Established Rheumatoid Arthritis Patients Research Articles

A study of carotid intima media thickness in patients with rheumatoid arthritis and its correlation with acute phase reactants and disease activity

Introduction: There is increased risk of cardiovascular morbidity and mortality in patients of rheumatoid arthritis (RA) due to accelerated atherosclerosis. In this study we measured Carotid artery intima media thickness (CIMT) as a surrogate marker for subclinical atherosclerosis in RA patients without pre-existing cardiovascular disease. This study also analyzed the correlation between CIMT, disease duration, Simplified Disease Activity Index (SDAI) and acute phase reactants. Methods: A cross-sectional study was conducted on 90 patients divided into two groups of 45 patients of RA and another 45 control subjects. Subjects with RA and age and sex matched healthy controls were included in the study without pre-existing CV risk factors. Complete clinical evaluation, hematological and biochemical profile done. ESR, CRP and platelet count were used as markers of acute phase reactants. All the RA patients included in the study were evaluated for their disease activity using Simplified Disease Activity Index (SDAI). All the subjects including the controls evaluated for carotid intima media thickness by using carotid ultrasonography. CIMT measured in common carotid artery bilaterally by examining throughout common carotid artery up to 2 cm proximal to bifurcation. CIMT measurement taken at the site of greatest thickness. All measurements taken in diastole, measured in phase when lumen diameter is at its smallest and IMT at its largest. Mean value of 6 readings (3 from each side) taken as final CIMT for evaluation. B mode (linear probe) USG was used to determine carotid IMT. Results: 45 cases and similar control subjects included in the study with mean age (SD) as 45.07 (14.81) years. We found female preponderance with 37 females out of 45 cases. Mean (SD) disease duration in male subjects was 5.38(2.40) years while in females was 5.09 (2.78) years. CRP was found to be significantly increased in cases group with mean (SD) of 5.75(8.85) mg/dl. ESR significantly raised to 35.22(13.55) mm/hour in cases group compared to control group where it was 16.16(5.71) mm/hr. Mean (SD) platelets (x10³/mm³) were 229.24(69.80) in cases while controls had 290.33(83.85), so platelets correlation with disease could not be established. CIMT was significantly raised in cases group. Mean (SD) CIMT in cases was 0.95(1.06) mm whereas in control group it was 0.60(0.16) mm with p value of 0.002. Moderate positive correlation was found between CIMT (mm) and SDAI and this correlation was statistically significant with p=0.001. For every 1 unit increase in CIMT, the SDAI increases by 2.92 units. A strong positive correlation between CIMT (mm) and Disease Duration (Years), and this correlation was statistically significant (rho = 0.9, p = <0.001). For every 1 unit increase in CIMT (mm), the Disease Duration (Years) increases by 1.26 units. Conversely, for every 1 unit increase in Disease Duration (Years), the CIMT (mm) increases by 0.19 units. Conclusion: A strong correlation was observed between CIMT and disease duration in rheumatoid arthritis. Hence, CIMT can be a useful surrogate marker for detecting atherosclerosis in patients with RA. In view of the relation to duration of disease, established RA patients should regularly be screened to identify the evidence of atherosclerosis and manage it earlier. Prevention of cardiovascular disease in RA requires an integrated approach encompassing cardiovascular risk factors screening and management, effective and sustained control of RA disease activity, high index of suspicion and prompt investigation of suspected cardiac disease.

Responsiveness and sensitivity of PROMs to change in disease activity status in early and established rheumatoid arthritis.

To determine whether patient reported outcome measures (PROMs) capturing activity limitations, health impact, pain, fatigue and work ability are responsive and sensitive to changes in disease activity status in patients with early and established rheumatoid arthritis (RA). All early RA patients (n = 557) from the tREACH-trial and established RA patients (n = 188) from the TARA-trial were included. Both studies were multicentre, single-blinded trials with a treat-to-target management approach. The following PROMs were studied: Health Assessment Questionnaire Disability Index(HAQ-DI), morning stiffness severity, EQ-5D, general health, 36-item short form(SF-36), joint pain, fatigue and productivity loss. Mean changes in PROMs between two consecutive visits were compared with changes in disease activity status(remission, low disease activity and active disease) using linear mixed models and standardised response means. Additionally, the proportion of individual observations that showed an expected PROM response to disease activity status alterations was calculated. HAQ-DI, morning stiffness severity, general health, EQ-5D and joint pain demonstrated responsiveness to improvement or worsening of disease activity status in both early and established RA. SF-36 physical and mental component scale, fatigue and productivity loss did not show this effect in both groups. Across nearly all PROMs, the magnitude of change and the proportion of individual observations that reflect a shift from and to active disease remained low. HAQ-DI, morning stiffness severity, EQ-5D, general health and joint pain are responsive to disease activity status alterations on a group level in both early and established RA. For the individual patient the responsiveness of these PROMs is poor. tREACH trial (www.isrctn.com, ISRCTN26791028) and TARA trial (www.onderzoekmetmensen.nl, NTR2754).

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.

Peripheral blood cellular dynamics of rheumatoid arthritis treatment informs about efficacy of response to disease modifying drugs

Rheumatoid arthritis (RA) is an autoimmune disease characterized by systemic inflammation and is mediated by multiple immune cell types. In this work, we aimed to determine the relevance of changes in cell proportions in peripheral blood mononuclear cells (PBMCs) during the development of disease and following treatment. Samples from healthy blood donors, newly diagnosed RA patients, and established RA patients that had an inadequate response to MTX and were about to start tumor necrosis factor inhibitors (TNFi) treatment were collected before and after 3 months of treatment. We used in parallel a computational deconvolution approach based on RNA expression and flow cytometry to determine the relative cell-type frequencies. Cell-type frequencies from deconvolution of gene expression indicate that monocytes (both classical and non-classical) and CD4+ cells (Th1 and Th2) were increased in RA patients compared to controls, while NK cells and B cells (naïve and mature) were significantly decreased in RA patients. Treatment with MTX caused a decrease in B cells (memory and plasma cell), and a decrease in CD4 Th cells (Th1 and Th17), while treatment with TNFi resulted in a significant increase in the population of B cells. Characterization of the RNA expression patterns found that most of the differentially expressed genes in RA subjects after treatment can be explained by changes in cell frequencies (98% and 74% respectively for MTX and TNFi).

Increased Galectin-9 Levels Correlate with Disease Activity in Patients with DMARD-Naïve Rheumatoid Arthritis and Modulate the Secretion of MCP-1 and IL-6 from Synovial Fibroblasts.

Background: Fibroblast-like synoviocytes (FLSs) are essential mediators in the expansive growth and invasiveness of rheumatoid synovitis, and patients with a fibroblastic-rich pauci-immune pathotype respond poorly to currently approved antirheumatic drugs. Galectin-9 (Gal-9) has been reported to directly modulate rheumatoid arthritis (RA) FLSs and to hold both pro- and anti-inflammatory properties. The objective of this study was to evaluate clinical and pathogenic aspects of Gal-9 in RA, combining national patient cohorts and cellular models. Methods: Soluble Gal-9 was measured in plasma from patients with newly diagnosed, treatment-naïve RA (n = 98). The disease activity score 28-joint count C-reactive protein (DAS28CRP) and total Sharp score were used to evaluate the disease course serially over a two-year period. Plasma and synovial fluid samples were examined for soluble Gal-9 in patients with established RA (n = 18). A protein array was established to identify Gal-9 binding partners in the extracellular matrix (ECM). Synovial fluid mononuclear cells (SFMCs), harvested from RA patients, were used to obtain synovial-fluid derived FLSs (SF-FLSs) (n = 7). FLSs from patients suffering from knee Osteoarthritis (OA) were collected from patients when undergoing joint replacement surgery (n = 5). Monocultures of SF-FLSs (n = 6) and autologous co-cultures of SF-FLSs and peripheral blood mononuclear cells (PBMCs) were cultured with and without a neutralizing anti-Gal-9 antibody (n = 7). The mono- and co-cultures were subsequently analyzed by flow cytometry, MTT assay, and ELISA. Results: Patients with early and established RA had persistently increased plasma levels of Gal-9 compared with healthy controls (HC). The plasma levels of Gal-9 were associated with disease activity and remained unaffected when adding a TNF-inhibitor to their standard treatment. Gal-9 levels were elevated in the synovial fluid of established RA patients with advanced disease, compared with corresponding plasma samples. Gal-9 adhered to fibronectin, laminin and thrombospondin, while not to interstitial collagens in the ECM protein array. In vitro, a neutralizing Gal-9 antibody decreased MCP-1 and IL-6 production from both RA FLSs and OA FLSs. In co-cultures of autologous RA FLSs and PBMCs, the neutralization of Gal-9 also decreased MCP-1 and IL-6 production, without affecting the proportion of inflammatory FLSs. Conclusions: In RA, pretreatment plasma Gal-9 levels in early RA were increased and correlated with clinical disease activity. Gal-9 levels remained increased despite a significant reduction in the disease activity score in patients with early RA. The in vitro neutralization of Gal-9 decreased both MCP-1 and IL-6 production in an inflammatory subset of RA FLSs. Collectively these findings indicate that the persistent overexpression of Gal-9 in RA may modulate synovial FLS activities and could be involved in the maintenance of subclinical disease activity in RA.

Anti-mutated citrullinated vimentin antibodies in rheumatoid arthritis; diagnostic utility and association with deformities and disease activity

Rheumatoid arthritis (RA) is a chronic autoimmune disease with multiple morbidity burdens. Early diagnosis of RA is the main key in management and prevention of disease complications. Much research nowadays is looking for a serological marker with high accuracy in diagnosis of early RA cases. Our aim in this study was to evaluate the role of anti-mutated citrullinated vimentin (anti-MCV) antibodies in the early diagnosis of RA. In addition to compare its diagnostic sensitivity and specificity with anti-cyclic citrullinated peptide antibodies (anti-CCP) and RF antibodies in early versus established RA patients. This prospective cross-sectional study included 80 participants: 40 RA patients (20 early RA patients and 20 established RA patients), 20 patients with other rheumatic diseases (as a disease control group), and 20 apparently healthy participants as normal controls. All participants underwent history taking, clinical examination (general, articular assessment and calculation of disease activity score (DAS28-ESR)) for RA patients, radiological and laboratory investigations (RF, anti-CCP2 and anti-MCV antibodies measurements by ELISA technique). The results showed that the mean values of anti-CCP2 and anti-MCV were significantly increased in RA cases compared to the control groups (p=0.00 and p=0.01, respectively). Anti-MCV had sensitivity and specificity of 63% and 83%, respectively for diagnosing of early RA at area under curve of 0.80 compared to sensitivity and specificity 37% and 100%, respectively for anti-CCP2. Also, both (anti-CCP2 and anti-MCV) had positive significant correlations with ESR (p < 0.001 and p=0.02, respectively), CRP (p=0.01 and p=0.02, respectively) and DAS 28 (p < 0.001 for both). In conclusion, our data indicated that anti-MCV antibodies may represent a valuable marker for diagnosis of early RA cases.

GPR15 expressed in T lymphocytes from RA patients is involved in leukocyte chemotaxis to the synovium.

The rheumatoid arthritis (RA) inflammatory process occurs in the joints where immune cells are attracted into the synovium to promote remodeling and tissue damage. GPR15 is a G protein-coupled receptor (GPCR) located on chromosome 3 and has similarity in its sequence with chemokine receptors. Recent evidence indicates that GPR15 may be associated with modulation of the chronic inflammatory response. We evaluated the expression of GPR15 and GPR15L in blood and synovial tissue samples from RA patients, as well as to perform a functional migration assay in response to GPR15L. The expression of GPR15 and c10orf99/gpr15l mRNA was analyzed by RT-qPCR. Samples of synovial fluid and peripheral blood were analyzed for CD45+CD3+CD4+GPR15+ and CD45+CD3+CD8+GPR15+ T cell frequency comparing RA patients versus control subjects by flow cytometry. Migration assays were performed using PBMCs isolated from these individuals in response to the synthetic GPR15 ligand. Statistical analysis included Kruskal-Wallis test, T-test, or Mann-Whitney U test, according to data distribution. A higher expression in the mRNA for GPR15 was identified in early RA subjects. The frequencies of CD4+/CD8+ GPR15+ T lymphocytes are higher in RA patients comparing with healthy subjects. Also, the frequency CD4+/CD8+ GPR15+ T lymphocytes are higher in synovial fluid of established RA patients comparing with OA patients. GPR15 and GPR15L are present in the synovial tissue of RA patients and GPR15L promotes migration of PBMCs from RA patients and healthy subjects. Our results suggest that GPR15/GPR15L have a pathogenic role in RA and their antagonizing could be a therapeutic approach in RA.

Tapering subcutaneous methotrexate causes more disease flares compared with tapering oral administration in established rheumatoid arthritis patients.

Tapering subcutaneous methotrexate causes more disease flares compared with tapering oral administration in established rheumatoid arthritis patients.

Lung involvement prevalence in patients with early rheumatoid arthritis without known pulmonary disease: a multicentric cross sectional study

BackgroundClinically evident interstitial lung disease (ILD) affects between 10 and 42% of the patients with rheumatoid arthritis (RA). Airway involvement seems to be even more common. Most of the available evidence comes from studies performed in established RA patients. The aim of our study was to know the prevalence of non-diagnosed lung disease (airway and interstitial involvement) in patients with early RA and look for associated factors.MethodsWe designed an observational, multicenter, cross-sectional study, and included patients with RA of less than two years since diagnosis. We performed a structured questionnaire, HRCT and lung functional tests looking for lung disease, together with joint disease evaluation. We analyzed which variables were associated with the presence of lung disease on HRCT.ResultsWe included 83 patients, 83% females. The median (IQR) of time since RA diagnosis was 3 (1–6) months. In the HRCT, 57 patients had airway compromisea (72%), and 6 had interstitial abnormalities (7.5%). The most common altertion found in lung functional tests was a reduced DLCO (14%). The presence of at least one abnormality in the physical exam was associated with lung involvement on HRCT [13 (21.6%) vs 0 (0%); p = 0.026]. Also, patients with lung involvement presented significantly lower values of FVC% and DLCO%, and higher values of RV/TLC. No variable related to joint involvement was found associated with alterations in HRCT.ConclusionOur study shows that a large proportion of early RA patients has abnormal findings in HRCT. Further studies are required to confirm these findings.

Effect of initiating biologics compared to intensifying conventional DMARDs on clinical and MRI outcomes in established rheumatoid arthritis patients in clinical remission: Secondary analyses of the IMAGINE-RA trial

Objectives: To compare the effect of treat-to-target-based escalations in conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologics on clinical disease activity and magnetic resonance imaging (MRI) inflammation in a rheumatoid arthritis (RA) cohort in clinical remission. Method: One-hundred patients with established RA, Disease Activity Score based on 28-joint count–C-reactive protein (DAS28-CRP) < 3.2, and no swollen joints (hereafter referred to as ‘in clinical remission’) who received csDMARDs underwent clinical evaluation and MRI of the wrist and second to fifth metacarpophalangeal joints every 4 months. They followed a 2 year MRI treatment strategy targeting DAS28-CRP ≤ 3.2, no swollen joints, and absence of MRI osteitis, with predefined algorithmic treatment escalation: first: increase in csDMARDs; second: adding a biologic; third: switch biologic. MRI osteitis and Health Assessment Questionnaire (HAQ) (co-primary outcomes) and MRI combined inflammation and Simplified Disease Activity Index (SDAI) (key secondary outcomes) were assessed 4 months after treatment change and expressed as estimates of group differences. Statistical analyses were based on the intention-to-treat population analysed using repeated-measures mixed models. Escalation to first biologic compared to csDMARD escalation more effectively reduced MRI osteitis (difference between least squares means 1.8, 95% confidence interval 1.0–2.6), HAQ score (0.08, 0.03–0.1), MRI combined inflammation (2.5, 0.9–4.1), and SDAI scores (2.7, 1.9–3.5). Treat-to-target-based treatment escalations to biologics compared to escalation in csDMARDs more effectively improved MRI inflammation, physical function, and clinical disease activity in patients with established RA in clinical remission. Treatment escalation in RA patients in clinical remission reduces clinical and MRI-assessed disease activity. Trial registration: Clinicaltrials.gov identifier: NCT01656278

Sex-Specific Association of Left Ventricular Hypertrophy With Rheumatoid Arthritis.

Objectives: Clinical expression of rheumatoid arthritis (RA) varies by gender, but whether cardiovascular disease (CVD) is gender related in RA is unknown. Left ventricular (LV) hypertrophy (LVH) is a hallmark of CVD in RA patients. We investigated whether the association of LVH with RA is gender driven.Methods: Consecutive outpatients with established RA underwent echocardiography with measurement of LVH at baseline and one follow-up. All participants had no prior history of CVD or diabetes mellitus. We assessed CVD risk factors associated with LVH at follow-up, including sex, age, arterial blood pressure, and body mass index (BMI). We also evaluated inflammatory markers, autoimmunity, disease activity, and the use of RA medications as predictors of LVH.Results: We recruited 145 RA patients (121 females, 83%) and reassessed them after a median (interquartile range) of 36 months (24–50). At baseline, women were more dyslipidemic but otherwise had fewer CVD risk factors than men, including less prevalent smoking habit and hypertension, and smaller waist circumference. At follow-up, we detected LVH in 42/145 (44%) RA patients. LV mass significantly increased only in women. In multiple Cox regression analysis, women with RA had the strongest association with LVH, independently from the presence of CVD risk factors (OR, 6.56; 95% CI, 1.34–30.96) or RA-specific characteristics (OR, 5.14; 95% CI, 1.24–21.34). BMI was also significantly and independently associated with LVH.Conclusion: Among established RA patients, women carry the highest predisposition for LVH.

Bone Loss and Radiographic Damage Profile in Rheumatoid Arthritis Moroccan Patients.

BackgroundRheumatoid arthritis (RA) is a known cause of joint destruction and systemic bone loss. In this study, we aimed to evaluate the bone damage and bone loss profiles of established RA patients.MethodsWe designed a cross-sectional study on a cohort of established RA patients. The bone evaluation was performed by obtaining standard X-ray images of hands and feet combined with bone mineral density (BMD) measurements. Radiographic joint damage was calculated by the modified total Sharp /van der Heijde score (mTSS). BMD was obtained by performing dual energy X-ray absorptiometry of the lumbar spine and femoral neck. Data on age, smoking, alcoholism, steroid prescription, body mass index (BMI), disease duration, disease activity, and functional disability were collected.ResultsA total of 93 RA patients were recruited. Their mean age was 51.59±12.38 years, with a mean disease duration of 12.07±9.19 years. A total of 36.6% of patients had osteoporosis, and the mean mTSS was 70.33±48.93. Both hip (P=0.0005) and lumbar BMD (P=0.0005) were correlated with mTSS. Backward regression analyses determined that bone damage was associated with high titers of rheumatoid factor, low lumbar BMD, and low BMI. General bone loss was associated with gender, steroid dose, steroid duration, menopause, and BMI.ConclusionsBone damage was associated with low BMI and axial bone loss in our RA population.

Responding to questions from Li and colleagues

We thank Dr Li and colleagues for their interest in our analysis of the diagnostic accuracy of 14-3-3η protein in rheumatoid arthritis (RA) and for the opportunity to respond. The study conducted by Carrier et al,1 used before and after disease progression as controls, and did not include healthy control groups or disease control groups, so the specificity of 14-3-3η protein in RA cannot be calculated. Therefore, we excluded this study based on the inclusion criteria of our meta-analysis. The detection of 14-3-3 η protein is not by enzyme-linked immunosorbent assay (ELISA) but by light-initiated chemiluminescent assay (LiCA) in the research conducted by Zhang et al.2 Therefore, we excluded this study based on the inclusion criteria of our meta-analysis. In the results section of the research conducted by Shovman et al,3 the authors clearly state that with a cut-off of 0.19 ng/mL, the specificity of 14-3-3η protein was 95.5% in both early RA and established RA. Thus, the value of FP and TN should be 8 and 159, respectively. The two publications by Maksymowych et al4, 5 fulfilled the inclusion and exclusion criteria of this meta-analysis, so we have no reason to exclude either of them. Second, although the 2 studies conducted by Maksymowych et al shared overlapping groups of established RA patients, the case numbers of early RA patients of the latter study5 is greater than the former study4 and the latter study is a supplement to the previous one, so it will not add inappropriate weight in this meta-analysis. Additionally, as the sensitivity and specificity of 14-3-3 η protein in the 2 studies were different, therefore, it is necessary to include these 2 studies in this meta-analysis. Sincerely yours

Commentaries on Viewpoint: The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies.

Commentaries on Viewpoint: The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies.

Maintenance to target was associated with radiological outcomes in patients with rheumatoid arthritis: a real-world observational cohort study.

To investigate the effect of different maintenance to target on radiologic outcomes in patients with rheumatoid arthritis (RA) in real-world setting. RA patients enrolled were screened from a longitudinal cohort. The radiographies were evaluated at baseline, after 1-2 years and thereafter every 2 years. An increase of mTSS > 3 from baseline was taken as the primary outcome and accelerated annual radiological progression as the secondary outcome of radiological progression. The maintenance rate (MR) to target was calculated as the proportion of the year fulfilling preset criteria of target over the whole follow-up period. COX regression and logistic analysis were used to determine the effect of variables on radiological outcomes. Two hundred forty-three patients were enrolled, with median follow-up of 2 years (3.00). Radiological progression was observed in 43 (17.7%) patients, with annual increase of mTSS 0.20 (1.33). In multivariate analysis, MR was the only independent protective factor of both primary and secondary radiological outcomes in two models [HR 0.09, 95% CI (0.04, 0.22), p < 0.001, model 1; OR 0.21, 95% CI (0.09, 0.49), p < 0.001, model 2]. ACPA positivity was another independent risk factor of secondary outcome [OR 2.96, 95% CI (1.27, 6.86), p = 0.012]. Higher MR was also associated with less radiological progression in established RA patients. Partial MR was not inferior to full maintenance within 4 years in terms of halting radiological progression. Low MR and ACPA positivity were independent risk factors of poor radiological outcomes in RA patients. No significant difference in radiological progression could be detected between partial and full maintenance group within 4 years in daily practice. • The first study showing that maintenance to target is beneficial to bone protection in established RA patients in real-world setting • No difference in radiological outcomes between partial and full maintenance group within 4 years.

Relationship between the physician-based clinical scale for foot and ankle surgery and patient-reported outcomes in patients with long-standing rheumatoid arthritis: Results from a multicenter prospective observational cohort study

Objectives To validate and establish targets for the physician-based clinical scale for foot surgery in rheumatoid arthritis (RA) patients based on patient-reported outcomes from a multicenter prospective cohort. Methods We collected data on demographics, values from the RA foot and ankle scale by the Japanese Society for Surgery of the Foot (JSSF-RA), and patient-reported outcomes (PROs) including the Health Assessment Questionnaire Disability Index (HAQ-DI) before (baseline) and 6 and 12 months after joint surgery. Target values for JSSF-RA were determined according to the lower limit of the 95% CI of JSSF-RA in patients with HAQ-DI ≤0.5 after adjusting for age and sex. We used multiple linear regression analysis to examine potential predictors of JSSF-RA target achievement at baseline. Results Cross-sectional analysis was conducted on data from 417 cases. The JSSF-RA target for foot and ankle surgery was set at 74 according to the JSSF-RA value corresponding to HAQ-DI ≤0.5 (mean 77.6, 95% CI: 74.3–80.9). Longitudinal analysis of patients who underwent foot surgery (N = 59) determined target cut-off values of 1.188 and 65 for HAQ-DI and JSSF-RA at baseline, respectively, as being predictive for achieving JSSF-RA ≥74 after surgery. Conclusions A JSSF-RA value of 74 represents an important target for patients with RA who have undergone foot surgery. In order to achieve this target, the timing of the surgery should be considered in the treatment of established RA patients.

Troublesome friends within us: the role of gut microbiota on rheumatoid arthritis etiopathogenesis and its clinical and therapeutic relevance.

The role of gut microbiota on immune regulation and the development of autoimmune diseases such as rheumatoid arthritis (RA) is an emerging research topic. Multiple studies have demonstrated alterations on gut microbiota composition and/or function (referred to as dysbiosis) both in early and established RA patients. Still, research delineating the molecular mechanisms by which gut microorganisms induce the loss of immune tolerance or contribute to disease progression is scarce. Available data indicate that gut microbiota alterations are involved in RA autoimmune response by several mechanisms including the post-translational modification of host proteins, molecular mimicry between bacterial and host epitopes, activation of immune system and polarization toward inflammatory phenotypes, as well as induction of intestinal permeability. Therefore, in this review we analyze recent clinical and molecular evidence linking gut microbiota with the etiopathogenesis of RA. The potential of the gut microbiota as a diagnostic or severity biomarker is discussed, as well as the opportunity areas for the development of complementary therapeutic strategies based on the modulation of gut microbiota in the rheumatic patient.

THU0129 SLEEP DISTURBANCE AND LOW INFLAMMATION PREDICT A PATTERN OF CHRONIC FATIGUE IN ACTIVELY TREATED PATIENTS WITH ESTABLISHED RA.

Background:Fatigue is common among patients with rheumatoid arthritis (RA) and has major impact on the burden of disease. There is little knowledge regarding the factors predicting the longitudinal development of chronic fatigue.Objectives:To identify baseline predictors for the development of chronic fatigue in patients with RA who initiate biological DMARD (bDMARD) treatment, and to compare disease courses across categories of fatigue for 12 months follow-up.Methods:Different trajectories of fatigue were calculated from a cohort of 209 established RA patients initiating bDMARDs. Fatigue was assessed by use of the fatigue Numeric Rating Scale (0-10) from the Rheumatoid Arthritis Impact of Disease (RAID) questionnaire. The patients were assessed at 0, 1, 2, 3, 6 and 12 months. We defined three groups: no fatigue (≤3 at all visits), improved fatigue (&gt;3 at baseline but ≤3 at follow-up) and chronic fatigue (≥ 4 at all visits). All patients had clinical/subjective assessments (28 tender/swollen joint count, assessor’s/patient’s global VAS, RAID score, widespread pain, pain catastrophizing, the Hospital Anxiety and Depression Scale and inflammatory markers (ESR, CRP and calprotectin (a major granulocyte protein sensitive for inflammation in RA patients)). All patients were assessed by ultrasound (grey scale (GS) and power Doppler (PD)) of 36 joints and 4 tendons with semi-quantitative scoring (0-3). Differences between groups at baseline was assessed by bivariate analyses, and logistic regression models adjusted for age and gender were used to explore baseline predictors of chronic vs improved fatigue. Trajectories of different groups were plotted as estimated marginal means in figures, and differences between groups assessed by mixed models with maximum likelihood random effects, adjusted for age and sex.Results:Table 1 describes demographics and clinical factors of the three groups with significant differences shown in bold. Logistic regression with multivariate assessments found anti-CCP and low inflammation (calprotectin) to be predictors of chronic versus improved fatigue. Sleep disturbance was highly predictive of chronic fatigue. Figure 1 illustrates the trajectories for the three groups at all visits, showing the chronic fatigue group to have significantly higher DAS28, level of widespread pain, depression and sleep disturbance in contrast to no higher level of inflammation assessed by CRP and ultrasound PD.Table 1.No fatigueImproved fatigueChronicfatigueNo fatigue vs Improved fatigueImproved fatigue vs chronic fatigueNo fatigue vs. chronic fatigue482943pppAge, mean (SD) years51 (2)48 (2)54 (2)0.280.090.28Female gender (%)35 (73)24 (83)38 (88)0.400.500.09Higher Education (%)31 (65)23 (79)20 (47)0.170.010.17Anti-CCP positive (%)29 (60)20 (69)36 (84)0.720.010.002RF positive (%)27 (56)17 (59)30 (70)0.760.110.15Disease duration, mean (SD) years7 (1)8 (1)11 (1)0.810.110.03RA disease activityDAS28CRP3.2 (0.1)3.9 (0.2)4.7 (0.2)0.0030.004&lt;0.001Swollen joints (28)5.7 (0.7)5.6 (1.0)6.2 (0.7)0.900.600.63CRP mg/L mean (SD)9.4 (2.4)15.6 (4.1)11.0 (2.6)0.020.020.58Calprotectin mg/L mean (SD)1.6 (0.3)2.0 (0.4)1.5 (0.2)0.440.200.92Sum score PD mean (SD)14.3 (1.8)13.8 (2.5)12.3 (1.9)0.850.620.43Sum score GS mean (SD)31.6 (2.8)29.3 (3.4)28.2 (2.7)0.610.810.39Psychosocial factorsRAID sleep (VAS 0-10)1.2 (0.3)4.3 (0.6)6.7(0.4)&lt;0.001&lt;0.001&lt;0.001RAID fatigue (VAS 0-10)1.4 (0.2)5.6 (0.3)7.1 (0.3)&lt;0.0010.003&lt;0.001Widespread pain (0-25)4.3 (0.4)7.0 (0.8)8.6 (0.7)0.0010.16&lt;0.001HADS anxiety1.5 (0.3)1.4 (0.6)3.4 (0.7)0.260.580.10HADS depression0.8 (0.2)0.9 (0.4)3.0 (0.8)0.980.360.05Pain Catastrophizing (0-6)1.0 (0.2)2.5 (0.3)2.9 (0.3)&lt;0.0010.31&lt;0.001Conclusion:Sleep disturbance is a modifiable factor presently found to predict chronic versus improved fatigue. Thus, attention should be given to RA patients with sleep problems to seek to avoid development of chronic fatigue. This issue should be explored in further studies.Disclosure of Interests:Hilde Berner Hammer Consultant of: Has received fees as consultant from Roche, AbbVie and Novartis., Speakers bureau: Has received fees for speaking from AbbVie, BMS, Pfizer, UCB, Roche, MSD and Novartis, Brigitte Michelsen Grant/research support from: Research support from Novartis, Consultant of: Consulting fees Novartis, Joe Sexton: None declared, Till Uhlig Consultant of: Lilly, Pfizer, Speakers bureau: Grünenthal, Novartis, Sella Aarrestad Provan Consultant of: Novartis

THU0158 ‘ONE IS NOT ENOUGH’ - RITUXIMAB SINGLE VS DOUBLE INFUSION PROTOCOL IN TREATMENT OF ESTABLISHED RHEUMATOID ARTHRITIS – REAL LIFE EXPERIENCE OF GARTNAVEL GENERAL HOSPITAL, GLASGOW, UK

Background: Rituximab (RTX), chimeric anti-CD20 monoclonal antibody, is recommended as a treatment option for rheumatoid arthritis (RA) patients who had inadequate response or are intolerant to other DMARDs including at least one anti-TNF inhibitor1. The most cost-effective dosing and retreatment schedule remains to be defined. Based on series of case reports and observational studies, it is suggested that retreatment with RTX 1g single infusion provides similar clinical outcomes compared with 2 x 1g infusions2. We report our experience of using single infusion in treatment of established RA. Objectives: Our unit adopted the single 1g infusion protocol in 2017. Patients were switched to RTX biosimilar – in September 2017. The aim of this study was to assess the effectiveness of single 1g infusion in maintaining the response in RA patients. Methods: 80 established RA patients on RTX were identified using clinical records held on our database. 67.50% (54/80) were on single 1g infusion and 28.75% (23/80) were receiving 2 x 1g infusions. Flare and inadequate response were assessed by comparing DAS scores pre and post RTX treatment and clinical judgement. We also assessed the effectiveness of biosimilar RTX, and in switching to biosimilar RTX. Results: RTX group: Overall retention rate was 57.41% (31/54) in single infusion retreatment group. 31.48% (17/54) flared and 76.47% (13/17) were switched back to 2 x 1g infusions with recapture of response in all patients. 1 patient continued single infusion due to recurrent cytopenia and 3 have not had retreatment yet. 11.11% (6/54) had secondary loss of effect (LOE). No flares were noted in 2 x 1g infusion group. 3.75% (3/80) had severe anaphylactic reaction needing to stop their treatment whereas 5% (4/80) experienced minor infusion reactions but managed to continue their treatment. Switch group: 52 patients switched from RTX to biosimilar. 42 received single 1g infusion and 10 had 2x1g infusions. In single infusion group, 53.38% (22/42) maintained response, 33.33% (14/42) flared with recapture of response in 92.86% (13/14) on 2x1g infusions and secondary LOE in 11.90% (5/42). In 2x1g infusion group, 90% (9/10) maintained response whereas 10% (1/10) had secondary LOE. Biosimilar RTX group: There were 25 patients on biosimilar RTX. 13/25 (52%) went onto single 1g infusion retreatment protocol. Of these, 3 (23.07%) had flare and 1 (7.69%) had secondary LOE. There were 6 (24%) primary response failures, 2 (8%) minor infusion reactions and 1 (4%) major infusion reaction in this group. Conclusion: One third of patients in our cohort failed to respond to single infusion protocol. These results were reproducible in all groups – RTX, switch and biosimilar RTX single infusion group. Our study suggests clinicians and patients need to be vary in using single infusion protocol as there is significant risk of losing disease control.

P88 Intensive management in moderate established rheumatoid arthritis: the titrate trial

Abstract Background Intensive management (IM) using treat-to-target principles has been shown to be effective in many trials of early rheumatoid arthritis (RA) in patients with high disease activity levels. There is no trial evidence that this approach benefits patients with moderately active RA - a dominant group in clinics. We tested the hypothesis that IM increases remission rates in established moderate RA patients (DAS28-ESR 3.2-5.1) receiving stable conventional synthetic disease modifying drugs (csDMARDs) compared to standard care (SC). IM comprised of: (a)monthly clinical assessments; (b)treat-to-target titrated medication including biologics; (c)psycho-social support delivered by trained nurses and other practitioners in motivational interviewing techniques. Methods A multicentre individually randomised trial compared IM (using combination DMARDs, depot steroid, biologics in non-responders, alongside supportive care using motivational interviewing techniques from trained nurses) to standard care (SC) patients receiving their usual clinical care. The primary outcome was 12-months remission by DAS28-ESR. Secondary outcomes: alternative remission assessments, disability via the health assessment questionnaire (HAQ), pain, fatigue, erosive progression and harm. Multivariable logistic and linear regression compared treatment approaches under intention-to-treat with multiple imputation for missing data. Cost, quality-adjusted life years (QALYs) from the EQ-5D-5L instrument mapped to EQ5D-3L, and incremental cost-effectiveness ratios (ICERs) were calculated, for within trial period. Results 459 patients were screened and 335 randomised (168 IM; 167 SC); 303(90%) gave 12-month outcome measures. 139(83%) IM patients attended sessions. At 12 months IM significantly increased DAS28-ESR remissions compared to SC (32% vs 18%, p = 0.004) and other remission assessments. IM increased DAS28-ESR low disease activity (48% vs 32%, p = 0.005). Clinically important reductions in HAQ were seen in patients who achieved remission following IM (mean change at 12-months -0.40; 95% confidence intervals -0.57,-0.22), as well as improvements in both fatigue and pain. There was a minimal increase in erosive damage over 12 months in both groups. Serious adverse events (IM = 15 vs SC = 11) and other adverse events (114 IM,151 SC) were similar between groups. The base case ICER was £43,972 (€51,474) with a probability of being cost effective at £30,000/€35,000 of 0.17. The ICER fell to £29,363 (€24,384) after including patients’ personal costs and lost working time with a probability IM is cost-effective of 0.5 at UK willing to pay thresholds. This estimate was based on the historic prices of biologics and the probability is higher when current drug acquisition costs are applied. Conclusion IM by trained nurses in motivational interviewing techniques is clinically effective in moderate established RA, achieving more remission without increasing harm. It also gave clinically important improvement in pain and fatigue. There is a strong case to adopt this approach in routine practice as increasing remission rates may improve long-term outcomes, reduce future biologic prescribing and thereby improve long term cost-effectiveness. Disclosures E. Nikiphorou None.