Damage In Rheumatoid Arthritis Research Articles

T2 Mapping as a New Method for Quantitative Assessment of Cartilage Damage in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is associated with damage of the articular cartilage and the periarticular bone. While imaging of bone damage has substantially improved in recent years, direct imaging of the articular cartilage of the hand joints in patients with RA is still challenging. The study used T2 mapping of the finger joints to assess cartilage damage in RA. Magnetic resonance imaging (MRI) at 3 Tesla was done in 30 patients with RA, and T2 relaxation times visualizing alteration in the collagen network and hydration of articular cartilage were mapped in 6 cartilage regions of the metacarpophalangeal (MCP) joints 2 and 3. Values were related to autoantibody status [anticitrullinated protein antibodies (ACPA), rheumatoid factor (RF)], disease duration, and disease activity as well as sex and age of the patients. T2 relaxation times could be reliably measured in the 6 regions of the MCP joints. Significantly higher relaxation times indicating more advanced cartilage alterations were observed in the metacarpal heads of ACPA-positive (p = 0.001-0.010) and RF-positive patients (p = 0.013-0.025) as well as those with longer disease duration (> 3 yrs; p = 0.028-0.043). Current disease activity, sex, and age did not influence T2 relaxation times. These data show that cartilage damage can be localized and quantified in the hand joints of patients with RA by T2 mapping. Further, ACPA and RF positivity as well as disease duration appear to be the crucial factors influencing cartilage damage.

The protease systems and their pathogenic role in juvenile idiopathic arthritis.

Numerous proteases produced by synovial cells of arthritic joints, chondrocytes, macrophages and polymorphonuclear cells have been identified as responsible for the joint damage in rheumatoid arthritis. There are few scientific contributions aimed to identify similar mechanisms in the joints of patients with juvenile idiopathic arthritis. Recently, some mechanisms emerged, triggered by the TH17 and TH1/TH17 lymphocytes, which could shed new light on unexpected pathogenic pathways of joint damage in the JIA, mainly regarding the RANK-RANKL pathway. Other novelties are linked to the mechanisms of acidification of the synovial fluid, which create a microenvironment suitable for the extracellular activity of lysosomal enzymes. Some biological drugs currently used in the therapy of JIA can interfere with these mechanisms.

Citrullination Controls Dendritic Cell Transdifferentiation into Osteoclasts.

An increased repertoire of potential osteoclast (OC) precursors could accelerate the development of bone-erosive OCs and the consequent bone damage in rheumatoid arthritis (RA). Immature dendritic cells (DCs) can develop into OCs, however, the mechanisms underlying this differentiation switch are poorly understood. We investigated whether protein citrullination and RA-specific anti-citrullinated protein Abs (ACPAs) could regulate human blood-derived DC-OC transdifferentiation. We show that plasticity toward the OC lineage correlated with peptidyl arginine deiminase (PAD) activity and protein citrullination in DCs. Citrullinated actin and vimentin were present in DCs and DC-derived OCs, and both proteins were deposited on the cell surface, colocalizing with ACPAs binding to the cells. ACPAs enhanced OC differentiation from monocyte-derived or circulating CD1c+ DCs by increasing the release of IL-8. Blocking IL-8 binding or the PAD enzymes completely abolished the stimulatory effect of ACPAs, whereas PAD inhibition reduced steady-state OC development, as well, suggesting an essential role for protein citrullination in DC-OC transdifferentiation. Protein citrullination and ACPA binding to immature DCs might thus promote differentiation plasticity toward the OC lineage, which can facilitate bone erosion in ACPA-positive RA.

DNA damage accumulation, defective chromatin organization and deficient DNA repair capacity in patients with rheumatoid arthritis

We investigated the DNA damage response and repair network in 18 patients with active rheumatoid arthritis and tested the hypothesis that treatment influences this network. A 3-fold increase of endogenous DNA damage (single- and double-strand breaks) was detected in patient-derived peripheral blood mononuclear cells than controls (alkaline comet assay; mean ± SD Olive Tail Moment of 11.8 ± 7.3 versus 4.3 ± 2.2, p < .001). Patients exhibited significantly higher formation of DNA damage (oxidative stress and abasic sites), deficient global genome repair and more condensed chromatin structure than controls. Twelve weeks following treatment, chromatin structure loosened, global genome repair capacity was restored, oxidative stress and abasic sites decreased and levels of endogenous DNA damage reached control values in all 8 patients examined. We conclude that deregulated chromatin organization, deficient DNA repair capacity and augmented formation of DNA damage, which are reversible after treatment, contribute to the accumulation of endogenous DNA damage in rheumatoid arthritis.

Predicting risk for radiographic damage in rheumatoid arthritis: comparative analysis of the multi-biomarker disease activity score and conventional measures of disease activity in multiple studies

Objective: To compare the multi-biomarker disease activity (MBDA) score with the DAS28-CRP and CRP for predicting risk of radiographic progression in patients with rheumatoid arthritis.Methods: Published studies of the MBDA score and radiographic progression with ≥100 patients per cohort were evaluated. Rates of radiographic progression over 1 year were determined across the low/moderate/high categories for MBDA score (low/moderate/high: <30, 30–44, >44), DAS28-CRP (low/moderate/high: ≤2.67, >2.67–4.09, >4.09) and CRP (low/moderate/high: ≤10, >10–30, >30 mg/L), with positive and negative predictive value (PPV, NPV) and relative risk (RR) determined for high vs. not-high (i.e. low and moderate combined) categories. Patient-level data from studies having all three measures was pooled to: (1) determine a combined RR for radiographic progression in the high vs. not-high categories for each measure; and (2) compare the predictive ability of MBDA score vs. DAS28-CRP by comparing the rates of radiographic progression observed in subgroups created by cross-classifying the high and not-high categories of each measure.Results: Five cohorts were identified for inclusion (total N=929). In each, radiographic progression was more frequent with increasing MBDA scores. Among the three cohorts with requisite data, PPVs were generally similar using categories of MBDA score, DAS28-CRP or CRP but NPVs were greater for MBDA score (93–97%) than DAS28-CRP or CRP (77–87%). RRs for radiographic progression were greater when based on categories of MBDA score than DAS28-CRP or CRP and the combined RR was greater for MBDA score (4.6, p < .0001) than DAS28-CRP (1.7, p = .02) or CRP (1.7, p = .002). For patients cross-classified by MBDA score and DAS28-CRP, high vs. not-high MBDA score significantly predicted radiographic progression independently of DAS28-CRP.Conclusions: High and not-high MBDA scores were associated with increased and low risk, respectively, for radiographic progression over one year. MBDA score was a better predictor of radiographic progression than DAS28-CRP or CRP.

Estimation of drug effect in radiographic progression for rheumatoid arthritis and psoriatic arthritis.

To demonstrate the treatment effect on structural damage in rheumatoid arthritis (RA) and psoriatic arthritis (PsA), radiographic images of hands and feet are scored according to Sharp scoring systems in randomized clinical trials. However, the quantification of such an effect is challenging because the overall mean progression is lack of clinical interpretation. This article attempts to shed a light on the statistical challenges resulted from its scoring methods and heterogeneity of the study population and proposes a mixture distribution model approach to fit radiographic progression data. With such a model, the drug effect is fully captured by the mean progression of those patients who would progress in the study period under the control treatment. The resulting regression model also lends a tool in examining prognostic factors for radiographic progression. Simulations have been carried out to evaluate the precision of the parameter estimation procedure. Using the data examples from RA and PsA, we will show that the mixture distribution approach provides a better goodness of fit and leads to a casual inference of the study drug, hence a clinically meaningful interpretation.

Myopenia is associated with joint damage in rheumatoid arthritis: a cross-sectional study.

BackgroundThe link between body mass index (BMI) and disease characteristics in rheumatoid arthritis (RA) remains controversial. Body composition (BC) has been more frequently recommended to be used instead of BMI for more accurate assessment. Our study aimed to investigate the characteristics of BC in RA patients and their associations with disease characteristics.MethodsBody composition was assessed in consecutive Chinese RA patients and control subjects by bioelectric impedance analysis. Overfat was defined by body fat percentage (BF%) as ≥25% for men and ≥35% for women. Myopenia was defined by appendicular skeletal muscle mass index (ASMI) ≤7.0 kg/m2 in men and ≤5.7 kg/m2 in women. BMI and clinical data including disease activity, function, and radiographic assessment were collected. Active disease was defined by disease activity score in 28 joints with four variables including C‐reactive protein (DAS28‐CRP) ≥2.6. Functional limitation was defined as Stanford health assessment questionnaire disability index (HAQ‐DI) >1. Radiographic joint damage (RJD) was defined as the Sharp/van der Heijde modified sharp score (mTSS) >10.ResultsThere were 457 RA patients (mean age 49.5 ± 13.1 years old with 82.7% women) and 1860 control subjects (mean age 34.3 ± 9.9 years old with 51.2% women) recruited. Comparisons of BMI and BC between RA patients and control subjects in age and gender stratification showed that lower BMI with 17.7% underweight and lower ASMI with 45.1% myopenia are the main characteristics in RA patients. Compared with those without myopenia, RA patients with myopenia had significantly higher DAS28‐CRP (median 3.5 vs. 3.0), higher HAQ‐DI (median 0.38 vs. 0.13) with higher rate of functional limitation (24.8% vs. 7.6%), and higher mTSS (median 22.3 vs. 9.0) with more RJD (71.8% vs. 45.8%) (all P < 0.001). Multivariate logistic regression analysis showed myopenia were positively associated with functional limitation (OR = 2.546, 95% CI: 1.043–6.217) and RJD (OR = 2.660, 95% CI: 1.443–4.904). All RA patients were divided into four BC subgroups according to overfat and myopenia. Those with both overfat and myopenia had the worst disease characteristics. After adjustment for confounding factors, significant additive interactions were observed between overfat and myopenia in active disease (AP = 0.528, 95% CI: 0.086–0.971), functional limitation (AP = 0.647, 95% CI: 0.356–0.937), and RJD (AP = 0.514, 95% CI: 0.139–0.890).ConclusionsMyopenia is very common in RA patients that is associated with functional limitation and joint damage in RA. Further research on the underlying mechanism and the effect of skeletal muscle mass improvement in RA management are worth exploring in the future.

Validity of the rheumatoid arthritis MRI score applied to the forefeet using the OMERACT filter: a systematic literature review

ObjectiveMRI depicts inflammation and structural damage in rheumatoid arthritis (RA). The validity of MRI-scoring of wrist-joints and metacarpophalangeal-joints according to the RA MRI score(RAMRIS) has been demonstrated. The Outcomes in...

Immune-bone interplay in the structural damage in rheumatoid arthritis.

The immune and bone systems maintain homeostasis by interacting closely with each other. Rheumatoid arthritis is a pathological consequence of their interplay, as activated T cell immune responses result in osteoclast-mediated bone erosion. An imbalance between forkhead box protein 3 (Foxp3)+ regulatory T (Treg ) cells and T helper type 17 (Th17) cells is often linked with autoimmune diseases, including arthritis. Th17 cells contribute to the bone destruction in arthritis by up-regulating receptor activator of nuclear factor kappa-Β ligand (RANKL) on synovial fibroblasts as well as inducing local inflammation. Studies on the origin of Th17 cells in inflammation have shed light on the pathogenic conversion of Foxp3+ T cells. Th17 cells converted from Foxp3+ T cells (exFoxp3 Th17 cells) comprise the most potent osteoclastogenic T cell subset in inflammatory bone loss. It has been suggested that osteoclastogenic T cells may have developed originally to stop local infection in periodontitis by inducing tooth loss. In addition, Th17 cells also contribute to the pathogenesis of arthritis by modulating antibody function. Antibodies and immune complexes have attracted considerable attention for their direct role in osteoclastogenesis, and a specific T cell subset in joints was shown to be involved in B cell antibody production. Here we summarize the recent advances in our understanding of the immune-bone interplay in the context of the bone destruction in arthritis.

Acetazolamide protects rat articular chondrocytes from IL-1β-induced apoptosis by inhibiting the activation of NF-κB signal pathway.

Because the excessive apoptosis of articular chondrocytes contributes to extracellular matrix (ECM) loss and cartilage damage in rheumatoid arthritis (RA), inhibiting chondrocyte apoptosis might be a promising strategy for RA. Aquaporin1 (AQP1) is overexpressed in RA cartilage and synovial tissues, and play a vital pathogenic role in RA development. Particularly, we previously reported that acetazolamide (AZ) as an AQP1 inhibitor suppressed secondary inflammation and promoted ECM production in cartilage of adjuvant-induced arthritis rats. Here, we investigated the antiapoptotic effect of AZ on interleukin-1β (IL-1β)-induced apoptosis, a classic in vitro model of chondrocyte apoptosis. AZ treatment could inhibit IL-1β-induced apoptosis, evidenced by increasing cell viability, relieving apoptotic nuclear morphology, decreasing apoptosis rates, and restoring mitochondrial membrane potential. Additionally, AZ reversed IL-1β-induced decrease of Bcl-2 protein and reduced IL-1β-induced increases of Bax and caspase 3 protein, accompanied by inhibiting IκBα degradation and phosphorylation in cytoplasm, reducing NF-κB p65 protein level in nucleus and preventing NF-κB p65 translocation from cytoplasm to nucleus. In conclusion, our findings indicated that AZ could effectively attenuate IL-1β-induced chondrocyte apoptosis mediated by regulating the protein levels of apoptosis-related genes and inhibiting the activation of NF-κB signal pathway, suggesting that AZ might be of potential clinical interest in RA treatment.

Anti-carbamylated protein antibodies as a new biomarker of erosive joint damage in systemic lupus erythematosus

BackgroundThe application of more sensitive imaging techniques, such as ultrasonography (US), changed the concept of non-erosive arthritis in systemic lupus erythematosus (SLE), underlining the need for biomarkers to identify patients developing the erosive phenotype. Anti-citrullinated peptide antibodies (ACPA), associated with erosions in inflammatory arthritis, have been identified in about 50% of patients with SLE with erosive arthritis. More recently, anti-carbamylated proteins antibodies (anti-CarP) have been associated with erosive damage in rheumatoid arthritis. We aimed to assess the association between anti-CarP and erosive damage in a large SLE cohort with joint involvement.MethodsWe evaluated 152 patients (male/female patients 11/141; median age 46 years, IQR 16; median disease duration 108 months, IQR 168). All patients underwent blood draw to detect rheumatoid factor (RF) and ACPA (commercial enzyme-linked immunosorbent assay (ELISA) kit), and anti-CarP (“home-made” ELISA, cutoff 340 aU/mL). The bone surfaces of the metacarpophalangeal and proximal interphalangeal joints were assessed by US: the presence of erosions was registered as a dichotomous value (0/1), obtaining a total score (0–20).ResultsThe prevalence of anti-CarP was 28.3%, similar to RF (27.6%) and significantly higher than ACPA (11.2%, p = 0.003). Erosive arthritis was identified in 25.6% of patients: this phenotype was significantly associated with anti-CarP (p = 0.004). Significant correlation between anti-CarP titer and US erosive score was observed (r = 0.2, p = 0.01).ConclusionsSignificant association was identified between anti-CarP and erosive damage in SLE-related arthritis, in terms of frequency and severity, suggesting that these antibodies can represent a biomarker of severity in patients with SLE with joint involvement.

Association of nocturnal blood pressure patterns with inflammation and central and peripheral estimates of vascular health in rheumatoid arthritis.

Predictors of adverse cardiovascular outcomes include elevated nighttime systolic blood pressure (SBP) and a non-dipping pattern. We investigated whether these factors correlate with systemic inflammation, cardiovascular risk, and markers of central and peripheral vascular damage in rheumatoid arthritis (RA), a disease characterized by excess cardiovascular risk. Twenty-four-hour ambulatory blood pressure monitoring was applied in patients and controls. Vascular assessments included measurement of arterial stiffness (pulse wave velocity) and carotid atherosclerosis (carotid intima-media thickness). Peripheral vascular resistance was estimated from impedance cardiography. Cardiovascular risk was calculated from the Framingham Heart Study. RA patients exhibited a higher prevalence of non-dipping pattern, elevated nighttime SBP and blunted dipping, compared to controls without cardiovascular comorbidities. Among RA patients, dipping levels correlated with arterial stiffness, and nighttime SBP with all vascular markers and cardiovascular risk. After adjustment for inflammation, the above associations with vascular measures were no longer significant. Plain categorization to dippers and non-dippers did not reveal any differences regarding inflammation, vascular measurements, and cardiovascular risk. However, the combination of a non-dipping profile with high nighttime SBP was accompanied by significantly higher levels of arterial stiffness and cardiovascular risk, compared to non-dippers with normal nighttime SBP; these parameters were similar between the latter group and dippers. Inflammation appears to mediate the observed associations of nighttime SBP and dipping levels with markers of subclinical vascular damage in RA patients. In these patients, the combination of a non-dipping profile with elevated nighttime SBP is accompanied by prominent subclinical vascular impairment and confers the highest cardiovascular risk.

Identification of sarilumab pharmacodynamic and predictive markers in patients with inadequate response to TNF inhibition: a biomarker substudy of the phase 3 TARGET study

IntroductionInterleukin-6 (IL-6) orchestrates formation of an inflammatory pannus, leading to joint damage in rheumatoid arthritis (RA). Sarilumab is a human monoclonal antibody blocking the IL-6Rα. In TARGET (NCT01709578), a phase...

A cross sectional study of bone and cartilage biomarkers: correlation with structural damage in rheumatoid arthritis

ABSTRACTThe aim of our study was to assess the relationship between bone and cartilage remodeling biomarkers and joint damage in Rheumatoid Arthritis (RA), and to detect whether they have the capacity to predict the progression of joint disease assessment by computed tomography (CT) erosion score. We analyzed 65 female patients with established RA in our Rheumatology Department. Serum levels of bone and cartilage markers were measured: osteocalcin (OC), N-propeptide of type I collagen (PINP), collagen type I and II, C-telopeptide (CTX I, CTX-II) and cartilage oligomeric matrix protein (COMP). Radiography of both wrist and MCP joints were available. Two expert-readers independently scored articular damage and progression using the High-resolution low dose CT scan in a blinded fashion. 65 female patients with established RA with a median age of 44 years were included. The median disease-duration was two years and the median (Disease activity score) DAS 28 score at 4.46 [2.65–7.36]. The percentage of patient with low disease activity was 13.8%, while 55.4 and 30.8% for those with moderate and high disease activity respectively. The resorption bone markers were high in active versus non-active RA. Wrist and MCP erosion scores were also associated with RA activity. Our study shows that biomarkers of bone and cartilage collagen breakdown were related to specific joint erosion in RA and could predict subsequent radiographic damage in RA. Further larger scale longitudinal studies maybe needed to confirm our data.

Intracellular apoptotic pathways: a potential target for reducing joint damage in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that results in both local and systemic bone erosion, causing significant joint deformities and functional disability. The increased number of synovial fibroblasts, inflammatory cells and osteoclasts in RA is associated with reduced apoptosis in these cells. The ability to modulate the cell proliferation or death (particularly apoptosis) is recognised for its immense therapeutic potential. Identifying new therapeutics to assist in stimulating apoptosis within the synovial joints therefore may be beneficial in reducing inflammation and bone loss in RA patients. In this review, the roles of anti-apoptotic proteins that are upregulated in RA synovial joints will be discussed in relation to their actions on bone destruction and inflammation. Evidence recently published suggests that intracellular apoptotic inhibitory molecules can be targeted by current or new therapeutics to reduce joint damage in RA. However, the therapeutics that target these molecules are yet to reach clinical trial stages. Even so it is evident that understanding the upregulation of anti-apoptotic molecules in RA is required to improve treatments currently available for RA patients.

The impact of smoking on disease activity, disability, and radiographic damage in rheumatoid arthritis: is cigarette protective?

The ojective of this study is to assess the effect of tobacco smoking on disease activity, functional ability, and joint damage in a cohort of patients with early onset rheumatoid arthritis (EORA). 129 EORA patients attending the Rheumatology Unit of the School of Medicine of the "Universidad Nacional de Colombia" and the "Clínica de Artritis y Rehabilitación" in Bogota, Colombia, were enrolled in a prospective observational cohort study with 3-year follow-up. Clinical, biological, immunogenetics, and radiographic data were analyzed. Active disease was defined as DAS28>2.6. Smoking status was assessed by self-report as "never smokers" and "ever smokers". Patient groups with different smoking status were compared for RA measures. Status as "never smokers" and "ever smokers" was reported by 81.3 and 18.7%. Ever smokers had less risk of disability (HAQ-DI≥0.5) at 36month (Ever smokers vs. Never smokers OR for HAQ≥0.5 0.25, 95% CI 0.06-0.97, p=0.04). When former smokers were excluded in analysis, we found that current smoking was also associated with less disability and less risk of active disease. The percentage of erosive disease, radiographic progression, and SvdH score were similar in all smoking categories. In Colombian patients with EORA, smoking was associated with less disease activity and disability. Radiographic joint damage progressed at an equivalent rate in smokers and non-smokers. These data suggest a more benign, or at least not deleterious clinical course in smokers with RA.

Elevated serum 14-3-3η protein may be helpful for diagnosis of early rheumatoid arthritis associated with secondary osteoporosis in Chinese population.

Osteoporosis (OP) is one of the signs of bone damage in rheumatoid arthritis (RA). The 14-3-3η protein is an inflammatory protein, which has been reported to be associated with rheumatoid arthritis (RA). This is to determine the serum levels of 14-3-3η protein, evaluate its diagnostic value in early RA, and clear out its significance in RA with secondary osteoporosis. Two hundred fifty-nine RA patients and 80 age and sex-matched healthy controls were included. Assays of serum 14-3-3η protein were done for all participants by enzyme-linked immunosorbent assay (ELISA). Dual-energy X-ray absorptiometry (DEXA) was used to measure bone mineral density (BMD). Serum 14-3-3η protein level was significantly high in RA (2.49/4.72), compared with controls (P<0.0001). Positive rate of 14-3-3η protein in RA was 97.3%, which was higher than that in controls (χ 2=276.641, P<0.0001). Serum 14-3-3η protein level in early RA was significantly higher than that in established RA (3.91/4.82 vs 2.01/3.29, Z=2.624, P<0.05). The positive rate among three groups (normal control, early RA group, established RA group) differed from each other (χ 2=131.396, P<0.0001). Results of ROC curve indicated the cutoff point of 14-3-3η protein for diagnosis of early RA was 0.879ng/ml (P<0.0001). Linear correlation analysis found that serum 14-3-3η protein positively correlated with VAS and HAQ (P<0.0001), negatively correlated with BMD at lumbar spine and femur in RA (P<0.0001). Serum 14-3-3η protein among groups of bone mass normal (2.73/3.79), osteopenia (3.15/4.86), and osteoporosis (6.34/6.42) was different in early RA patients (χ 2=7.974, P<0.05). Serum 14-3-3η protein levels increase significantly in patients with RA (especially in early RA). There are close relationships between serum 14-3-3η protein and clinical symptoms and osteoporosis in patients with RA.

Patterns of circulatory and peripheral blood mononuclear cytokines in rheumatoid arthritis.

An imbalance in pro- and anti-inflammatory cytokines is suggested to contribute to tissue damage in rheumatoid arthritis (RA). This study was aimed at investigating profiles of cytokines in circulation and cytokines produced by mitogen-stimulated peripheral blood mononuclear cells (PBMC) in RA patients and healthy controls, and to explore correlations of cytokines with disease activity. Our aim was to identify patterns of cytokine expression as possible indicators of disease activity. Levels of plasma cytokines and PBMC-secreted cytokines were estimated in 26 female RA patients and 28 controls. Five pro-inflammatory cytokines (IFN-γ, TNF-α, IL-6, IL-17, IL-12) and three anti-inflammatory cytokines (IL-4, IL-10, IL-13) were assayed in a multiplex ELISA. RA patients had significantly higher plasma levels of TNF-α, IL-12, and IL-4 compared to healthy controls. On the other hand, mitogen-activated PBMC secreted significantly higher levels of the pro-inflammatory cytokines TNF-α, IFN-γ, IL-17, and IL-12, but lower levels of the anti-inflammatory cytokine IL-10 in RA compared to healthy subjects. The ratios TNF-α/IL-10, IFN-γ/IL-10, IL-17/IL-10, IL-12/IL-10, and IFN-γ/IL-13 were significantly higher in RA patients compared to healthy controls. The range and expression of cytokines were higher in PBMC than in the plasma in all the groups studied. Multivariate pattern analysis of eight cytokines revealed a prediction accuracy of 69% in differentiating RA patients from healthy controls, and of 73% in classifying patients as in remission or active RA. Our data suggest that it is worthwhile to explore ratios of pro- to anti-inflammatory cytokines produced by mitogen-stimulated PBMC in RA, and the use of multivariate cytokine pattern and algorithms for better delineation of this condition.

Cellular and molecular pathways of structural damage in rheumatoid arthritis.

Structural damage of cartilage and bone tissue is a hallmark of rheumatoid arthritis (RA). The resulting joint destruction constitutes one of the major disease consequences for patients and creates a significant burden for the society. The main cells executing bone and cartilage degradation are osteoclasts and fibroblast-like synoviocytes, respectively. The function of both cell types is heavily influenced by the immune system. In the last decades, research has identified several mediators of structural damage, ranging from infiltrating immune cells and inflammatory cytokines to autoantibodies. These factors result in an inflammatory milieu in the affected joints which leads to an increased development and function of osteoclasts and the transformation of fibroblast-like synoviocytes towards a highly migratory and destructive phenotype. In addition, repair mechanisms mediated by osteoblasts and chondrocytes are strongly impaired by the presence of pro-inflammatory cytokines. This article will review the current knowledge on the mechanisms of joint inflammation and the destruction of bone and cartilage.

Establishment of an in vitro three-dimensional model for cartilage damage in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to progressive joint destruction. To further understand the process of rheumatoid cartilage damage, an in vitro model consisting of an interactive tri-culture of synovial fibroblasts (SFs), LPS-stimulated macrophages and a primary chondrocyte-based tissue-engineered construct was established. The tissue-engineered construct has a composition similar to that of human cartilage, which is rich in collagen type II and proteoglycans. Data generated from this model revealed that healthy chondrocytes were activated in the presence of SFs and macrophages. The activated chondrocytes subsequently displayed aberrant behaviours as seen in a disease state such as increased apoptosis, decreased gene expression for matrix components such as type II collagen and aggrecan, increased gene expression for tissue-degrading enzymes (MMP-1, -3, -13 and ADAMTS-4, -5), and upregulation of inflammatory mediator gene expression (TNF-α, IL-1β, IL-6 and IKBKB). Additionally, the inclusion of SFs and macrophages in the model enabled both cell types to more closely replicate an in vivo role in mediating cartilage destruction. This is evidenced by extensive matrix loss, detected in the model through immunostaining and biochemical analysis. Subsequent drug treatment with celecoxib has shown that the model was able to respond to the therapeutic effects of this drug by reversing cartilage damage. This study showed that the model was able to recapitulate certain pathological features of an RA cartilage. If properly validated, this model potentially can be used for screening new therapeutic drugs and strategies, thereby contributing to the improvement of anti-rheumatic treatment. Copyright © 2017 John Wiley & Sons, Ltd.