Established Rheumatoid Arthritis Research Articles

The importance of early arthritis in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic inflammatory disorder that manifests predominantly in the synovial joint, where it causes a chronic inflammatory process, leading to early osteoarticular destructions. These destructions are progressive and irreversible, generating a significant functional deficiency. During the last years, the diagnostic approach of RA has focused on early arthritis. Early arthritis can develop into established RA or another established arthropathy, like systemic lupus erythematosus or psoriatic arthritis. It can have a spontaneous resolution or may remain undifferentiated for indefinite periods of time.

Effectiveness of a Web-Based Personalized Rheumatoid Arthritis Risk Tool With or Without a Health Educator for Knowledge of Rheumatoid Arthritis Risk Factors.

To assess knowledge of rheumatoid arthritis (RA) risk factors among unaffected first-degree relatives (FDRs) and to study whether a personalized RA education tool increases risk factor knowledge. We performed a randomized controlled trial assessing RA educational interventions among 238 FDRs. The web-based Personalized Risk Estimator for RA (PRE-RA) tool displayed personalized RA risk results (genetics, autoantibodies, demographics, and behaviors) and educated about risk factors. Subjects were randomly assigned to a Comparison arm (standard RA education; n = 80), a PRE-RA arm (PRE-RA alone; n = 78), or a PRE-RA Plus arm (PRE-RA and a one-on-one session with a trained health educator; n = 80). The RA Knowledge Score (RAKS), the number of 8 established RA risk factors identified as related to RA, was calculated at baseline and post-education (immediate/6 weeks/6 months/12 months). We compared RAKS and its components at each post-education point by randomization arm. At baseline before education, few FDRs identified behavioral RA risk factors (15.6% for dental health, 31.9% for smoking, 47.5% for overweight/obesity, and 54.2% for diet). After education, RAKS increased in all arms, higher in PRE-RA and PRE-RA Plus than Comparison at all post-education points (P < 0.05). PRE-RA subjects were more likely to identify risk factors than those who received standard education (proportion agreeing that smoking is a risk factor at 6 weeks: 83.1% in the PRE-RA Plus arm, 71.8% in the PRE-RA arm, and 43.1% in the Comparison arm; P < 0.05 for PRE-RA versus Comparison). Despite being both familiar with RA and at increased risk, FDRs had low knowledge about RA risk factors. A web-based personalized RA education tool successfully increased RA risk factor knowledge.

Circulating serum miR-223-3p and miR-16-5p as possible biomarkers of early rheumatoid arthritis.

Small non-coding RNAs have emerged as possible biomarkers for various diseases including autoimmune diseases. A number of studies have demonstrated that the expression of specific microRNAs (miRNAs) is dysregulated in rheumatoid arthritis (RA). So far, all studies on miRNAs in RA patients have been performed using either microarray or reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analyses. Compared to RT-qPCR and microarray analyses, next-generation sequencing (NGS) allows the genome-wide analysis of small RNAs and the differentiation between miRNAs that differ by a single nucleotide. The application of NGS to the analysis of small RNAs circulating in sera of RA patients has not been reported. This study provides a global overview of the circulating small RNAs in the sera of RA patients and healthy subjects and identifies differences between these groups using NGS. Several classes of small RNAs, including hY RNA-derived fragments, tRNA-derived fragments and miRNAs, were determined. Differentially expressed individual small RNAs were verified by RT-qPCR. The levels of two miRNAs, miR-223-3p and miR-16-5p, were significantly lower in the sera from early RA patients than in those from established RA patients and healthy controls. In contrast, the serum level of miR-16-5p was higher in patients with established RA than in healthy control samples. These miRNAs may not only serve as biomarkers, but may also shed more light on the pathophysiology of RA.

1,25(OH)2D3 and dexamethasone additively suppress synovial fibroblast activation by CCR6+ T helper memory cells and enhance the effect of tumor necrosis factor alpha blockade

BackgroundDespite recent improvements in the treatment of rheumatoid arthritis (RA), an insufficient treatment response and the development of treatment resistance in many patients illustrates the need for new therapeutic strategies. Chronic synovial inflammation could be suppressed by targeting RA synovial fibroblast (RASF) activation by, for example, interleukin (IL)-17A-producing CCR6+ T helper memory (memTh) cells. Here, we modulated this interaction by combining the active vitamin D metabolite 1,25(OH)2D3 with dexamethasone (DEX) and explored the potential therapeutic applications.MethodsCCR6+ memTh cells from peripheral blood mononuclear cells (PBMCs) of healthy donors or treatment-naive early RA patients were cultured alone or with RASF from established RA patients for 3 days and treated with or without 1,25(OH)2D3, DEX, or etanercept. Treatment effects were assessed using enzyme-linked immunosorbent assay (ELISA) and flow cytometry.Results1,25(OH)2D3, and to lesser extent DEX, reduced production of the pro-inflammatory cytokines IL-17A, IL-22, and interferon (IFN)γ in CCR6+ memTh cells. Tumor necrosis factor (TNF)α was only inhibited by the combination of 1,25(OH)2D3 and DEX. In contrast, DEX was the strongest inhibitor of IL-6, IL-8, and tissue-destructive enzymes in RASF. As a result, 1,25(OH)2D3 and DEX additively inhibited inflammatory mediators in CCR6+ memTh-RASF cocultures. Interestingly, low doses of mainly DEX, but also 1,25(OH)2D3, combined with etanercept better suppressed synovial inflammation in this coculture model compared with etanercept alone.ConclusionThis study suggests that 1,25(OH)2D3 and DEX additively inhibit synovial inflammation through targeting predominantly CCR6+ memTh cells and RASF, respectively. Furthermore, low doses of DEX and 1,25(OH)2D3 enhance the effect of TNFα blockade in inhibiting RASF activation, thus providing a basis to improve RA treatment.

Subgingival microbiome of rheumatoid arthritis patients in relation to their disease status and periodontal health.

ObjectiveRheumatoid arthritis (RA) and periodontitis are chronic inflammatory diseases that share common risk factors. However, the bidirectional relationship between RA and periodontal disease is not fully understood.This study was undertaken to describe the bacterial component of the subgingival microbiome in RA patients and to relate this to RA disease activity and periodontal status.MethodsPatients with chronic established RA (N = 78) were periodontally examined and their subgingival plaque samples were collected; their clinical and laboratory data on RA status and medication were obtained from medical records. Bacterial DNA was quantified by universal 16S rDNA qPCR, and Porphyromonas gingivalis by species-specific qPCR. For microbiome assessment, 16S rDNA amplicon sequencing was performed.ResultsActive RA was diagnosed in 58% of the patients and periodontitis in 82% (mild: 9%, moderate: 55%, severe: 18%). P. gingivalis was present in 14% of the samples. Different levels of gingival bleeding, periodontal probing depth, RA disease status, prednisolone use and smoking were associated with significantly different microbiome compositions. Two subgingival microbial community types were discerned.ConclusionIn RA patients with active disease, anti-inflammatory medication as part of RA therapy was associated with better oral health status and a healthier subgingival microbiome compared to that of RA patients in remission, especially those in remission who were current smokers. RA patients in remission with current smoking status may particularly benefit from a systematic periodontal treatment program. The potential role of microbial community types in patient stratification and personalized therapy should be assessed in longitudinal studies.

PMS8 - The Evolving Cost of Illness of Rheumatoid Arthritis: A Systemic Review

Over the past couple of decades, there has been major advances in the management of rheumatoid arthritis (RA). It is now recognised that early diagnosis and intensive treatment can limit disease progression and restore physical function in patients with RA. One of the major developments have been the introduction of disease-modifying antirheumatic drugs (DMARDs) and biolgoics. However, these drugs are expensive, and have transformed the composition of and the total cost of illness of RA. The objective of this study is to synthesise the knowledge about contemporary cost of illness (COI) studies and understand the full burden of patients with recent-onset and established RA. We performed a systematic review of all COI studies of RA, published after the year 2000. Multiple databases using relevant keywords and search filters were searched. We synthesised the data from all relevant studies through a narrative synthesis, with specific focus on the impact of the various settings and methodological approaches used to estimate costs in the studies. There were substantial variations in patient case-mix, healthcare settings, and methodological approaches to estimating COI of RA. The majority of the studies adopted the prevalence-based approach from a societal perspective to estimate an annual cost per patient. Direct costs tended to increase over the past decade mainly because of the introduction of biologics. However, this rising drug costs reached a plateau around 2009 and was subsequently offset by a general reduction in hospitalisation and in productivity loss. Productivity loss was mostly estimated by the human capital approach, accounted for the largest part of total annual cost, (45%-70% of total costs in the Western society). In the management of RA, early and intensive treatment may increase the short-term direct costs, but in the longer-term, this was associated with reduced hospitalisation and productivity loss in the society.

Osteoporosis Self-Assessment Tool As a Screening Tool for Predicting Osteoporosis in Elderly Chinese Patients With Established Rheumatoid Arthritis

Osteoporosis Self-Assessment Tool for Asians (OSTA) is an indicator for assessing osteoporosis in postmenopausal women. The aim of this study was to investigate the value of OSTA index on predicting osteoporosis in elderly Chinese patients with established rheumatoid arthritis (RA). A total of 320 patients with RA and 158 normal individuals were recruited from January 2015 to October 2017. Bone mineral density (BMD) at the femur and lumbar spine was measured by dual-energy X-ray absorptiometry. RA group and control group were divided into low risk (values≥−1), medium risk (values between −4 and −1), and high risk (values ≤−4) group according to the value of OSTA index. One-way analysis of variance showed that BMD at all detected regions among the 3 groups were obviously different (p < 0.0001). Incidences of osteoporosis among different OSTA groups were 21.76% (47/216), 56.41% (44/78), and 80.77% (21/26), separately (x2 = 67.389, p < 0.0001). In RA group including premenspausal or postmenspausal female subgroup, prevalences of osteoporosis among different OSTA groups were different (p < 0.05–0.0001). We also found a positive linear correlation between OSTA index and BMD (p < 0.0001) both in RA and in control groups. Logistic regression revealed OSTA index (odds ratio = 0.734, p < 0.0001, 95% confidence interval: 0.657–0.819) was a protective factor for occurrence of RA-induced osteoporosis. OSTA had the highest discriminatory power, with an estimated Area Under Curve (AUC) of 0.750 (95% confidence interval 0.694–0.807, p < 0.0001), sensitivity of 76.9% and specificity of 66.5%. Our findings indicated that OSTA index was closely associated with BMD in RA patients, the degree of correlation was much stronger than age or BMI. OSTA index was a predictor for osteoporosis in RA, but it might have little relationship with disease status in RA.

Recommendations for the management of rheumatoid arthritis in the Eastern Mediterranean region: an adolopment of the 2015 American College of Rheumatology guidelines

Clinical practice guidelines can assist rheumatologists in the proper prescription of newer treatment for rheumatoid arthritis (RA). The objective of this paper is to report on the recommendations for the management of patients with RA in the Eastern Mediterranean region. We adapted the 2015 American College of Rheumatology guidelines in two separate waves. We used the adolopment methodology, and followed the 18 steps of the “Guidelines 2.0” comprehensive checklist for guideline development. For each question, we updated the original guidelines’ evidence synthesis, and we developed an Evidence Profile (EP) and an Evidence to Decision (EtD) table. In the first wave, we adoloped eight out of the 15 original questions on early RA. The strength changed for five of these recommendations from strong to conditional, due to one or more of the following factors: cost, impact on health equities, the balance of benefits, and harms and acceptability. In the second wave, we adoloped eight out of the original 44 questions on established RA. The strength changed for two of these recommendations from strong to conditional, in both cases due to cost, impact on health equities, balance of benefits and harms, and acceptability. The panel also developed a good practice recommendation. We successfully adoloped 16 recommendations for the management of early and established RA in the Eastern Mediterranean region. The process proved feasible and sensitive to contextual factors.

The diagnostic value of 14-3-3η protein levels in patients with rheumatoid arthritis.

14-3-3η may represent a useful diagnostic biomarker for rheumatoid arthritis (RA). We assessed the prevalence and serum levels of 14-3-3η in patients with RA and in patients with other rheumatic diseases. Serum levels of 14-3-3η were measured in 96 patients with RA, in 101 patients with other rheumatic diseases, and in 66 healthy subjects. All of the sera samples were evaluated by JOINT stat 14-3-3η ELISA test kits (Augurex Life Sciences Corp.). Median (IQR) 14-3-3η levels were significantly higher in the early RA group [0.25ng/ml (0.075-3.11)] and in patients with established RA [0.15ng/ml (0.08-1.26)] than in healthy subjects [0ng/ml (0-0)] and disease controls: SLE [0.01ng/ml (0-0.055)], AS [0.05ng/ml (0-0.255)], and PsA [0.01ng/ml (0-0.065)]. The prevalence of 14-3-3η positivity in patients with early RA was 58%, significantly higher than that in disease controls and healthy subjects (p<0.001). In patients with established RA, this prevalence was 43%, and it was significantly higher than that in patients with other rheumatic diseases and healthy subjects (p<0.05), excluding the AS group (p=0.054). In the early RA cohort, the positivity for 14-3-3η, RF, and anti-CCP was 58%, 67%, and 71%, respectively. Eighty-two percent of the patients in this cohort were positive for at least one of these biomarkers. The concentration of 14-3-3η protein may be used to distinguish between patients with early RA and patients with other rheumatic diseases.

Prospective assessment of cardiovascular risk parameters in patients with rheumatoid arthritis

BackgroundThe study presents a prospective follow-up assessment of cardiovascular (CV) risk parameters in patients with rheumatoid arthritis (RA) in comparison with control subjects.MethodsThe study group consisted of 41 RA patients. The following parameters were assessed at subsequent visits [initial (T0), follow-up after 6 years (T6)]: traditional CV risk factors, carotid intima media thickness (cIMT), QTc duration, serum concentration of amino-terminal pro-brain natriuretic peptide (NT-proBNP). A comparative cIMT assessment was performed on 23 healthy controls of comparable age.ResultsThe mean (SD) cIMT value in RA patients was significantly higher at T6 than at T0 [0.87 (0.21) vs 0.76 (0.15) mm, p < 0.001], the increase in patients with atherosclerotic plaques was noted. Patients with plaques were significantly older, had higher inflammatory parameters. The mean cIMT was significantly higher in RA patients than in controls at both T6, T0 visits. Certain traditional CV risk factors exacerbated during follow up. Unfavorable metabolic parameters and significantly higher cIMT were found in male patients than in female patients at T6. During follow-up, no significant differences in NT-proBNP, QTc were found. There were no significant relationships between cIMT, NT-proBNP, QTc and parameters of disease activity at T6.ConclusionsDuring the 6-year course of established RA, significant exacerbation of atherosclerosis was found, revealed by higher cIMT. A careful monitoring should be applied to patients with atherosclerotic plaques and of male gender due to higher burden of CV risk. In long-standing disease, traditional CV risk factors seem to play a key role, beyond the inflammatory activity.

Latent profile analysis approach to the relationship between patient and physician global assessments of rheumatoid arthritis activity

ObjectivePatients and physicians commonly differ in their assessments of rheumatoid arthritis (RA) activity. Clinically meaningful discordance thresholds or validation of their ability to predict functional outcomes are lacking. We explored...

Phenotypic and Transcriptomic Analysis of Peripheral Blood Plasmacytoid and Conventional Dendritic Cells in Early Drug Naïve Rheumatoid Arthritis.

Dendritic cells (DCs) are key orchestrators of immune function. To date, rheumatoid arthritis (RA) researchers have predominantly focused on a potential pathogenic role for CD1c+ DCs. In contrast, CD141+ DCs and plasmacytoid DCs (pDCs) have not been systematically examined, at least in early RA. In established RA, the role of pDCs is ambiguous and, since disease duration and treatment both impact RA pathophysiology, we examined pDCs, and CD1c+ and CD141+ conventional DCs (cDCs), in early, drug-naïve RA (eRA) patients. We analyzed the frequency and phenotype of pDCs, CD1c+, and CD141+ DCs from eRA patients and compared findings with healthy controls. In parallel, we performed transcriptional analysis of >600 immunology-related genes (Nanostring) from peripheral blood pDCs, CD1c+ DCs, B cells, T cells, and monocytes. All DC subsets were reduced in eRA (n = 44) compared with healthy controls (n = 30) and, for pDCs, this was most marked in seropositive patients. CD141+ and CD1c+ DCs, but not pDCs, had a comparatively activated phenotype at baseline (increased CD86) and CD1c+ DC frequency inversely associated with disease activity. All DC frequencies remained static 12 months after initiation of immunomodulatory therapy despite a fall in activation markers (e.g., HLA-DR, CD40). There was no association between the whole blood interferon gene signature (IGS) and pDC or CD1c+ DC parameters but an inverse association between CD141+ DC frequency and IGS was noted. Furthermore, IFN-I and IFN-III mRNA transcripts were comparable between eRA pDC and other leukocyte subsets (B cells, CD4+, and CD8+ T cells and monocytes) with no obvious circulating cellular source of IFN-I or IFN-III. Transcriptomic analysis suggested increased pDC and CD1c+ DC proliferation in eRA; pDC differentially expressed genes also suggested enhanced tolerogenic function, whereas for CD1c+ DCs, pro-inflammatory transcripts were upregulated. This is the first detailed examination of DC subsets in eRA peripheral blood. Compared with CD1c+ DCs, pDCs are less activated and may be skewed toward tolerogenic functions. CD141+ DCs may be implicated in RA pathophysiology. Our findings justify further investigation of early RA DC biology.

Clinical significance of serum B cell chemokine (CXCL13) in early rheumatoid arthritis patients

BackgroundThe diagnosis of early rheumatoid arthritis (RA) is challenging. B-cell chemokine (CXCL13) plays a critical role in the disease pathogenesis. Aim of the workTo assess the diagnostic value of serum CXCL13 in early RA and compare it with rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies. Patients and methodsThe study included 60 RA patients; 30 early, 30 established RA and 30 healthy controls. The modified health assessment questionnaire (MHAQ), modified Sharp-van der Heijde score (MSS) and disease activity score (DAS28) were assessed in RA patients. RF, anti-CCP and serum level of CXCL13 were measured. ResultsPatients had a mean age of 39 ± 7.4 years and disease duration of 4.4 ± 5.7 years; they were 46 females and 12 males (F:M 3.8:1). Serum CXCL13 was significantly higher in early (191.7 ± 74.4 pg/ml) compared to established (136.4 ± 79 pg/ml) RA (p = 0.007) which were not observed with RF and anti-CCP; both were higher than in control (30.4 ± 13.5 pg/ml) (p < 0.001). In early RA, the frequencies of CXCL13, RF and anti-CCP positivity were 90%, 73.3% and 56.7% while in the established cases the frequencies were 36.7%, 66.7% and 63.3% respectively. CXCL13 significantly correlated with DAS28 (early: 0.49, p = 0.006; established: r = 0.38, p = 0.04) but not with MHAQ or MSS. The CXCL13 significantly correlated with both the RF and anti-CCP in both early and established cases (p < 0.001). ConclusionCXCL13 is an important for the diagnosis of early RA with a superior diagnostic performance compared to RF and anti-CCP. It may also be considered a potential biomarker of disease activity.

Integrative analysis reveals CD38 as a therapeutic target for plasma cell-rich rheumatoid arthritis, pre-rheumatoid arthritis and systemic lupus erythematosus

Abstract Autoantibodies play a significant role in the progression and pathogenesis of many autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). No studies have analyzed the expression of plasma cell/plasmablast genes during RA disease progression and the potential of an anti-CD38 antibody in depleting plasma cells and plasmablasts for efficacy in autoimmunity. Therefore, we interrogated the rationale of daratumumab, an anti-CD38 monoclonal antibody, as a potential therapeutic in RA and SLE. RNA-Seq analysis of synovial biopsies from various stages of RA disease development shows that plasma cell/plasmablast-related genes CD38, XBP1, IRF4, PRDM1, IGJ and TNFSF13B are significantly up-regulated in synovial biopsies from arthralgia, undifferentiated arthritis, early RA and established RA compared to healthy and osteoarthritis controls. In addition, flow cytometry analysis reveals highest CD38 expression on plasma cells and plasmablasts compared to natural killer cells, classical dendritic cell (DC), plasmacytoid DC, and T cells, in peripheral blood of healthy control, SLE and RA donors. We show that IGJ expression mRNA strongly correlates with the number of plasma cell/plasmablast in SLE patient PBMCs. Most importantly, IGJ mRNA down-regulation correlates with daratumumab-mediated depletion of these cells ex vivo. The data indicates a potential use of IGJ mRNA as a surrogate pharmacodynamic biomarker in clinical testing of daratumumab. Taken together, our data provides rationale for daratumumab in the treatment of RA and SLE.

PMD8 - Serum Autoantibodies Multi-Testing in Rheumatoid Arthritis in Primary Care can Reduce Avoidable Costs Associated to False Positives. A Simulation Study in the United States of America

Rheumatoid arthritis (RA) diagnosis requires a combination of clinical, laboratory and imaging investigations. The consequences of wrong serology test results are costly: False Positive results (FPs) are initially managed as RA-patients, bringing about extra costs until correct diagnosis is made. The study goals were to: simulate the diagnostic performance of Rheumatoid Factor (RF)-IgA, RF-IgM, and cyclic citrullinated peptides (CCP2), used alone or in multi-testing parallel/sequential combinations; quantify the economic consequences of serology FPs in the United States. 190 established RA patients and 197 controls were used to assess the diagnostic performance of mono-/multi-serology testing. A 12-month Markov model simulated 500,000 RA-suspected individuals tested in Primary Care with mono- or multi-testing. Costs came from the published literature. Uncertainty was addressed with sensitivity analysis. The mono-testing diagnostic performance was: 1=RF-IgA: sensitivity[95%CI]=40.5%[33.5%-47.9%], specificity=92.4%[87.8%-95.7%]; 2=RF-IgM: sensitivity=59.0%[51.6%-66.0%], specificity=89.3%[84.2%-93.3%]; 3=CCP2: sensitivity=59.5%[52.1%-66.5%], specificity=96.5%[92.8%-98.6%]. Defining a “positive result” as “positivity to at least one test” increased sensitivity; “positivity to all the tests” increased specificity: multi-parallel testing: multi.parallel.1) using CCP2+RF-IgM increased specificity to 99.5[97.2-100]; multi.parallel.2) the 3 tests used simultaneously maximized specificity (100[98.1-100]), reducing sensitivity (35.8[29.0-43.1]); multi-sequential testing: testing positive to RF IgA + RF IgM followed by CCP testing led to 90.7[81.7-96.2] sensitivity and to 0[54.1-100.0] specificity. Multi-testing simulation results reduced the number of FPs: mono.1=32,908, mono.2=46,331, mono.3=14,722, multi.1.parallel.1=2,165, multi.parallel.2=0, multi.sequential=0. Multi-testing allowed for important cost savings due to reduced clinical procedures and resource utilization of FPs. In all the scenarios considered, the cost-savings of multi-testing ranged between $9.488.406-$55.032.756-$ compared with CCP mono-testing, and ranged between $56,930,438-$64,521,163 compared with RF-IgM-mono-testing. Simulation results show that multi-serology testing can improve the diagnostic accuracy of serology in RA: the inclusion of CCP2/RF-IgA/RF-IgM individual isotypes minimizes the number of FPs, reducing avoidable costs. Consequently, multi-testing for RA demonstrates superior value from patient and payer perspective.

Influence of Blue Mussel (Mytilus edulis) Intake on Disease Activity in Female Patients with Rheumatoid Arthritis: The MIRA Randomized Cross-Over Dietary Intervention.

Rheumatoid Arthritis (RA) is a chronic inflammatory disease. This study evaluates the effect of blue mussel intake on disease activity and quality of life in women with RA. Thirty-nine women with established RA and a disease activity score 28 (DAS28) >3.0 were recruited to a randomized 2 × 11-week cross-over dietary intervention. The participants continued with their medication and habitual diet and exchanged one cooked meal a day, five days a week, with a meal including 75 g blue mussels or 75 g meat. Diets were switched after an eight week washout period. Data regarding quality of life (SF-36), blood lipids, erythrocyte sediment rate (ESR), C-reactive protein (CRP) and tender and swollen joints were examined at the start and end of each dietary period. Thirty women completed one period, and twenty-three completed both. Intake of the blue mussel diet led to a significant reduction of DAS28-CRP (p = 0.048), but not DAS28. The number of EULAR (European League Against Rheumatism) criteria moderate and good responders were higher when consuming blue mussel diet (p = 0.036). Blood lipids did not change. To conclude, blue mussel intake reduced disease symptoms in women with RA and improved perceived health. The reported effects need to be confirmed by non-patient reported outcomes, such as inflammation markers.

Pain Catastrophizing, Subjective Outcomes, and Inflammatory Assessments Including Ultrasound: Results From a Longitudinal Study of Rheumatoid Arthritis Patients.

Pain catastrophizing is conceptualized as a negative cognitive-affective response to anticipated or actual pain and has been associated with important pain-related outcomes. The objective of this prospective study of established rheumatoid arthritis (RA) patients was to explore how pain catastrophizing was related to patient-reported outcomes (PROs), composite scores, and assessments of inflammatory activity. RA patients starting biologic disease-modifying antirheumatic drugs were examined at baseline and after 1, 2, 3, 6, and 12 months with PROs (joint pain/patient's global visual analog scale [VAS], modified Health Assessment Questionnaire, Rheumatoid Arthritis Impact of Disease score), clinical and laboratory assessments (tender/swollen joint count, assessor's global VAS, erythrocyte sedimentation rate/C-reactive protein [CRP] level), ultrasound (US) (gray scale [GS]/power Doppler [PD] of 36 joints and 4 tendons), and pain catastrophizing. The composite scores for Disease Activity Score in 28 joints, Clinical Disease Activity Index, and Simplified Disease Activity Index were calculated. Statistical calculations included independent samples t-test, paired samples t-test, one-way analysis of variance, Pearson's correlations, and linear and logistic regression. Of 209 patients included, 152 (72.7%) completed 12-month followup. Pain catastrophizing, PROs, and clinical and inflammatory assessments decreased significantly (P < 0.001). Pain catastrophizing was strongly correlated with the PROs and composite scores (P < 0.001) but not with the inflammatory parameters (swollen joint count, CRP level, and GS/PD US). Patients with higher levels of pain catastrophizing had higher PROs and composite scores during the study (P < 0.001) but not inflammatory assessments. Baseline pain catastrophizing was negatively associated with achievement of remission at 6 and 12 months (P < 0.05). Pain catastrophizing was strongly associated with PROs and composite measures, but not with markers of inflammation. High levels of pain catastrophizing reduced the likelihood of achieving composite score remission and should be a factor to consider in a treat-to-target strategy.

Muscle loss following a single high-dose intramuscular injection of corticosteroids to treat disease flare in patients with rheumatoid arthritis.

Adverse changes in body composition, specifically decreased muscle mass (MM) and increased fat mass, characterize rheumatoid arthritis (RA). These changes, termed rheumatoid cachexia (RC), are important contributors to the disability and elevated co-morbidity risk of RA. Recently, we observed substantial muscle loss (~2 kg) in a patient with RA following a single intramuscular (IM) corticosteroid (CS) injection to treat a disease flare. The aim of the current study is to determine whether this apparent iatrogenic effect of IM CS is typical, i.e., does this routine, recommended treatment contribute to RC? Body composition was assessed by dual-energy X-ray absorptiometry (DXA) in eight patients with established RA who received a 120 mg IM methylprednisolone injection to treat a disease flare. DXA scans estimated appendicular lean mass (ALM; a surrogate measure of MM), total lean mass (LM), and total and regional adiposity at baseline (injection day) and 4 weeks and 6-9 months post-injection. Statistical analysis was performed using one-way ANOVA. There was significant loss of ALM (-0.93 kg, p=0.001, 95% CI [-0.49, -1.36]) and a trend toward reduced LM (-1.10 kg, p=0.165, 95% CI [0.58, -2.79]) at 4 weeks relative to baseline. At 6-9 months despite control of inflammation and disease activity, these losses remained. Substantial muscle loss occurred in patients with RA following IM CS injection to treat a disease flare. Thus, this recommended treatment appears to exacerbate RC, thereby potentially increasing disability and co-morbidity risk. If this effect is confirmed by larger studies, the role of one-off high-dose CS in the treatment of RA should be reviewed.

Prevalence of sustained remission in rheumatoid arthritis: impact of criteria sets and disease duration, a Nationwide Study in Sweden.

The aims of this national study in Sweden of patients with RA were to: examine the prevalence of sustained remission (SR), that is, remission lasting for at least 6 months; compare the prevalence of SR in patients with early RA and established RA; study the timing of onset of and time spent in SR; and study possible predictors of SR. Adult patients with RA included in the Swedish Rheumatology Quality registry were studied. The registry was searched for patients fulfilling remission criteria: DAS28-ESR, Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI) and ACR/EULAR remission for at least 6 months. Early RA was defined as symptom duration ⩽6 months at inclusion in the Swedish Rheumatology Quality. Of 29 084 patients, 12 193 (41.9%) reached DAS28 SR at some time point during follow-up compared with 6445 (22.2%), 6199 (21.3%) and 5087 (17.5%) for CDAI, SDAI and ACR/EULAR SR, respectively. SR was more common in early RA (P < 0.001). The median time from symptom onset to SR was 1.9, 2.4, 2.4 and 2.5 years according to DAS28, CDAI, SDAI and ACR/EULAR criteria, respectively. Lower age, male sex and milder disease characteristics were associated with SR. The majority of patients in this nationwide study never reached SR. Patients with early RA are more likely to reach SR than patients with established RA.

Immune checkpoint inhibitor PD-1 pathway is down-regulated in synovium at various stages of rheumatoid arthritis disease progression.

Immune checkpoint blockade with therapeutic anti-cytotoxic T lymphocyte-associated antigen (CTLA)-4 (Ipilimumab) and anti-programmed death (PD)-1 (Nivolumab and Pembrolizumab) antibodies alone or in combination has shown remarkable efficacy in multiple cancer types, concomitant with immune-related adverse events, including arthralgia and inflammatory arthritis (IA) in some patients. Herein, using Nivolumab (anti-PD-1 antagonist)-responsive genes along with transcriptomics of synovial tissue from multiple stages of rheumatoid arthritis (RA) disease progression, we have interrogated the activity status of PD-1 pathway during RA development. We demonstrate that the expression of PD-1 was increased in early and established RA synovial tissue compared to normal and OA synovium, whereas that of its ligands, programmed death ligand-1 (PD-L1) and PD-L2, was increased at all the stages of RA disease progression, namely arthralgia, IA/undifferentiated arthritis, early RA and established RA. Further, we show that RA patients expressed PD-1 on a majority of synovial tissue infiltrating CD4+ and CD8+ T cells. Moreover, enrichment of Nivolumab gene signature was observed in IA and RA, indicating that the PD-1 pathway was downregulated during RA disease progression. Furthermore, serum soluble (s) PD-1 levels were increased in autoantibody positive early RA patients. Interestingly, most of the early RA synovium tissue sections showed negative PD-L1 staining by immunohistochemistry. Therefore, downregulation in PD-1 inhibitory signaling in RA could be attributed to increased serum sPD-1 and decreased synovial tissue PD-L1 levels. Taken together, these data suggest that agonistic PD1 antibody-based therapeutics may show efficacy in RA treatment and interception.