The current status of anti-citrullinated protein antibodies and citrullinated protein-reactive B cells in the pathogenesis of rheumatoid arthritis

2021 ◽  
Author(s):  
Jia He ◽  
JiYu Ju ◽  
XiaoDong Wang
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cells ◽  
Current Status ◽  
Citrullinated Protein

scholarly journals Persistence of Disease‐Associated Anti–Citrullinated Protein Antibody–Expressing Memory B Cells in Rheumatoid Arthritis in Clinical Remission

2017 ◽  
Vol 69 (6) ◽  
pp. 1176-1186 ◽  
Author(s):  
Adam J. Pelzek ◽  
Caroline Grönwall ◽  
Pamela Rosenthal ◽  
Jeffrey D. Greenberg ◽  
Mandy McGeachy ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cells ◽  
Clinical Remission ◽  
Memory B Cells ◽  
Citrullinated Protein

scholarly journals B cell autoimmunity and bone damage in rheumatoid arthritis

Reumatismo ◽  
2016 ◽  
Vol 68 (3) ◽  
pp. 117 ◽  
Author(s):  
S. Bugatti ◽  
L. Bogliolo ◽  
C. Montecucco ◽  
A. Manzo
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cells ◽  
Bone Remodeling ◽  
Mechanistic Explanation ◽  
Multiple Roles ◽  
Persistent Inflammation ◽  
Bone Damage ◽  
Substantial Progress ◽  
Citrullinated Protein ◽  
Made In

Rheumatoid arthritis (RA) is a chronic immune-inflammatory disease associated with significant bone damage. Pathological bone remodeling in RA is primarily driven by persistent inflammation. Indeed, pro-inflammatory cytokines stimulate the differentiation of bone-resorbing osteoclasts and, in parallel, suppress osteoblast function, resulting in net loss of bone. Abating disease activity thus remains the major goal of any treatment strategy in patients with RA. Autoantibody-positive patients, however, often show a rapidly progressive destructive course of the disease, disproportionate to the level of inflammation. The epidemiological association between RA-specific autoantibodies, in particular anti-citrullinated protein autoantibodies, and poor structural outcomes has recently found mechanistic explanation in the multiple roles that B cells play in bone remodeling. In this review, we will summarize the substantial progress that has been made in deciphering how B cells and autoantibodies negatively impact on bone in the course of RA, through both inflammation-dependent and independent mechanisms.

scholarly journals O36. TARGETING MIR-155 IN RHEUMATOID ARTHRITIS B CELLS TO REDUCES ANTI-CITRULLINATED PROTEIN ANTIBODY PRODUCTION

Rheumatology ◽  
2017 ◽  
Vol 56 (suppl_2) ◽  
Author(s):  
Aziza Elmesmari ◽  
Stefano Alivernini ◽  
David McCarey ◽  
James Reilly ◽  
Shauna Kerr ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cells ◽  
Antibody Production ◽  
Citrullinated Protein

scholarly journals POS0441 DEVELOPMENT OF RHEUMATOID ARTHRITIS AMONG ANTI-CITRULLINATED PROTEIN ANTIBODIES POSITIVE ASYMPTOMATIC INDIVIDUALS: A PROSPECTIVE OBSERVATIONAL STUDY

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 449.1-449
Author(s):  
S. Mizuki ◽  
K. Horie ◽  
K. Imabayashi ◽  
K. Mishima ◽  
K. Oryoji
Keyword(s):  
Rheumatoid Arthritis ◽  
Risk Factors ◽  
Observational Study ◽  
Rheumatoid Factor ◽  
Prospective Observational Study ◽  
Enzyme Linked Immunosorbent Assay ◽  
P Value ◽  
Healthy Population ◽  
Asymptomatic Individuals ◽  
Citrullinated Protein

Background:In the idividuals with genetic and enviromental risk factors, immune events at mucosal surfaces occur and may precede systemic autoimmunity. Anti-citrullinated protein antibodies (ACPA) are present in the serum for an average of 3-5 years prior to the onset of rheumatoid arthritis (RA) during an asymptomatic period. In ACPA-positivite individuals, the additional presence of RA-related risk factors appears to add significant power for the development of RA. To date, there have been few reports in which clinical courses of ACPA-positive asymptomatic individuals were investigated prospectively.Objectives:To observe the clinical time course of ACPA-positive healthy population for the development of RA.Methods:Healthy volunteers without joint pain or stiffness, who attended the comprehensive health screening of our hospital, were enrolled in this prospective observational study. The serum ACPA levels were quantified by Ig-G anti-cyclic citrullinated peptide enzyme-linked immunosorbent assay with levels > 4.4 U/mL considered positive. ACPA-positive subjects were followed by rheumatologists of our department clinically or a questionnaire sent by mail for screening to detect arthritis.Results:5,971 healthy individuals without joint symptons were included. Ninty-two (1.5%) were positive for ACPA. Of these, 19 (20.7%) developed RA and two were suspected as RA by mail questionnaire. Their average age were 58-years, and women were 68%. The average duration between the date of serum sampling and diagnosis was 10.7 months. ACPA-positive individuals who developed to RA had higher serum ACPA and Ig-M rheumatoid factor levels than ACPA-positive individuals who did not (P value by Mann-Whitney U test: 0.002, 0.005, respectively).Conclusion:Among ACPA-positive asymptomatic individuals, 20% developed RA. The higher titer of ACPA and Ig-M rheumatoid factor levels are risk factors for devoloping RA.Disclosure of Interests:None declared

ASSOCIATIONS BETWEEN SERUM ANTIBODIES TO PERIODONTAL PATHOGENS AND PRECLINICAL PHASES OF RHEUMATOID ARTHRITIS

Rheumatology ◽  
2021 ◽  
Author(s):  
Daniel Manoil ◽  
Delphine S Courvoisier ◽  
Benoit Gilbert ◽  
Burkhard Möller ◽  
Ulrich A Walker ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Primary Outcome ◽  
Signs And Symptoms ◽  
Serum Levels ◽  
Study Cohort ◽  
Periodontal Pathogens ◽  
Serum Antibodies ◽  
Current Smoking ◽  
Clinical Arthritis ◽  
Citrullinated Protein

Abstract Objectives To examine whether serum antibodies against selected periodontal pathogens are associated with early symptoms of rheumatoid arthritis (RA) development in healthy individuals at risk of developing the disease. Methods Within an ongoing study cohort of first-degree relatives of patients with RA (RA-FDRs), we selected four groups corresponding to specific preclinical phases of RA development (n = 201). (1) RA-FDR controls without signs and symptoms of arthritis nor RA-related autoimmunity (n = 51); (2) RA-FDRs with RA-related autoimmunity (n = 51); (3) RA-FDRs with inflammatory arthralgias without clinical arthritis (n = 51); (4) RA-FDRs who have presented at least one swollen joint (“unclassified arthritis”) (n = 48). Groups were matched for smoking, age, sex and shared epitope status. The primary outcome was IgG serum levels against five selected periodontal pathogens and one commensal oral species assessed using validated-in-house ELISA assays. Associations between IgG measurements and preclinical phases of RA development were examined using Kruskal-Wallis or Mann-Whitney tests (α = 0.05). Results None of the IgGs directed against individual periodontal pathogens significantly differed between the four groups of RA-FDRs. Further analyses of cumulated IgG levels into bacterial clusters representative of periodontal infections, revealed significantly higher IgG titers against periodontopathogens in anti-citrullinated protein antibodies (ACPA)-positive RA-FDRs (p = 0.015). Current smoking displayed a marked trend towards reduced IgG titers against periodontopathogens. Conclusion Our results do not suggest an association between serum IgG titers against individual periodontal pathogens and specific preclinical phases of RA development. However, associations between cumulative IgG titers against periodontopathogens and the presence of ACPAs suggest a synergistic contribution of periodontopathogens to ACPA development.

scholarly journals AB0332 IMMUNOSUPPRESSIVE AND IMMONOMODULATING AGENTS IN RHEUMATOID ARTHRITIS: A SYSTEMATIC REVIEW OF CLINICAL TRIALS AND THEIR CURRENT DEVELOPMENT STAGE

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1464.1-1465
Author(s):  
J. Blaess ◽  
J. Walther ◽  
J. E. Gottenberg ◽  
J. Sibilia ◽  
L. Arnaud ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Systematic Review ◽  
B Cells ◽  
Phase I ◽  
Phase Ii ◽  
Clinical Development ◽  
Phase Iii ◽  
Jak Inhibitors ◽  
Exclusion Criteria ◽  
Immunomodulating Drugs

Background:Rheumatoid arthritis (RA) is the most frequent chronic inflammatory diseases with an incidence of 0.5% to 1%. Therapeutic arsenal of RA has continuously expanded in recent years with the recent therapeutic progress with the arrival of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), biological (bDMARDs) and targeted synthetic (tsDMARDs), JAK inhibitors. However, there are still some unmet needs for patients who do not achieve remission and who continue to worsen despite treatments. Of note, only approximately 40% of patients are ACR70 responders, in most randomized controlled trials. For these patients, finding new therapeutic avenues is challenging.Objectives:The objective of our study was to analyze the whole pipeline of immunosuppressive and immunomodulating drugs evaluated in RA and describe their mechanisms of action and stage of clinical development.Methods:We conducted a systematic review of all drug therapies in clinical development in RA in 17 databases of international clinical trials. Inclusion criterion: study from one of the databases using the keywords “Rheumatoid arthritis” (search date: June 1, 2019). Exclusion criteria: non-drug trials, trials not related to RA or duplicates. We also excluded dietary regimen or supplementations, cellular therapies, NSAIDs, glucorticoids or their derivatives and non-immunosuppressive or non-immunomodulating drugs. For each csDMARD, bDMARD and tsDMARD, we considered the study at the most advanced stage. For bDMARDs, we did not take into account biosimilars.Results:The research identified 4652 trials, of which 242 for 243 molecules met the inclusion and exclusion criteria. The developed molecules belong to csDMARDs (n=21), bDMARDs (n=117), tsDMARDs (n=105).Among the 21 csDMARDs molecules: 8 (38%) has been withdrawn, 4 (19%) are already labelled in RA (hydroxychloroquine, leflunomide, methotrexate and sulfasalazine) and 9 (43%) are in development: 1 (11%) is in phase I/II, 5 (56%) in phase II, 3 (33%) in phase IV.Among the 117 bDMARDs molecules: 69 (59%) has been withdrawn, 9 (8%) are labeled in RA (abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, sarilumab, tocilizumab) and 39 (33%) are in development: 9 (23%) in phase I, 3 (8%) in phase I/II, 21 (54%) in phase II, 5 (12%) are in phase III, 1 (3%) in phase IV. bDMARDs currently under development target B cells (n=4), T cells (n=2), T/B cells costimulation (n=2),TNF alpha (n=2), Interleukine 1 or his receptor (n=3), Interleukine 6 or his receptor (n=7), Interleukine 17 (n=4), Interleukine 23 (n=1), GM-CSF (n=1), other cytokines or chemokines (n=5), integrins or adhesion proteins (n=3), interferon receptor (n=1) and various other targets (n=4).Among the 105 tsDMARDs molecules: 64 (61%) has been withdrawn, 6 (6%) JAK inhibitors, have just been or will probably soon be labelled (baricitinib, filgotinib, peficitinib, tofacitinib and upadacitinib), 35 (33%) are in development: 8 (24%) in phase I, 26 (74%) in phase II, 1 (3%) in phase III and. tsDMARDs currently under development target tyrosine kinase (n=12), janus kinase (JAK) (n=3), sphingosine phostate (n=3), PI3K pathway (n=1), phosphodiesterase-4 (n=3) B cells signaling pathways (n=3) and various other targets (n=10).Conclusion:A total of 242 therapeutic trials involving 243 molecules have been or are being evaluated in RA. This development does not always lead to new treatments since 141 (58%) have already been withdrawn. Hopefully, some of the currently evaluated drugs will contribute to improve the therapeutic management of RA patients, requiring a greater personalization of therapeutic strategies, both in the choice of molecules and their place in therapeutic sequences.Disclosure of Interests:Julien Blaess: None declared, Julia Walther: None declared, Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB, Jean Sibilia: None declared, Laurent Arnaud: None declared, Renaud FELTEN: None declared

scholarly journals POS0460 ASSOCIATION OF ANTI-CITRULLINATED PROTEIN ANTIBODIES OF IgA SUBCLASSES WITH SUSTAINED REMISSION AND FLARE IN RHEUMATOID ARTHRITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 461-461
Author(s):  
M. V. Sokolova ◽  
J. Rech ◽  
M. Hagen ◽  
G. Schett ◽  
U. Steffen (née Harre)
Keyword(s):  
Rheumatoid Arthritis ◽  
Enzyme Linked Immunosorbent Assay ◽  
Sustained Remission ◽  
Das28 Score ◽  
Effector Functions ◽  
Conventional Dmards ◽  
The Impact ◽  
Citrullinated Protein ◽  
Iga Subclasses ◽  
Over Time

Background:Understanding key mechanisms of flare development and sustained remission is one of the acute goals in modern rheumatology. Anti-citrullinated protein antibodies (ACPA) are the most abundant and specific autoantibodies in rheumatoid arthritis (RA) patients. However, the impact of ACPA of IgA isotype is poorly defined. IgA ACPA were previously shown to have a higher percentage of IgA2 in comparison to total IgA; and a correlation between IgA2% ACPA with the DAS28 score was observed in a previous study [1]. Of note, IgA1 and IgA2 were shown to exhibit different effector functions, with IgA2 being pro-inflammatory, which might be the background for its role in RA [1].Objectives:We aimed to investigate, whether IgA ACPA could be used as a predictive factor for flare development in RA; and to look further into the changes in IgA ACPA levels in patients remaining in stable remission versus patients developing flare.Methods:We analysed serum of 111 patients from a multicentre randomized controlled trial ‘RETRO’. The study observational period was 12 months. Patients in the trial had to be in stable remission (DAS28-ESR<2.6) for a minimum of 6 months and were randomized into 3 different treatment arms: continuation of treatment, tapering by 50% or a gradual tapering until discontinuation [2]. IgA ACPA concentrations were measured with an enzyme-linked immunosorbent assay on CCP2-pre-coated plates.Results:60% of patients had IgG-ACPA. IgA ACPA levels were higher among the IgG-ACPA-positive patients (median 4.7 versus 2.24 µg/ml, p<0.0001). Baseline IgA1 and 2 ACPA levels were not different between patients who had a flare later on in the study period and those remaining in remission, showing no predictive value for flare development. However, the percentage of IgA2 in ACPA was correlating with the first registered DAS28 after flare (r=0.36, p=0.046). After the 12 months study period, IgA2 ACPA as well as IgA2% ACPA decreased significantly in patients who remained in stable remission by 17.5% (median, p<0.0001) and 13.6% (p=0.0006), respectively. By contrast, there was no significant change in IgA2 ACPA levels over time in patients who developed a flare. IgA1 ACPA levels remained stable over time. Disease management strategies did not seem to influence IgA ACPA levels in a specific way, as baseline levels were similar between patients on biological and conventional DMARDs and changes in levels after 12 months did not depend on the assignment to either of the study arms.Conclusion:Neither IgA1 nor IgA2 ACPA levels were predictive of flare development or associated with treatment strategies (though rituximab, JAK-inhibitors and abatacept were not amongst treatment options). However, in patients remaining in sustained remission after 1 year a decrease in IgA2 and IgA2% ACPA was observed and IgA2% ACPA was associated with DAS28 score registered after flare. This could be an indication towards ACPA of IgA2 isotype contributing to the severity of flare, alongside other factors, and its reduction being associated with a prolonged state of remission.References:[1]Steffen U, Koeleman CA, Sokolova MV, et al. IgA subclasses have different effector functions associated with distinct glycosylation profiles. Nat Commun 11, 120 (2020).[2]Haschka J, Englbrecht M, Hueber AJ, et al. Relapse rates in patients with rheumatoid arthritis in stable remission tapering or stopping antirheumatic therapy: interim results from the prospective randomised controlled RETRO study. Ann Rheum Dis. 75:45-51 (2016).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

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