Very Early Rheumatoid Arthritis Research Articles

POS0259 ULTRASOUND AS AN IMAGING BIOMARKER OF EARLY RESPONSE TO TOCILIZUMAB AND METHOTREXATE IN VERY EARLY RHEUMATOID ARTHRITIS, TOVERA – A LONGITUDINAL STUDY

Background:The combination of methotrexate (MTX) and tocilizumab (TCZ) has been proven to be superior to MTX alone in early rheumatoid arthritis (RA)1 and was able to prevent radiographic progression. Ultrasound (US) has become a valid imaging modality in managing RA. Together with clinical examination, US may allow a comprehensive monitoring of response to therapy. So far, few data are available concerning the early response to TCZ plus MTX in very early RA (VERA).Objectives:In this study we aimed to assess the early US response to TCZ plus MTX in VERA, DMARD-naïve patients.Methods:In this open-label, single-arm study, VERA patients received TCZ (162 mg/week, subcutaneously) and MTX (15-20 mg/week, per os) for 24 weeks as induction therapy, followed by MTX as maintenance therapy. RA was diagnosed according to the 2010 ACR/European league against rheumatism (EULAR) criteria. All patients who fulfilled the inclusion criteria (ClinicalTrials.gov: NCT02837146) underwent blood tests, clinical and ultrasound examinations at the predefined time-points: 0,2,4,8,12,24,32,48,54 weeks (w). Ultrasound examination of 34 joints (elbows, wrists, MCP [1-5, bilateral], PIP ([2-5, bilateral], knees, ankles and MTP [2-5, bilateral]) was performed blindly to clinical data. Gray-scale (GS), power-Doppler (PD) scores, and the global OMERACT-EULAR synovitis score (GLOESS) were assessed in each joint. The sum of individual scores was calculated for 17-joint score (JS) (whole joint set), 10-JS (wrists, MCP, ankles and MTP joints), 12-JS2, and 7-JS3.Results:Forty-four patients (77% women), aged 46.7 ± 12.4 years, completed the 24-week period. Two-thirds (72.7%) were positive for anti-citrullinated protein antibody (ACPA) and 18.2% had bone erosions. At baseline, the mean 28 swollen joints count (28-SJC) was 7.55± 4.5, mean disease activity score (DAS28)-CRP score was 5.2 ± 0.15, mean simplified clinical activity score (SDAI) was 31.4 ± 1.9, mean clinical activity score (CDAI) was 29.1 ± 1.8 and mean health assessments questionnaire (HAQ) score was 1.3 ± 0.1. The C-reactive protein (CRP) decreased significantly at 2w (p<0.05) and, accordingly DAS28-CRP score decreased significantly at 4w (p<0.05). The 28-SJC and CDAI scores decreased significantly at 8w (p<0.05). The HAQ and visual analogue scale (VAS) disease activity reported by patients decreased significantly at 8w (p<0.05) and VAS fatigue at 12w (p<0.05).The GLOESS and GS scores allowed us detecting the earliest significant treatment response at 2w and PD scores at 4w (p<0.05). Among US joint subsets, 17-JS (p<0.01), 12-JS (p<0.05) and 10-JS (p<0.05) were able to detect the earliest treatment response at 2w. The 7-joint score detected the earliest response at 4w, both in GS and PD (p<0.05).Conclusion:US scores were able to detect therapeutic response to TCZ plus MTX earlier than clinical scores and may therefore be a promising imaging biomarker.

Prevalence and factors associated with diagnosis of early rheumatoid arthritis in the south of Brazil

BackgroundRheumatoid arthritis (RA) is an autoimmune inflammatory disease characterized by peripheral and symmetrical polyarthritis. It can be divided into Very Early Rheumatoid Arthritis (VERA) diagnosed up to 3 months of symptoms and late onset (Late Early Rheumatoid Arthritis – LERA), diagnosed between 3 and 12 months. Currently, it is recommended to evaluate the patient with joint symptoms as early as possible, and the first 12 weeks of manifestations represent the ideal phase for the diagnosis, favoring a better evolution of the treatment. The present study aimed to determine the prevalence of early diagnosis of rheumatoid arthritis, mean time of diagnosis and to determine possible associated factors in the municipality of Blumenau, Santa Catarina, Brazil.MethodsA cross-sectional study using the 1987 American College of Rheumatology diagnostic criteria to select patients attended at primary or secondary health care units in Blumenau, Santa Catarina, southern Brazil, in 2014. Diagnostic time was verified by self-report of the time elapsed between the onset of symptoms and the diagnosis made by a rheumatologist. To test the associations, the chi-square test, the Wald linear trend test and the Poisson regression analysis were used.ResultsThe mean time of diagnosis was 28 months. The prevalence of diagnosis up to 3 and 12 months was 27.7% and 64.8%, respectively. Obesity was associated with time diagnosis in both periods. The 0–4 years category of the variable education was associated only with the period up to 12 months.ConclusionThe mean time of diagnosis was similar to the national context. Among socioeconomic factors, lower education was associated with the diagnosis of late onset RA. The anthropometric variable presented a progressive increase in the prevalence due to the longer time to diagnosis.

Profiling of B-Cell Factors and Their Decoy Receptors in Rheumatoid Arthritis: Association With Clinical Features and Treatment Outcomes.

Introduction: B-cell activation is pivotal in rheumatoid arthritis (RA) pathogenesis and represents a relevant therapeutic target. The main aim of this study was to characterize the profiles of B-cell factors and their decoy receptors in RA and evaluate their clinical relevance.Methods: sBLyS, sAPRIL, sBCMA, sTACI, sBLyS-R, and several cytokines' serum levels were measured by immunoassays in 104 RA patients and 33 healthy controls (HC). An additional group of 42 systemic lupus erythematosus (SLE) patients were enrolled as disease controls. Whole blood IFI44, IFI44L, IFI6, and MX1 gene expression was measured and averaged into an IFN-score. BLyS membrane expression (mBLyS) was assessed on blood cell subsets by flow cytometry.Results: increased sAPRIL and sBCMA levels were found in RA, whereas BLyS was elevated in very early RA (VERA). No differences were observed for sTACI and sBLyS-R. An increased sBLyS/sBLyS-R ratio was associated with poor clinical outcome at 6 and 12 months in VERA, whereas a positive association with disease activity was observed in established disease. Increased mBLyS expression was found on monocytes, mDCs, neutrophils and B-cells in RA, to a similar extent that in SLE patients. Cluster analysis identified a specific B-cell factors profile overrepresented in RA and associated with autoantibodies, elevated proinflammatory cytokines (IFNα, MIP1α, TNFα, IL-37, and GM-CSF) and increased type-I IFN signature. Increasing sBCMA and sBLyS serum levels upon treatment and mBLyS expression at baseline on monocytes and mDCs, but not B-cells, were associated with poor clinical outcome upon TNFα-blockade.Conclusions: profound and complex alterations of soluble and membrane-bound B-cell factors are observed in RA associated with clinical outcomes, thus supporting its applicability to guide patient stratification along disease course.

Heterogeneity of the Type I Interferon Signature in Rheumatoid Arthritis: A Potential Limitation for Its Use As a Clinical Biomarker.

An increased expression of interferon (IFN)-responding genes (IRGs), the so-called IFN signature, has been reported in rheumatoid arthritis (RA). However, some controversy exists concerning its clinical relevance. The main aim of this study is to evaluate whether quantitative and qualitative differences in the activation of the IFN pathway may account for these findings. The expression of IFN-induced protein 44 (IFI44), IFN-induced protein 44 like (IFI44L), IFN alpha inducible protein 6, and MX dynamin-like GTPase 1 (MX1) was determined in peripheral blood in 98 RA patients (IFI6) and 28 controls. RA patients were classified into groups according to their clinical stage and treatments received: very early RA (VERA), biological disease-modifying antirheumatic drug (bDMARD) naive, and bDMARD. An additional group of 13 RA patients candidates for tumor necrosis factor alpha (TNFα) blockade was also recruited. The associations among IRGs were evaluated by network and principal component analyses. The expression of all IRGs was increased in RA to different levels. The IFN score was increased in all RA groups (VERA, bDMARD-naïve, and bDMARD), but important differences in their degree of activation and in the relationships among IRGs were observed. The IFN score correlated with the accumulated disease activity score 28-joints, and it was found to be a predictor of clinical outcome in VERA. No differences in the IFN score were observed between the bDMARD-naive and bDMARD groups, but opposite associations with the clinical parameters were noted. Interestingly, the correlations among IRGs delineate different pictures between these two groups. The IFN score at baseline predicted poor clinical outcome upon TNFα blockade. Although no absolute changes in the IFN score were found, TNFα-blockade shifted the associations among IRGs. A certain heterogeneity within the IFN signature can be recognized in RA, depending on the clinical stage. The structure of the IFN signature may be a potential explanation for the controversy in this field and must be considered to decipher its clinical relevancein RA.

Anti-MCV antibodies predict radiographic progression in Greek patients with very early (

This study aimed to assess the diagnostic and prognostic value of anti-mutated citrullinated vimentin (MCV) antibodies in very early rheumatoid arthritis (VERA) and in established rheumatoid arthritis (RA). Seventy-one patients with undifferentiated arthritis (UA) of <3months duration, 141 with established RA, 53 with other rheumatic diseases, and 40 healthy individuals were included in the study. Anti-MCV, anti-cyclic citrullinated peptide (CCP) antibodies, and rheumatoid factor (RF) were determined and hand radiographs were recorded. Patients were assessed prospectively for 2years, and hand radiographs were repeated. Diagnostic performance of anti-MCV was studied with receiver operating characteristic (ROC) curves and evaluation of sensitivity, specificity, and likelihood ratios. Forty-six percent of UA patients progressed to RA at 2years. In VERA patients, sensitivity of anti-MCV was 52%, compared to 44% of anti-CCP and 37% of RF, while specificity was 91%, compared to 91% of RF and 84% of anti-CCP. Anti-MCV were detected in 25% of VERA patients negative for both anti-CCP and RF. In established RA, anti-MCV did not sustain its diagnostic performance. By multivariable analysis, anti-MCV, but not anti-CCP or RF, showed significant correlation with radiographic progression in VERA patients. In established RA, anti-MCV, anti-CCP, and RF were associated with active disease (p≤0.03) and joint damage (p≤0.004). By multivariate analysis, the strongest factors for radiographic damage were disease duration (p=0.000), HAQ score (p=0.000), and RF (p=0.002). In conclusion, in patients with very early UA, anti-MCV predict both progression to RA and radiological damage, and therefore, anti-MCV antibody testing may be useful in every day practice.

DKK1 expression by synovial fibroblasts in very early rheumatoid arthritis associates with lymphocyte adhesion in an in vitro flow co-culture system.

BackgroundSynovial fibroblasts play a key role in joint destruction and regulation of the inflammatory infiltrate in established rheumatoid arthritis (RA). The mechanisms by which this occurs in the earliest stages of RA are largely unknown. We investigated the role of Dickkopf-related protein 1 (DKK1) produced by synovial fibroblasts of patients with very early rheumatoid arthritis (VeRA).MethodsFibroblasts were isolated from the disease-modifying anti-rheumatic drug–naive Birmingham early arthritis cohort of patients with new onset of clinically apparent arthritis and inflammatory symptoms of ≤12 weeks’ duration, who at follow-up had either resolving arthritis or RA. Endothelial fibroblast co-cultures were formed using porous filters, and lymphocyte adhesion to co-cultures was assessed using phase-contrast microscopy. DKK1 gene expression and secretion were quantified by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively.ResultsSynovial fibroblasts from patients with VeRA expressed significantly higher levels of DKK1 messenger RNA than those from patients with resolving arthritis. A similar trend was observed for DKK1 protein secretion. In co-culture constructs, more DKK1 tended to be secreted in co-cultures incorporating fibroblasts from VeRA than in co-cultures from non-inflamed joints and resolving arthritis. DKK1 secretion during co-culture positively correlated with lymphocyte adhesion.ConclusionsAlterations in DKK1 could be involved in the pathogenesis and perpetuation of the inflammatory response in the earliest clinically apparent stages of RA.

FRI0029 The Impact of Very Early Treatment on Patient Reported Outcomes in Rheumatoid Arthritis

BackgroundDespite substantial advances in the treatment of rheumatoid arthritis (RA), patients continue to report long term limitations. The combination of TNFα antagonists and methotrexate (MTX) in early RA (ERA), defined...

AB0085 Serum Levels of CXCL13 Are Increased in Untreated Patients with Rheumatoid Arthritis from the First Weeks of Disease Development

BackgroundCXCL13 (C-X-C motif ligand 13), also known as B-cell chemo-attractant, is an important B-cell chemokine that directly affects the migration and organization of B cells within follicles of lymphoid tissues....

A1.74 Serum levels of CXCL13 are increased in untreated patients with rheumatoid arthritis from the first weeks of disease development

Background and ObjectivesCXCL13 (C-X-C motif ligand 13), also known as B-cell chemo-attractant, is an important B-cell chemokine that directly affects the migration and organization of B cells within follicles of...

SAT0107 Ultrasound defined tenosynovitis improves the prediction of rheumatoid arthritis and persistent disease in patients with very early synovitis

BackgroundTenosynovitis (TS) is a common manifestation of rheumatoid arthritis and postulated to be an early marker of disease but requires imaging to reliably detect its presence. The prevalence of tenosynovitis...

Synovium CD20 expression is a potential new predictor of bone erosion progression in very-early arthritis treated by sequential DMARDs monotherapy – A pilot study from the VErA cohort

ObjectiveBecause available biomarkers (rheumatoid factors [RF], anti-cyclic citrullinated autoantibodies [anti-CCP2], erythrocyte sedimentation rate at 1st hour [ESR]/C-reactive peptide [CRP] and bone erosions) are insufficient to predict rheumatoid arthritis (RA) structural damage, to determine whether synovium expression of greater or equal to 1 markers could constitute new prognostic factor(s). MethodThe study was conducted on 18 prospectively enrolled disease-modifying anti-rheumatic drug (DMARD)- and glucocorticoid-naïve, VErA cohort patients with very-early arthritis (median duration: 4months). Recorded at baseline were: clinical and biological (serum ESR, CRP, RF-isotypes, anti-CCP2, osteoprotegerin, receptor activator of nuclear κB-ligand [RANK-L] and cartilage oligomeric matrix protein [COMP] levels) data; synovium expression (HLA-DR, CD163, CD3, CD20, VEGF, osteoprotegerin, RANK-L, Bcl2 and global inflammation index) for a metacarpophalangeal joint-synovium biopsy. Baseline and 3-year hand-and-foot X-rays were graded with the van der Heijde-modified-Sharp score; the judgment criterion was its progression during follow-up. Pearson's product moment correlation statistics were used to test for association between paired samples. ResultsA baseline, a significant relationship was found between erosive damage and markers of B-cell activation, notably the synovium CD20 expression (r=0.68; P=0.0001). Quantified by the modified-Sharp erosion score variation, the 3-year structural damage progression was significantly correlated with: serum levels of RF-IgG (r=0.75; P=0.0003), -IgM (r=0.69; P=0.001), anti-CCP2 (r=0.53; P=0.02) and RANK-L (r=0.61; P=0.007); synovium CD20 expression (r=0.70; P=0.001). ConclusionThis analysis of the prognostic value of a large panel of synovium markers in a limited sample of prospectively followed, well-documented patients suggested that both synovial CD20 and serum RANK-L levels might be new predictors of structural damage progression in very-early RA.

Very early rheumatoid arthritis is the major predictor of major outcomes: clinical ACR remission and radiographic non-progression

ObjectivesTo identify predictors of clinical remission as well as of no x-ray progression in a cohort of early rheumatoid arthritis (ERA) treated with a tight-control protocol.MethodsA total of 121 consecutive...

BAFF AND TACI mRNA expression are increased in very early rheumatoid arthritis patients

BackgroundB cells play several important roles in rheumatoid arthritis (RA). Previous studies by our group have demonstrated that very early rheumatoid arthritis (VERA) patients have disturbances in peripheral blood memory...

The usefulness of magnetic resonance imaging of the hand and wrist in very early rheumatoid arthritis

IntroductionMagnetic resonance imaging (MRI) was used to study the hand and wrist in very early rheumatoid arthritis (RA), and the results were compared with early and established disease.MethodsFifty-seven patients fulfilling the new American College of Rheumatology criteria for RA, 26 with very early RA (VERA), 18 with early RA (ERA), and 13 with established RA (ESTRA), (disease duration < 3 months, < 12 months, and > 12 months, respectively) were enrolled in the study. MRI of the dominant hand and wrist was performed by using fat-suppressed T2-weighted and plain and contrast-enhanced T1-weighted sequences. Evaluation of bone marrow edema, synovitis, and bone erosions was performed with the OMERACT RA MRI scoring system.ResultsEdema, erosions, and synovitis were present in VERA, and the prevalence was 100%, 96.15%, and 92.3%, respectively. Significant differences in edema and erosions were found between VERA and ESTRA (P < 0.05). No significant difference was found in synovitis.ConclusionsEdema, erosions, and synovitis are findings of very early RA. MRI, by detecting these lesions, may play an important role in the management of these patients.

Is it possible to identify early predictors of the future cost of chronic arthritis? The VErA project

This study was conducted to identify early predictors of the total cost of inflammatory arthritis (IA). One hundred and eighty patients affected by undifferentiated arthritis (UA) or rheumatoid arthritis (RA) were included in the French Very Early rheumatoid Arthritis (VErA) cohort between 1998 and 2001. Health economic data for 2003 were collected using a patient self-questionnaire. Results were analysed in terms of direct, indirect and total costs in 2003 euros (2003euro) for the population as a whole and in diagnostic subgroups. A payor perspective (the French National Health Insurance, in this case) was adopted. Multiple linear regression models were used to identify predictors of total cost from among the criteria assessed on recruitment. Results of the study showed that for the study population as a whole, the mean total cost was euro4700 per patient. The costs attributable to the RA and UA sub-groups were euro5928 and euro2424 per patient, respectively. In a univariate analysis, certain parameters were significantly correlated with a higher cost of illness. In the multivariate analysis, some of these parameters were further identified as being predictive of higher cost. Two strong significant, early predictors of total cost were identified: higher pain (P = 0.002) and the presence of rheumatoid factor (P = 0.004). In the RA sub-group, lower grip strength of the dominant hand (P = 0.039) was another predictor of the illness's subsequent economic impact. In conclusion, our data show that simple clinical and laboratory parameters can be used early in the course of IA to predict the condition's impact on healthcare budgets.

Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis.

Delay of disease-modifying anti-rheumatic drug (DMARD) therapy is a major contributing factor for poor outcome in rheumatoid arthritis (RA). Although early therapy has been shown to be particularly effective, there is still uncertainty about the optimal time point of DMARD introduction. We wanted to test if a therapeutic window of opportunity may exist within the first few months of the disease. In this case-control parallel-group study, 20 very early RA (VERA) patients with median disease duration of 3 months were age and gender matched to a group of 20 late early RA (LERA) patients with median disease duration of 12 months until first DMARD initiation. Follow-up time was 36 months. Primary outcome measures were the disease activity score (DAS28) and radiological joint destruction using the Larsen method. Already after 3 months of DMARD therapy we found a significant difference of improvement in favour of the VERA patients in the DAS28. This trend continued over the study period. At study end the DAS28 showed an improvement of 2.8+/-1.5 in the VERA vs 1.7+/-1.2 in the LERA group (P(c)<0.05). The Larsen scores showed a statistically significant retardation of progression in the VERA compared with the LERA. Our results indicate that there is a window of opportunity for highly successful treatment of RA in the first year, and especially within the first 3 months of therapy. Thus, early diagnosis and therapy may be the crucial step in achieving optimal control of disease progression and prognosis in RA.