Joint Damage In Rheumatoid Arthritis Research Articles

THU0469 Genetic Variants in IL-6, IL-10, C5-TRAF1 and FCRL3 and Progression of Joint Damage in Rheumatoid Arthritis; A Study on Six Cohorts

BackgroundThanks to the introduction of novel treatments and up-to-date treatment strategies, the severity of joint destruction in rheumatoid arthritis (RA) has decreased considerably. Nonetheless, in daily clinical practice radiographic progression...

THU0515 C5orf30 A Novel Regulator of Tissue Damage in Rheumatoid Arthritis

BackgroundA recent genome wide association study identified the variant rs26232 in the first intron of the uncharacterized gene, C5orf30, as a rheumatoid arthritis (RA) susceptibility variant1. In addition, it has...

SAT0179 Mri Pattern of Arthritis in Sle: A Comparative Study with Rheumatoid Arthritis and Healthy Subjects

BackgroundArthritis in systemic lupus erythematosus (SLE) is traditionally considered mild and non erosive, however chronic pain, hand disability and deformities are frequently reported by patients with longstanding disease. Magnetic resonance...

Infecciones en pacientes con artritis reumatoide: medicamentos moduladores de la respuesta biológica versus fármacos modificadores de la enfermedad. Seguimiento a un año

BackgroundDisease modifying anti-rheumatic drugs and biological disease modifying drugs are used to control inflammation and prevent progression of joint damage in rheumatoid arthritis. It is still controversial whether these drugs increase the incidence of infection in this disease. MethodsA retrospective cohort study was conducted on a population sample of 383 inpatients and outpatients from a university hospital and referral rheumatology tertiary hospital complex in northwestern Colombia. They were classified according to American College of Rheumatology 1987 classification criteria, with 83 in the biological therapy group, and 300 in the disease modifying antirheumatic drugs group, in order to establish the incidence and risk factors for serious and non-serious infections at 12 months follow-up. ResultsThe majority were females (85%). The biological therapy group presented a greater risk for non-serious [HR 1.73 (95% CI 1.07–2.77; P=.023)] and serious infections [HR 2.56 (95% CI 1.09–6.01; P=.030)]. This finding remained when adjusting for other variables associated with infection (number of disease modifying antirheumatic drugs received, methotrexate, leflunomide and steroids use, diabetes mellitus), with HR for non-serious infection [(1.67, 95% CI 1.05–2.70; P=.030)], and HR for serious infection [(2.67, 95% CI 1.12–6.34; P=.026)]. Chronic lung disease [HR 5.11 (95% CI 1.18–22.08; P=.029)] was an additional risk factor for serious infections. ConclusionsBiological therapy increases the risk of serious and non-serious infections at 12 months, compared to disease modifying drugs, in a group of patients with rheumatoid arthritis. The risk of serious infections also increases with the presence of chronic lung disease

Predicting the severity of joint damage in rheumatoid arthritis; the contribution of genetic factors

BackgroundThe severity of radiologic progression is variable between rheumatoid arthritis (RA) patients. Recently, several genetic severity variants have been identified and were replicated, these belong to 12 loci. This study...

Induction of bone loss in DBA/1J mice immunized with citrullinated autologous mouse type II collagen in the absence of adjuvant

Joint damage in rheumatoid arthritis (RA) is characterized by cartilage and bone loss resulting in pain, deformity, and loss of joint function. Anti-citrullinated protein antibody (ACPA) has been implicated in RA pathogenesis and predicts radiographical joint damage and clinical severity. Therefore, the purpose of this study was to assess bone loss by micro-CT, histological joint damage, and ACPA levels using a mouse model of RA. Arthritis was induced by immunizing DBA/1 mice with autologous citrullinated type II mouse collagen (CIT-CII) weekly for 4 weeks. Mice immunized with autologous CII served as controls. At week 5, mice were killed, ACPA levels determined, and micro-CT performed to quantitatively analyze bone damage. Micro-CT analysis revealed significant loss of bone density, volume, and surface (p < 0.05) in bone peripheral to the inflamed joints of CIT-CII animals compared to CII controls. Histological staining demonstrated cartilage, proteoglycan, joint collagen, and bone collagen loss in the CIT-CII group compared to CII. Serum ACPA levels were increased (p = 0.03) in the CIT-CII group compared to CII, and these levels were inversely correlated with bone quantity and quality. In this study, we demonstrate that immunization with autologous CIT-CII initiates significant systemic bone and articular cartilage loss in the absence of adjuvant. Significant inverse correlations of circulating ACPA and bone quality/quantity were present. ACPA levels predict the adverse bone morphological changes in this model of early RA.

Brief Report: Association of Genetic Variants in the IL4 and IL4R Genes With the Severity of Joint Damage in Rheumatoid Arthritis: A Study in Seven Cohorts

ObjectiveThe progression of joint destruction in rheumatoid arthritis (RA) is determined by genetic factors. Changes in IL4 and IL4R genes have been associated with RA severity, but this finding has not been replicated. This study was undertaken to investigate the association between IL4‐ and IL4R‐tagging single‐nucleotide polymorphisms (SNPs) and the progression rate of joint damage in RA in a multicohort candidate gene study.MethodsIL4‐ and IL4R‐tagging SNPs (n = 8 and 39, respectively) were genotyped in 600 RA patients for whom 2,846 sets of radiographs of the hands and feet were obtained during 7 years of followup. Subsequently, SNPs significantly associated with the progression of joint damage were genotyped and studied in relation to 3,415 radiographs of 1,953 RA patients; these included data sets from Groningen (The Netherlands), Lund (Sweden), Sheffield (UK), the North American Rheumatoid Arthritis Consortium (US), Wichita (US), and the National Data Bank (US). The relative increase in progression rate per year in the presence of a genotype was determined in each cohort. An inverse variance weighting meta‐analysis was performed on the 6 data sets that together formed the replication phase.ResultsIn the discovery phase, none of the IL4 SNPs and 7 of the IL4R SNPs were significantly associated with the joint damage progression rate. In the replication phase, 2 SNPs in the IL4R gene were significantly associated with the joint damage progression rate (rs1805011 [P = 0.02] and rs1119132 [P = 0.001]).ConclusionGenetic variants in IL4R were identified, and their association with the progression rate of joint damage in RA was independently replicated.

Missing Radiographic Data Handling in Randomized Clinical Trials in Rheumatoid Arthritis

In recent years, there has been increasing interest in compounds that have potential to slow down the structural joint damage in rheumatoid arthritis (RA) patients. Radiographs are instrumental in assessing structure damage in RA. Radiographic analyses results have become essential in establishing a “delay in structural progression” claim in newly developed agents for the treatment of RA. It is well known that the radiographic progression data generally follow a nonnormal distribution that is loaded with excessive zeros. A special concern about the radiographic data analyses is the handling of the seemingly high rate of missing values due to dropout or unreadable images. There are no uniform ways to handle missing radiographic data, and such data usually show considerable sensitivity to the imputation method chosen under the complexity of the nonnormal data and the unique missing mechanism. In this research, we proposed both an innovative multiple-imputation algorithm and a novel method called the mean rank imputation method under the nonparametric framework for sensitivity analyses. A simulation study was designed using rank analysis of covariance (ANCOVA) to extensively assess and compare the finite performance of these two new methods along with four other missing data handling methods previously used in the RA trials, namely, linear extrapolation, last observation carried-forward (LOCF), median quartile bin imputation, and median imputation under various settings. Our simulation results suggest that the multiple-imputation algorithm, providing an mITT analysis population, yields an inflated type I error and artificially good power. The proposed mean rank imputation method, following a true ITT principle, both is powerful and maintains type I error at the nominal level.

Socialinių paslaugų naudingumas reumatoidiniu artritu sergantiems asmenims

Rheumatic joint diseases, such as rheumatoid arthritis are recognized as the second most common diseases in causing disability. Rheumatoid arthritis affects more than 12 thousand of the population in Lithuania. Rheumatoid arthritis with increasing age of the population and the increasing number of patients with the diagnosis of the disease becomes an important and relevant social issue not only from the medical, financial but also from the social side. Because of rheumatoid arthritis joint damage, patients with advanced disability face many issues: financial, emotional, and psychological and of course social. Therefore it is appropriate to carry out research and to find out whether social services are useful to persons with rheumatoid arthritis and which of the social services provide the greatest benefits. Aim of the work – to analyze benefits of social services to persons with rheumatoid arthritis. Practical meaning of the research. The research data showed that social services are useful to persons with rheumatoid arthritis. Analysis of the research, conclusions and recommendations may be practically useful to social workers in providing social services to persons with rheumatoid arthritis. Research method – quantitative research. Non -probabilistic purposive sampling was executed among 31 persons with rheumatoid arthritis. Conclusion of the research. The research data showed that social services are more used almost by every person with rheumatoid arthritis. From the general social services were mentioned technical and compensatory equipment, housing and environmental applications, special transportation services. From the special social home care services were mentioned food purchasing and food preparation, documentation management, doctor’s appointments at home, drug purchasing from pharmacies services. The benefit of all social services most of the respondents rated as average, because of their opinion that social services system is still not well developed to provide the maximum benefit. doi:10.5200/sm-hs.2013.100

Allele‐Dose Association of the C5orf30 rs26232 Variant With Joint Damage in Rheumatoid Arthritis

There is increasing evidence to indicate that genetic factors contribute significantly to radiologic joint damage in rheumatoid arthritis (RA). The aim of the present study was to determine whether genotypes of 10 recently identified RA susceptibility loci are associated with radiologic severity. A 2-stage study was performed using 3 Northern European RA populations: a British cross-sectional population (discovery cohort; n=885) and the Leiden Early Arthritis Clinic (EAC) cohort (n=581) and Yorkshire Early Arthritis Register (YEAR) cohort (n=418) (validation cohorts). Radiologic damage was assessed using a modified Larsen method for scoring radiographs (in the discovery cohort) or modified Sharp/van der Heijde score (in the 2 validation cohorts). A meta-analysis was performed to bring together the evidence from the 3 studies, using data on radiologic severity of joint damage from a single time point. An allele-dose association of rs26232 was present in the discovery population (P=4×10(-4)); the median modified Larsen scores of radiologic joint damage per genotype were 31 (for those with CC), 27 (for those with CT), and 16 (for those with TT). The allele-dose association of rs26232 was replicated in both the Leiden EAC cohort during the initial 7 years of RA (P=0.04) and the YEAR cohort (P=0.039). In a fixed-effects meta-analysis of all 3 studies, the per T allele effect on the ratio of radiologic severity scores was 0.90 (95% confidence interval 0.84, 0.96; P=0.004). The variant rs26232, in the first intron of the C5orf30 locus, is associated with the severity of radiologic damage in RA and is independent of established prognostic biomarkers. The biologic activities of C5orf30 are unknown, but our genetic data suggest that it is involved in mediating joint damage in RA.

Analyses of synovial tissues from arthritic and protected congenic rat strains reveal a new core set of genes associated with disease severity

Little is known about the genes regulating disease severity and joint damage in rheumatoid arthritis (RA). In the present study we analyzed the gene expression characteristics of synovial tissues from four different strains congenic for non-MHC loci that develop mild and nonerosive arthritis compared with severe and erosive DA rats. DA.F344(Cia3d), DA.F344(Cia5a), DA.ACI(Cia10), and DA.ACI(Cia25) rats developed mild arthritis compared with DA. We found 685 genes with significantly different expression between congenics and DA, independent of the specific congenic interval, suggesting that these genes represent a new nongenetic core group of mediators of arthritis severity. This core group includes genes not previously implicated or with unclear role in arthritis severity, such as Tnn, Clec4m, and Spond1 among others, increased in DA. The core genes also included Scd1, Selenbp1, and Slc7a10, increased in congenics. Genes implicated in nuclear receptor activity, xenobiotic and lipid metabolism were also increased in the congenics, correlating with protection. Several disease mediators were among the core genes reduced in congenics, including IL-6, IL-17, and Ccl2. Analyses of upstream regulators (genes, pathways, or chemicals) suggested reduced activation of Stat3 and TLR-related genes and chemicals in congenics. Additionally, cigarette smoking was among the upstream regulators activated in DA, while p53 was an upstream regulator activated in congenics. We observed congenic-specific differential expression and detection in each individual strain. In conclusion, this new nongenetically regulated core genes of disease severity or protection in arthritis should provide new insight into critical pathways and potential new environmental risk factor for arthritis.

Validity of a computer-assisted manual segmentation software to quantify wrist erosion volume using computed tomography scans in rheumatoid arthritis.

BackgroundTo investigate the performance of conventional radiography (CR) for the detection of bone erosions of wrist in rheumatoid arthritis (RA) using multidetector computed tomography (CT) as the reference method and to evaluate the validity of a computer-assisted manual segmentation (outlining) technique to quantify erosion volume on CT scans.MethodsTwenty five RA patients and six controls underwent CT and radiographic evaluation of the dominant wrist on the same day. CT was performed by using a 64 GE light Speed VCT power. Wrists images were evaluated separately and scored for the presence of erosions according to the Outcome Measures in Rheumatology Rheumatoid Arthritis MRI Scoring System (RAMRIS) and the Sharp/van der Heijde scoring method. Measurements of bone erosion volumes were obtained using OsiriX medical imaging software. The mean value of the volumes of the CT bone erosions detected at two readings was used to calculate inter-rater agreement.ResultsThe overall sensitivity, specificity and accuracy of radiography for detecting erosions were 25.5%, 98.3% and 70.1%, respectively. Using computer-assisted manual segmentation (outlining) technique, erosion volume on CT measurements per subject was ranged from 0.001 cm3 to 2.01 cm3. Spearman’s RAMRIS score of each wrist bones in all subjects (n = 25) were correlated with the total erosion volume on CT (p < 0.0001), with the ratio between erosion volume and the corresponding bone volume on a percentage basis (p < 0.0001). The total Sharp/van der Heijde erosion score of the all wrist bones was correlate with the RAMRIS score (p = 0.008). The intraclass correlation coefficients (ICC) for manual segmentation showed high agreement (ICC = 0.901).ConclusionsConsidering CT as the reference method, CR showed very low sensitivity. A close correlation with CT erosion volumes supports the OMERACT RAMRIS erosion score as a semiquantitative measure of joint damage in RA. Although the computer-assisted manual segmentation can be beneficial for diagnostic decision in cross-sectional CT examinations of the wrist in RA, this technique will require further evaluation in terms of responsiveness.

Increased Levels of Interleukin 34 in Serum and Synovial Fluid Are Associated with Rheumatoid Factor and Anticyclic Citrullinated Peptide Antibody Titers in Patients with Rheumatoid Arthritis

Interleukin 34 (IL-34) is a recently discovered cytokine that binds macrophage colony-stimulating factor (M-CSF) receptor. Rheumatoid arthritis (RA) is characterized by increased osteoclastogenesis. To identify the significance of IL-34 in RA, the IL-34 concentration was measured in serum and synovial fluid (SF). IL-34 concentrations were measured in serum from patients with RA (n = 113), patients with osteoarthritis (OA; n = 56), and controls (n = 36), and in SF isolated from patients with RA (n = 36) or OA (n = 24). Correlations between serum IL-34 levels and clinical features in RA were assessed. The levels of IL-1β, IL-6, IL-17α, interferon-γ-induced protein 10, receptor activator of nuclear factor κB ligand (RANKL), and Dickkopf-1 were also measured. Patients with RA had a higher mean serum level of IL-34 than did patients with OA and controls (188.0 ± 550.3, 36.6 ± 38.0, and 49.1 ± 78.5 pg/ml, respectively). Similarly, SF IL-34 concentration was higher in patients with RA than in those with OA. IL-34 levels were positively associated with IL-6 levels in serum from patients with RA and OA. SF IL-34 concentration correlated significantly with IL-6 and RANKL levels only in RA. The serum level of IL-34 was not correlated with systemic osteoporosis and radiographic joint damage in RA. IL-34 levels in the serum from patients with RA were positively correlated with rheumatoid factor and anticyclic citrullinated peptide antibody titers (r = 0.282 and 0.491, respectively). Circulating IL-34 levels in RA correlated with autoantibody production. Further investigations of localized and systemic effects of IL-34 are warranted to elucidate RA pathogenesis.

Early increase in serum-COMP is associated with joint damage progression over the first five years in patients with rheumatoid arthritis

BackgroundCurrently available biomarkers for the early tissue process leading to joint damage in rheumatoid arthritis are insufficient and lack prognostic accuracy, possibly a result of variable activity of the disease over time. This study represents a novel approach to detect an altered activity of the disease process detected as increasing serum-COMP levels over a short time and whether this would correlate with joint damage progression over the first 5 years of disease.MethodsIn all, 349 patients from the Swedish BARFOT early RA study were examined. Serum-COMP was analysed by ELISA at diagnosis and after 3 months. Based on changes in serum-COMP levels, three subgroups of patients were defined: those with unchanged levels (change ≤ 20%) (N=142), decreasing levels (> 20%) (N=173) and increasing levels (> 20%) (N=34). Radiographs of hands and feet were obtained at inclusion, after 1, 2 and 5 years and scored according to Sharp van der Heijde (SHS). Radiographic progression was defined as increase in SHS by ≥5.8.ResultsThe group of patients with increasing COMP levels showed higher median change in total SHS and erosion scores at 1, 2 and 5 year follow-up compared with the groups with stable or decreasing COMP levels. Furthermore, the odds ratio of radiographic progression was 2.8 (95% CI 1.26-6.38) for patients with increasing COMP levels vs. patients with unchanged levels.The group of patients with increasing COMP levels had higher ESR at inclusion but there were no baseline differences between the groups for age, gender, disease duration, disease activity (DAS28), function (HAQ), CRP, nor presence of rheumatoid factor or anti-CCP. Importantly, neither did changes over the 3-month period in DAS28, HAQ, ESR nor CRP differ between the groups and these variables did not correlate to joint damage progression.ConclusionIncreasing serum-COMP levels between diagnosis and the subsequent 3 months in patients with early RA represents a novel indicator of an activated destructive process in the joint and is a promising tool to identify patients with significant joint damage progression during a 5-year period.

Biomarkers of Joint Damage in Rheumatoid Arthritis: Where Are We in 2013?

The search for biomarkers identifying key targets for the assessment of major outcomes in chronic diseases has become one of the most interesting topics of research in different areas of clinical medicine, in particular in oncology, hematology, and rheumatology. In rheumatoid arthritis (RA), one of the leading causes of disability among chronic diseases, possible biomarkers should help the rheumatologist to identify (in very early or early RA) the patients who are going to respond quickly and favorably to disease-modifying antirheumatic drugs (DMARD), those not responding to DMARD and receiving biologic therapies (among which there is great need of biomarkers to choose a “personalized” biologic agent), those not responding to any of the several biologics, and finally, in all the previous settings, those who will develop structural damage more rapidly. Currently, researchers have great interest in the field of “personalized medicine,” which should allow physicians to optimally match patient with treatment1. The ideal biomarker should be similar to glycated hemoglobin (i.e., target for HbA1c less than 7)2, which gives significant information on the metabolic status of the patient with diabetes before and after therapy, particularly the metabolic status that allows or prevents progression of vascular damage in terms of diabetes-related comorbidities such as acute myocardial infarction, stroke, or diabetic nephropathy3. RA is characterized by synovitis and joint tissue destruction, including cartilage loss and bone erosion, with variability in outcome in different patients, that is, a self-limiting disease in some, and one characterized by progressive joint destruction in others. Biomarkers could be devised to define the aggressiveness of synovitis and to monitor the structural damage, or there could be 1 ideal biomarker summarizing both aspects. The possibility of identifying the individual RA patient’s future disease severity could guide the choice of the best treatment … Address correspondence to Prof. G. Ferraccioli, Division of Rheumatology, Institute of Rheumatology and Affiliated Sciences, University of the Sacred Heart, Complesso Integrato Columbus, Via Giuseppe Moscati 31, 00168 Rome, Italy. E-mail: gf.ferraccioli{at}rm.unicatt.it

Roles of Adipocytes and Fibroblasts in Activation of the Alternative Pathway of Complement in Inflammatory Arthritis in Mice

The complement system is involved in mediation of joint damage in rheumatoid arthritis, with evidence suggesting activation of both the classical and alternative pathway (AP). The AP is both necessary and sufficient to mediate collagen Ab-induced arthritis, an experimental animal model of immune complex-induced joint disease. The AP in mice is dependent on MASP-1/3 cleavage of pro-factor D (pro-FD) into mature factor D (FD). The objectives of the current study were to determine the cells synthesizing MASP-1/3 and pro-FD in synovial tissue. Collagen Ab-induced arthritis was studied in wild-type C57BL/6 mice, and the localization of mRNA and protein for FD and MASP-1/3 in synovial adipose tissue (SAT) and fibroblast-like synoviocytes (FLS) was determined using various techniques, including laser capture microdissection. SAT was the sole source of mRNA for pro-FD. Cultured differentiated 3T3 adipocytes, a surrogate for SAT, produced pro-FD but no mature FD. FLS were the main source of MASP-1/3 mRNA and protein. Using cartilage microparticles (CMPs) coated with anti-collagen mAb and serum from MASP-1/3(-/-) mice as a source of factor B, pro-FD in 3T3 supernatants was cleaved into mature FD by MASP-1/3 in FLS supernatants. The mature FD was eluted from the CMP, and was not present in the supernatants from the incubation with CMP, indicating that cleavage of pro-FD into mature FD by MASP-1 occurred on the CMP. These results demonstrate that pathogenic activation of the AP can occur in the joint through immune complexes adherent to cartilage and the local production of necessary AP proteins by adipocytes and FLS.

OP0049 A Genetic Variant in the Region of MMP-9 is Associated with Serum Levels and Progression of Joint Damage in Rheumatoid Arthritis

BackgroundThe severity of joint destruction is highly variable between Rheumatoid Arthritis (RA) patients. The majority of its heritability is still unexplained. Several auto-immune diseases share genetic risk variants that may...

THU0168 How Low Should You Go? Towards Personalized Treatment Targets for Disease Activity in RA

BackgroundPrevention of joint damage is a main goal of treatment in Rheumatoid Arthritis (RA). However, not all patients have the same risk for joint damage during the course of disease....

SAT0474 Differences of clinical and ultrasound (US) remission in rheumatoid arthritis (RA) depend on the stringency of the us methodology

BackgroundProgression of joint damage in RA occurs primarily in joints that are clinically swollen, and repair is seen only in joints with no clinical swelling.1;2 On the other hand, joints...

AB0106 Serum and synovial interleukin-15 (IL-15) in rheumatoid arthritis (RA)

BackgroundIL-15 is a proinflammatory cytokine that contributes to local inflammation and joint damage in RA. A locally overproduced IL-15 may be responsible for the activation and proliferation of T cells...