Radiographic Joint Destruction Research Articles

Cartilage destruction in early rheumatoid arthritis patients correlates with CD21−/low double-negative B cells

BackgroundInvolvement of B cells in the pathogenesis of rheumatoid arthritis (RA) is supported by the presence of disease-specific autoantibodies and the efficacy of treatment directed against B cells. B cells that express low levels of or lack the B cell receptor (BCR) co-receptor CD21, CD21−/low B cells, have been linked to autoimmune diseases, including RA. In this study, we characterized the CD21+ and CD21−/low B cell subsets in newly diagnosed, early RA (eRA) patients and investigated whether any of the B cell subsets were associated with autoantibody status, disease activity and/or joint destruction.MethodsSeventy-six eRA patients and 28 age- and sex-matched healthy donors were recruited. Multiple clinical parameters were assessed, including disease activity and radiographic joint destruction. B cell subsets were analysed in peripheral blood (PB) and synovial fluid (SF) using flow cytometry.ResultsCompared to healthy donors, the eRA patients displayed an elevated frequency of naïve CD21+ B cells in PB. Amongst memory B cells, eRA patients had lower frequencies of the CD21+CD27+ subsets and CD21−/low CD27+IgD+ subset. The only B cell subset found to associate with clinical factors was the CD21−/low double-negative (DN, CD27−IgD−) cell population, linked with the joint space narrowing score, i.e. cartilage destruction. Moreover, in SF from patients with established RA, the CD21−/low DN B cells were expanded and these cells expressed receptor activator of the nuclear factor κB ligand (RANKL).ConclusionsCartilage destruction in eRA patients was associated with an expanded proportion of CD21−/low DN B cells in PB. The subset was also expanded in SF from established RA patients and expressed RANKL. Taken together, our results suggest a role for CD21−/low DN in RA pathogenesis.

A genome-wide association study identifying the SNPs predictive of rapid joint destruction in patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is a common chronic autoimmune disease leading to joint destruction. The aim of the present study was to identify the genomic factors predictive of susceptibility to joint destruction in patients with RA by performing a genome-wide association study of genetic variants, including single nucleotide polymorphisms (SNPs). The study sample included 228 patients with a diagnosis of RA in the past 5 years. Patients were classified into rapid (total Sharp score/years of RA, ≥50) and slow (total Sharp score/years of RA, <50) joint destruction groups for analysis. The association between the genome-wide SNP analysis and joint destruction was evaluated. The following SNPs were strongly associated with rapid radiographic joint destruction: rs2295926 (P<1x10-7), belonging to the N-acetylgalactosaminyltransferase 12 (GALNT12) gene and rs11958855 (P<1x10-6), belonging to the KCNN2 gene (associated with the potassium calcium-activated channel subfamily). The identification of genetic predictors of rapid joint destruction in RA (GALNT12 and KCNN2) may provide information regarding potential therapeutic targets, and this information may be used to assist in the management RA disease progression, thereby improving the functional outcomes for patients.

Different Original and Biosimilar TNF Inhibitors Similarly Reduce Joint Destruction in Rheumatoid Arthritis-A Network Meta-Analysis of 36 Randomized Controlled Trials.

The effect of five approved tumour necrosis factor inhibitors (TNFi: infliximab, etanercept, adalimumab, certolizumab, and golimumab) on joint destruction in rheumatoid arthritis (RA) have been compared versus methotrexate (MTX) in randomized controlled trials (RCTs) but have not been compared directly to each other or to an otherwise untreated placebo control. The present analysis compares effects of standard doses, high doses, and low doses of TNFis on radiographic joint destruction in RA and relate these effects to MTX and placebo by means of a Bayesian network meta-analysis. We identified 31 RCTs of the effect of TNFis on joint destruction and 5 RCTs with controls, which indirectly could link otherwise untreated placebo controls to the TNFi treatments in the network. The previously untested comparison with placebo was performed to estimate not only the effect relative to another drug, but also the absolute attainable effect. Compared to placebo there was a highly significant inhibitory effect on joint destruction of infliximab, etanercept, adalimumab, certolizumab, and golimumab, which was about 0.9% per year as monotherapy and about 1.2% per year when combined with MTX. Although significantly better than MTX and placebo, golimumab seemed inferior to the remaining TNFis. There was no difference between original reference drugs (Remicade, Enbrel) and the almost identical copy drugs (biosimilars).

Activation of the Peroxisome Proliferator-Activated Receptor γ Coactivator 1β/NFATc1 Pathway in Circulating Osteoclast Precursors Associated With Bone Destruction in Rheumatoid Arthritis.

ObjectiveActivation of osteoclastogenesis at the bone site in rheumatoid arthritis (RA) is well established. The mechanisms by which circulating osteoclast precursors contribute are still unclear. Peroxisome proliferator–activated receptor γ coactivator 1β (PGC‐1β) is implicated in transcriptional regulation of osteoclastogenesis in mouse models. This study was undertaken to investigate the contribution of PGC‐1β to circulating osteoclast precursors and its link to bone destruction in RA.MethodsPGC‐1β expression in RA peripheral blood CD14+ monocytes was increased and showed correlation with joint destruction shown on radiographs. Cells from RA patients or healthy controls were transfected with a lentivirus vector for PGC‐1β gene silencing or overexpression and cultured with macrophage colony‐stimulating factor and RANKL. Bone resorption activity, bone‐degrading enzymes, and signaling molecules were measured in these mature osteoclasts.ResultsIncreased nuclear accumulation of PGC‐1β was observed in RA peripheral blood CD14+ monocytes, and these cells had stronger osteoclastogenesis than in healthy controls. PGC‐1β protein expression was positively correlated with radiographic joint destruction (r = 0.396–0.413; all P < 0.05). PGC‐1β knockdown suppressed (51–82% reduction) the expression of cathepsin K, tartrate‐resistant acid phosphatase (TRAP), and matrix metalloproteinase 9 (MMP‐9), as well as osteoclast differentiation and bone resorption activity. Conversely, PGC‐1β overexpression increased these markers (by 1.5–1.8‐fold) and osteoclastogenesis. VIVIT, an inhibitor of NFATc1 activation, inhibited the effect of overexpressed PGC‐1β by reducing cathepsin K, TRAP, and MMP‐9 expression. Chromatin immunoprecipitation assay and dual‐luciferase reporter gene assay showed PGC‐1β bound to NFATc1 promoter, leading to transcriptional activation.ConclusionActivation of the PGC‐1β/NFATc1 pathway in circulating osteoclast precursors was associated with bone destruction in RA. This may represent a new treatment target.

Development and validation of a deep-learning model for scoring of radiographic finger joint destruction in rheumatoid arthritis.

ObjectiveThe purpose of this research was to develop a deep-learning model to assess radiographic finger joint destruction in RA.MethodsThe model comprises two steps: a joint-detection step and a joint-evaluation step. Among 216 radiographs of 108 patients with RA, 186 radiographs were assigned to the training/validation dataset and 30 to the test dataset. In the training/validation dataset, images of PIP joints, the IP joint of the thumb or MCP joints were manually clipped and scored for joint space narrowing (JSN) and bone erosion by clinicians, and then these images were augmented. As a result, 11 160 images were used to train and validate a deep convolutional neural network for joint evaluation. Three thousand seven hundred and twenty selected images were used to train machine learning for joint detection. These steps were combined as the assessment model for radiographic finger joint destruction. Performance of the model was examined using the test dataset, which was not included in the training/validation process, by comparing the scores assigned by the model and clinicians.ResultsThe model detected PIP joints, the IP joint of the thumb and MCP joints with a sensitivity of 95.3% and assigned scores for JSN and erosion. Accuracy (percentage of exact agreement) reached 49.3–65.4% for JSN and 70.6–74.1% for erosion. The correlation coefficient between scores by the model and clinicians per image was 0.72–0.88 for JSN and 0.54–0.75 for erosion.ConclusionImage processing with the trained convolutional neural network model is promising to assess radiographs in RA.

Impact of switching oral bisphosphonates to denosumab or daily teriparatide on the progression of radiographic joint destruction in patients with biologic-naïve rheumatoid arthritis.

The aim of this study was to clarify the effects of switching oral bisphosphonates (BPs) to denosumab (DMAb) or daily teriparatide (TPTD) on the progression of radiographic joint destruction in patients with biologic-naïve rheumatoid arthritis (RA). A retrospective, case-controlled study involving 90 female RA patients (mean age 68.2years, 96.7% postmenopausal, disease activity score assessing 28 joints with CRP (DAS28-CRP) 2.4, methotrexate treatment 81.1%, prednisolone treatment 68.9%, and prior BP treatment 44.8months), who were allocated depending on each patient's and physician's wishes, to (1) the BP-continue group (n = 30), (2) the switch-to-DMAb group (n = 30), or (3) the switch-to-TPTD group (n = 30), was conducted. Patients were retrospectively selected to minimize the difference of possible clinical backgrounds that may affect the joint destruction of RA. The primary endpoint was to clarify the change of the modified total Sharp score (mTSS) from baseline to 12months. After 12months, the mean changes of the modified Sharp erosion score were significantly lower in the switch-to-DMAb group (0.2 ± 0.1; mean ± standard error) than in the switch-to-TPTD group (1.3 ± 0.5; P < 0.05), and mTSS was significantly lower in the switch-to-DMAb group (0.3 ± 0.2) than in the BP-continue group (1.0 ± 0.3; P <0.05) and the switch-to-TPTD group (1.7 ± 0.6; P < 0.05). The logistic regression analysis showed that mTSS changes were significantly associated with the percent changes of TRACP-5b at 6months (β = 0.30, 95% CI = 0.002-0.016; P <0.01). Changes of systemic bone turnover induced by switching BPs to DMAb or TPTD may affect not only systemic bone mass, but also local joint destruction, and its clinical relevance should be considered comprehensively.

Association of polymorphisms of HLA-DRB1 and TNF-308 G/A with radiographic joint damage in patients with early rheumatoid arthritis with high inflammatory activity, treated according to the principle of "Treat to target" (REMARKA study).

To clarify the association between HLA-DRB1 and TNFα (-308G&gt;A) genes polymorphism and joint destruction/further progression during 12 months of the follow-up period (FUP) in patients with early (&lt;6 months), active, predominantly antibodies to cyclic citrullinated peptide (ACCP) and rheumatoid factor (RF)-positive rheumatoid arthritis (RA) treated according to &quot;Treat to target&quot; strategy. The study included 85 patients with early RA and duration of symptoms &lt;6 months. All patients were initially assigned to subcutaneous methotrexate (MTX) with rapid dose escalation to 20-25 mg/week. Combination MTX + biological therapy, mainly adalimumab, was used when MTX was ineffective. Joint destruction was assessed by Sharp-Van der Heijde modification scoring method at baseline and after 12 months FUP. Real time polymerase chain reaction (PCR-RT) was used for TNFα gene polymorphism (-308G&gt;A) genotyping. Low resolution PCR-RT with subsequent sequence-based typing of *04 were performed to study HLA-DRB1 gene polymorphism. The HLA-DRB1*01, *04:01, *04:04, *04:05, *04:08, *10 alleles were categorized as SE+ (Shared Epitope) alleles. As for TNFα gene polymorphism, it was demonstrated that the number of narrowings and total Sharp score values were almost twice as high at baseline in GG genotype carriers as compared to GA genotype carriers (р&lt;0,005, and р&lt;0,004 respectively). Similar association was found after 12mo FUP. The progression of joint destruction, assessed as the change (∆) in the number of erosions, joint space narrowings and the total score, was statistically significantly associated with HLA-DRB1*(SE) genotypes: the carriers of SE (SE+/SE+) double-dose had more advanced progression as compared to (SE+/SE-)/(SE-/SE-) carriers (р&lt;0,028, р&lt;0,019, р&lt;0,035 respectively). Our data suggest that HLA-DRB1 (SE+) gene and TNFα (-308G&gt;A) polymorphisms are associated with the progression of radiographic joint destruction in early, active RA patients managed according to &quot;Treat to target&quot; stratagy.

Syndrome of Remitting Seronegative Symmetrical Synovitis with Pitting Edema (RS3PE): A Case Report and Review of the Literature

Remitting Seronegative Symmetrical Synovitiswith Pitting Edema (RS3PE) is a rare clinical entitythat is easilymissed due to lack of knowledge. Syndrome is characterized by suddenonset of edema with swellingon thedorsum of thehandsand by synovitis. Serological tests are negative and radiographic joint destruction does not occurs. Etiology of RS3PE syndrome is not known. It can occur as an idiopathic phenomenon, but also is in association with rheumatic diseases. In addition, several reports have described RS3PE as a paraneoplasticsyndrome can occuron concomitantly with both hematological and solidmalignancies. Because of this clinical association, it is not very easy to diagnose this syndrome. We discuss a case of RS3PE where the patient presented with acute onset polyarthritis and pitting edema of the extremities without an underlying systemic cause. Patient showed dramatic response with low dose steroid therapy.

Computerised versus conventional methodology of radiographic joint destruction assessment in early rheumatoid arthritis

ObjectivesTo compare computerised and conventional methodology of radiographic joint destruction assessment in early rheumatoid arthritis (RA).MethodsWe investigated the contribution of the 3rd-to-5th carpometacarpal joints (CMC3-5, which are excluded in computerised...

Genetic Factors for the Severity of ACPA-negative Rheumatoid Arthritis in 2 Cohorts of Early Disease: A Genome-wide Study.

Rheumatoid arthritis (RA) that is negative for anticitrullinated protein antibodies (ACPA) is a subentity of RA, characterized by less severe disease. At the individual level, however, considerable differences in the severity of joint destruction occur. We performed a study on genetic factors underlying the differences in joint destruction in ACPA-negative patients. A genome-wide association study was done with 262 ACPA-negative patients with early RA included in the Leiden Early Arthritis Clinic and related to radiographic joint destruction over 7 years. Significant single-nucleotide polymorphisms (SNP) were evaluated for association with progression of radiographic joint destruction in 253 ACPA-negative patients with early RA included in the Better Anti-Rheumatic Farmaco Therapy (BARFOT) study. According to the Bonferroni correction of the number of tested SNP, the threshold for significance was p < 2 × 10(-7) in phase 1 and 0.0045 in phase 2. In both cohorts, joint destruction was measured by Sharp/van der Heijde method with good reproducibility. Thirty-three SNP associated with severity of joint destruction (p < 2 × 10(-7)) in phase 1. In phase 2, rs2833522 (p = 0.0049) showed borderline significance. A combined analysis of both the Leiden and BARFOT datasets of rs2833522 confirmed this association with joint destruction (p = 3.57 × 10(-9)); the minor allele (A) associated with more severe damage (for instance, after 7 yrs followup, patients carrying AA had 1.22 times more joint damage compared to patients carrying AG and 1.50 times more joint damage than patients carrying GG). In silico analysis using the ENCODE and Ensembl databases showed presence of H3K4me3 histone mark, transcription factors, and long noncoding RNA in the region of rs2833522, an intergenic SNP located between HUNK and SCAF4. Rs2833522 might be associated with the severity of joint destruction in ACPA-negative RA.

FRI0018 Radiographic Joint Damage and Mortality in Rheumatoid Arthritis Patients: 20 Years Survival Study

BackgroundRheumatoid arthritis (RA) is a chronic inflammatory disease associated with increased mortality and reduced life expectancy compared with the general population. This mortality gap has increased in the last years...

THU0502 Ad Promotes the Differentiation of TH17 Cell and Exacerbates Disease Progression in CIA Model via Enhancing TH17 Response

BackgroundAdiponectin (AD), produced prevalently by adipose tissues, has suggested playing a significant role in chronic inflammation and immune response. The relation between AD and rheumatoid arthritis (RA) has been a...

AB0091 Decreased expression of bcl6 in peripheral blood monocytes from rheumatoid arthritis patients

BackgroundRheumatoid arthritis (RA) is a common chronic inflammatory disease which could lead to joint destruction and disability. Osteoclasts are essential for bone resorption and play key roles in joint destruction...

THU0020 Serum pyridinoline levels predict the severity of future joint destruction in rheumatoid arthritis

BackgroundThe identification of early rheumatoid arthritis (RA) patients that will develop a progressive destructive disease course is important to enable adjusting the treatment strategy to individual patients’ prospects. Previous studies...

OP0021 Genetic Factors for the Severity of ACPA-Negative Rheumatoid Arthritis in Two Cohorts of Early Disease: A Genome-Wide Study

BackgroundACPA-negative and ACPA-positive Rheumatoid Arthritis (RA) are increasingly regarded as separate clinical entities. Although ACPA-negative patients have a less severe disease course at group level, considerable inter-individual differences in the...

THU0402 Effects of Raloxifene for Prevention of Bone Loss in Rheumatoid Arthritis Women Receiving Long-Term Glucocorticoids

BackgroundThe inflammatory disease, oestrogen deficiency and glucocorticoids contribute to the generalized bone loss seen in postmenopausal rheumatoid arthritis (RA).ObjectivesThe aim of this study is to prove that raloxifene treatment is...

SAT0087 Does the season of symptom onset influence the severity of radiographic joint destruction in rheumatoid arthritis?

BackgroundSeveral season-associated environmental factors have been related to the onset of rheumatoid arthritis (RA) and the severity of joint complaints. A recent study on early arthritis demonstrated that onset of...

Patients with Very Early-onset Systemic Juvenile Idiopathic Arthritis Exhibit More Inflammatory Features and a Worse Outcome

Systemic juvenile idiopathic arthritis (SJIA) frequently leads to disability and damage. Predictive factors for a poor outcome include persistent systemic features and younger age at onset. We describe and analyze disease features in patients with early-onset (EO) SJIA (disease onset before age 18 mo) and compare them to patients with later-onset (LO) disease. Clinical features at onset, activity measures (occurrence of macrophage activation syndrome, remission), and outcome measures for disability [Childhood Health Assessment Questionnaire (CHAQ) ≥ 0.5] and damage [radiographic joint destruction, Juvenile Arthritis Damage Index (JADI) score, growth retardation] observed during followup were analyzed retrospectively in patients with SJIA followed for ≥ 3 years since disease onset. In total 132 patients were included. SJIA started at age ≤ 18 months in 19 (14%) patients and at a later age in 113 (86%) children. At onset, serositis (p < 0.01) and hepatomegaly (p < 0.05) were more frequent in EO patients, who also exhibited lower hemoglobin levels (p < 0.03) and higher platelet counts (p < 0.03) than patients with LO. Macrophage activation syndrome occurred in 20 patients (11 EO and 9 LO; p < 0.0001). Remission was achieved by 49 patients (37%; 4 EO and 45 LO). At last visit, destructive hip disease (p < 0.04), growth retardation (p < 0.01), radiographic damage (p < 0.02), and disability (p < 0.04) were more frequent in patients with EO disease, who had higher JADI scores (p < 0.003). Patients with EO exhibited a more aggressive and destructive disease course than patients with LO SJIA.

Upregulation of tumor necrosis factor receptor-associated factor 6 correlated with synovitis severity in rheumatoid arthritis

IntroductionRheumatoid arthritis (RA) is a chronic inflammatory disease leading to joint destruction and disability. Focal bone erosion is due to excess bone resorption of osteoclasts. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is one of the critical mediators both in inflammatory signal pathway and differentiation and resorption activity of osteoclasts. Here we aimed to investigate TRAF6 expression in RA synovium and its correlation with histological synovitis severity and radiological joint destruction in RA.MethodsSynovitis score was determined in needle biopsied synovium from 44 patients with active RA. Synovium from nine patients with osteoarthritis (OA) and seven with orthopedic arthropathies (Orth.A) were enrolled as "less inflamed" disease controls. Serial sections were stained immunohistochemically for TRAF6 as well as CD68 (macrophage), CD3 (T cell), CD20 (B cell), CD38 (plasmocyte), CD79a (B lineage cells from pre-B cell to plasmocyte stage), and CD34 (endothelial cell). Double immunofluorescence staining of TRAF6 and CD68 were tested. Densities of positive staining cells were determined and correlated with histological disease activity (synovitis score) and radiographic joint destruction (Sharp score).ResultsTRAF6 expression was found in the intimal and subintimal area of RA synovium, with intense staining found in the endochylema and nucleus of intimal synoviocytes and subintimal inflammatory cells. Double immunofluorescence staining showed TRAF6 was expressed in most of the intimal cells and obviously expressed in CD68+ cells and some other CD68- cells in subintimal area. Synovial TRAF6 was significantly over-expressed in the RA group compared with the OA and Orth.A group (2.53 ± 0.94 vs. 0.72 ± 0.44 and 0.71 ± 0.49, P < 0.0001). Synovial TRAF6 expression in RA correlated significantly with synovitis score (r = 0.412, P = 0.006), as well as the inflammatory cell infiltration (r = 0.367, P = 0.014). Significant correlation was detected between synovial TRAF6 expression and intimal CD68+ cells, as well as the cell density of subintimal CD68+ cells, CD3+ cells, CD20+ cells, CD38+ cells, and CD79a+ cells (all P < 0.05).ConclusionsElevated synovial TRAF6 expression correlated with synovitis severity and CD68+ cell density in RA. It is, therefore, hypothesized that synovial TRAF6 is involved in the pathogenesis of synovial inflammation and osteoclast differentiation in RA.

Synovial Infiltration with CD79a-positive B Cells, But Not Other B Cell Lineage Markers, Correlates with Joint Destruction in Rheumatoid Arthritis

The efficacy of B cell depletion in the treatment of patients with rheumatoid arthritis (RA) has revitalized interest in the pathogenic role(s) of B cells in RA. We evaluated the distribution of synovial B lineage cells and their correlation with histologic disease activity and joint destruction in RA. Synovial tissue samples were obtained by closed-needle biopsy from 69 Chinese patients with active RA, from 14 patients with osteoarthritis (OA), and from 15 with orthopedic arthropathies (OrthA) as disease controls. Serial tissue sections were stained immunohistochemically for CD79a (pro-B cell to plasma cell), CD20 (B cells), CD38 (plasma cells), CD21 (follicular dendritic cells), CD68 (macrophages), CD3 (T cells), and CD34 (endothelial cells). Densities of positive-staining cells were determined and correlated with histologic disease activity (Krenn 3-component synovitis score) and radiographic joint destruction (Sharp score). Mean sublining CD79a-positive cell density was significantly higher in RA than in OA (p <0.001) or OrthA (p = 0.003). Receiver operating characteristic curve analysis showed that CD79a-positive cell density differentiated RA well from OA [area under the curve (AUC) = 0.79] or OrthA (AUC = 0.75). Spearman's rank order correlation showed significant correlations between sublining CD79a-positive cell density and the synovitis score (r = 0.714, p < 0.001), total Sharp score (r = 0.490, p < 0.001), and the erosion subscore (r = 0.545, p < 0.001), as well as the joint space narrowing subscore (r = 0.468, p = 0.001) in RA. Synovial CD79a-positive B cells may be a helpful biomarker for histologic disease activity in RA and may be involved in the pathogenesis of joint destruction in RA.