Antimodified protein antibody response pattern influences the risk for disease relapse in patients with rheumatoid arthritis tapering disease modifying antirheumatic drugs

2016 ◽  
Vol 76 (2) ◽  
pp. 399-407 ◽  
Author(s):  
Camille P Figueiredo ◽  
Holger Bang ◽  
Jayme Fogagnolo Cobra ◽  
Matthias Englbrecht ◽  
Axel J Hueber ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Antibody Response ◽  
Multivariate Logistic Regression Analysis ◽  
Sustained Remission ◽  
Disease Relapse ◽  
Serum Samples ◽  
Baseline Serum ◽  
Dmard Therapy ◽  
Relapse Risk ◽  
Disease Modifying

ObjectiveTo perform a detailed analysis of the autoantibody response against post-translationally modified proteins in patients with rheumatoid arthritis (RA) in sustained remission and to explore whether its composition influences the risk for disease relapse when tapering disease modifying antirheumatic drug (DMARD) therapy.MethodsImmune responses against 10 citrullinated, homocitrullinated/carbamylated and acetylated peptides, as well as unmodified vimentin (control) and cyclic citrullinated peptide 2 (CCP2) were tested in baseline serum samples from 94 patients of the RETRO study. Patients were classified according to the number of autoantibody reactivities (0–1/10, 2–5/10 and >5/10) or specificity groups (citrullination, carbamylation and acetylation; 0–3) and tested for their risk to develop relapses after DMARD tapering. Demographic and disease-specific parameters were included in multivariate logistic regression analysis for defining the role of autoantibodies in predicting relapse.ResultsPatients varied in their antimodified protein antibody response with the extremes from recognition of no (0/10) to all antigens (10/10). Antibodies against citrullinated vimentin (51%), acetylated ornithine (46%) and acetylated lysine (37%) were the most frequently observed subspecificities. Relapse risk significantly (p=0.011) increased from 18% (0–1/10 reactivities) to 34% (2–5/10) and 55% (>5/10). With respect to specificity groups (0–3), relapse risk significantly (p=0.021) increased from 18% (no reactivity) to 28%, 36% and finally to 52% with one, two or three antibody specificity groups, respectively.ConclusionsThe data suggest that the pattern of antimodified protein antibody response determines the risk of disease relapse in patients with RA tapering DMARD therapy.Trial registration number2009-015740-42; Results.

scholarly journals Prediction of disease relapses by multibiomarker disease activity and autoantibody status in patients with rheumatoid arthritis on tapering DMARD treatment

2015 ◽  
Vol 75 (9) ◽  
pp. 1637-1644 ◽  
Author(s):  
Juergen Rech ◽  
Axel J Hueber ◽  
Stephanie Finzel ◽  
Matthias Englbrecht ◽  
Judith Haschka ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Regression Analysis ◽  
Disease Activity ◽  
Controlled Trial ◽  
Multivariate Logistic Regression Analysis ◽  
Multivariate Regression Analysis ◽  
Sustained Remission ◽  
Serum Samples ◽  
Baseline Serum ◽  
Randomised Controlled

ObjectiveTo analyse the role of multibiomarker disease activity (MBDA) score in predicting disease relapses in patients with rheumatoid arthritis (RA) in sustained remission who tapered disease modifying antirheumatic drug (DMARD) therapy in RETRO, a prospective randomised controlled trial.MethodsMBDA scores (scale 1–100) were determined based on 12 inflammation markers in baseline serum samples from 94 patients of the RETRO study. MBDA scores were compared between patients relapsing or remaining in remission when tapering DMARDs. Demographic and disease-specific parameters were included in multivariate logistic regression analysis for defining predictors of relapse.ResultsModerate-to-high MBDA scores were found in 33% of patients with RA overall. Twice as many patients who relapsed (58%) had moderate/high MBDA compared with patients who remained in remission (21%). Baseline MBDA scores were significantly higher in patients with RA who were relapsing than those remaining in stable remission (N=94; p=0.0001) and those tapering/stopping (N=59; p=0.0001). Multivariate regression analysis identified MBDA scores as independent predictor for relapses in addition to anticitrullinated protein antibody (ACPA) status. Relapse rates were low (13%) in patients who were MBDA−/ACPA−, moderate in patients who were MBDA+/ACPA− (33.3%) and MBDA−ACPA+ (31.8%) and high in patients who were MBDA+/ACPA+ (76.4%).ConclusionsMBDA improved the prediction of relapses in patients with RA in stable remission undergoing DMARD tapering. If combined with ACPA testing, MBDA allowed prediction of relapse in more than 80% of the patients.Trial registration numberEudraCT 2009-015740-42.

scholarly journals FRI0596 NOVEL AUTOANTIBODY BIOMARKERS FOR THE PREDICTION OF THERAPY RESPONSE IN RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 904.1-904
Author(s):  
P. Vandormael ◽  
A. Pues ◽  
E. Sleurs ◽  
P. Verschueren ◽  
V. Somers
Keyword(s):  
Rheumatoid Arthritis ◽  
Therapy Response ◽  
Autoimmune Disorder ◽  
First Line ◽  
Research Support ◽  
Serum Samples ◽  
Glucocorticoid Treatment ◽  
Baseline Serum ◽  
Disease Remission ◽  
Antibody Reactivity

Background:Rheumatoid arthritis (RA) is an autoimmune disorder that is characterized by chronic inflammation of the joint synovium and presence of autoantibodies in most patients. For RA, many treatments are currently available but each treatment will only induce disease remission in a subset of patients. Moreover, finding out which patients respond well to first-line therapy with classical synthetic disease modifying anti-rheumatic drugs (csDMARDs), still largely depends on trial and error.Objectives:In this study, we aim to find novel RA autoantibody biomarkers that predict therapy response to csDMARDs before the initiation of treatment.Methods:In the CareRA trial, a Flemish multicenter study of different treatment regimes, serum samples were collected from RA patients that did or did not show disease remission (DAS28(CRP)<2.6) in response to csDMARDs, combined with a step down glucocorticoid treatment. In our study, baseline samples, collected before the start of treatment, were used to determine predictive antibody reactivity. A cDNA phage display library, representing the antigens from RA synovial tissue, was constructed and screened for antibody reactivity in baseline serum samples of RA patients that failed to reach remission at week 16. Using enzyme-linked immunosorbent assays (ELISA), antibody reactivity against the identified antigens was initially determined in pooled baseline serum samples of RA patients that did (n=50) or did not (n=40) reach disease remission at week 16. Antigenic targets that showed increased antibody reactivity in pools from patients that did not reach disease remission, were further validated in individual serum samples of 69 RA patients that did not reach DAS28(CRP) remission at week 16, and 122 RA patients that did.Results:Screening and validation of antibody reactivity resulted in 41 novel antigens. The retrieved antigenic sequences correspond to (parts of) known proteins and to randomly formed peptides. A panel of 3 of these peptide antigens could be composed, whose baseline antibody reactivity correlated with lack of therapy response at week 16. Presence of antibodies against at least one of these 3 antigens was significantly higher in individual samples of RA patients that did not reach DAS28(CRP) remission (43 vs. 29%, p=0.041), or that failed to reach ACR 70 (42 vs. 26%, p=0.029) response criteria at week 16, compared to RA patients that did reach these respective criteria. In addition, RA patients which were positive for this antibody panel at baseline, also showed less DAS(CRP) remission at week 4 and week 8.Conclusion:We have identified a set of 3 antibody biomarkers that can predict failure of early disease remission after first-line RA therapy, which might contribute to personalized medicine decisions.Disclosure of Interests:Patrick Vandormael: None declared, Astrid Pues: None declared, Ellen Sleurs: None declared, Patrick Verschueren Grant/research support from: Pfizer unrestricted chair of early RA research, Speakers bureau: various companies, Veerle Somers Grant/research support from: Research grant from Pfizer and BMS

scholarly journals BAFF Predicts Immunogenicity in Older Patients With Rheumatoid Arthritis Treated With TNF Inhibitors

2020 ◽  
Author(s):  
Borja Hernández-Breijo ◽  
Victoria Navarro-Compán ◽  
Chamaida Plasencia-Rodríguez ◽  
Ioannis Parodis ◽  
Johanna E. Gehin ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Older Patients ◽  
Operating Characteristic ◽  
Certolizumab Pegol ◽  
Positive Likelihood Ratio ◽  
Characteristic Analysis ◽  
Serum Samples ◽  
Chi Square ◽  
Baseline Serum ◽  
Logistic Regression Models

Abstract Background: Immunogenicity related to treatment with TNF inhibitors (TNFi) is one of the causes for the decreased attainment of clinical response in patients with rheumatoid arthritis (RA). The B-cell activating factor (BAFF) may be playing a role in the development of immunogenicity. The objective of this study was to analyse the association of baseline concentration of serum BAFF with immunogenicity after 6 months of TNFi treatment.Methods: A total of 139 patients with RA starting a TNFi (infliximab, adalimumab, certolizumab pegol or golimumab) were followed-up for 6 months. Serum samples were obtained at baseline and at 6 months and anti-drug antibody (ADA) and BAFF concentrations were measured. Logistic regression models were employed in order to analyse the association between BAFF concentrations and immunogenicity. Receiver operating characteristic analysis was performed to determine the BAFF concentrations with a greater likelihood of showing immunogenicity association.Results: At 6 months, 39 patients (28%) developed ADA. A significant interaction between the age and baseline BAFF concentration was found for the development of ADA (Wald chi-square value=5.30; p=0.02); therefore, subsequent results were stratified according to mean age (≤/>55 years). Baseline serum BAFF concentration was independently associated with ADA development only in patients over 55 years (OR=1.55; 95% CI: 1.03-2.12). Baseline serum BAFF≥1034pg/mL predicted the presence of ADA at 6 months (positive likelihood ratio=3.7).Conclusions: Our results suggest that the association of BAFF concentration and immunogenicity depends on the patient’s age. Baseline serum BAFF concentration predicts the presence of ADA within 6 months of TNFi therapy in older patients with RA.

scholarly journals Sustained discontinuation of infliximab with a raising-dose strategy after obtaining remission in patients with rheumatoid arthritis: the RRRR study, a randomised controlled trial

2019 ◽  
Vol 79 (1) ◽  
pp. 94-102
Author(s):  
Yoshiya Tanaka ◽  
Koji Oba ◽  
Takao Koike ◽  
Nobuyuki Miyasaka ◽  
Tsuneyo Mimori ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Treatment Group ◽  
Treatment Strategy ◽  
Activity Index ◽  
Randomised Trial ◽  
Standard Group ◽  
Sustained Remission ◽  
Inadequate Response ◽  
Baseline Serum ◽  
Tnf Α

ObjectivesThe aim of this study is to determine whether the ‘programmed’ infliximab (IFX) treatment strategy (for which the dose of IFX was adjusted based on the baseline serum tumour necrosis factor α (TNF-α)) is beneficial to induction of clinical remission after 54 weeks and sustained discontinuation of IFX for 1 year.MethodsIn this multicentre randomised trial, patients with IFX-naïve rheumatoid arthritis with inadequate response to methotrexate were randomised to two groups; patients in programmed treatment group received 3 mg/kg IFX until week 6 and after 14 weeks the dose of IFX was adjusted based on the baseline levels of serum TNF-α until week 54; patients in the standard treatment group received 3 mg/kg of IFX. Patients who achieved a simplified disease activity index (SDAI) ≤3.3 at week 54 discontinued IFX. The primary endpoint was the proportion of patients who sustained discontinuation of IFX at week 106.ResultsA total of 337 patients were randomised. At week 54, 39.4% (67/170) in the programmed group and 32.3% (54/167) in the standard group attained remission (SDAI ≤3.3). At week 106, the 1-year sustained discontinuation rate was not significantly different between two groups; the programmed group 23.5% (40/170) and the standard group 21.6% (36/167), respectively (2.2% difference, 95% CI −6.6% to 11.0%; p=0.631). Baseline SDAI <26.0 was a statistically significant predictor of the successfully sustained discontinuation of IFX at week 106.ConclusionProgrammed treatment strategy did not statistically increase the sustained remission rate after 1 year discontinuation of IFX treatment.

Circulating Small Noncoding RNA Biomarkers of Response to Triple Disease-modifying Antirheumatic Drug Therapy in White Women With Early Rheumatoid Arthritis

2020 ◽  
Vol 47 (12) ◽  
pp. 1746-1751
Author(s):  
Andrew D. Foers ◽  
Alexandra L. Garnham ◽  
Gordon K. Smyth ◽  
Susanna M. Proudman ◽  
Lesley Cheng ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Early Rheumatoid Arthritis ◽  
Noncoding Rna ◽  
Differential Expression Analysis ◽  
Antirheumatic Drug ◽  
Small Rna Sequencing ◽  
Dmard Therapy ◽  
Small Noncoding Rna ◽  
Disease Modifying ◽  
Disease Modifying Antirheumatic Drug

ObjectiveTo identify small noncoding RNA (sncRNA) serum biomarkers that predict response to triple disease-modifying antirheumatic drug (DMARD) therapy in patients with early rheumatoid arthritis (RA).MethodsEarly RA patients entered into a treat-to-target management algorithm, with triple DMARD therapy (methotrexate, sulfasalazine, hydroxychloroquine). Patients were assessed following 6 months of therapy and classified as European League Against Rheumatism responders or nonresponders. RNA was isolated from 42 archived serum samples, collected prior to commencement of triple DMARD therapy. Small RNA sequencing was performed and the reads mapped to annotations in a database of human sncRNA. Differential expression analysis was performed, comparing responders (n = 24) and nonresponders (n = 18).ResultsPretreatment levels of 4 sncRNA were significantly increased in nonresponders: chr1. tRNA131-GlyCCC (4.1-fold, adjusted P = 0.01), chr2.tRNA13-AlaCGC (2.2-fold, adjusted P = 0.02), U2-L166 (6.6-fold, adjusted P = 0.02), and piR-35982 (2.4-fold, adjusted P = 0.03). 5S-L612 was the only sncRNA significantly increased in responders (3.3-fold; adjusted P = 0.01). Reads for chr1. tRNA131-GlyCCC and chr2.tRNA13-AlaCGC mapped to the 5′ end of each tRNA gene and were truncated at the anticodon loop, consistent with these sncRNA having roles as 5′ translation interfering tRNA halves (tiRNA).ConclusionPretreatment levels of specific serum sncRNA might facilitate identification of patients more likely to respond to triple DMARD therapy.

scholarly journals Blood pro-resolving mediators are linked with synovial pathology and are predictive of DMARD responsiveness in rheumatoid arthritis

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Esteban A. Gomez ◽  
Romain A. Colas ◽  
Patricia R. Souza ◽  
Rebecca Hands ◽  
Myles J. Lewis ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Treatment Initiation ◽  
Plasma Concentrations ◽  
Docosapentaenoic Acid ◽  
Lipid Mediator ◽  
Disease Modifying Antirheumatic Drugs ◽  
Antirheumatic Drugs ◽  
Dmard Therapy ◽  
Disease Modifying ◽  
Learning Analysis

Abstract Biomarkers are needed for predicting the effectiveness of disease modifying antirheumatic drugs (DMARDs). Here, using functional lipid mediator profiling and deeply phenotyped patients with early rheumatoid arthritis (RA), we observe that peripheral blood  specialized pro-resolving mediator (SPM) concentrations are linked with both DMARD responsiveness and disease pathotype. Machine learning analysis demonstrates that baseline plasma concentrations of resolvin D4, 10S, 17S-dihydroxy-docosapentaenoic acid, 15R-Lipoxin (LX)A4 and n-3 docosapentaenoic-derived Maresin 1 are predictive of DMARD responsiveness at 6 months. Assessment of circulating SPM concentrations 6-months after treatment initiation establishes that differences between responders and non-responders are maintained, with a decrease in SPM concentrations in patients resistant to DMARD therapy. These findings elucidate the potential utility of  plasma SPM concentrations as biomarkers of DMARD responsiveness in RA.

Safety of Biologic and Nonbiologic Disease-modifying Antirheumatic Drug Therapy in Veterans with Rheumatoid Arthritis and Hepatitis C Virus Infection

2017 ◽  
Vol 44 (5) ◽  
pp. 565-570 ◽  
Author(s):  
Mary Jane Burton ◽  
Jeffrey R. Curtis ◽  
Shuo Yang ◽  
Lang Chen ◽  
Jasvinder A. Singh ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antirheumatic Drug ◽  
Hcv Infection ◽  
Hcv Rna ◽  
Dmard Therapy ◽  
Biologic Dmard ◽  
Disease Modifying ◽  
Disease Modifying Antirheumatic Drug

Objective.To examine the effect of disease-modifying antirheumatic drug (DMARD) therapy on hepatotoxicity among patients with rheumatoid arthritis (RA) and hepatitis C virus (HCV) infection.Methods.We identified biologic and nonbiologic treatment episodes of patients with RA using the 1997–2011 national data from the US Veterans Health Administration. Eligible episodes had HCV infection (defined by detectable HCV RNA) and subsequently initiated a new biologic or nonbiologic DMARD. Cohort entry required a baseline alanine aminotransferase (ALT) < 66 IU/l and quantifiable HCV RNA within 90 days prior to starting biologic/DMARD therapy. The primary outcome of interest was hepatotoxicity, defined as ALT elevation ≥ 100 IU/l or increase in HCV RNA of 1 log or more, and was examined within the first year of biologic/DMARD use. Results were reported as the cumulative incidence of treatment episodes achieving predefined hepatotoxicity at 3, 6, and 12 months after biologic/DMARD initiation.Results.RA patients with HCV (n = 748) were identified and contributed 1097 biologic/DMARD treatment episodes. Overall, ALT elevations were uncommon, with 37 (3.4%) hepatotoxicity events occurring within 12 months. Treatment episodes with biologic DMARD demonstrated more frequency of hepatotoxicity than did nonbiologic DMARD (4.8% vs 2.3%, p = 0.03). Among treatment episodes involving hepatotoxicity events, the majority occurred within 6 months of DMARD initiation (29/37, 78%).Conclusion.In US veterans with HCV and RA receiving biologic and nonbiologic DMARD, the frequency of hepatotoxicity (ALT ≥ 100 IU/l) was low, with a higher frequency observed in treatment episodes with current biologic use.

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