Articular Rheumatoid Arthritis Research Articles

Rheumatoid Synovial Fluid and Acidic Extracellular pH Modulate the Immunomodulatory Activity of Urine-Derived Stem Cells.

Urine-derived stem cells (UdSCs) possess a remarkable anti-inflammatory and immune-modulating activity. However, the clinical significance of UdSCs in autoimmune inflammatory diseases such as rheumatoid arthritis (RA) is yet to be explored. Hence, we tested the UdSCs response to an articular RA microenvironment. To simulate the inflamed RA joint more authentically in vitro, we treated cells with rheumatoid synovial fluids (RASFs) collected from RA patients, serum deprivation, acidosis (pH 7.0 and 6.5), and their combinations. Firstly, the RASFs pro-inflammatory status was assessed by cytokine quantification. Then, UdSCs were exposed to the RA environmental factors for 48 h and cell proliferation, gene expression and secretion of immunomodulatory factors were evaluated. The immunosuppressive potential of pre-conditioned UdSCs was also assessed via co-cultivation with activated peripheral blood mononuclear cells (PBMCs). In all experimental conditions, UdSCs' proliferation was not affected. Conversely, extracellular acidosis considerably impaired the viability/proliferation of adipose tissue-derived stem cells (ATSCs). In the majority of cases, exposure to RA components led to the upregulated expression of IL-6, TSG6, ICAM-1, VCAM-1, and PD-L1, all involved in immunomodulation. Upon RASFs and acidic stimulation, UdSCs secreted higher levels of immunomodulatory cytokines: IL-6, IL-8, MCP-1, RANTES, GM-CSF, and IL-4. Furthermore, RASFs and combined pretreatment with RASFs and acidosis promoted the UdSCs-mediated immunosuppression and the proliferation of activated PBMCs was significantly inhibited. Altogether, our data indicate that the RA microenvironment certainly has the capacity to enhance UdSCs' immunomodulatory function. For potential preclinical/clinical applications, the intra-articular injection might be a reasonable approach to maximize UdSCs' therapeutic efficiency in the RA treatment.

A Closer Look at the Role of Anti-CCP Antibodies in the Pathogenesis of Rheumatoid Arthritis-Associated Interstitial Lung Disease and Bronchiectasis.

Rheumatoid arthritis (RA) is an articular disease with extra-articular manifestations. Pulmonary manifestations are not uncommon and can involve all compartments of the lungs with airway disease in the form of bronchiectasis or bronchiolitis, interstitial lung disease (ILD), pleural effusions and parenchymal lung nodules. The pulmonary features may present synchronously or after the articular disease, but, importantly, it may be the first presentation in 10% of patients in the absence of articular symptoms. Here we discuss the pathogenesis of RA lung involvement, particularly interstitial lung disease and bronchiectasis, focusing on the role anti-CCP antibodies (ACPAs). We highlight the complex interplay among genetic, environmental and immune factors. Furthermore, we explore the relationship of citrullination and smoking as well as the concept of interstitial pneumonia with autoimmune features (IPAF), where patients do not have evidence of another known cause of interstitial pneumonia and have incomplete features of connective tissue disease (CTD). We surmise that the frequency and titers of rheumatoid factor (RF) and ACPAs are increased in bronchiectasis and RA-bronchiectasis compared to RA patients without lung disease. ACPA is associated with more severe disease in both RA-ILD and RA-bronchiectasis even in the absence of articular symptoms. There is no clear prediction of development of articular RA with high ACPA levels in the context of positive ACPA and ILD; however, in RA-bronchiectasis, patients with positive antibodies can develop RA within a year after diagnosis of bronchiectasis. Though the primary focus of this narrative is to highlight the role of ACPA in pathogenesis and clinical practice, we also discuss the current treatment options and trials in RA-ILD and RA-bronchiectasis. Currently, there are no clear treatment guidelines. The treatments are now focusing on using a combination of immunosuppression and antifibrotic agents. Combination treatment targets both the fibrotic and inflammatory components of the disease process. Further studies are needed to identify the use of ACPA as a biomarker to tailor the treatment in RA-ILD and RA-bronchiectasis.

Comparison of intra-articular steroid injection and hyaluronic acid in mono-articular synovitis knee

Introduction: Mono articular presentation of rheumatoid arthritis is infrequent and has been previously reported to involve the hip and knee joints. Rheumatoid arthritis is a common symmetrical chronic inflammatory arthritis with the prevalence of 1% worldwide. Mono- articular rheumatoid arthritis is a rare entity reported to initially affect large joints such as hips and knees, progressing to a poly articular presentation within 3 to 5 years. Synovitis is an important component of rheumatoid arthritis, so we conducted a study to include all the recurrent effusion of knee cases, and we have compared the functional outcome of intra-articular steroid injection and hyaluronic acid in the treatment of such cases. Material and Methods: 40 cases of recurrent effusion of knee joint attending the OPD or emergency services at Government Medical College and Rajindra hospital, Patiala between July 2016 to July 2019 were evaluated with the clinical examination, haematological investigations and radiological investigations. In all the cases, the joint was aspirated with a 16 G Needle and aspirated fluid was sent for pus cultural sensitivity in a microbiology Department of our hospital and was sent for CBNAAT to chest and TB hospital of our hospital. In Group 1, following the aspiration, injection of local corticosteroid (methylprednisolone acetate 80 mg) was given and in group 2, injection of hyaluronic acid was given, followed by a short course of antibiotics for 5 days and short course of non-steroidal anti-inflammatory drugs was given for 10 days and a crêpe bandage was applied for 2 days. The results were assessed by VAS for pain and KOOS (Knee Injury and Osteoarthritis Outcome Score) scores. Results: In all 40 patients, the pus cultural sensitivity was negative for any microorganism and CBNAAT was negative in all the 40 patients. By comparing the results obtained in KOOS scale it was seen that symptoms improved after six months in both steroid (P = 0.017) and HA groups (P = 0.004). Besides, daily activity improved in both steroid (P = 0.027) and HA groups (P = 0.047). On the contrary, pain did not decrease 6 months after intervention in both steroid (P = 0.096) and HA groups (P = 0.17) Conclusion: Mono articular synovitis in an otherwise seronegative patient is due to recurrent inflammatory response due to recurrent stress or any other intra articular pathology. Patients are advised rest, and a short course of steroidal anti-inflammatory drugs, which also helped to relieve the inflammation. This was markedly improved by intra-articular HA injection as shown by the recovery in intra-articular HA injection group as compared to the steroid group.

Mechanisms of lung disease development in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder that causes joint inflammation and damage. Extra-articular manifestations occur in many patients and can include lung involvement in the form of airway or parenchymal inflammation and fibrosis. Although the pathophysiology of articular RA has been extensively investigated, the mechanisms causing airway and parenchymal lung disease are not well defined. Infections, cigarette-smoking, mucosal dysbiosis, host genetics and premature senescence are all potentially important contributors to the development of lung disease in patients with RA. RA-associated lung disease (which can predate the onset of articular disease by many years) probably originates from chronic airway and alveolar epithelial injury that occurs in an individual with a genetic background that permits the development of autoimmunity, leading to chronic inflammation and subsequent airway and lung parenchymal remodelling and fibrosis. Further investigations into the specific mechanisms by which lung disease develops in RA will be crucial for the development of effective therapies. Identifying mechanisms by which environmental and host factors cooperate in the induction of autoimmunity in the lung might also help to establish the order of early events in RA.

Anti-Citrullinated Protein Antibodies Are Associated With Neutrophil Extracellular Traps in the Sputum in Relatives of Rheumatoid Arthritis Patients.

Studies suggest that rheumatoid arthritis (RA)-related autoimmunity is initiated at a mucosal site. However, the factors associated with the mucosal generation of this autoimmunity are unknown, especially in individuals who are at risk of future RA. Therefore, we tested anti-cyclic citrullinated peptide (anti-CCP) antibodies in the sputum of RA-free first-degree relatives (FDRs) of RA patients and patients with classifiable RA. We evaluated induced sputum and serum samples from 67 FDRs and 20 RA patients for IgA anti-CCP and IgG anti-CCP, with cutoff levels for positivity determined in a control population. Sputum was also evaluated for cell counts, neutrophil extracellular traps (NETs) using sandwich enzyme-linked immunosorbent assays for protein/nucleic acid complexes, and total citrulline. Sputum was positive for IgA and/or IgG anti-CCP in 14 of 20 RA patients (70%) and 17 of 67 FDRs (25%), including a portion of FDRs who were serum anti-CCP negative. In the FDRs, elevations of sputum IgA and IgG anti-CCP were associated with elevated sputum cell counts and NET levels. IgA anti-CCP was associated with ever smoking and with elevated sputum citrulline levels. Anti-CCP is elevated in the sputum of FDRs, including seronegative FDRs, suggesting that the lung may be a site of anti-CCP generation in this population. The association of anti-CCP with elevated cell counts and NET levels in FDRs supports a hypothesis that local airway inflammation and NET formation may drive anti-CCP production in the lung and may promote the early stages of RA development. Longitudinal studies are needed to follow the evolution of these processes relative to the development of systemic autoimmunity and articular RA.

Can rheumatoid vasculitis predate a diagnosis of rheumatoid arthritis?

We report regarding a male patient who presented with a systemic vasculitis that was consistent with a diagnosis of polyarteritis nodosa. At presentation, he had no features of inflammatory arthritis but had a high rheumatoid factor titer and low C4 level. Withdrawal of immunosuppression after 6 years resulted in the development of classical rheumatoid arthritis (RA). This case supports previous reports that revealed that vasculitis may predate the development or occur very early in the course of articular RA.

Pulmonary vasculitis as the first manifestation of rheumatoid arthritis

In this report, we describe a 61-year-old man that presented with isolated pulmonary vasculitis and a positive anti-cyclic citrullinated peptide (CCP) antibody. Within a few months, the patient developed the symmetric polyarthritis consistent with rheumatoid arthritis (RA). Because the anti-CCP antibody is highly specific for RA and vasculitis is a known association of RA, we suspect the pulmonary vasculitis in this patient was the first manifestation of underlying RA. This case extends on previous reports that have shown that lung disease may predate the development of articular RA and that anti-CCP positivity and lung disease may represent a pre-RA phenotype. To our knowledge, this is the first case report of pulmonary vasculitis as the first manifestation of RA.

Brief Report: Airways abnormalities and rheumatoid arthritis–related autoantibodies in subjects without arthritis: Early injury or initiating site of autoimmunity?

To evaluate the presence of pulmonary abnormalities in rheumatoid arthritis (RA)-related autoantibody-positive subjects without inflammatory arthritis. Forty-two subjects who did not have inflammatory arthritis but were positive for anti-cyclic citrullinated peptide antibodies and/or ≥2 rheumatoid factor isotypes (a profile that is 96% specific for RA), 15 autoantibody-negative controls, and 12 patients with established seropositive early RA (<1-year duration) underwent spirometry and high-resolution computed tomography (HRCT) lung imaging. The median age of autoantibody-positive subjects was 54 years, 52% were female, and 38% were ever-smokers; these characteristics were not significantly different from those of autoantibody-negative control subjects. No autoantibody-positive subject had inflammatory arthritis based on joint examination. HRCT revealed that 76% of autoantibody-positive subjects had airways abnormalities including bronchial wall thickening, bronchiectasis, centrilobular opacities, and air trapping, compared with 33% of autoantibody-negative controls (P = 0.005). The prevalence and type of lung abnormalities among autoantibody-positive subjects were similar to those among patients with early RA. In 2 autoantibody-positive subjects with airways disease, inflammatory arthritis classifiable as articular RA developed ∼13 months after the lung evaluation. Airways abnormalities that are consistent with inflammation are common in autoantibody-positive subjects without inflammatory arthritis and are similar to airways abnormalities seen in patients with early RA. These findings suggest that the lung may be an early site of autoimmune-related injury and potentially a site of generation of RA-related autoimmunity. Further studies are needed to define the mechanistic role of lung inflammation in the development of RA.

Lung disease with anti-CCP antibodies but not rheumatoid arthritis or connective tissue disease

We sought to characterize a novel cohort of patients with lung disease, anti-cyclic citrullinated peptide (CCP) antibody positivity, without rheumatoid arthritis (RA) or other connective tissue disease (CTD). The study sample included 74 subjects with respiratory symptoms, evaluated January 2008-January 2010 and found to have a positive anti-CCP antibody but no evidence for RA or other CTD. Each underwent serologic testing, pulmonary physiology testing, and thoracic high-resolution computed tomography (HRCT) scan as part of routine clinical evaluation. The majority of subjects were women, and most were former cigarette smokers. Four distinct radiographic phenotypes were identified: isolated airways disease (54%), isolated interstitial lung disease (ILD) (14%), mixed airways disease and ILD (26%), and combined pulmonary fibrosis with emphysema (7%). This cohort had a predominance of airways disease, either in isolation or along with a usual interstitial pneumonia-pattern of ILD. Among subjects with high-titer anti-CCP positivity (n=33), three developed the articular manifestations of RA during a median follow-up of 449 days. We have described a unique cohort of patients with anti-CCP antibody positivity and lung disease in the absence of existing RA or other CTD. The lung phenotypic characteristics of this cohort resemble those of established RA and a few of these patients have developed articular RA within a short period of follow-up. The implications of a positive anti-CCP antibody among patients with lung disease but not RA are not yet known, but we believe requires further investigation.

Rheumatoid arthritis (RA)-specific autoantibodies in patients with interstitial lung disease and absence of clinically apparent articular RA

The purpose of this study was to identify rheumatoid arthritis (RA)-related autoantibodies in subjects with interstitial lung disease (ILD) and no articular findings of RA, supporting the hypothesis that RA-related autoimmunity may be generated in non-articular sites, such as the lung. This was a retrospective chart review utilizing clinic databases of patients with ILD to identify cases with lung disease, RA-related autoantibody positivity, and no clinical evidence of articular RA. Four patients with ILD, RF, and anti-CCP positivity and no articular findings of RA were identified. All four patients were male with a mean age at time of diagnosis of ILD of 70 years old. All had a history of smoking. Three patients died within 2 years of diagnosis of ILD and never developed articular symptoms consistent with RA; the final case met full criteria for articular RA several months after stopping immunosuppressive treatment for ILD. RF and anti-CCP can be present in smokers with ILD without clinical evidence of articular RA and in one case symptomatic ILD and autoantibody positivity preceded the development of articular RA. These findings suggest that RA-specific autoimmunity may be generated due to immunologic interactions in the lung and may be related to environmental factors such as smoking.

Corticosteroid prescribing in rheumatoid arthritis--the fiction and the fact.

The results of a postal questionnaire to consultant rheumatologists (80% response rate) suggest that most comply with current teaching regarding the indications for systemic corticosteroids in articular rheumatoid arthritis (RA). They are prescribed as a last resort and most frequently in the elderly. However, a review of 100 consecutive RA out-patients revealed 24 patients currently taking corticosteroids at a mean prednisolone dosage of 5.6 mg daily. Only two had been prescribed these drugs for extra-articular problems. In 11 cases the treatment was not initiated by a rheumatologist. The discrepancies between the two surveys are discussed.

IgE class immune complexes in Felty's syndrome: characterisation of antibody activities in isolated complexes.

By means of a double polyethylene glycol (PEG) precipitation and PRIST technique IgE was detected in 3% PEG precipitates and in the immune complex enriched fractions purified by solid-phase Clq adsorption from sera of 11 of 20 patients with Felty's syndrome. No correlation was found between the occurrence of complexed IgE and total protein content of the immune complex enriched material. IgE rheumatoid factor and anti-IgE antibody activity were detected in some of the immune complex fractions. Serum levels of complement C3, C4, and factor B were low in IgE immune complex positive cases. Only 4 of 20 patients with articular rheumatoid arthritis had IgE-containing immune complexes.

Impaired polymorphonuclear leucocyte chemotaxis in rheumatoid arthritis.

This study has investigated the chemotactic activity of polymorphonuclear cells (PMNs) isolated from the blood of patients with either articular rheumatoid arthritis (RA) or RA with extra-articular manifestations. A double fluorochrome immunofluorescent staining test has been employed to identify cell-associated immunoglobulins, probably immune complexes. The results suggest an inverse relationship between PMN chemotaxis and staining for cell-associated immunoglobulins, either surface bound or internalised. PMNs from RA patients showed reduced chemotaxis, and this was further reduced when RA PMNs were incubated for 30 minutes in autologous serum. A similar reduction in chemotaxis of normal PMNs occurred after incubation in RA sera. Preincubation of both RA and normal PMNs in RA serum (but not normal serum) resulted in an increase in the number of cells in which cell-associated immunoglobulins were demonstrable. This further reduction in RA PMN chemotaxis after exposure to autologous serum, together with an increase in immunoglobulin staining, may indicate selection of certain PMNs at the time of venepuncture due to cell margination. Such a selection process would call for a re-evaluation of previous studies of RA PMN function in relation to the disease process.