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- Circiumaru, A, et al.
(författare)
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SPECIFIC ACPA REACTIVITIES AND INFLAMMATORY BIOMARKERS ALONG WITH ULTRASOUND TENOSYNOVITIS ARE ASSOCIATED WITH ARTHRITIS ONSET IN A POPULATION AT RISK FOR RHEUMATOID ARTHRITIS
- 2020
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 79, s. 1247-1247
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Anti-citrullinated protein antibodies (ACPA) are characteristic markers for rheumatoid arthritis (RA), developing years before disease onset. Early clinical and biological biomarkers could provide useful information on the onset of RA in predisposed individuals.Objectives:The aim of the study was to investigate whether ACPA along with inflammatory markers and musculoskeletal ultrasound changes could predict arthritis development in individuals at risk for RA.Methods:ACPA-positive individuals with musculoskeletal complaints were referred from primary care to a rheumatology clinic, recruited in the Risk-RA research program and followed-up for up to 3 years, between April 2014 and October 2019. All individuals lacked arthritis both at clinical examination by a trained rheumatologist and ultrasound assessment of hands and feet and any other symptomatic joints (according to EULAR-OMERACT definition). Blood samples were collected at inclusion and were analyzed for 15 ACPA fine specificities (by custom made peptide array), 92 inflammation-associated protein biomarkers (by multiplex immunoassay with Olink extension technology) and HLA-SE (DR low resolution kit). Statistical analysis used univariate and multivariate models with backwards selection and cox regression.Results:268 individuals with a median age of 48 (36-58) were recruited, out of which 212 (79%) were females. 75 (28%) developed arthritis within 11 months of follow-up while the median follow-up for those not developing arthritis was 21 months (14-28). Increased ACPA levels, shorter symptom duration and RF positivity were the main differences between individuals developing arthritis and those who did not. In univariate models, the presence of HLA-SE, specific ACPA reactivities, certain inflammatory markers and ultrasound-detected tenosynovitis were associated with arthritis development. In multivariate analysis the presence of anti-cit-fillagrin (HR 2.1 (95% CI 1.2-3.7, p 0.01), IL6 levels (HR 1.4 (95% CI 1.2-1.7, p 0.0001) and tenosynovitis (HR 2.9 (95% CI 1.7-5.0, p 0.0001) remained significant predictors for arthritis onset.Conclusion:Certain ACPA reactivities together with inflammatory markers and ultrasound-detected tenosynovitis predict arthritis development in predisposed individuals for developing RA.Disclosure of Interests:None declared
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- Kisten, Y, et al.
(författare)
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TENOSYNOVITIS, SYNOVIAL HYPERTROPHY AND FEET BURSITIS ARE USEFUL ULTRASOUND BIOMARKERS FOR PREDICTING ARTHRITIS DEVELOPMENT IN A POPULATION AT-RISK FOR RHEUMATOID ARTHRITIS
- 2021
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 87-87
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Musculoskeletal ultrasound (MSUS) evaluation of individuals at risk for developing rheumatoid arthritis (RA) having Anti-Citrullinated Protein Antibody (ACPA) positivity and musculoskeletal complaints, may play an important role in the very early detection of RA.Objectives:We aimed to identify which ultrasound markers could predict arthritis development.Methods:Individuals with musculoskeletal complaints with a positive anti-CCP2 test were referred to the rheumatology department for a detailed clinical (68 joint count) and MSUS examination of the hands, feet and any symptomatic joints. Only those without clinical and/or MSUS detected arthritis were included in the RISK RA prospective cohort and followed-up over 3 years/ or until arthritis onset. Using EULAR-OMERACT guidelines1, MSUS markers for synovial hypertrophy (SH) and hyperemia (Doppler activity) were documented for each visit. Finger and wrist tendons were screened for any signs of tenosynovitis (TS), and between metatarsal joints for bursitis. Association of MSUS biomarkers with arthritis development was tested (comparing proportions) using Chi-Squared or Fisher’s exact tests.Results:288 individuals were included from January 2014 to October 2019 (79% female, 35% RF positive, median age 48 years: IQR: 36-58). Within a median of 38 months (IQR: 1-72) since recruitment, 84 individuals (28%) developed an arthritis diagnosis.Prior to obtaining any diagnosis (at inclusion and/or follow-up visit), 95 of the 288 individuals (33%) had at least one type of MSUS anatomical modification present (around the tendons, joint synovium and/or within bursal cavities), and 56% (53/95) of these individuals eventually developed arthritis. Of the remaining 193 that did not present with any obvious MSUS changes, 16% progressed towards arthritis development.The presence of tenosynovitis was detected in 64 of 288 individuals scanned prior to diagnosis and were more frequent in those developing arthritis (44%, 37/84) as compared to those with TS not developing arthritis (13%, 27/204), p<0.0001. The extensor carpi ulnaris wrist tendons were mostly involved. Sonographic changes within the synovium were noted in 11% (32/288) of all individuals, mostly affecting the metacarpophalangeal (MCP) and metatarsophalangeal (MTP) joints. There was a higher incidence of synovial hypertrophy detected in those developing arthritis (22%, 18/24), as compared to those that remained arthritis free (7%, 14/204), p<0.0001. The MCP joints with synovial hypertrophy were more prone to arthritis development as compared to the MTP’s. Furthermore, we observed a higher frequency of bursitis between the MTP joints in individuals developing arthritis, as compared to individuals having a bursitis who did not develop arthritis (13%, 11/84 versus 7%, 14/204, p=0.009).Conclusion:Ultrasound biomarkers such as tenosynovitis of the extensor carpi ulnaris, synovial hypertrophy of the MCP joints and feet bursitis have good potential to predict arthritis development in a population at-risk for rheumatoid arthritis.References:[1]Maria-Antonietta D’Agostino et al. RMD Open 2017;3:e 000428Acknowledgements:All study participants and patients, including researchers that are part of the multidisciplinary laboratory, clinical and academic teams of the RISK RA study group, as well as all assisting this research in one form or the other are greatly acknowledged.Disclosure of Interests:None declared
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- Turcinov, S, et al.
(författare)
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ULTRASOUND GUIDED BIOPSIES OF RA JOINTS AT TIME OF CLINICAL DIAGNOSIS CONTAIN PROFOUND T CELL CLONALITIES
- 2020
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 79, s. 1321-1321
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Rheumatoid arthritis (RA) is a disease characterized by synovial joint inflammation, mainly affecting small joints. Histological findings in synovial biopsies ranges from inflammatory infiltration including ectopic lymphoid structures, to a cell sparse fibroid phenotype. T cells in affected joints are non-naïve and have by flow cytometry approaches been shown to have a wide TCR-beta chain gene usage. New technologies allow for analyses of paired TCR sequences and their antigen-specificities.Objectives:To study the alpha/beta-T cell receptor repertoire in single sorted T cells from synovial biopsies at time of RA-diagnosis.Meth ods:Synovial biopsies were taken, primarily using an ultrasound guided technique, from seventeen patients (12 ACPA+, 5 ACPA-) with rheumatoid arthritis. Fresh biopsies were enzymatically digested, followed by mild mechanical treatment, prior to flow cytometry cell sorting. Single cell index sorting of T cells was made into 384-well plates with PCR-buffer followed by a nested PCR and deep sequencing of the TCR amplicons. TCR-receptor sequences showing clonal expansion from four ACPA+ HLA-DRB1*0401 patients were further cloned into SKW3 cells for studies of their reactivity byin vitrostimulation with peptides of viral and citrullinated origin from the literature. A positive response, as measured by CD69-up regulation or IL-2 production, was used to define specificity.Results:Fourteen of the assessed joints were small (1 MTP, 4 MCP and 8 wrists), whereas the remaining three were large joints (2 knees and 1 ankle), table 1. Individual T cells could be isolated from all of these biopsies, with a variating CD4:CD8 ratio. Based on the flow cytometry phenotyping we could identify CD4 T cells of both Treg and T peripheral helper phenotype already at this early time point. Productive alpha/beta-TCR sequences could be retrieved from 16 out of 17 patients and clonal expansion (>1 copy/TCR) was seen in all but one of these patients, with clone sizes ranging between 2 – 34 copies of each TCR.Table 1.Patient characteristics.PatientsGender(F/M)HLA-SE allelesJointsJoint swelling prior to biopsy (months)Stiffness specific joint (median VAS)Pain specific joint (median VAS)ACPA+ (n = 12)9/3*0401, *0404, *0408, *01 and *101 MTP, 4 MCP, 6 wrists, 1 knee4 (1-12)a46 (0-84)45 (22-99)ACPA- (n = 5)3/2*04011 MCP, 2 wrists, 1 ankle, 1 knee5 (0.25-7)59 (15-73)47 (33-81)SKW3 cell lines(patients n = 4)4/0*0401/0404 n=2*0401 n=21 MTP, 3 wrists2 (1-6)50.5 (42-84)50 (40-99)aData not available for one patient. One patient with prior RA-diagnosis, but after 9 months of treatment remission lasting for 20 years.Artificial T cell lines were generated from the expanded clones of HLA-DRB1*04:01 RA subjects. Ourin vitrostimulation protocol identified virus specific CD4 T cells in all samples. So far, no citrulline reactivity has been found. HCMV, followed by HHV were the most commonly found viral reactivities, whereas others were found only in one donor (e.g. JCV, EBV). The majority of clones are thus “orphans”, to which we are still seeking the driving antigen.Conclusion:Clonally expanded T cells are found in the synovium of early RA patients and include virus-specific CD4+ T cells. Our data show that the local T cell repertoire is broad already at the time of RA diagnosisDisclosure of Interests:Sara Turcinov: None declared, Erik af Klint Paid instructor for: Abbvie (courses and lectures), An De Bondt Employee of: Janssen., Muhammad Sohel Mia: None declared, Anca Catrina: None declared, Frederik Stevenaert Employee of: Janssen, Vivianne Malmström Grant/research support from: VM has had research grants from Janssen Pharmaceutica
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