scholarly journals POS1441 SYMPTOMS CHARACTERISTICS OF SEROPOSITIVE INDIVIDUALS AT-RISK FOR DEVELOPING RHEUMATOID ARTHRITIS ARE VERSATILE AND COMPARABLE TO THOSE IN PEOPLE WITH EARLY RHEUMATOID ARTHRITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1005.3-1005
Author(s):  
P. Studenic ◽  
A. Circiumaru ◽  
D. Aletaha ◽  
K. Chatzidionysiou ◽  
A. Hensvold ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
At Risk ◽  
Symptom Burden ◽  
Sensitivity Analyses ◽  
Medical Attention ◽  
Pain Patient ◽  
Symptom Duration ◽  
Early Ra ◽  
Quality Register ◽  
Patient Reported

Background:The symptom burden of typical rheumatoid arthritis (RA) symptoms in those at risk for developing RA - positive for anti-citrullinated peptide antibodies (ACPA) and musculoskeletal complaints - has not been explored.Objectives:To evaluate patient-reported symptoms in individuals at-risk to develop RA in comparison to people with newly diagnosed, early seropositive RA.Methods:Two datasources from the region of Stockholm were used: The RISK RA cohort follows up ACPA positive individuals with arthralgia, but without signs of joint inflammation in a structured program over 3 years. The baseline visit of this cohort was used. Patients with early seropositive (ACPA and/or rheumatoid factor positive) RA (symptom duration of 12 months maximum) reported in the Swedish Rheumatology Quality Register (SRQ) at their closest visit to their diagnosis date before receiving DMARD treatment have been identified. At-risk individuals were matched 1:3 by sex and age using the nearest neighbour method utilizing Mahalanobis distance, corrected for sample bias and exact matches on sex. Effect estimates of being at-risk compared to early RA for pain, patient global (GH), fatigue (all visual analogue scales), health assessment questionnaire (HAQ), TJC28 and the EuroQol-5D (EQ5D; range: 0-1) have been derived. Propensity score matching was used as sensitivity analyses.Results:A total of 223 individuals at risk for developing RA were compared to 820 matched early RA patients. The summary of distribution of variables and effect estimates of differences between at-risk and early RA individuals are shown in the Figure 1. At-risk individuals show 24mm of lower pain scores than early RA. This difference is even less (-17mm, 95%CI: -24 to -11) when the estimate is additionally matched for the number of tender joints. The TJC28 was on average 5.4 joints lower than in early RA patients. People at-risk show 22mm lower GH scores (rate themselves better) and 17mm lower fatigue scores than early RA patients. Fatigue was scored highest (mean:35mm, 95%CI: 30 to 29) among the three VAS. HAQ was on average lower by 0.6 points in at-risk individuals and EQ5D showed 0.24 higher index-values, outlining a better health status. Still the mean EQ5D in at-risk individuals was only 0.74 (95%CI: 0.71 to 0.77), which is lower than average values of an age-matched general population (0.92 to 0.96). Sensitivity analyses revealed similar results.Figure 1.Boxplots of pain, global health, fatigue, TJC28, EQ5D and HAQ, separately displayed for people with early seropositive RA and individuals at-risk. Population effect estimates (all p<0.001) comparing at-risk to early RA are provided for every pair, with 95% confidence interval in brackets.Conclusion:Not surprisingly, individuals at risk for RA report less symptom burden then early diagnosed RA patients. However, these differences only range around minimal clinically important differences and for fatigue even below, which stresses the need for medical attention and management strategies for symptomatic at-risk individuals.Acknowledgements:This study was supported through the New Horizon Fellowship and the FOREUM research fellowship grant and is part of the Innovative Medicines Initiative Joint Undertaking under grant agreement no 777357 (RTCure).Hensvold AH and Catrina IA contributed equally.Disclosure of Interests:None declared

scholarly journals AB0179 INFLUENCE OF AINFLUENCE OF ANTI-CITRULLINATED PROTEIN/PEPTIDE ANTIBODIES (ACPAS)ON ARTICULAR MANIFESTATIONS, DISEASE ACTIVITY AND STRUCTURAL SEVERITY IN ALGERIAN PATIENTS WITH EARLY RHEUMATOID ARTHRITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1115.1-1115
Author(s):  
F. Rahal ◽  
N. Brahumi ◽  
A. Ladjouze-Rezig ◽  
S. Lefkir
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Early Rheumatoid Arthritis ◽  
Disease Activity Score ◽  
Activity Score ◽  
Symptom Duration ◽  
Early Ra ◽  
The Mean ◽  
Citrullinated Protein ◽  
Peptide Antibodies

Background:Anti-citrullinated protein/peptide antibodies (ACPA) are highly specific and sensitive markers for rheumatoid arthritis (RA). There are also suggested to have a more severe rheumatoid arthritis.Objectives:The aim of this study was to assess the influence of ACPA on disease activity, radiological severity, and functional disability in Algerian patient with early rheumatoid arthritis (RA).Methods:Consecutive early RA patients (symptom duration ≤24 months) recruited were included in the descriptive, longitudinal, prospective study. Demographic, biological, immunological and radiographic data were collected at the time of inclusion in the study. Disease activity as determined by the Disease Activity Score 28-CPR (DAS28- CPR: 4 variables), functional handicap as calculated by Heath Assessment Score (HAQ), and bone and joint damage as evaluated by Sharp-Van der Heijde (SVDH) erosion and narrowing score.Results:One hundred and sixty-one patients with RA were recruited. Patients mean age 43.71±14 years and mean symptom duration at inclusion was 10.48±7 months. Small and larges were affected in 64,3%. The mean ESR was 23,53±15,2 mm/1st hour, and the mean CRP level was 19,42±39.8 mg/l. Rheumatoid Factors (RFs) and Anti-Citrullinated Protein Antibodies (ACPAs) were present in 74% and 88% of patients, respectively. The presence of ACPAs was significantly associated with DAS28 (p=0,004) and HAQ (p=0,002). There was no significant difference in inflammatory markers and radiographic SVDH score between patients with and without ACPAs. Stepwise regression analysis showed that the presence of ACPAs was independently associated with localization when RA affected smalls and larges joint in the same time (OR=5,24; IC 95% 1,224-22,483; p=0,026).Conclusion:These data show that in patients with early RA, ACPAs positivity was significantly associated with articular manifestations, activity disease and functional handicap, but not with structural damage.References:[1]Nikiphorou E, Norton S, Young A, et al. Association between rheumatoid arthritis disease activity, progression of functional limitation and long-term risk of orthopaedic surgery: combined analysis of two prospective cohorts supports EULAR treat to target DAS thresholds. Ann Rheum Dis. 2016;75(12):2080-2086. doi:10.1136/annrheumdis-2015-208669.[2]Karimifar M, Salesi M, Farajzadegan Z. The association of anti-CCP1 antibodies with disease activity score 28 (DAS-28) in rheumatoid arthritis. Adv Biomed Res. 2012;1:30. doi:10.4103/2277-9175.98156.[3]Boman A, Brink M, Lundquist A, et al. Antibodies against citrullinated peptides are associated with clinical and radiological outcomes in patients with early rheumatoid arthritis: a prospective longitudinal inception cohort study. RMD Open. 2019;5(2):e000946. Published 2019 Sep 3. doi:10.1136/rmdopen-2019-000946.Disclosure of Interests:None declared

scholarly journals FRI0020 CLINICAL TREATMENT RESPONSE STILL DOES NOT MATCH PATIENT REPORTED IMPROVEMENT, EVEN IN EARLY RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 582.1-582
Author(s):  
S. Pazmino ◽  
A. Lovik ◽  
A. Boonen ◽  
D. De Cock ◽  
V. Stouten ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Early Rheumatoid Arthritis ◽  
Health Assessment ◽  
Sustained Remission ◽  
Research Support ◽  
Early Ra ◽  
Severity Scores ◽  
Patient Reported ◽  
Over Time

Background:Commonly used disease activity scores in rheumatoid arthritis (RA) include one patient reported outcome (PRO) -the patient’s global health assessment (PGA). Exploratory factor analysis (EFA) was performed on data from the 2 year Care in early Rheumatoid Arthritis (CareRA) trial to explain the evolution of disease burden extracting 3 factors.1Objectives:To assess the evolution and relative responsiveness over time of clinical, laboratory and patient assessments included in composite scores, together with other PROs like pain, fatigue and functionality in patients with early RA (≤1 year) treated to target (T2T) within the CareRA trial.Methods:DMARD naïve patients with early RA (n=379) were included, randomized to remission induction with COBRA-like treatment schemes (n=332) or MTX monotherapy (n=47) and T2T.Components of disease activity scores (swollen/tender joint count (S/TJC), C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR), and physician (PhGH) or patient (PGA) global health assessment), pain and fatigue (both on 0-100 scale) and HAQ were recorded at every visit.Missing data was handled with multiple imputation (n=15). Clustering was removed with multiple outputation (n=1000), then each of the 15 000 datasets was analyzed by EFA with principal component extraction and oblimin rotation. The analyses were combined after re-ordering the factors by maximizing factor congruence. The 3 extracted factors and their individual components (with their loadings) were: 1. Patient containing PGA (0.87), pain (0.86), fatigue (0.90) and HAQ (0.5) 2.Clinical with SJC (0.92), TJC (0.89) and PhGH (0.76) and 3.Laboratory with CRP(0.87) and ESR (0.78).1(Pazmino, ACR 2019 abstract, Table 3)Afterwards, variables were first normalized to a 0-1 scale, then multiplied -weighted- by the factor loadings previously obtained.1For each Patient, Clinical and Laboratory severity score, the weighted variables belonging to each score were summed together and then re-scaled to 0-1 (higher values suggest more burden).The percentage (%) improvement from baseline to week 104 and the area under the curve (AUC) across time points were calculated per factor.Differences in % improvement and AUC were compared between patients not achieving and achieving early and sustained (week 16 to 104) disease activity score remission (DAS28CRP <2.6) with ANOVA. Bonferroni correction was used for multiple testing.Results:Severity scores of Patient, Clinical and Laboratory factors improved rapidly over time (Figure 1). In patients achieving sustained remission (n=122), Patient, Clinical and Laboratory scores improved 56%, 90% and 27% respectively. In patients not achieving sustained remission (n=257) the improvement was 32%, 78% and 9% respectively (p<0.001 only for clinical improvement).Patients in CareRA who achieved sustained remission had an AUC of 15.1, 3.4 and 4.7 in Patient, Clinical and Laboratory scores respectively, compared to 32.3, 10.0, and 7.2 in participants not achieving sustained remission (p<0.001 for all comparisons).Conclusion:Patient, Clinical and Laboratory severity scores improved rapidly over time in patients achieving rapid and sustained disease control. However, overall, Patient burden seemed not to improve to the same extent as Clinical burden. Patient’s unmet needs in terms of pain, fatigue, functionality and overall well-being should thus be given more attention, even in patients in sustained remission.References:[1]Pazmino S,et al.Including Pain, Fatigue and Functionality Regularly in the Assessment of Patients with Early Rheumatoid Arthritis Separately Adds to the Evaluation of Disease Status [abstract]. ACR. 2019.Disclosure of Interests:Sofia Pazmino: None declared, Anikó Lovik: None declared, Annelies Boonen Grant/research support from: AbbVie, Consultant of: Galapagos, Lilly (all paid to the department), Diederik De Cock: None declared, Veerle Stouten: None declared, Johan Joly: None declared, Delphine Bertrand: None declared, Rene Westhovens Grant/research support from: Celltrion Inc, Galapagos, Gilead, Consultant of: Celltrion Inc, Galapagos, Gilead, Speakers bureau: Celltrion Inc, Galapagos, Gilead, Patrick Verschueren Grant/research support from: Pfizer unrestricted chair of early RA research, Speakers bureau: various companies

scholarly journals Dysbiosis in the oral microbiomes of anti-CCP positive individuals at risk of developing rheumatoid arthritis

2020 ◽  
pp. annrheumdis-2020-216972
Author(s):  
Zijian Cheng ◽  
Thuy Do ◽  
Kulveer Mankia ◽  
Josephine Meade ◽  
Laura Hunt ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
At Risk ◽  
Risk Group ◽  
Orthologous Gene ◽  
Oral Microbiome ◽  
Periodontal Pathogen ◽  
P Value ◽  
Illumina Hiseq ◽  
Early Ra ◽  
Taxonomic Profile

ObjectivesAn increased prevalence of periodontitis and perturbation of the oral microbiome has been identified in patients with rheumatoid arthritis (RA). The periodontal pathogen Porphyromonas gingivalis may cause local citrullination of proteins, potentially triggering anti-citrullinated protein antibody production. However, it is not known if oral dysbiosis precedes the onset of clinical arthritis. This study comprehensively characterised the oral microbiome in anti-cyclic citrullinated peptide (anti-CCP) positive at-risk individuals without clinical synovitis (CCP+at risk).MethodsSubgingival plaque was collected from periodontally healthy and diseased sites in 48 CCP+at risk, 26 early RA and 32 asymptomatic healthy control (HC) individuals. DNA libraries were sequenced on the Illumina HiSeq 3000 platform. Taxonomic profile and functional capability of the subgingival microbiome were compared between groups.ResultsAt periodontally healthy sites, CCP+at risk individuals had significantly lower microbial richness compared with HC and early RA groups (p=0.004 and 0.021). Microbial community alterations were found at phylum, genus and species levels. A large proportion of the community differed significantly in membership (523 species; 35.6%) and structure (575 species; 39.1%) comparing CCP+at risk and HC groups. Certain core species, including P. gingivalis, had higher relative abundance in the CCP+at risk group. Seventeen clusters of orthologous gene functional units were significantly over-represented in the CCP+at risk group compared with HC (adjusted p value <0.05).ConclusionAnti-CCP positive at-risk individuals have dysbiotic subgingival microbiomes and increased abundance of P. gingivalis compared with controls. This supports the hypothesis that the oral microbiome and specifically P. gingivalis are important in RA initiation.

scholarly journals Patient-reported Outcomes as Predictors of Change in Disease Activity and Disability in Early Rheumatoid Arthritis: Results from the Yorkshire Early Arthritis Register

2017 ◽  
Vol 44 (9) ◽  
pp. 1331-1340 ◽  
Author(s):  
Sarah Twigg ◽  
Elizabeth M.A. Hensor ◽  
Paul Emery ◽  
Alan Tennant ◽  
Ann W. Morgan ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Early Rheumatoid Arthritis ◽  
Multilevel Models ◽  
Early Arthritis ◽  
Joint Disease ◽  
Symptom Duration ◽  
Rates Of Change ◽  
Patient Reported ◽  
Predictors Of Change

Objective.To assess patient-reported variables as predictors of change in disease activity and disability in early rheumatoid arthritis (RA).Methods.Cases were recruited to the Yorkshire Early Arthritis Register (YEAR) between 1997 and 2009 (n = 1415). Predictors of the 28-joint Disease Activity Score (DAS28) and the Health Assessment Questionnaire-Disability Index (HAQ-DI) at baseline and change over 12 months were identified using multilevel models. Baseline predictors were sex, age, symptom duration, autoantibody status, pain and fatigue visual analog scales (VAS), duration of early morning stiffness (EMS), DAS28, and HAQ-DI.Results.Rates of change were slower in women than men: DAS28 fell by 0.19 and 0.17 units/month, and HAQ-DI by 0.028 and 0.023 units/month in men and women, respectively. Baseline pain and EMS had small effects on rates of change, whereas fatigue VAS was only associated with DAS28 and HAQ-DI at baseline. In patients recruited up to 2002, DAS28 reduced more quickly in those with greater pain at baseline (by 0.01 units/mo of DAS28 per cm pain VAS, p = 0.024); in patients recruited after 2002, the effect for pain was stronger (by 0.01 units/mo, p = 0.087). DAS28 reduction was greater with longer EMS. In both cohorts, fall in HAQ-DI (p = 0.006) was greater in patients with longer EMS duration, but pain and fatigue were not significant predictors of change in HAQ-DI.Conclusion.Patient-reported fatigue, pain, and stiffness at baseline are of limited value for the prediction of RA change in disease activity (DAS28) and activity limitation (HAQ-DI).

scholarly journals EULAR definition of arthralgia suspicious for progression to rheumatoid arthritis

2016 ◽  
Vol 76 (3) ◽  
pp. 491-496 ◽  
Author(s):  
Hanna W van Steenbergen ◽  
Daniel Aletaha ◽  
Liesbeth J J Beaart-van de Voorde ◽  
Elisabeth Brouwer ◽  
Catalin Codreanu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
At Risk ◽  
Phase Ii ◽  
Clinical Characteristics ◽  
Characteristic Curve ◽  
Early Morning ◽  
Phase Iii ◽  
Symptom Duration ◽  
Degree Relative ◽  
Delphi Approach

BackgroundDuring the transition to rheumatoid arthritis (RA) many patients pass through a phase characterised by the presence of symptoms without clinically apparent synovitis. These symptoms are not well-characterised. This taskforce aimed to define the clinical characteristics of patients with arthralgia who are considered at risk for RA by experts based on their clinical experience.MethodsThe taskforce consisted of 18 rheumatologists, 1 methodologist, 2 patients, 3 health professionals and 1 research fellow. The process had three phases. In phase I, a list of parameters considered characteristic for clinically suspect arthralgia (CSA) was derived; the most important parameters were selected by a three-phased Delphi approach. In phase II, the experts evaluated 50 existing patients on paper, classified them as CSA/no-CSA and indicated their level of confidence. A provisional set of parameters was derived. This was studied for validation in phase III, where all rheumatologists collected patients with and without CSA from their outpatient clinics.ResultsThe comprehensive list consisted of 55 parameters, of which 16 were considered most important. A multivariable model based on the data from phase II identified seven relevant parameters: symptom duration <1 year, symptoms of metacarpophalangeal (MCP) joints, morning stiffness duration ≥60 min, most severe symptoms in early morning, first-degree relative with RA, difficulty with making a fist and positive squeeze test of MCP joints. In phase III, the combination of these parameters was accurate in identifying patients with arthralgia who were considered at risk of developing RA (area under the receiver operating characteristic curve 0.92, 95% CI 0.87 to 0.96). Test characteristics for different cut-off points were determined.ConclusionsA set of clinical characteristics for patients with arthralgia who are at risk of progression to RA was established.

scholarly journals Multi-HLA class II tetramer analyses of citrulline-reactive T cells and early treatment response in rheumatoid arthritis

2020 ◽  
Author(s):  
Christina Gerstner ◽  
Sara Turcinov ◽  
Aase H Hensvold ◽  
Karine Chemin ◽  
Hannes Uchtenhagen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
At Risk ◽  
T Cells ◽  
Peripheral Blood ◽  
Ex Vivo ◽  
Class Ii ◽  
Hla Class Ii ◽  
Phenotypic Characterization ◽  
Early Ra

Abstract Background: HLA class II tetramers can be used for ex vivo enumeration and phenotypic characterization of antigen-specific CD4+ T cells. They are increasingly applied in settings like allergy, vaccination and autoimmune diseases. Rheumatoid arthritis (RA) is a chronic autoimmune disorder for which many autoantigens have been described. Results: Using multi-parameter flow cytometry, we developed a multi-HLA class II tetramer approach to simultaneously study several antigen specificities in RA patient samples. We focused on previously described citrullinated HLA-DRB1*04:01-restricted T cell epitopes from α-enolase, fibrinogen-b, vimentin as well as cartilage intermediate layer protein (CILP).First, we examined inter-assay variability and the sensitivity of the assay in peripheral blood from healthy donors (n=7). Next, we confirmed the robustness and sensitivity in a cohort of RA patients with repeat blood draws (n=14). We then applied our method in two different settings. We assessed lymphoid tissue from seropositive arthralgia (n=5) and early RA patients (n=5) and could demonstrate autoreactive T cells in individuals at risk of developing RA. Lastly, we studied peripheral blood from early RA patients (n=10) and found that the group of patients achieving minimum disease activity (DAS28 <2.6) at 6 months follow-up displayed a decrease in the frequency of citrulline-specific T cells. Conclusions: Our study demonstrates the development of a sensitive tetramer panel allowing simultaneous characterization of antigen-specific T cells in ex vivo patient samples including RA ‘at risk’ subjects. This multi-tetramer approach can be useful for longitudinal immune-monitoring in any disease with known HLA-restriction element and several candidate antigens.

THU0111 T-Cell Subsets in Lymph Node Biopsies of Autoantibody Positive Subjects at Risk of Rheumatoid Arthritis (RA) and Early RA Patients

2013 ◽  
Vol 72 (Suppl 3) ◽  
pp. A200.1-A200
Author(s):  
T. H. Ramwadhdoebe ◽  
J. Hähnlein ◽  
K. I. Maijer ◽  
J. Boorsma ◽  
L. J. van Boven ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
At Risk ◽  
Lymph Node ◽  
T Cell ◽  
T Cell Subsets ◽  
Early Ra

scholarly journals Secular changes in the progression of clinical markers and patient-reported outcomes in early rheumatoid arthritis

Rheumatology ◽  
2020 ◽  
Vol 59 (9) ◽  
pp. 2381-2391 ◽  
Author(s):  
Lewis Carpenter ◽  
Elena Nikiphorou ◽  
Patrick D W Kiely ◽  
David A Walsh ◽  
Adam Young ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Visual Analogue Scale ◽  
Early Rheumatoid Arthritis ◽  
Analogue Scale ◽  
Patient Reported Outcomes ◽  
Short Form ◽  
Clinical Markers ◽  
Short Form 36 ◽  
Early Ra ◽  
Patient Reported

Abstract Objectives To examine secular trends in the progression of clinical and patient-reported outcomes in early RA. Methods A total of 2701 patients recruited to the Early Rheumatoid Arthritis Study or Early Rheumatoid Arthritis Network with year of diagnosis from 1986 to 2011. The 5-year progression rates for patients diagnosed at different points in time were modelled using mixed-effects regression; 1990, 2002 and 2010, were compared. Clinical markers of disease included the 28-joint count DAS and the ESR. Patient-reported markers included the HAQ, visual analogue scale of pain and global health, and the Short-Form 36. Results Statistically significant improvements in both 28-joint count DAS and ESR were seen over the 5 years in patients diagnosed with RA compared with those diagnosed earlier. By 5 years, 59% of patients with diagnosis in 2010 were estimated to reach low disease activity compared with 48% with diagnosis in 2002 and 32% with diagnosis in 1990. Whilst HAQ demonstrated statistically significant improvements, these improvements were small, with similar proportions of patients achieving HAQ scores of ≤1.0 by 5 years with a diagnosis in 1990 compared with 2010. Levels of the visual analogue scale and the Mental Component Scores of the Short-Form 36 indicated similar, statistically non-significant levels over the 5 years, irrespective of year diagnosed. Conclusion This study demonstrates improvements in inflammatory markers over time in early RA, in line with improved treatment strategies. These have not translated into similar improvements in patient-reported outcomes relating to either physical or mental health.

scholarly journals THU0033 ALTERATIONS IN THE PHENOTYPIC LANDSCAPE AND SPECIFICITY OF CD4+ T CELLS IN CCP+ AT RISK SUBJECTS BEFORE THE ONSET OF RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 230.1-230
Author(s):  
C. Rims ◽  
V. Muir ◽  
K. Deane ◽  
S. Nagpal ◽  
N. Rao ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
At Risk ◽  
Flow Cytometry ◽  
T Cells ◽  
Immune Responses ◽  
Cd4 T Cells ◽  
Research Support ◽  
Phenotypic Analysis ◽  
Tetramer Staining ◽  
Early Ra

Background:The “Targeting Immune Responses for Prevention of RA” (TIP-RA) collaboration studies individuals at high risk for developing rheumatoid arthritis (RA) because of serum anti-citrullinated protein antibody (ACPA) positivity in absence of arthritis at baseline, and is focused on defining how they transition from at-risk to classifiable disease. One potential mechanism is the expansion of antigen specific T cells that recognize self-antigens and acquisition of disease associated T cell phenotypes. ACPA emerge years prior to clinically apparent disease and subsequently increase in their titer and breadth of specificity. However, few studies have characterized T cells during this transition.Objectives:To identify features associated with progression to RA by examining the specificity and surface phenotype of CD4+ T cells in individuals from the TIP-RA cohort by HLA class II tetramer staining and multi-parameter flow cytometry.Methods:Tetramer staining and flow cytometry were performed on peripheral blood samples from a baseline visit from CCP3- controls (n=34), CCP3+ at-risk (n=26), CCP3+ positive individuals who transitioned in the near-term to RA (called “RA converters”, n=4), and seropositive early-RA (n=21). Our staining panel allowed us to measure the frequencies of T cells specific for citrullinated alpha-enolase, aggrecan, cartilage intermediate layer protein (CILP), fibrinogen and vimentin. We then applied both supervised phenotyping and a cluster-based computational approach to compare the phenotypic landscape and specificity of antigen specific and total CD4+ T cells in each cohort.Results:We observed higher overall frequencies of T cells that recognize citrullinated epitopes in CCP3+ at-risk subjects than CCP- controls (p< 0.05). Among the individual specificities, elevated frequencies prior to disease onset were most prominent for CILP specific T cells. Supervised phenotypic analysis revealed an increase in CCR4+ CD4+ T cells in CCP3+ at risk subjects (p< 0.001) and a corresponding decrease in CXCR3+ CD4+ T cells that was most pronounced in RA converters and seropositive early-RA (p< 0.05). Cluster-based phenotypic analysis defined ten distinct phenotypic states present within all subjects. Each of these ten immunotypes contained T cells that recognize citrullinated epitopes. However, the predominant immunotype varied for different antigens. During progression, the frequencies of Ag specific T cells diminished when onset was imminent, but rebounded shortly after diagnosis. Concomitantly, Ag specific T cells with memory phenotypes were diminished, but subsequently reverted to TSCM, Th1, and Th1-17 like phenotypes.Conclusion:Our data show that disease associated changes in the antigen specificity of CD4+ T cells are present in CCP3+ at-risk subjects. Furthermore, the number of antigen specific T cells and their phenotype are perturbed before the onset of symptoms and development of classified RA. These findings support a continuum of immunologic changes that underlie risk and drive disease, motivating new approaches for early intervention.Acknowledgments:We gratefully acknowledge the Targeting Immune Responses for Prevention of Rheumatoid Arthritis (TIP-RA) for designing and executing this collaborative studyDisclosure of Interests:Cliff Rims: None declared, Virginia Muir: None declared, Kevin Deane Grant/research support from: Janssen, Consultant of: Inova, ThermoFisher, Janseen, BMS and Microdrop, Sunil Nagpal Shareholder of: Janssen Pharmaceuticals, Employee of: Janssen Pharmaceuticals, Navin Rao Shareholder of: Janssen Pharmaceuticals, Employee of: Janssen Pharmaceuticals, Frederic Baribaud Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, George Vratsanos Shareholder of: Janssen Pharmaceuticals, Employee of: Janssen Pharmaceuticals, V. Michael Holers Grant/research support from: Janssen, Celgene, and BMS, Peter Linsley Consultant of: BMS, Eddie A. James Grant/research support from: Janssen, Pfizer, Sanofi, Novartis, Jane Buckner Grant/research support from: Bristol-Myers Squibb, Janssen

scholarly journals Multi-HLA class II tetramer analyses of citrulline-reactive T cells and early treatment response in rheumatoid arthritis

2020 ◽  
Author(s):  
Christina Gerstner ◽  
Sara Turcinov ◽  
Aase H Hensvold ◽  
Karine Chemin ◽  
Hannes Uchtenhagen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
At Risk ◽  
T Cells ◽  
Peripheral Blood ◽  
Ex Vivo ◽  
Class Ii ◽  
Hla Class Ii ◽  
Phenotypic Characterization ◽  
Early Ra

Abstract Background: HLA class II tetramers can be used for ex vivo enumeration and phenotypic characterization of antigen-specific CD4+ T cells. They are increasingly applied in settings like allergy, vaccination and autoimmune diseases. Rheumatoid arthritis (RA) is a chronic autoimmune disorder for which many autoantigens have been described.Results: Using multi-parameter flow cytometry, we developed a multi-HLA class II tetramer approach to simultaneously study several antigen specificities in RA patient samples. We focused on previously described citrullinated HLA-DRB1*04:01-restricted T cell epitopes from α-enolase, fibrinogen-b, vimentin as well as cartilage intermediate layer protein (CILP). First, we examined inter-assay variability and the sensitivity of the assay in peripheral blood from healthy donors (n=7). Next, we confirmed the robustness and sensitivity in a cohort of RA patients with repeat blood draws (n=14). We then applied our method in two different settings. We assessed lymphoid tissue from seropositive arthralgia (n=5) and early RA patients (n=5) and could demonstrate autoreactive T cells in individuals at risk of developing RA. Lastly, we studied peripheral blood from early RA patients (n=10) and found that the group of patients achieving minimum disease activity (DAS28 <2.6) at 6 months follow-up displayed a decrease in the frequency of citrulline-specific T cells. Conclusions: Our study demonstrates the development of a sensitive tetramer panel allowing simultaneous characterization of antigen-specific T cells in ex vivo patient samples including RA ‘at risk’ subjects. This multi-tetramer approach can be useful for longitudinal immune-monitoring in any disease with known HLA-restriction element and several candidate antigens.

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