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)

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

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 449.1-449
Author(s):  
S. Mizuki ◽  
K. Horie ◽  
K. Imabayashi ◽  
K. Mishima ◽  
K. Oryoji

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


2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 559.2-560
Author(s):  
V. Rivera Teran ◽  
S. Sicsik ◽  
D. Vega-Morales ◽  
F. Irazoque-Palazuelos ◽  
D. Miranda ◽  
...  

Background:Rheumatoid arthritis (RA) is the most common autoimmune disease. Older patients treated with biologic DMARDs (bDMARDs) are at a significantly greater risk of adverse effects (AEs) [1]. However, the rate of drug discontinuation because of adverse effects caused by bDMARDs has not differed in elderly compared to younger patients in different registries.Objectives:Determine if drug discontinuation of bDMARDs differs by age in patients with rheumatoid arthritis in the Mexican Adverse Events Registry (BIOBADAMEX).Methods:BIOBADAMEX is a Mexican ongoing cohort of patients using bDMARDs since 2016. In this analysis we included all patients with diagnosis of RA with at least two assessments. Survival on bDMARDs was estimated using Kaplan-Meier analysis. Predictors of discontinuation, including age older than median age in the sample were investigated by Cox regression analyses.Results:Among 743 patients in the registry, 497 had RA diagnosis, from which, 214 had at least two assessments. At baseline, patients had a median (IQR) age of 53.4 (45-61) years old, median disease duration of 10.7 (6-17) months and median DAS28 of 4.7 (3-6). Conventional DMARDS were used by 185 (87%) patients and 94 (44%) patients used corticosteroids. Comorbidities were present in 194 (91%). The most common bDMARDs received at baseline were abatacept 59 (27%), tocilizumab 45(21%), adalimumab 31 (15%) and certolizumab 30 (14%). At the time of analysis, the median bDMARDs treatment duration was 21.0(13-34) months, 128 (59%) had discontinued treatment, 66 for inefficacy, 32 for adverse events and 30 for others. Fig 1 shows discontinuation rate curves in patients younger and older than median age. Cox proportional-hazards demonstrated no significant differences regarding age older than median age (HR 1.1, 95% CI 0.8-1.4, p=0.7), female sex (HR 1.2, 95% CI 0.7-1.9, p=0.44), use of corticosteroids (HR 1.2, 95% CI 0.9-1.6, p=0.20), comorbidities (HR 0.9, 95% 0.6-1.5, p=0.78), DAS28 (HR 0.9, 95% 0.9-1.1, p=0.93) or other factors.Figure 1.Discontinuation rate curves in patients younger and older than median age (< 53.4 and >=53.4 years old)Conclusion:This analysis did not show a role of age on discontinuation of bDMARDs in Mexican RA patients. Further longitudinal analyses will be performed including more patients to assess retention rate of bDMARDs and identify predictive variables of discontinuation in Mexican population.References:[1]Akter R, et al. Can Geriatr J. 2020 May 1;23(2):184-189.[2]Ikari Y, et al. Medicine (Baltimore). 2020 Dec 24;99(52):e23861.Disclosure of Interests:None declared


2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 582.1-582
Author(s):  
S. Pazmino ◽  
A. Lovik ◽  
A. Boonen ◽  
D. De Cock ◽  
V. Stouten ◽  
...  

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


2018 ◽  
Vol 38 (6) ◽  
pp. 719-729 ◽  
Author(s):  
Eva-Maria Didden ◽  
Yann Ruffieux ◽  
Noemi Hummel ◽  
Orestis Efthimiou ◽  
Stephan Reichenbach ◽  
...  

Background. Decision makers often need to assess the real-world effectiveness of new drugs prelaunch, when phase II/III randomized controlled trials (RCTs) but no other data are available. Objective. To develop a method to predict drug effectiveness prelaunch and to apply it in a case study in rheumatoid arthritis (RA). Methods. The approach 1) identifies a market-approved treatment ( S) currently used in a target population similar to that of the new drug ( N); 2) quantifies the impact of treatment, prognostic factors, and effect modifiers on clinical outcome; 3) determines the characteristics of patients likely to receive N in routine care; and 4) predicts treatment outcome in simulated patients with these characteristics. Sources of evidence include expert opinion, RCTs, and observational studies. The framework relies on generalized linear models. Results. The case study assessed the effectiveness of tocilizumab (TCZ), a biologic disease-modifying antirheumatic drug (DMARD), combined with conventional DMARDs, compared to conventional DMARDs alone. Rituximab (RTX) combined with conventional DMARDs was identified as treatment S. Individual participant data from 2 RCTs and 2 national registries were analyzed. The model predicted the 6-month changes in the Disease Activity Score 28 (DAS28) accurately: the mean change was -2.101 (standard deviation [SD] = 1.494) in the simulated patients receiving TCZ and conventional DMARDs compared to -1.873 (SD = 1.220) in retrospectively assessed observational data. It was -0.792 (SD = 1.499) in registry patients treated with conventional DMARDs. Conclusion. The approach performed well in the RA case study, but further work is required to better define its strengths and limitations.


Rheumatology ◽  
2020 ◽  
Author(s):  
Camille Valdeyron ◽  
Martin Soubrier ◽  
Bruno Pereira ◽  
Arnaud Constantin ◽  
Jacques Morel ◽  
...  

Abstract Objectives Patients with RA have a higher prevalence of infertility than the general population. This study sought to examine the impact of RA disease activity and treatments on ovarian reserve measured by serum anti-Müllerian hormone (AMH) levels in the ESPOIR cohort. We sought to better define the indications for fertility preservation. Methods Patients and serum analysis data were derived from the French national cohort ESPOIR. Enrolled patients (n = 102; 18–37-year-olds) fulfilled ACR/EULAR 2010 criteria for RA. Serum AMH levels were measured at T0, T6, T12, T24 and T36 months post-diagnosis. The impacts of RA activity (DAS28 and CRP level) and treatments (MTX only or with other medications) were evaluated at each study visit. Results A gradual decrease in patients’ serum AMH levels was observed over time, in line with the descending curve described for healthy women. Serum AMH levels of RA patients in comparison with the values considered normal for age did not reveal any significant differences (P &gt; 0.05). We did not observe any impact of RA treatments. We demonstrated an inverse correlation between AMH variation and disease activity (DAS28: r = –0.27, P = 0.003; CRP: r = –0.16, P = 0.06). Conclusion This is the first study to determine serum AMH levels of a large cohort of RA patients over 36 months. Rapid disease activity control appears to be required to limit changes in the ovarian reserve. Fertility preservation is not likely to be necessary if inflammation is promptly controlled. ClinicalTrials.gov Identifier: NCT03666091.


2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 554.1-554
Author(s):  
K. Almutairi ◽  
J. Nossent ◽  
D. Preen ◽  
H. Keen ◽  
C. Inderjeeth

Background:Rheumatoid arthritis (RA) carries a substantial burden for patients and society in terms of morbidity, enduring disability, and costs [1]. The Australian Pharmaceutical Benefits Scheme (PBS) has subsidised biological disease-modifying anti-rheumatic drugs (B-DMARDs) since 2003 [2].Objectives:We examined the impact of B-DMARDs availability on RA hospitalisation rate in the Western Australia (WA) population pre- and post- B-DMARDs introduction to the PBS (1995-2002 and 2003-2014).Methods:Population PBS dispensing data for WA of DMARD were obtained and converted to defined daily doses (DDD)/1000 population/day using the WA population census. RA inpatient records were extracted from the WA Hospital Morbidity Data Collection using ICD-9 codes 714 and ICD-10 codes M05.00–M06.99). Principal component analysis (PCA) was applied to determine the relationship between DMARDs use and RA hospital admission rates.Results:There was a total of 17,125 patients who had 50,353 admissions with a diagnostic code for RA during the study period. DMARD use for RA rose from 1.45 to 3.19 DDD/1000 population/day over 1995-2014 (Figure 1). In 1995-2002, the number of RA admissions fell from 7.9 to 2.6 per 1000 hospital separations, then dropped further from 2.9 to 1.9 per 1000 hospital separations in 2003-2014. Based on PCA analysis, conventional DMARDs (methotrexate) and B-DMARDs dispensing had an inverse association with hospital admissions for RA.Conclusion:The increased availability of conventional and biological DMARDs for RA was associated with a significant decline in hospital admissions for RA patients in WA.References:[1]Boonen A, Severens JL (2011) The burden of illness of rheumatoid arthritis. Clin Rheumatol 30:3-8.[2]Medicare Australia (2020) Pharmaceutical Benefits Schedule statistics. http://medicarestatistics.humanservices.gov.au/statistics/pbs_item.jsp.Figure 1.The hospital separations and total drugs use patterns of RA in 1995-2014 in Western Australia.Acknowledgements:Supported by an Australian Government Research Training Program PhD Scholarship at the University of Western Australia.Disclosure of Interests:Khalid Almutairi: None declared, Johannes Nossent Speakers bureau: Janssen, David Preen: None declared, Helen Keen Speakers bureau: Pfizer Australia, Abbvie Australia, Charles Inderjeeth Speakers bureau: bureau: Eli Lilly


2010 ◽  
Vol 69 (6) ◽  
pp. 1110-1116 ◽  
Author(s):  
Diane van der Woude ◽  
Silje W Syversen ◽  
Ellen I H van der Voort ◽  
Kirsten N Verpoort ◽  
Guro L Goll ◽  
...  

BackgroundThe presence of anti-citrullinated protein antibodies (ACPA) is a powerful predictive factor for the development and progression of rheumatoid arthritis (RA). The ACPA response has been shown to consist of various isotypes, but the consequences of differences in isotype distribution have not been extensively investigated.ObjectiveTo investigate the relationship between ACPA isotypes, disease progression and radiological outcome.MethodsACPA isotypes were determined in sera of anti-cyclic citrullinated peptide 2-positive patients by enzyme-linked immunosorbent assay (ELISA). To investigate whether the ACPA response continues to evolve during disease development, the ACPA isotype profile during progression of undifferentiated arthritis (UA) to RA was studied. The association of disease progression with ACPA isotype use was assessed using long-term radiographic follow-up data from patients with RA in two independent cohorts.ResultsThe ACPA isotype distribution did not expand during disease progression from UA to RA, but was relatively stable over time. In both RA cohorts, the baseline ACPA isotype profile was a significant predictor of disease severity, with more isotypes indicating a higher risk of radiographic damage (odds ratio for every additional isotype: 1.4 (95% CI 1.1 to 1.9) p<0.001). ACPA isotypes supplied additional prognostic information to ACPA status alone, even after correction for other predictive factors.ConclusionsThe magnitude of the ACPA isotype profile at baseline reflects the risk of future radiographic damage. These results indicate that the presence and the constitution of the ACPA response are relevant to the disease course of RA.


2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1401.3-1401
Author(s):  
H. Bettaieb ◽  
A. Fazaa ◽  
S. Miladi ◽  
M. Sellami ◽  
O. Kmar ◽  
...  

Background:During rheumatoid arthritis (RA), initiating conventional synthetic Disease Modifying Anti-Rheumatic Drug (csDMARD) at the early stages of the disease is a mandatory condition to achieve DMARD-free sustained remission (1). Limited data studying the relationship between RA treatment delay and disease activity are available.Objectives:The aim of this study was to assess the impact of csDMARD initiation delay during RA on disease activity.Methods:This is a cross-sectional study including patients with RA (ACR/EULAR criteria).Delays were collected from patients’ interview and were represented respectively by D1, D2 and D3. D1 stands for the lag time separating the first RA symptom onset and rheumatologist consultation. D2 stands for the lag time separating the first RA symptom onset and RA diagnosis. D3 stands for lag time separating the first RA symptom onset and csDMARD initiation. Disease activity was evaluated by: Visual Analogue Scale for pain (VAS), number of tender joints, number of swollen joints, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and Disease Activity Score28 (DAS28).The data were analyzed with descriptive statistics, Student’s t test, chi (2) test, and Spearman correlation using the SPSS statistical package. A p value < 0.05 was considered significant.Results:The study included 100 RA patients (86 women and 14 men), with a mean age of 56.5 ± 12.4 years. The mean age at the onset of RA was 47.5 ± 12.4 years. Median D1, D2 and D3 were respectively 12 months [0-242], 15.7 months [2-252] and 18 months [2-270].Methotrextate was prescribed in 86% of cases. At RA diagnosis, the median values for the following parameters were: VAS 80 [30-100], number of tender joints 10[0-28], number of swollen joints 5 [0-17], ESR 43mm/hour [6-133], CRP 14.1 mg/l [1-120], DAS28 (ESR) 5.22 [2-7.52] and DAS28 (CRP) 4.6 [1-6.93]. After one year of follow-up, the median parameters of the disease activity were respectively: VAS 60 [0-100], number of tender joints 6[0-28], number of swollen joints 2 [0-22], ESR 32 mm/hour [2-106], CRP 7.5 mg/l [1.2-94], DAS28 (ESR) 4.1 [1.4-7.1] and DAS28 (CRP) 3.7 [1.68-6.22]. Significant positive correlation was found between delays in csDMARD initiation and DAS28 (CRP) scores over the first year (p=0.02, r=0.29).Conclusion:In this study, delays in treatment were associated with higher DAS28 (CRP) scores after one year of follow-up. Our results suggest that early identification and treatment of RA leads to improved outcomes and even improved rates of drug-free remission.References:[1]Van Nies JA, Krabben A, Schoones JW, et al. What is the evidence for the presence of a therapeutic window of opportunity in rheumatoid arthritis? A systematic literature review. Ann Rheum Dis 2014;73:861–70.Disclosure of Interests:None declared


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