template, cyclic and linear truncated peptide versions were tested for reactivity to the monoclonal antibody. Factors such as structure, peptide length and flanking amino acids were found to have a notable impact on antibody cross-reactivity. The results achieved contribute to the understanding of the interactions between citrullinated peptides and ACPA, which may aid in the development of improved diagnostics of ACPA.

The gene expression profile of preclinical autoimmune arthritis and its modulation by a tolerogenic disease-protective antigenic challenge

IntroductionAutoimmune inflammation is a characteristic feature of rheumatoid arthritis (RA) and other autoimmune diseases. In the natural course of human autoimmune diseases, it is rather difficult to pinpoint the precise timing of the initial event that triggers the cascade of pathogenic events that later culminate into clinically overt disease. Therefore, it is a challenge to examine the early preclinical events in these disorders. Animal models are an invaluable resource in this regard. Furthermore, considering the complex nature of the pathogenic immune events in arthritis, microarray analysis offers a versatile tool to define the dynamic patterns of gene expression during the disease course.MethodsIn this study, we defined the profiles of gene expression at different phases of adjuvant arthritis (AA) in Lewis rats and compared them with those of antigen mycobacterial heat shock protein 65 (Bhsp65)-tolerized syngeneic rats. Purified total RNA (100 ng) extracted from the draining lymph node cells was used to generate biotin-labeled fragment cRNA, which was then hybridized with an oligonucleotide-based DNA microarray chip. Significance analysis of microarrays was used to compare gene expression levels between the two different groups by limiting the false discovery rate to < 5%. Some of the data were further analyzed using a fold change ≥2.0 as the cutoff. The gene expression of select genes was validated by quantitative real-time PCR.ResultsIntriguingly, the most dramatic changes in gene expression in the draining lymphoid tissue ex vivo were observed at the preclinical (incubation) phase of the disease. The affected genes represented many of the known proteins that participate in the cellular immune response. Interestingly, the preclinical gene expression profile was significantly altered by a disease-modulating, antigen-based tolerogenic regimen. The changes mostly included upregulation of several genes, suggesting that immune tolerance suppressed disease by activating disease-regulating pathways. We identified a molecular signature comprising at least 12 arthritis-related genes altered by Bhsp65-induced tolerance.ConclusionsThis is the first report of microarray analysis in the rat AA model. The results of this study not only advance our understanding of the early phase events in autoimmune arthritis but also help in identifying potential targets for the immunomodulation of RA.

The synovial lining micromass system: Toward rheumatoid arthritis in a dish?

A characteristic feature of rheumatoid arthritis (RA) is the hyperplasia of the synovial lining. In RA, the synovial tissue undergoes a marked transformation, due to the influx of immune cells including monocytes, lymphocytes, mast cells, neutrophils, as well as increased angiogenesis, and synovial fibroblast hyperpasia, resulting in the destruction of cartilage and bone. The synovial lining, which consists of synovial fibroblasts and macrophages derived from circulating monocytes, is attached at the bone-cartilage junction and is the site at which joint damage in RA begins. In normal individuals the synovial lining is 1–3 cell layers thick, but increases to as much as 13 cell layers in patients with RA. The hyperplasia of the synovial lining is a result of an increased number of synovial fibroblasts and macrophages, which occurs due to enhanced proliferation, recruitment, and/or survival. The normal function of synovial fibroblasts is to produce extracellular matrix and contribute to the lubrication of joint by secreting molecules such as hyaluronan and lubricin. Recently, a three dimensional synovial lining type membrane was generated in culture using synovial fibroblasts and matrigel and this lining behaved similar to a normal synovial tissue (1,2). In the current issue of Arthritis & Rheumatism Kiener et al (3) furthered these studies by demonstrating that synovial fibroblasts uniquely orchestrate the incorporation of monocytes into the cultured synovial lining. The mechanisms by which synovial fibroblasts contribute to the pathogenesis of RA have been the focus of studies for many years. Synovial fibroblasts from patients with RA have been shown to display anchorage independence, enhanced invasiveness into cartilage, increased proliferation, and decreased cell death as compared to synovial fibroblasts from patients with osteoarthritis or disease free controls. Further, RA synovial fibroblasts spontaneously secrete numerous cytokines, chemokines, and matrix-metalloproteinases (MMPs) that promote inflammation and joint destruction through autocrine and paracrine mechanisms (4). Thus, the RA synovial fibroblasts do not appear to be innocent bystanders in the pathogenesis of RA, but rather active and crucial participants. Despite these insights, the techniques employed to characterize the mechanisms by which synovial fibroblasts contribute to the pathogenesis of disease may not always reveal the whole story accurately (5). In vitro cell culture employing synovial fibroblasts adherent to plastic culture dishes following 3 or more passages, is the most commonly used approach. This system relies on examining a spontaneous or induced function, such as expression of a cytokine, transcription factor, survival factor or proliferation by RA synovial fibroblasts. While the ease and accessibility of this system is appealing for researchers to conduct their studies, it has become clear that the behavior of synovial fibroblasts may change once they were placed on “plastic” compared with the in vivo observations made by the direct examination of synovial tissue (6). For example, spontaneous differences between RA and control synovial fibroblasts

Therapeutic index of methotrexate depends on circadian cycling of tumour necrosis factor-α in collagen-induced arthritic rats and mice

Rheumatoid arthritis is an autoimmune disorder of unknown aetiology. Morning stiffness, a characteristic feature of rheumatoid arthritis, shows a 24-h rhythm. Noticing this rhythm, we hypothesized the presence of a similar rhythm for a rheumatoid arthritis indicator, in addition to dosing-time dependency of the anti-rheumatic effect of methotrexate in arthritis induced by collagen in rats and mice, which reflect the symptomatology of rheumatoid arthritis patients. To measure tumour necrosis factor (TNF)-alpha concentration, blood was taken at different times (2, 6, 10, 14, 18 or 22 h after the light was turned on (HALO)) in collagen-induced arthritic mice. Methotrexate was administered at two different dosing times based on these findings to estimate arthritis. The arthritis score was significantly lower in the 22 HALO-treated group than in the control and 10 HALO-treated groups in collagen-induced arthritic rats and mice. Plasma TNF-alpha concentrations showed obvious 24-h rhythms, with higher levels at light phase and lower levels at dark phase after rheumatoid arthritis crisis. Arthritis was relieved after administration of methotrexate during the dark phase in synchronization with the 24-h rhythm. Our findings suggest that choosing an optimal dosing time associated with the 24-h cycling of TNF-alpha could lead to effective treatment of rheumatoid arthritis by methotrexate.

Therapeutic index of methotrexate depends on circadian cycling of tumour necrosis factor-α in collagen-induced arthritic rats and mice

Abstract Objectives Rheumatoid arthritis is an autoimmune disorder of unknown aetiology. Morning stiffness, a characteristic feature of rheumatoid arthritis, shows a 24-h rhythm. Noticing this rhythm, we hypothesized the presence of a similar rhythm for a rheumatoid arthritis indicator, in addition to dosing-time dependency of the anti-rheumatic effect of methotrexate in arthritis induced by collagen in rats and mice, which reflect the symptomatology of rheumatoid arthritis patients. Methods To measure tumour necrosis factor (TNF)-α concentration, blood was taken at different times (2, 6, 10, 14, 18 or 22 h after the light was turned on (HALO)) in collagen-induced arthritic mice. Methotrexate was administered at two different dosing times based on these findings to estimate arthritis. Key findings The arthritis score was significantly lower in the 22 HALO-treated group than in the control and 10 HALO-treated groups in collagen-induced arthritic rats and mice. Plasma TNF-α concentrations showed obvious 24-h rhythms, with higher levels at light phase and lower levels at dark phase after rheumatoid arthritis crisis. Arthritis was relieved after administration of methotrexate during the dark phase in synchronization with the 24-h rhythm. Conclusions Our findings suggest that choosing an optimal dosing time associated with the 24-h cycling of TNF-α could lead to effective treatment of rheumatoid arthritis by methotrexate.

Efficacy of Biologicals in the Treatment of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic multisystem disease. A characteristic feature of RA is persistent inflammatory synovitis, usually involving the peripheral joints in a symmetric distribution. The prevalence of RA is approximately 0.8% of the population (range: 0.3–2.1%); women are affected approximately 3 times more often than men. The current therapeutic approach is to start a disease-modifying agent early in the illness to prevent eventual joint damage. Older disease-modifying anti-rheumatic drugs include methotrexate, sulphasalazine and hydroxychloroquine. Newer ones such as leflunomide and cyclosporin are also used. A recent advance in the management of rheumatoid arthritis is the use of biological agents, which block certain key molecules involved in the pathogenesis of the illness. They include tumour-necrosis-factor-α-blocking agents such as infliximab, etanercept and adalimumab, the anti-CD-20 agent, rituximab, and CTLA-4 Ig abatacept. The present study was planned with the aim of evaluating the efficacy of such newer biological therapies in refractory RA at various time points. Databases including Medline, Embase and the Cochrane Library were searched for all relevant studies up to January 2007. A total of 26 studies were included in present meta-analysis. The method of DerSimonian and Laird [Control Clin Trials 1986;7:177–188] was used to calculated a pooled odds ratio (OR) for the American College of Rheumatology (ACR) criteria 20, 50 and 70, at 24, 54 and 96 weeks. The overall pooled OR were found to be significantly more than the placebo at all 3 time points for all 3 criteria (ACR 20, 50 70). In conclusion, biologicals as a group are highly effective in the treatment of RA. Biologicals were efficacious both in treatment naïve and methotrexate-refractory patients.

Rheumatoid peripheral blood phagocytes are primed for activation but have impaired Fc-mediated generation of reactive oxygen species

Significant levels of circulating immune complexes (ICs) containing rheumatoid factors and immunoglobulin G in peripheral blood are a characteristic feature of rheumatoid arthritis (RA). ICs interact through Fcγ receptors (FcγR) to activate phagocytes in numerous inflammatory processes. The high concentration of neutrophils in synovial fluid during active phases of the disease, together with their destructive capacity, pose important questions as to their role in the pathogenesis of RA. Functional defects in RA or control peripheral blood neutrophil FcγRs were examined with a specific FcγR-mediated reactive oxygen species (ROS) assay. Heterologous cross-linking of FcγRIIa and FcγRIIIb on neutrophils resulted in a significantly decreased production of ROS by RA cells compared with controls matched for age and sex. However, expression and homologous ligation of receptors did not differ between these groups. These data suggest that neutrophil priming does occur before emigration into the joint and that blood neutrophils from patients with RA have a functional impairment in cooperative FcγR-mediated ROS generation. This may account for the increased susceptibility to bacterial infection that arises in patients with severe disease.

The Anti-rheumatic Gold Salt Aurothiomalate Suppresses Interleukin-1β-induced Hyaluronan Accumulation by Blocking HAS1 Transcription and by Acting as a COX-2 Transcriptional Repressor

Gold compounds are among the oldest disease-modifying drugs and are still widely used today for treating rheumatoid arthritis. Despite decades of use, little is known about the mode of action of this class of drugs. Here we have demonstrated that aurothiomalate (AuTM) suppresses hyaluronan accumulation by blocking interleukin (IL)-1beta-induced hyaluronan synthase-1 transcription. We have further demonstrated that, in fibroblast-like synoviocytes (FLSs), AuTM acts as a specific COX-2 transcriptional repressor in that IL-1beta-induced COX-2 transcription is blocked, whereas COX-1 transcription and translation is unaffected. As a consequence, PGE2 levels released by FLS are dose-dependently reduced in cells exposed to AuTM. Of similar importance is the demonstration that AuTM does block NFkappaB-DNA interaction. In addition, two other transcription factors implicated in inflammatory events, namely AP-1 and STAT3, are blocked as well. The effect on NFkappaB likely explains the inhibition of COX-2 as well as that of HAS1, as both are genes that depend on the activation of NFkappaB. Interestingly, AuTM does not interfere with IL-1beta-induced IkappaB alpha degradation, in most cases a prerequisite for subsequent NFkappaB activation. Furthermore, evidence is presented that, in FLS, AuTM blocks NFkappaB-DNA interaction neither by binding to NFkappaB binding sites nor by interacting with activated NFkappaB proteins. Taken together, AuTM treatment of FLS blocks two of the most important proinflammatory events that are associated with rheumatoid arthritis. AuTM blocks the release of PGE2 and prevents the activation of NFkappaB, therefore blocking IL-1beta-induced hyaluronan accumulation and likely a series of other pro-inflammatory NFkappaB-dependent genes.

Role of PGE2 and EP Receptors in the Pathogenesis of Rheumatoid Arthritis and as a Novel Therapeutic Strategy

Recent progress in understanding the pathogenesis of rheumatoid arthritis (RA) in parallel with elucidation of the functional role of the prostaglandin receptor subfamily has revealed an important regulatory role of PGE2, in addition to its well-known proinflammatory role in the progression of RA. Characteristic features of RA are synovial proliferation and pannus formation, which result in the destruction of cartilage and bone. Pannus tissue is mainly composed of macrophages and fibroblast-like synoviocytes. Both T cell-derived IL-17 and macrophage-derived TNF-alpha seem to play a central role in the progression of proinflammatory cascades in RA. PGE2 is also produced in response to proinflammatory cytokines, which in turn negatively regulates both IL-17 and TNF-alpha expression and TNF/IL-1-induced activation of fibroblast-like synoviocytes through EP2/EP4 receptors, resulting in the modulation of proinflammatory cascades. IL-17- and TNF-activated macrophages differentiate into osteoclasts in the presence of M-CSF and RANKL expressed by fibroblast-like synoviocytes. PGE2 binding to EP4 stimulates osteoclastogenesis through enhancing RANKL expression. At the same time, PGE2 suppresses osteoclastogenesis by inhibiting M-CSF expression of fibroblast-like synoviocytes as well as both IL-17 and IL-17-induced TNF-alpha expression of macrophages. PGE2-EP4 also activates osteoblastogenesis through increasing cbfa1 and osterix, two essential transcription factors required for bone formation. The net effect of PGE2 may direct toward repair of eroding bone through the suppression of inflammation and enhancement of bone remodeling. Here, we discuss a diverse action of PGE2/EP receptors and their important regulatory roles in the pathogenesis of RA, which may lead to a novel therapeutic strategy.