Joints Of Rheumatoid Arthritis Patients Research Articles

Immunological Roles of Fibroblast-Like Synoviocyte Cells in Rheumatoid Arthritis

Introduction: Fibroblast-like synoviocytes (FLS), also known as synovial fibroblasts or type B synoviocytes, are the primary cells responsible for the structure of the synovial lining. They are crucial for the formation of a healthy, organized synovial lining. In rheumatic synovium affected by inflammation, the typical three-layered synovial lining transforms into a pannus-like structure. Various pro-inflammatory conditions in the joints of rheumatoid arthritis (RA) patients, characterized by elevated levels of cytokines, growth factors, and infiltration of inflammatory cells, strongly activate FLS cells. Moreover, environmental conditions in the joints of RA patients, such as high pressure and hypoxia, induce changes that further contribute to FLS activation and the development of aggressive characteristics. These changes include increased proliferation, reduced apoptosis, and enhanced cell migration, collectively referred to as a tumor-like phenotype. Additionally, FLS cells release inflammatory cytokines, amplifying inflammation and attracting immune cells to the joint. They also play a role in degrading the extracellular matrix and causing cartilage and bone damage through the production of enzymes like matrix metalloproteinases (MMPs), collagenase, aggrecans, and cathepsins. Recent therapeutic approaches have been directed at targeting the signaling pathways that activate FLS cells and inhibiting factors and cytokines produced by these cells to alleviate inflammatory symptoms and reduce joint damage. It is anticipated that these treatment strategies will complement existing therapies in the near future.
 Conclusion: FLS cells are the main components of maintaining the health and nutrition of joints. These cells produce various cytokines, chemokines, angiogenic factors, as well as factors that contribute to the breakdown of matrix and cartilage. The main drivers of significant changes in inflamed joints are proliferation and resistance to apoptosis. Treatment strategies have been developed to target the signaling pathways that activate these cells, with a focus on improving inflammatory symptoms. It is expected that these treatment strategies will be incorporated into existing therapies in the near future.

High Fracture Rate of AVANTA Silicone Implant Following Arthroplasty of the Thumb MCP Joint of Rheumatoid Arthritis Patients with Boutonniere Deformities.

We retrospectively investigated the mid-term outcomes of arthroplasty using the AVANTA silicone implant for thumb metacarpophalangeal (MCP) joints with boutonniere deformity in patients with rheumatoid arthritis (RA). This study involved 36 thumbs of 33 RA patients with a mean follow-up period of 5.1 years (range, 2.0-13.3). Postoperatively, the mean extension was significantly increased and the mean flexion was significantly decreased (p<0.001, p<0.001, respectively), resulting in the mean arc of range of motion (ROM) shifting in the direction of extension after surgery. Implant fracture was observed in 10 thumbs (28%), and 4 of these (11%) underwent revision surgery. The survivorship with implant fracture and revision surgery as endpoints were 73.4% and 91.8% at 5 years, respectively. The preoperative arc of ROM and the postoperative flexion range of the implant-fracture group were significantly greater than those in the no-implant-fracture group (p=0.039, 0.034, respectively). These results suggest the importance of patient education and careful rehabilitation to prevent excessive flexion. Overall, the AVANTA silicone implant showed a relatively high rate of implant fracture at our institute.

Screening for early rheumatoid arthritis using high-frequency ultrasound, serum RANKL, and OPG detection.

To conduct a comparative study of high-frequency ultrasound and magnetic resonance imaging (MRI) combined with serum RANKL and OPG detection, and assess the efficacy of high-frequency ultrasound with RANKL and OPG detection in screening early rheumatoid arthritis (RA). High-frequency ultrasound and MRI were performed on both carpal joints of 60 patients with early RA, and the frequencies of synovitis, joint effusion, tenosynovitis, and bone erosion detected by high-frequency ultrasound and MRI were observed. The serum levels of receptor activator for nuclear factor-κB ligand (RANKL) and osteoclastogenesis inhibitory factor (OPG) were also detected. The serum levels of RANKL and OPG were also detected in 80 normal healthy examinees. The data were recorded and statistically analyzed. The detection rates of carpal synovitis, joint effusion, tenosynovitis, and bone erosion in RA patients by high-frequency ultrasound were 81.66%, 69.16%, 63.33%, and 1.66%, respectively, while the detection rates by MRI were 80.00%, 71.66%, 65.00%, and 15.00%, respectively. There was no significant difference between high-frequency ultrasound and MRI in the detection rates of carpal synovitis, joint effusion, and tenosynovitis in RA patients (P>0.05), while the detection rate of bone erosion by high-frequency ultrasound was significantly lower than that by MRI. The serum levels of RANKL and OPG in RA patients were 231.47 and 68.71, respectively, while the serum levels of RANKL and OPG in normal healthy examinees were 123.51 and 385.05, respectively. The serum RANKL levels of RA patients were significantly higher than those of healthy examinees, while the serum OPG levels of RA patients were significantly lower than those of healthy examinees, which were statistically significant (P < 0.01). The AUC values of the ROC curves obtained by high-frequency ultrasound and MRI combined with serum RANKL and OPG detection in Synovitis modeling were 0.955 and 0.954, respectively. The AUC values of the ROC curves obtained from the joint fusion modeling using high-frequency ultrasound and MRI combined with serum RANKL and OPG detection were 0.949 and 0.950, respectively. The AUC values of the ROC curves obtained from modeling Tenosynovitis using high-frequency ultrasound and MRI combined with serum RANKL and OPG detection were 0.941 and 0.949, respectively. The AUC values of ROC curves obtained by combining high-frequency ultrasound and MRI with serum RANKL and OPG detection in Bone erosion modeling were 0.908 and 0.923, respectively. High-frequency ultrasound combined with serum RANKL and OPG detection has comparable effects to MRI on screening early RA, providing a safe, simple, and cost-effective screening method for the early detection of RA patients. Key Points • High-frequency ultrasound and MRI can effectively detect early lesions of the wrist joints in RA patients. • Ultrasound diagnosis has the advantages of being quick, inexpensive, and repeatable, making it the preferred choice of imaging examination for RA patients at an early stage.

Comparison of Angio PLanewave UltraSensitive and Power Doppler Ultrasound in Detecting Synovial Blood Flow in Wrist and Finger Joints of Rheumatoid Arthritis Patients

The purpose of this study is to conduct a comparison between the newly introduced Angio PLanewave UltraSensitive (AngioPLUS) method and the power Doppler ultrasound (PDUS) technique, evaluating the efficacy of these two methods in detecting synovial blood flow in wrist and finger joints of rheumatoid arthritis (RA) patients. Furthermore, the study aimed to investigate the potential associations between the observed blood flow patterns and various symptoms and indicators associated with RA. A cohort of 101 patients diagnosed with RA was included and subsequently categorized into two groups: 20 male participants (19.80%) and 81 female participants (80.20%). Their grayscale ultrasound, PDUS, and AngioPLUS were utilized to acquire data, and subsequent scoring was conducted. Serological tests of the patients were also performed, and DAS28 scores were calculated. The McNemar and Wilcoxon tests were used to compare the blood flow display rate and grading of PDUS as well as AngioPLUS, respectively. AngioPLUS blood was significantly improved compared to PDUS. In all joints, the proportion of slight and significant improvement in wrist joints was the highest (14.11% and 1.98%, respectively). AngioPLUS was moderately correlated with C-reactive Protein (CRP), Disease Activity Score that includes 28-joint counts, and swollen joint counts and weakly correlated with platelet, hemoglobin, tender joint counts, and CRP before and after treatment. Compared to PDUS, AngioPLUS has a better auxiliary diagnostic role in evaluating disease activity and can provide a reference to improve the management of RA further.

The multifaceted role of mast cells in the pathogenesis of rheumatoid arthritis.

Mast cells (MC) are tissue duelling cells playing an active role in both innate and adaptive immune system. They act as first players in different microbial infections and exert a crucial role in allergy, chronic inflammation, fibrosis, and rheumatic diseases (RD), including rheumatoid arthritis (RA). MC are normally present in human synovia and they increase in the joints of RA patients, contributing to inflammatory and remodelling processes. Due to their great plasticity and multifunctionality, MC exert a wide range of roles in different stages of the disease. To date, the results obtained by in-vitro and in-vivo studies have contributed to better clarify the dynamic role of MC in local arthritis of RA and have improved our knowledge on different aspect of the disease. Although different mice models have been extensively used to investigate the contribution of MC in different stages of RA, those models often fail to reproduce the complexity and the heterogeneity of the human disease. Here, we provide an overview on different roles of MC in RA pathogenesis and how these cells might influence some clinical features of the disease.

18F-FDG and 18F-NaF PET/CT Global Assessment of Large Joint Inflammation and Bone Turnover in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) involves chronic inflammation of synovial joints, causing pain, stiffness, and limited mobility. 18F-sodium fluoride (NaF) is a PET tracer whose uptake reflects bone turnover, while 18F-fludeoxyglucose (FDG) shows glucose metabolism and can serve as a marker for inflammation. The aim of this study is to determine the feasibility of calculating the FDG and NaF mean standardized uptake value (SUVmean) in the knee joint, hip joint, and sacroiliac (SI) joint of RA patients and to determine their association with patient characteristics. Prospective FDG-PET/CT as well as NaF-PET/CT imaging was performed on 18 RA patients. The global SUVmean was calculated on FDG-PET/CT and NaF-PET/CT images using a semiautomated CT-based method of segmentation. FDG and NaF uptake were found to be significantly correlated in the knee (r = 0.77, p < 0.001), but not in the hip and SI joints. In the knee, both NaF SUVmean and FDG SUVmean were significantly correlated with body weight, BMI, leptin, and sclerostin levels (p < 0.05). NaF SUVmean was significantly positively correlated with BMI and leptin for both the hip and SI joints (p < 0.05). No significant correlation was observed between either PET parameter and age, height, erythrocyte sedimentation rate (ESR), and interleukins 1 and 6 (IL-1 and IL-6); however, FDG was correlated with inflammatory markers such as C-reactive protein (CRP) and patient global visual analogue scale (VAS-PtGlobal) in some joints. In this study, both FDG and NaF uptake were quantified in large joints of patients with RA using CT segmentation. NaF and FDG SUVmean were correlated with clinical variables related to body weight and adiposity, suggesting that degenerative joint disease may play a larger role in influencing the uptake of these tracers in large joints than RA disease activity. FDG and its correlation with markers of inflammation such as CRP and VAS-PtGlobal suggests that this tracer may serve as a more specific marker for RA disease activity than NaF. Larger prospective and longitudinal data are necessary to gain a better understanding of the roles of FDG and NaF in evaluating RA joint activity in these joints.

Factors associated with subclinical inflammation of wrist joints in rheumatoid arthritis patients with low or no disease activity- a RA ultrasound registry study

BackgroundTo evaluate the factors to predict subclinical inflammation of wrist joints in patients with RA who are in clinical remission or low disease activity.MethodsGray scale and power Doppler ultrasound were performed on the dorsal radio-lunate of both wrists. The presence of synovitis, comorbidities, and use of disease modifying anti-rheumatic drugs were recorded. A Multivariable forward logistical regression model was used to identify factors associated with subclinical inflammation.ResultsThere were 1248 patients (1010 females, 238 males; mean age: 60.0 ± 10.5 years ). 57.4% of patients in complete remission and low disease activity had sonographic inflammation. Multivariable forward logistic regression analysis indicated that male sex, smoking are positively associated with inflammation and that age, alcohol consumption, and use of methotrexate, glucocorticoid, or a biological therapy are negatively associated with inflammation. Use of biological agents decreased the risk of inflammation by 40.9%.ConclusionsThere was evidence of subclinical inflammation in most patients who were in low or no disease activity, those with biological therapy had lower risk of subclinical inflammation.

Elevated serum soluble CD27 levels are associated with both disease activity and humoral immune activity in patients with rheumatoid arthritis.

To investigate the serum level of soluble CD27 (sCD27) and its potential clinical significance in rheumatoid arthritis (RA). Serum sCD27 levels in RA patients, idiopathic inflammatory myopathy (IIM) patients, systemic lupus erythematosus (SLE) patients and healthy controls (HCs) were detected by enzyme-linked immunosorbent assay. The medical information and laboratory data of the patients were collected. Serum sCD27 levels in RA patients with different clinical features were analysed, as was the correlation between the clinical data and serum sCD27 levels. Independent samples t test, the Mann-Whitney U-test or Wilcoxon signed-rank test, and Spearman correlation were used for statistical analysis. Levels of sCD27 were elevated in RA patients (3898 [2525, 5834] pg/mL) compared with IIM patients (2467 [1939, 3324] pg/mL) or HCs (1659 ± 648 pg/mL) (p 0.001). In addition, serum sCD27 levels correlated with age, erythrocyte sedimentation rate, C-reactive protein (CRP), rheumatoid factor (RF), immunoglobulin A, immunoglobulin G, complement 4 and disease activity score in 28 joints in RA patients. Levels of sCD27 were higher in RF-positive RA patients (6054 ± 5842 pg/mL) than in RF-negative patients (3902 ± 2098 pg/mL), and a similar finding was also observed in anti-cyclic citrullinated peptide (anti-CCP) antibody-positive (5810 ± 5671 pg/mL) and anti-CCP-negative (4183 ± 2187 pg/mL) RA patients. Serum ESR, RF, IgA, IgG levels and DAS28-CRP were elevated in RA patients with higher sCD27 levels than in those with lower sCD27 levels (p<0.01). Serum sCD27 might be a promising biomarker that reflects both disease activity and humoral immunity activity in RA.

Interaction between Mesenchymal Stem Cells and the Immune System in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease that causes damage to joints. This review focuses on the possibility of influencing the disease through immunomodulation by mesenchymal stem cells (MSCs). There is an occurrence of rheumatoid factor and RA-specific autoantibodies to citrullinated proteins in most patients. Citrulline proteins have been identified in the joints of RA patients, and are considered to be the most suitable candidates for the stimulation of anti-citrulline protein antibodies production. Fibroblast-like proliferating active synoviocytes actively promote inflammation and destruction in the RA joint, in association with pro-inflammatory cells. The inflammatory process may be suppressed by MSCs, which are a population of adherent cells with the following characteristic phenotype: CD105+, CD73+, CD90+, CD45−, CD34− and HLA DR−. Following the stimulation process, MSCs are capable of immunomodulatory action through the release of bioactive molecules, as well as direct contact with the cells of the immune system. Furthermore, MSCs show the ability to suppress natural killer cell activation and dendritic cells maturation, inhibit T cell proliferation and function, and induce T regulatory cell formation. MSCs produce factors that suppress inflammatory processes, such as PGE2, TGF-β, HLA-G5, IDO, and IL-10. These properties suggest that MSCs may affect and suppress the excessive inflammation that occurs in RA. The effect of MSCs on rheumatoid arthritis has been proven to be a suitable alternative treatment thanks to successful experiments and clinical studies.

Correlation and agreement between physical and ultrasound examination after a training session dedicated to the standardization of synovitis assessment in rheumatoid arthritis patients

ObjectivesAssessing disease activity in rheumatoid arthritis (RA) patients requires comprehensive quantification of tender and swollen joints. We aimed to evaluate the correlation and agreement between rheumatologists after a training session dedicated to the standardization of synovitis assessment and compare its performance with a reference imaging modality such as musculoskeletal ultrasonography (MSUS).MethodsIn this cross-sectional study, a total of 28 and 10 joints in RA patients were evaluated by physical examination and ultrasound (US), respectively. After participating in a training session, individual joint assessment for tenderness and swelling was performed by three rheumatologists. MSUS examination was performed separately by an experimented radiologist in a standardized manner, evaluating findings according to the Outcome Measures in Rheumatology Clinical Trial (OMERACT) guidelines.ResultsA total of 80 RA patients were included, with a mean Disease Activity Score based on 28 joints (DAS28)-ESR of 4.02. The interobserver overall agreement and concordance rate in a total of 2240 joints assessed was 81.7% (k = 0.449, p < 0.0001) for tender joints and 66% (k = 0.227, p < 0.0001) for swollen joints. The overall concordance rate was fair (Fleiss' kappa = 0.21, p = 0.027) with an overall agreement of 67.18% yet, more joints were found to be swollen by the US assessment, compared to the physical examination (43% vs 39%).ConclusionIn our study population, joint tenderness showed better interobserver agreement, correlation, and concordance rate than joint swelling. When comparing the US assessment to the physical examination, a fair overall concordance rate supports the need for the implementation of training sessions dedicated to standardization in rheumatology clinics.

Biomechanical Analysis of the Joint and Muscle Forces of the Lower Extremities in Walking of Rheumatoid Arthritis Patient

Summary. Rheumatoid arthritis (RA) is an immunomodulated, chronic inflammatory disease, accompanied by the proliferation of the inflamed synovium and destruction of the articular cartilage, which leads to the formation of contracture of lower extremities joints and disability. Understanding the values of biomechanical loads on the articular surfaces with contracture of the joints of the lower extremities in patients with RA and the muscle forces (MF) participation in this process with the formation of adaptation and compensation mechanisms can contribute to the development of new views and approaches to the tactics of therapeutic measures specific to each stage of the disease.&#x0D; Objective: to analyze the behavior of the musculoskeletal system of an RA patient in his walking pattern by calculating the forces acting in the main muscle groups and joints of the lower extremities.&#x0D; Materials and Methods. Initial data were obtained from the examination of a female patient K., who was diagnosed with stage 2 phase 3 RA with a predominant lesion of the hip and knee joints and severe pain in the left hip joint. A video system of 6 cameras, reflective markers and a force platform were used for motion capture of the walking. A simulation musculoskeletal model of the gait of the RA patient using the AnyBody Modeling System 6.0 software (Denmark) was created. Joint reaction forces (JRF) and MF were calculated.&#x0D; Results. Normal mode of loading of the lower extremities was altered to compensate for structural disorders in joints of RA patients. The peaks of vertical component of the ground reaction force (GRF) are lower compared to the normal population; the gait is static and asymmetric, sparing. MF increase in m. gluteus (maximus, medius, minimus) with increasing amplitude of movements in the frontal plane. JRF of both hips increase in all planes.&#x0D; Conclusions. Walking of RA patients with limitation of active extensions in the hip and knee joints occurs due to an increase in the amplitude of the frontal plane compensatory movements. Postural muscle imbalance increases the m. gluteus, m. biceps femoris, m. semitendinosus and m. semimembranosus MF. Other lower extremities muscles decrease their MF. The MF redistribution is compensatory and aimed to keep the RA patient in the upright position and optimize the biomechanics of walking due to less painful movements. Biomechanical overloading of the hip and knee articular surfaces can serve as a factor in maintaining the inflammatory response, the development of degenerative processes, or the further progression of arthrosis and stiffness of the joints of the lower extremities in this category of patients.

Direct tissue-sensing reprograms TLR4+ Tfh-like cells inflammatory profile in the joints of rheumatoid arthritis patients

CD4+ T cells mediate rheumatoid arthritis (RA) pathogenesis through both antibody-dependent and independent mechanisms. It remains unclear how synovial microenvironment impinges on CD4+ T cells pathogenic functions. Here, we identified a TLR4+ follicular helper T (Tfh) cell-like population present in the blood and expanded in synovial fluid. TLR4+ T cells possess a two-pronged pathogenic activity whereby direct TLR4+ engagement by endogenous ligands in the arthritic joint reprograms them from an IL-21 response, known to sponsor antibody production towards an IL-17 inflammatory program recognized to fuel tissue damage. Ex vivo, synovial fluid TLR4+ T cells produced IL-17, but not IL-21. Blocking TLR4 signaling with a specific inhibitor impaired IL-17 production in response to synovial fluid recognition. Mechanistically, we unveiled that T-cell HLA-DR regulates their TLR4 expression. TLR4+ T cells appear to uniquely reconcile an ability to promote systemic antibody production with a local synovial driven tissue damage program.

Rheumatoid arthritis activity scores in patients with and without fibromyalgia syndrome.

BACKGROUND: Fibromyalgia syndrome (FM) is a systemic disease of unknown etiology, which can cause widespread musculoskeletal pain. In patients with rheumatoid arthritis (RA), FM can cause an additional symptom burden, which can affect some variables on the RA disease activity score 28 (DAS28), a tool that evaluates 28 joints in RA patients.OBJECTIVE: Compare the results of four different versions of the DAS28 and the parameters used to determine disease activity scores in RA patients with and without FM, and determine whether there are treatment differences between RA patients with and without FM.DESIGN: Retrospective, cross-sectional.SETTING: Tertiary hospital.PATIENTS AND METHODS: We identified patients diagnosed with RA between 1 September 2016 and 1 February 2020 and identified patients with and without FM.MAIN OUTCOME MEASURES: Differences between variables in the DAS28 calculations (tender joint count [TJC], patient global assessment [PGA], and others), between patients with and without FM, and differences between patients with and without FM who were using or not using biological agents.SAMPLE SIZE: 381, including 322 females (84.5%).RESULTS: The frequency of FM in RA patients was 25.7% (89 females, 24.6%). In RA patients with FM, the TJC and PGA median values were significantly higher than in patients without FM (P<.05). The use of corticosteroids and biological therapy in patients with FM was more frequent than in patients without FM (P<.05). Compared to patients without FM, patients with FM switched treatment more often because of non-response to treatment (P=.01) Median values of the DAS28 scores (calculated by four different versions of the instrument) in RA patients with FM were higher than in patients without FM (P<.05).CONCLUSION: The presence of FM in RA patients may affect the subjective variables in different versions of DAS28 scores, causing the disease activity to score higher on the instrument, erroneously indicating worse disease than is actually present.LIMITATIONS: A single center, retrospective study.CONFLICTS OF INTEREST: None.

Positive rate and prognostic significance of the superb microvascular imaging signal in joints of rheumatoid arthritis patients in remission with normal C-reactive protein levels and erythrocyte sedimentation rates.

This study aimed to evaluate the positive rate and prognostic significance of superb microvascular imaging (SMI) in rheumatoid arthritis (RA) patients in remission with normal C-reactive protein (CRP) levels and erythrocyte sedimentation rates (ESR). The study enrolled 112 RA patients, and ultrasound (US) assessment was performed on 28 joints of each patient. The SMI signal-positive rates for each joint were: metacarpophalangeal (MCP) joints: 20.5%, wrist joints: 43.8%, metatarsophalangeal (MTP) joints: 17.0%, and other foot joints: 25.0%. Investigation of the prognostic significance of the SMI signal in each joint revealed that only in the MTP joints was the total score of the SMI signal in the patients with relapse significantly higher than that in the patients with remission (P = 0.01). Comparison of the receiver operating characteristics curves for predicting relapse showed that the area under the curve (AUC) of the MTP joints was the highest (AUC = 0.66) of the investigated joints. The optimal threshold for the total MTP SMI score was 1 (accuracy = 83.3%). Positive/negative data of the SMI signal in the MTP joints were not significantly associated with the values of conventional disease activity markers. In RA patients in remission with normal CRP and ESR levels, the percentage of positive SMI signal was highest in the wrist joints. However, the accuracy of the SMI signal for predicting relapse was greatest for the MTP joints, suggesting that US assessment of the MTP joints by SMI is useful for predicting relapse in these patients.

Autoreactivity of Peripheral Helper T Cells in the Joints of Rheumatoid Arthritis.

Autoreactive CD4 T cells are thought to play pivotal roles in the pathogenesis of rheumatoid arthritis (RA). Recently, a subset of CD4 T cells that express high levels of programmed death-1 (PD-1) but are distinct from follicular helper T cells have been identified in the joints of RA patients and named peripheral helper T (Tph) cells. Because PD-1 is expressed on T cells chronically stimulated with the Ags, we tested a hypothesis that Tph cells are the pathogenic autoreactive CD4 T cells in RA. We found that human Tph cells in RA joints produce proinflammatory effector cytokines, including IFN-γ, TNF-α, and GM-CSF, in addition to B cell-helping cytokines, such as IL-21 and CXCL13. Flow cytometric analysis showed different bias of TCR Vβ usage between PD-1high Tph cells and PD-1low/neg CD4 T cells, including Th1 cells, in the joint or memory CD4 T cells in the peripheral blood, whereas there was little difference between the latter two subsets. In line with this, deep sequencing of TCR demonstrated an overlap of expanded clones between peripheral blood memory CD4 T cells and PD-1low/neg CD4 T cells but not Tph cells in the joint. Interestingly, Tph cells preferentially exhibited autologous MLR in vitro, which required recognition of self-MHC class II and was pronounced by blocking PD-1 signaling. Taken together, these results suggest that Tph cells are the pathogenic autoreactive CD4 T cells in RA, which expand locally in the joints and are regulated by PD-1 signaling.

Periodontal inflammation and distinct inflammatory profiles in saliva and gingival crevicular fluid compared with serum and joints in rheumatoid arthritis patients.

The association of periodontitis and Porphyromonas gingivalis (Pg) with rheumatoid arthritis (RA) is incompletely understood. To gain further insights, we evaluated periodontal status, oral, serum and joint inflammatory profiles, and Pg biomarkers in RA patients. In this cross-sectional study, we evaluated 33 patients with predominantly untreated new-onset RA, 20 healthy individuals (HIs), and 20 non-RA chronic periodontitis patients. Thirteen mediators (IFN-γ, IL-10, IL-17A, IL-6, IL-8, CXCL10, TNF-α, CXCL13, IL-23, MMP-1, MMP-3, MMP-8, MMP-9) were measured in serum, synovial fluid, saliva and gingival crevicular fluid (GCF) by multiplex immunoassay. Serum Pg IgG antibodies and subgingival Pg DNA were determined. Most RA patients (91%) received routine dental care; only one currently smoked. Ten (30.3%) had periodontal health, 13 (39.4%) had gingivitis, and 10 (30.3%) had periodontitis. Th1 and innate immune responses predominated in serum. Many mediators were concentrated in joints, particularly IL-6, IL-8, and CXCL10. However, salivary and GCF profiles were more restricted, emphasizing neutrophilic inflammation (IL-8, MMP-8) and MMP-9. Compared with HI, most RA patients, regardless of periodontal status, had significantly elevated oral fluid levels of these mediators, with suppression of GCF IL-10, a pattern similar to non-RA periodontitis patients. Pg antibodies or DNA however were primarily associated with clinical periodontitis. Despite routine dental care, RA patients often had inflammation in oral fluids, but inflammatory profiles differed from serum and joints. Neutrophilic inflammatory profiles in oral fluids, regardless of periodontal status, suggests that gingival tissues are a common, and often unrecognized, site of extra-articular inflammation in RA.

Ultrasonography-detected synovitis of hand is associated with the presence of synovitis in the forefoot of patients with rheumatoid arthritis

BackgroundIn rheumatoid arthritis, forefoot disease activity can lead to joint damage, pain, and disability during weight-bearing activities; therefore, the evaluation and control of forefoot disease activity is important. We aimed to investigate an association between the prevalence of abnormalities in the forefoot based on ultrasonography (US) and the clinical and US findings related to arthritis and identify factors related to the presence of synovitis in the forefoot of RA patients. MethodsIn total, 810 metatarsophalangeal joints of 81 rheumatoid arthritis patients were examined using US. Patients were assigned to either a forefoot synovitis group (n = 22), with foot synovitis detected using US, or a non-forefoot synovitis group (n = 59). We assessed associations between clinical parameters and US finding of the hand and US finding of the metatarsophalangeal joints. ResultsThe following were significantly higher in forefoot synovitis group than in non-forefoot synovitis group: swollen joint count [P < 0.001]; Disease Activity Score 28 based on C-reactive protein [P < 0.05]; clinical disease activity index [P < 0.001]; and total Power Doppler score of the hand [P < 0.001]. Receiver-operating characteristic analysis for total Power Doppler scores of the hand to suggest the presence of synovitis in the metatarsophalangeal joints showed that a total Power Doppler score of the hand of ≥5 was associated with synovitis in the metatarsophalangeal joints, with a sensitivity of 68% and a specificity of 85% (odds ratio = 11.9). ConclusionTotal Power Doppler scores of the hand had a good valuable score for suggesting the presence of synovitis in metatarsophalangeal joints of rheumatoid arthritis patients.

Thermography in rheumatoid arthritis: a comparison with ultrasonography and clinical joint assessment

To compare thermography with ultrasonography and clinical joint assessment in patients with rheumatoid arthritis (RA). Thermography and ultrasonography (power Doppler (PD) and grey-scale (GS) joint inflammation scored semi-quantitatively 0-3) were performed sequentially on both hands of 37 RA patients. Using generalised estimating equations analysis, (a) thermographic parameters (TP) were compared between joints based on their PD and GS joint inflammation positivity/negativity status, while (b) TP and ultrasound-detected joint inflammation were compared between joints categorised by their clinical swelling/tenderness status. Comparing PD positive versus negative joints, the differences in mean values (95% CI) for TP including maximum (Tmax), minimum (Tmin), average (Tavg), and Tmax minus Tmin (Tmax-min) temperatures (in °C) were 1.37 (0.86, 1.87), 0.91 (0.46, 1.36), 1.16 (0.67, 1.64), and 0.46 (0.28, 0.64), respectively. Comparing GS positive versus negative joints, the corresponding results for thermography were 1.09 (0.67, 1.52), 0.66 (0.32, 1.00), 0.86 (0.47, 1.26), and 0.45 (0.28, 0.62), respectively. p-Values were all <0.001. The differences in mean values (95% CI) for ultrasound scores, but not for TP, were statistically significant for (a) swollen tender joints (PD: 0.67 [0.39, 0.96], p<0.001; GS: 0.86 [0.54, 1.18], p<0.001) and (b) swollen non-tender joints (PD: 0.46 [0.07, 0.84], p=0.021; GS: 0.83 [0.37, 1.29], p<0.001) when compared to non-swollen non-tender joints. Joints in RA patients have significantly higher temperature readings when ultrasound-detected joint inflammation is present. Swollen tender/non-tender joints exhibited a greater degree of ultrasound-detected joint inflammation than non-swollen non-tender joints, although their temperature readings were not significantly higher.

Mass-spectrometric identification of carbamylated proteins present in the joints of rheumatoid arthritis patients and controls

Antibodies targeting post-translationally modified proteins, such as anti-carbamylated protein antibodies (anti-CarP antibodies) are present in the sera of rheumatoid arthritis (RA) patients. These autoantibodies associate with increased risk of RA development and with severity of joint destruction. It is not known which proteins in the RA joint are recognised by anti-CarP antibodies. Therefore, we investigated the presence and identity of carbamylated proteins in the human (inflamed) joint. We obtained synovium, cartilage and synovial fluid from RA joints. Cartilage and synovium were obtained from controls. Samples were processed and used for immunohistochemistry or mass-spectrometric analysis to investigate the presence of carbamylated proteins. Anti-CarP antibody reactivity towards identified carbamylated proteins was tested by ELISA. Immunohistochemistry showed extensive staining of RA and control synovial tissue. Whole proteome analyses of the joint tissues revealed a large number of carbamylated peptidyllysine residues. We identified many carbamylated proteins in cartilage and were also able to detect carbamylation in synovial tissue and synovial fluid. Carbamylation was not exclusive to the RA joint and was also present in the joints of controls. Anti-CarP antibodies in the sera of RA patients were able to recognise the identified carbamylated proteins. We conclude that numerous carbamylated proteins are present in the RA joint. These carbamylated proteins can be recognised by anti-CarP antibodies, substantiating the notion that anti-CarP antibodies may play a role in the pathogenesis of RA.

An imbalance between blood CD4+CXCR5+Foxp3+ Tfr cells and CD4+CXCR5+Tfh cells may contribute to the immunopathogenesis of rheumatoid arthritis

BackgroundFollicular helper T (Tfh) cells are a subgroup of activated CD4+ T cells which can assist the formation and maintenance of germinal centers. Follicular regulatory T (Tfr) cells are a new class of regulatory T cells which play a major role in suppressing cells in humoral immunity. In contrast to the role of Tfh cells, Tfr cells can inhibit the function of Tfh cells and B cells. Imbalance of blood Tfr/Tfh ratio resulted in the expansion of auto-reactive B cells and auto-antibody production (). However, the effect of Tfr cells and Tfh cells in the pathogenesis of RA (rheumatoid arthritis) is unclear. The purpose of this study was to investigate the function of Tfr cells and Tfh cells in the pathogenesis of RA. MethodsWe recruited 20 patients fulfilled the the American College of Rheumatology diagnosis criteria and 20 healthy controls (HCs). The number of CD4+CXCR5+Foxp3+ Tfr cells and CD4+CXCR5+ Tfh cells in 20 RA patients were measured by flow cytometry analysis. Furthermore, the correlations between the Tfr/Tfh ratio and the characteristic clinical parameters were assessed. The serum levels of IL-21(interleukin-21), CXCL13 (chemokine (C-X-C motif) ligand 13) and TGF-β (Transforming growth factor-β) were measured by ELISA. The formation of ectopic germinal center (GC) of synovial membrane was examined by H&E staining. The transcriptional levels of CXCR5 (C-X-C chemokine receptor type 5), CXCL13, ICOS (inducible co-stimulater) and TGF-β mRNA were also analyzed. In addition, the expression of Bcl-6 (B-cell lymphoma 6), CXCR5, CXCL13 and ICOS in synovial membrane were examined by immunohistochemistry. ResultsRA patients had more Tfh cells in peripheral blood, conversely, the frequency of blood Tfr cells (p < 0.05) and the ratio of Tfr/Tfh were significantly decreased compared to healthy controls (p < 0.05, p < 0.01). Furthermore, the ratio of Tfr/Tfh was negatively correlated with values of ESR (r=-0.57, p < 0.05), RF (r=-0.5275, p < 0.001), CRP (r=-0.4486, p < 0.001), IgG (r=-0.4631, p < 0.05), DAS28 scores (r=-0.5645, p < 0.01), as well as the levels of IL-21(r=-0.7398, p < 0.01), CXCL13 (r=-0.4832, p < 0.05). However, the ratio of Tfr/Tfh was positively with the serum level of TGF-β (r=0.5115, p < 0.05). Higher mRNA expression of CXCR5, CXCL13, ICOS and lower TGF-β mRNA expression were observed in RA patients. The serum expression level of IL-21, CXCL13 was significantly increased and expression of TGF-β was significantly decreased in RA patients. Furthermore, ectopic germinal center formation and higher expression of Bcl-6, CXCR5, ICOS, CXCL13 in the synovial membrane of the joints in RA patients were observed. ConclusionsThe decreased blood CD4+CXCR5+Foxp3+ Tfr cells/CD4+CXCR5+ Tfhcells may be responsible for the immunopathogenesis of RA.