Synovial cellular and molecular signatures stratify clinical response to csDMARD therapy and predict radiographic progression in early rheumatoid arthritis patients

ObjectivesTo unravel the hierarchy of cellular/molecular pathways in the disease tissue of early, treatment-naïve rheumatoid arthritis (RA) patients and determine their relationship with clinical phenotypes and treatment response/outcomes longitudinally.Methods144 consecutive treatment-naïve early RA patients (<12 months symptoms duration) underwent ultrasound-guided synovial biopsy before and 6 months after disease-modifying antirheumatic drug (DMARD) initiation. Synovial biopsies were analysed for cellular (immunohistology) and molecular (NanoString) characteristics and results compared with clinical and imaging outcomes. Differential gene expression analysis and logistic regression were applied to define variables correlating with treatment response and predicting radiographic progression.ResultsCellular and molecular analyses of synovial tissue demonstrated for the first time in early RA the presence of three pathology groups: (1) lympho-myeloid dominated by the presence of B cells in addition to myeloid cells; (2) diffuse-myeloid with myeloid lineage predominance but poor in B cells nd (3) pauci-immune characterised by scanty immune cells and prevalent stromal cells. Longitudinal correlation of molecular signatures demonstrated that elevation of myeloid- and lymphoid-associated gene expression strongly correlated with disease activity, acute phase reactants and DMARD response at 6 months. Furthermore, elevation of synovial lymphoid-associated genes correlated with autoantibody positivity and elevation of osteoclast-targeting genes predicting radiographic joint damage progression at 12 months. Patients with predominant pauci-immune pathology showed less severe disease activity and radiographic progression.ConclusionsWe demonstrate at disease presentation, prior to pathology modulation by therapy, the presence of specific cellular/molecular synovial signatures that delineate disease severity/progression and therapeutic response and may pave the way to more precise definition of RA taxonomy, therapeutic targeting and improved outcomes.

Download Full-text

Mast cells in early rheumatoid arthritis associate with disease severity and support B cell autoantibody production

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2018-213418 ◽

2018 ◽

Vol 77 (12) ◽

pp. 1773-1781 ◽

Cited By ~ 20

Author(s):

Felice Rivellese ◽

Daniele Mauro ◽

Alessandra Nerviani ◽

Sara Pagani ◽

Liliane Fossati-Jimack ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

B Cells ◽

Mast Cells ◽

Disease Activity ◽

B Cell ◽

Synovial Tissue ◽

Autoantibody Production ◽

Early Ra ◽

Treatment Naïve

ObjectivesMast cells (MCs) are involved in the pathogenesis of rheumatoid arthritis (RA). However, their contribution remains controversial. To establish their role in RA, we analysed their presence in the synovium of treatment-naïve patients with early RA and their association and functional relationship with histological features of synovitis.MethodsSynovial tissue was obtained by ultrasound-guided biopsy from treatment-naïve patients with early RA (n=99). Immune cells (CD3/CD20/CD138/CD68) and their relationship with CD117+MCs in synovial tissue were analysed by immunohistochemistry (IHC) and immunofluorescence (IF). The functional involvement of MCs in ectopic lymphoid structures (ELS) was investigated in vitro, by coculturing MCs with naïve B cells and anticitrullinated protein antibodies (ACPA)-producing B cell clones, and in vivo in interleukin-27 receptor alpha (IL27ra)-deficient and control mice during antigen-induced arthritis (AIA).ResultsHigh synovial MC counts are associated with local and systemic inflammation, autoantibody positivity and high disease activity. IHC/IF showed that MCs reside at the outer border of lymphoid aggregates. Furthermore, human MCs promote the activation and differentiation of naïve B cells and induce the production of ACPA, mainly via contact-dependent interactions. In AIA, synovial MC numbers increase in IL27ra deficient mice, in association with ELS and worse disease activity.ConclusionsSynovial MCs identify early RA patients with a severe clinical form of synovitis characterised by the presence of ELS.

Download Full-text

Adalimumab, a human anti-TNF monoclonal antibody, outcome study for the prevention of joint damage in Japanese patients with early rheumatoid arthritis: the HOPEFUL 1 study

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2012-202433 ◽

2013 ◽

Vol 73 (3) ◽

pp. 536-543 ◽

Cited By ~ 59

Author(s):

Tsutomu Takeuchi ◽

Hisashi Yamanaka ◽

Naoki Ishiguro ◽

Nobuyuki Miyasaka ◽

Masaya Mukai ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Early Rheumatoid Arthritis ◽

Radiographic Progression ◽

Joint Damage ◽

Japanese Patients ◽

High Disease Activity ◽

Double Blind ◽

American College Of Rheumatology ◽

Modified Total Sharp Score

ObjectivesTo evaluate the efficacy and safety of adalimumab+methotrexate (MTX) in Japanese patients with early rheumatoid arthritis (RA) who had not previously received MTX or biologics.MethodsThis randomised, double-blind, placebo-controlled, multicentre study evaluated adalimumab 40 mg every other week+MTX 6–8 mg every week versus MTX 6–8 mg every week alone for 26 weeks in patients with RA (≤2-year duration). The primary endpoint was inhibition of radiographic progression (change (Δ) from baseline in modified total Sharp score (mTSS)) at week 26.ResultsA total of 171 patients received adalimumab+MTX (mean dose, 6.2±0.8 mg/week) and 163 patients received MTX alone (mean dose, 6.6±0.6 mg/week, p<0.001). The mean RA duration was 0.3 years and 315 (94.3%) had high disease activity (DAS28>5.1). Adalimumab+MTX significantly inhibited radiographic progression at week 26 versus MTX alone (ΔmTSS, 1.5±6.1 vs 2.4±3.2, respectively; p<0.001). Significantly more patients in the adalimumab+MTX group (62.0%) did not show radiographic progression (ΔmTSS≤0.5) versus the MTX alone group (35.4%; p<0.001). Patients treated with adalimumab+MTX were significantly more likely to achieve American College of Rheumatology responses and achieve clinical remission, using various definitions, at 26 weeks versus MTX alone. Combination therapy was well tolerated, and no new safety signals were observed.ConclusionsAdalimumab in combination with low-dose MTX was well tolerated and efficacious in suppressing radiographic progression and improving clinical outcomes in Japanese patients with early RA and high disease activity.

Download Full-text

Calprotectin as a marker of inflammation in patients with early rheumatoid arthritis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2017-211695 ◽

2017 ◽

Vol 76 (12) ◽

pp. 2031-2037 ◽

Cited By ~ 22

Author(s):

Maria Karolina Jonsson ◽

Nina Paulshus Sundlisæter ◽

Hilde Haugedal Nordal ◽

Hilde Berner Hammer ◽

Anna-Birgitte Aga ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Treatment Response ◽

Radiographic Progression ◽

Activity Index ◽

Inflammatory Marker ◽

Target Therapy ◽

Power Doppler ◽

Treat To Target ◽

Symptom Duration

ObjectivesCalprotectin is an inflammatory marker of interest in rheumatoid arthritis (RA). We evaluated whether the level of calprotectin was associated with disease activity, and if it was predictive of treatment response and radiographic progression in patients with early RA.MethodsPlasma from disease-modifying antirheumatic drug (DMARD)-naïve patients with RA fulfilling 2010 American College of Rheumatology/European League Against Rheumatism classification criteria with symptom duration <2 years was analysed for calprotectin at baseline, and after 1, 3 and 12 months. All patients received treat-to-target therapy, as part of a randomised controlled strategy trial (ARCTIC). The association between calprotectin, erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) and measures of disease activity were assessed by correlations. We used likelihood ratios and logistic regression models to assess the predictive value of the baseline inflammatory markers for treatment response and radiographic damage.Results215 patients were included: 61% female, 82% anti-citrullinated peptide antibody positive, mean (SD) age 50.9 (13.7) years and median (25, 75 percentile) symptom duration 5.8 (2.8, 10.5) months. Calprotectin was significantly correlated with Clinical Disease Activity Index (r=0.32), ESR (r=0.50) and ultrasonography power Doppler (r=0.42) before treatment onset. After 12 months of treatment, calprotectin, but not ESR and CRP, was significantly correlated with power Doppler (r=0.27). Baseline levels of calprotectin, ESR and CRP were not predictive of treatment response, but high levels of calprotectin were associated with radiographic progression in multivariate models.ConclusionsCalprotectin was correlated with inflammation assessed by ultrasound before and during DMARD treatment, and was also associated with radiographic progression. The data support that calprotectin may be of interest as an inflammatory marker when assessing disease activity in different stages of RA.Trial registration numberNCT01205854; Post-results.

Download Full-text

Five-year Favorable Outcome of Patients with Early Rheumatoid Arthritis in the 2000s: Data from the ESPOIR Cohort

The Journal of Rheumatology ◽

10.3899/jrheum.121515 ◽

2013 ◽

Vol 40 (10) ◽

pp. 1650-1657 ◽

Cited By ~ 26

Author(s):

Bernard Combe ◽

Nathalie Rincheval ◽

Joelle Benessiano ◽

Francis Berenbaum ◽

Alain Cantagrel ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Early Rheumatoid Arthritis ◽

Radiographic Progression ◽

Health Assessment ◽

Daily Practice ◽

Joint Disease ◽

Early Ra ◽

American College Of Rheumatology ◽

Biologic Dmard

Objective.To report the 5-year outcome of a large prospective cohort of patients with very early rheumatoid arthritis (RA), and to identify factors predictive of outcome.Methods.Patients were recruited if they had early arthritis of < 6 months’ duration, had a high probability of developing RA, and had never been prescribed disease-modifying antirheumatic drugs (DMARD) or steroids. Logistic regression analysis was used to determine factors that predict outcome.Results.We included 813 patients from December 2002 to April 2005. Age was 48.1 ± 12.6 years, delay before referral 103.1 ± 52.4 days, 28-joint Disease Activity Score (DAS28) 5.1 ± 1.3, Health Assessment Questionnaire (HAQ) 1.0 ± 0.7; 45.8% and 38.7% had rheumatoid factor or antibodies to cyclic citrullinated peptide (anti-CCP), respectively; 22% had hand or foot erosions; 78.5% fulfilled the American College of Rheumatology/European League Against Rheumatism criteria for RA at baseline and 93.8% during followup. At 5 years, 573 patients were evaluated. The outcome was mild for most patients: disease activity (median DAS28 = 2.5) and HAQ disability (median 0.3) were well controlled over time; 50.6% achieved DAS28 remission and 64.7% low disease activity. Radiographic progression was low (2.9 Sharp unit/year) and only a few patients required joint surgery. Nevertheless, some patients developed new comorbidities. During the 5 years, 82.7% of patients had received at least 1 DMARD (methotrexate, 65.9%), 18.3% a biological DMARD, and about 60% prednisone at least once. Anti-CCP was the best predictor of remaining in the cohort for 5 years, of prescription of synthetic or biologic DMARD, and of radiographic progression.Conclusion.The 5-year outcome of an early RA cohort in the 2000s was described. Anti-CCP was a robust predictor of outcome. The generally good 5-year outcome could be related to early referral and early effective treatment, key processes in the management of early RA in daily practice.

Download Full-text

Clusterin serum levels are elevated in patients with early rheumatoid arthritis and predict disease activity and treatment response

Scientific Reports ◽

10.1038/s41598-021-90973-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Tereza Kropáčková ◽

Heřman Mann ◽

Olga Růžičková ◽

Olga Šléglová ◽

Lucia Vernerová ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Treatment Response ◽

Early Rheumatoid Arthritis ◽

Roc Analysis ◽

Predictive Biomarker ◽

Serum Levels ◽

Serum Concentrations ◽

Low Disease Activity ◽

Treatment Naïve

AbstractClusterin (CLU) is a molecular chaperone that participates in a variety of biological processes. Recent studies indicate its possible involvement in the development of bone erosions and autoimmunity. The aim of this study was to investigate its serum concentrations in patients with early rheumatoid arthritis (RA) and to explore their potential relationship with disease activity and treatment response. Serum levels of CLU were measured in 52 patients before and 3 months after the initiation of treatment and in 52 healthy individuals. CLU levels at baseline were significantly increased in patients with early RA compared with healthy subjects (p < 0.0001). After 3 months of treatment, the levels of CLU decreased and reached concentrations comparable to those in controls. Even though there was no relationship between CLU levels and disease activity at baseline, CLU levels positively correlated with disease activity at months 3, 6 and 12 after treatment initiation. Using ROC analysis, lower CLU baseline levels predicted achieving the therapeutic target of low disease activity and remission at months 3, 6 and 12. In summary, we found increased serum concentrations of clusterin in treatment-naïve patients with early rheumatoid arthritis, and we suggest clusterin as a predictive biomarker of disease activity and treatment response.

Download Full-text

Biologics in rheumatoid arthritis

Batna Journal of Medical Sciences (BJMS) ◽

10.48087/bjmstf.2014.1109 ◽

2014 ◽

Vol 1 (1) ◽

pp. 34-37

Author(s):

Khalid Testas ◽

◽

Samy Slimani ◽

Lamia Djeghader ◽

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

B Cells ◽

Disease Activity ◽

Small Molecule ◽

Radiographic Progression ◽

Tnf Alpha ◽

Janus Kinases ◽

Low Disease Activity ◽

The World

Remission of low disease activity has become the main goal in the management of rheumatoid arthritis (RA), thanks to immunosuppressants but more importantly to a new emerging drug called biologics. Biologics used in RA have proved their efficacy on symptoms as well as radiographic progression, and they have been integrated into the recommendations for the management of RA. TNF alpha inhibitors with their five different molecules are the most prescribed bDMARDs in the world since their approval during the 1990s. Since then, more molecules were made available, targeting other compounds of the rheumatoid inflammation: IL1 (Anakinra), CD20 B cells (Rituximab), costimulation molecules of T cells (Abatacept), IL6 (Tocilizumab) and more recently small molecule inhibitors (Janus kinases), Tofacitinib.

Download Full-text

Effects of Smoking on Disease Activity and Radiographic Progression in Early Rheumatoid Arthritis

The Journal of Rheumatology ◽

10.3899/jrheum.110410 ◽

2011 ◽

Vol 38 (12) ◽

pp. 2536-2539 ◽

Cited By ~ 27

Author(s):

VIRGINIA RUIZ-ESQUIDE ◽

JOSÉ A. GÓMEZ-PUERTA ◽

JUAN D. CAÑETE ◽

EDUARD GRAELL ◽

IVONNE VAZQUEZ ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Early Rheumatoid Arthritis ◽

Therapeutic Response ◽

Radiographic Progression ◽

Disease Onset ◽

Current Smoking ◽

Larsen Score ◽

Early Ra ◽

European League Against Rheumatism

Objective.To analyze the effects of cigarette smoking on disease activity and radiographic damage in patients with early rheumatoid arthritis (RA).Methods.Study subjects were 156 patients with early RA (< 2 yrs). Disease activity, therapeutic response, and radiographic progression were compared in smokers and nonsmokers at 24 months.Results.At baseline, ever-smokers had earlier disease onset and a closer association with the shared epitope (SE), but not more seropositive disease. No significant differences were observed in disease activity and European League Against Rheumatism therapeutic responses between smokers and nonsmokers. Multivariate analysis showed that baseline Larsen score, the HLA-DRB*04 genotype, being female, and current smoking were associated with radiographic progression.Conclusion.In patients with early RA, smoking was associated with earlier disease onset and the SE. Smoking was an independent factor of radiographic progression.

Download Full-text

A Multibiomarker Disease Activity Score for Rheumatoid Arthritis Predicts Radiographic Joint Damage in the BeSt Study

The Journal of Rheumatology ◽

10.3899/jrheum.131412 ◽

2014 ◽

Vol 41 (11) ◽

pp. 2114-2119 ◽

Cited By ~ 30

Author(s):

Iris M. Markusse ◽

Linda Dirven ◽

Marianne van den Broek ◽

Casper Bijkerk ◽

K. Huub Han ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Disease Activity Score ◽

Radiographic Progression ◽

Joint Damage ◽

Activity Score ◽

Serum Samples ◽

Radiographic Damage ◽

Damage Progression ◽

Increased Risk

Objective.To determine whether a multibiomarker disease activity (MBDA) score predicts radiographic damage progression in the subsequent year in patients with early rheumatoid arthritis.Methods.There were 180 serum samples available in the BeSt study (trial numbers NTR262, NTR 265): 91 at baseline (84 with radiographs available) and 89 at 1-year followup (81 with radiographs available). Radiographs were assessed using the Sharp/van der Heijde Score (SvdH). Twelve serum biomarkers were measured to determine MBDA scores using a validated algorithm. Receiver-operating curves and Poisson regression analyses were performed, with Disease Activity Score (DAS) and MBDA score as independent variables, and radiographic progression as dependent variable.Results.At baseline, MBDA scores discriminated more between patients who developed radiographic progression (increase in SvdH ≥ 5 points) and patients who did not [area under the curve (AUC) 0.767, 95% CI 0.639–0.896] than did DAS (AUC 0.521, 95% CI 0.358–0.684). At 1 year, MBDA score had an AUC of 0.691 (95% CI 0.453–0.929) and DAS had an AUC of 0.649 (95% CI 0.417–0.880). Adjusted for anticitrullinated protein antibody status and DAS, higher MBDA scores were associated with an increased risk for SvdH progression [relative risk (RR) 1.039, 95% CI 1.018–1.059 for baseline MBDA score; 1.037, 95% CI 1.009–1.065 for Year 1 MBDA score]. Categorized high MBDA scores were also correlated with SvdH progression (RR for high MBDA score at baseline 3.7; low or moderate MBDA score as reference). At 1 year, high MBDA score gave a RR of 4.6 compared to low MBDA score.Conclusion.MBDA scores predict radiographic damage progression at baseline and during disease course.

Download Full-text

Association Between Vitamin D Deficiency and Disease Activity, Disability, and Radiographic Progression in Early Rheumatoid Arthritis: The ESPOIR Cohort

The Journal of Rheumatology ◽

10.3899/jrheum.190795 ◽

2019 ◽

Vol 47 (11) ◽

pp. 1624-1628

Author(s):

Gaël Mouterde ◽

Etienne Gamon ◽

Nathalie Rincheval ◽

Cédric Lukas ◽

Raphaele Seror ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Vitamin D ◽

Disease Activity ◽

Vitamin D Deficiency ◽

Early Rheumatoid Arthritis ◽

Radiographic Progression ◽

Early Arthritis ◽

Baseline Serum ◽

Link Type ◽

Early Ra

Objective.To evaluate the association of baseline serum level of vitamin D with disease activity, disability, and radiographic damage over the first year in early rheumatoid arthritis (RA).Methods.Among early arthritis patients included in the ESPOIR cohort, patients with early RA were evaluated. Levels of 25-hydroxy vitamin D2 and D3 were measured at baseline. Baseline associations between vitamin D level and 28-joint count Disease Activity Score based on erythrocyte sedimentation rate (DAS28-ESR), Health Assessment Questionnaire–Disability Index (HAQ-DI), and van der Heijde modified total Sharp score (mTSS) were assessed. Bivariate analysis was used to assess the association between vitamin D level and radiographic progression (mTSS increased by ≥ 1 point) or disability (HAQ-DI ≥ 0.5) over 12 months. Forward stepwise multiple logistic regression was used to evaluate the independent association of baseline variables and outcomes.Results.Among 813 patients with early arthritis, data for 645 patients with RA were analyzed. Vitamin D level was < 10 ng/mL (deficiency, group 1), 10–29.9 ng/mL (low level, group 2), and ≥ 30 ng/mL (normal, group 3) for 114 (17.7%), 415 (64.54%), and 114 (17.7%) patients, respectively. At baseline, DAS28-ESR and HAQ-DI were higher with vitamin D deficiency compared with groups 2 and 3 combined (P = 0.007 and P = 0.001, respectively), as was mean mTSS, but not significantly (p = 0.076). On multivariate analysis, baseline vitamin D deficiency was associated with HAQ-DI at 6 months (OR 1.70) and mTSS at 12 months (OR 1.76).Conclusion.Vitamin D deficiency was associated with more active and severe disease at baseline and may predict disability and radiographic progression over 1 year in early RA patients. [ClinicalTrials.gov: NCT03666091]

Download Full-text

Serum and synovial fluid levels of matrix metalloproteinase-3 as a biomarker of joint damage in patients with rheumatoid arthritis

QJM ◽

10.1093/qjmed/hcaa064.003 ◽

2020 ◽

Vol 113 (Supplement_1) ◽

Author(s):

E A Hafez ◽

S A Elbakry ◽

M A Abdelrahman ◽

H M Sakr ◽

N A Mohamed ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Matrix Metalloproteinase ◽

Disease Activity ◽

Healthy Volunteers ◽

Joint Damage ◽

Serum Levels ◽

Common Disease ◽

Special Role ◽

Matrix Metalloproteinase 3 ◽

Early Ra

Abstract Background Rheumatoid arthritis (RA) is one of the systemic autoimmune diseases characterized by chronic synovitis and progressive joint destruction leading to decline in functional capacity, eventual work disability, and reduced quality of life. Considering the common disease activity indicators are unspecific for arthritis, novel biomarkers have been rapidly developed for predicting structural destruction progression in RA. Matrix metalloproteinase-3 plays a special role in rheumatoid arthritis pathogenesis and has been suggested as a marker of disease activity and joint damage. Patients and Methods MMP-3 was measured by ELISA in serum samples of 40 early RA patients and compared to age and sex matched control group of 40 healthy volunteers. Synovial levels of MMP-3 were measured only in 8 RA patients, who were indicated for knee arthrocentesis. Joint damage was assessed using SENS score on plain radiography. Results Serum MMP-3 levels were significantly higher in RA patients than healthy volunteers (P-value <0.001). Measured synovial levels of MMP-3 were significantly correlated to the serum levels. There were statistically significant positive correlations between serum MMP-3 with RF titers, AntiCCP titres, CRP, and DAS28 -ESR activity score. There was no significant correlation to total SENS score. ROC curve was used to define the best cut off value of serum MMP3 to discriminate between RA and healthy controls, which was found to be >50ng/ml. Conclusion Serum levels of MMP-3 can be used as noninvasive biomarker of RA, and also indicator of disease activity in early RA patients.

Download Full-text