THU0066 DOES PORPHYROMONAS GINGIVALLIS MODULATE GUT MICROBIOME RESULTING IN AGGRAVATION OF DISEASE ACTIVITY IN RHEUMATOID ARTHRITIS?

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 245.1-246
Author(s):  
K. Kitamura ◽  
K. Terato ◽  
R. Fukai ◽  
K. Katayama ◽  
T. Waritani ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Porphyromonas Gingivalis ◽  
Rank Correlation ◽  
Inverse Correlation ◽  
Inadequate Response ◽  
Positive Correlation ◽  
E Coli ◽  
Antibody Levels ◽  
Total Bacteria

Background:Oral Porphyromonas gingivalis (Pg) infection in rheumatoid arthritis (RA) model revealed aggravation of arthritis, dysbiosis and higher serum LPS (1). We reported that IgA/IgG antibody against Pg-LPS ratio among the patients with RA related to disease marker levels and disease activities (2). However, there are still few reports related to Gut-Oral axis.Objectives:Firstly, how total intestinal bacteria, well-known 5 species of gut bacteria behave in relation to disease activities and markers. Secondly, how infection by Pg aggravate RA in relation to microflora, disease activities and markers.Methods:Eighty-seven RA patients with inadequate response to conventional synthetic DMARDs were evaluated. Age: 68.1±8.7 years, female (%): 79.3, disease duration: 136±91 months, DAS28-ESR: 4.68±0.98. Fecal bacteria numbers of total bacteria, Bifidobacterium, Lactobacillus, E. coli, Bacteroides and Staphylococcus were determined by PCR analysis. Fecal and serum LPS levels were measured by LAL assay. Serum endotoxin neutralizing activity (ENC) was determined along with RA disease activity and markers measurement. Infection of Pg was proofed by IgG and IgA anti-LPS antibody measurement. The statistical relationships between variables were analyzed by Spearman’s non-parametric rank correlation analysis and expressed as Spearman’s rank correlation coefficient “ρ”.Results:At first, we could neglect background effects as duration, methotrexate dose for measuring total or each bacterial number (data not shown). As shown in Figure 1, total bacteria only showed positive correlation with IL-6 levels (ρ= 0.230, p = 0.034), however inversely correlated with disease activities such as pVAS (ρ= -0.223, p = 0.038) and Pain VAS (ρ= -0.260, p = 0.015). While no significant relationship was observed between the numbers of each of 5 species of bacteria and the disease activities and makers except Bifidobacterium. In contrast, LPS-related markers showed positive correlation with disease activities and markers. Among LPS-related biomarker values, serum LBP levels mainly correlated with most of RA biomarker-ESR (ρ= 0.497, p <0.0001), CRP (ρ= 0.697, p <0.0001), MMP3 (ρ= 0.546, p <0.0001) and so on. Fecal LPS level was shown significant positive correlation with disease activities, however almost no correlation was observed in serum LPS level. IgA anti-LPS antibody levels to Pg, resulted in inverse correlation with total bacteria (ρ= -0.441, p<0.0001), Lactobacillus (ρ= -0.224, p=0.037), Bacteroides (ρ = -0.200, p = 0.064) and E. coli (ρ= -0.260, p = 0.015), moreover, positive correlation with serum LPS (ρ= 0.284, p = 0.008) and LBP (ρ= 0.247, p = 0.021) and inverse correlation with ENC (ρ = -0.321, p = 0.002) were found. On the other hand, IgG anti-Pg-LPS antibody levels which reflect systemic infection, inversely correlated SDAI (ρ = -0.308, p = 0.004), PainVAS (ρ = -0.433, p < 0.0001), and so on.Conclusion:Serum LBP highly associated with RA activity and markers, which suggests bacterial LPS as roles in triggering and perpetuating disease activity in RA. In contrast, IgA anti-Pg-LPS, IgG anti-Pg-LPS antibody reflecting infection of Pg, negatively associated with intestinal total bacteria (ρ=-0.4405, p<0.0001), RA disease activities, respectively. These results may show a possible oral -gut relationship resulting in aggravation of disease activity in RA.Disclosure of interest:None declaredReferences:[1]Sato K, Takahashi N, Kato T et al. Aggravation of collagen induced arthritis by orally administered Porphyromonas gingivalis through modulation of the gut microbiota and gut immune system. Sci Rep 2017; 7:6955.[2]Kuniaki Terato, Takaki Waritani, Richio Fukai et al. Contribution of bacterial pathogens to evoking serological disease markers and aggravating disease activity in rheumatoid arthritis. PloS One. 2018;13(2): e0190588.Disclosure of Interests:None declared

Evaluation of Toll-like Receptor 2 Gene Expression in Rheumatoid Arthritis and Correlation with the Disease Activity

2019 ◽  
Vol 13 (2) ◽  
pp. 140-148
Author(s):  
Mai Nasser ◽  
Noha M. Hazem ◽  
Amany Atwa ◽  
Amina Baiomy
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Autoimmune Diseases ◽  
Disease Activity ◽  
Mrna Expression ◽  
Disease Activity Score ◽  
Activity Score ◽  
Tlr2 Expression ◽  
Positive Correlation ◽  
Tlr2 Mrna

Background: Rheumatoid Arthritis (RA) is an autoimmune, chronic, and systematic disease. It affects joints and bones. The exact etiology of RA is still unclear. Varied genetic and environmental factors have been associated with the increased risk for RA. Overactivation of Toll-Like Receptors (TLRs) could initiate the development of autoimmune diseases including RA. Objective: The aim of the study was to evaluate TLR2 gene expression in rheumatoid arthritis patients and investigate its correlation with the disease activity. Materials and Methods: This study included 60 patients and 20 healthy individuals. The patients were diagnosed with RA according to the 2010 American College of Rheumatology/ European League Against Rheumatism criteria (ACR/EULAR). All included subjects did not have any joint disorders and /or autoimmune diseases. RA disease activity was determined by the disease activity score of 28 joints. Whole blood was collected from all participants. Total RNA extraction was done. TLR2 mRNA expression was assessed by reverse transcription-PCR (RT-PCR). Results: TLR2 mRNA expression was found to be significantly higher in RA patients compared to healthy controls. Also, a strong positive correlation was found between TLR2 expression level and the disease activity score. A non significant positive correlation was found between TLR2 expression and serum Rheumatoid Factor (RF) level. Conclusion: TLR2 pathway may have an important role in RA pathogenesis and could be a new biomarker for diagnosis and monitoring disease activity.

scholarly journals AB0330 HIGH REMISSION RATES IN RA – REAL LIFE DATA FROM BARITICINIB

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1463.2-1464
Author(s):  
S. Bayat ◽  
K. Tascilar ◽  
V. Kaufmann ◽  
A. Kleyer ◽  
D. Simon ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Cox Regression ◽  
Real Life ◽  
Inadequate Response ◽  
Research Support ◽  
Das 28 ◽  
Patient Reported ◽  
One Year

Background:Recent developments of targeted treatments such as targeted synthetic DMARDs (tsDMARDs) increase the chances of a sustained low disease activity (LDA) or remission state for patients suffering rheumatoid arthritis (RA). tsDMARDs such as baricitinib, an oral inhibitor of the Janus Kinases (JAK1/JAK2) was recently approved for the treatment of RA with an inadequate response to conventional (cDMARD) and biological (bDMARD) therapy. (1, 2).Objectives:Aim of this study is to analyze the effect of baricitinb on disease activity (DAS28, LDA) in patients with RA in real life, to analyze drug persistance and associate these effects with various baseline characteristics.Methods:All RA patients were seen in our outpatient clinic. If a patient was switched to a baricitinib due to medical reasons, these patients were included in our prospective, observational study which started in April 2017. Clinical scores (SJC/TJC 76/78), composite scores (DAS28), PROs (HAQ-DI; RAID; FACIT), safety parameters (not reported in this abstract) as well as laboratory biomarkers were collected at each visit every three months. Linear mixed effects models for repeated measurements were used to analyze the time course of disease activity, patient reported outcomes and laboratory results. We estimated the probabilities of continued baricitinib treatment and the probabilities of LDA and remission by DAS-28 as well as Boolean remission up to one year using survival analysis and explored their association with disease characteristics using multivariable Cox regression. All patients gave informed consent. The study is approved by the local ethics.Results:95 patients were included and 85 analyzed with available follow-up data until November 2019. Demographics are shown in table 1. Mean follow-up duration after starting baricitinib was 49.3 (28.9) weeks. 51 patients (60%) were on monotherapy. Baricitinib survival (95%CI) was 82% (73% to 91%) at one year. Cumulative number (%probability, 95%CI) of patients that attained DAS-28 LDA at least once up to one year was 67 (92%, 80% to 97%) and the number of patients attaining DAS-28 and Boolean remission were 31 (50%, 34% to 61%) and 12(20%, 9% to 30%) respectively. Median time to DAS-28 LDA was 16 weeks (Figure 1). Cox regression analyses did not show any sufficiently precise association of remission or LDA with age, gender, seropositivity, disease duration, concomitant DMARD use and number of previous bDMARDs. Increasing number of previous bDMARDs was associated with poor baricitinib survival (HR=1.5, 95%CI 1.1 to 2.2) while this association was not robust to adjustment for baseline disease activity. Favorable changes were observed in tender and swollen joint counts, pain-VAS, patient and physician disease assessment scores, RAID, FACIT and the acute phase response.Conclusion:In this prospective observational study, we observed high rates of LDA and DAS-28 remission and significant improvements in disease activity and patient reported outcome measurements over time.References:[1]Keystone EC, Taylor PC, Drescher E, Schlichting DE, Beattie SD, Berclaz PY, et al. Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate. Annals of the rheumatic diseases. 2015 Feb;74(2):333-40.[2]Genovese MC, Kremer J, Zamani O, Ludivico C, Krogulec M, Xie L, et al. Baricitinib in Patients with Refractory Rheumatoid Arthritis. The New England journal of medicine. 2016 Mar 31;374(13):1243-52.Figure 1.Cumulative probability of low disease activity or remission under treatment with baricitinib.Disclosure of Interests:Sara Bayat Speakers bureau: Novartis, Koray Tascilar: None declared, Veronica Kaufmann: None declared, Arnd Kleyer Consultant of: Lilly, Gilead, Novartis,Abbvie, Speakers bureau: Novartis, Lilly, David Simon Grant/research support from: Else Kröner-Memorial Scholarship, Novartis, Consultant of: Novartis, Lilly, Johannes Knitza Grant/research support from: Research Grant: Novartis, Fabian Hartmann: None declared, Susanne Adam: None declared, Axel Hueber Grant/research support from: Novartis, Lilly, Pfizer, EIT Health, EU-IMI, DFG, Universität Erlangen (EFI), Consultant of: Abbvie, BMS, Celgene, Gilead, GSK, Lilly, Novartis, Speakers bureau: GSK, Lilly, Novartis, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB

scholarly journals POS0407 PROTEOMICS ANALYSIS COMPARING THE MODE OF ACTION OF UPADACITINIB BETWEEN NON-BIOLOGIC-DMARD-IR AND BIOLOGIC-DMARD-IR PsA PATIENTS IDENTIFIES DISTINCT PATHOGENIC PATHWAYS IN THE SELECT-PsA 1 AND SELECT-PsA 2 PHASE 3 STUDIES

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 433.1-433
Author(s):  
T. Sornasse ◽  
J. Anderson ◽  
K. Kato ◽  
A. Lertratanakul ◽  
I. McInnes ◽  
...  
Keyword(s):  
Disease Activity ◽  
Clinical Response ◽  
Rheumatic Diseases ◽  
Inadequate Response ◽  
Protein Biomarkers ◽  
Research Support ◽  
Positive Correlation ◽  
Disease Biology ◽  
Biologic Dmard ◽  
Favorable Clinical Response

Background:Treatment of non-biologic-DMARD-IR1 (DMARD-IR) and biologic-DMARD-IR2 (bio-IR) PsA patients with upadacitinib (UPA) at 15 mg QD, an oral JAK1 selective inhibitor, resulted in significant improvement in signs and symptoms compared to placebo.Objectives:Using a pre-defined set of inflammation-related plasma protein biomarkers (pBM), to explore immunological pathway modulation by UPA 15 mg QD in PsA patients with active disease despite treatment with non-biologic or biologic DMARDs in the context of clinical response vs. non-response to treatment.Methods:Patients from the SELECT-PsA 1 (DMARD-IR) and the SELECT-PsA 2 (bio-IR) studies were randomly selected (PBO, n=100; UPA 15 mg QD, n=100 for each study). The levels of 92 inflammation related protein biomarkers (pBM) were analyzed using a multiplexed Proximity Extension Assay platform in plasma samples collected at baseline, week 2, and 12; change from baseline in protein levels was expressed as Log2 Fold Change; a Repeated Measure Mixed Linear Model was used to identify pBM modulated by UPA compared to Baseline, and those differentially modulated between responders (R) and non-responders (NR) according to ACR50, PASDAS Minimal Disease Activity, and PASI75 at week 12. Correlation of disease activity measures with relative levels of pBM were derived using Pearson’s correlation; PASI score was transformed as Log10 (x+1) prior to the analysis. Functional pathway prediction was performed in silico with a commercial distributed software.Results:At baseline, the relative levels of 37 pBM correlated with at least one baseline disease activity measure, with a marked positive correlation of IL6 with musculoskeletal end points (PASDAS and DAS28CRP), and a strong positive correlation of IL20, IL17A, IL17C, and TGFA with baseline PASI.At the single pBM-level, treatment with UPA 15 mg QD resulted in a down modulation of pBM associated with T cells, myeloid cells, and IFN-, IL6-, and TNF-related pathways in both DMARD-IR and bio-IR PsA patients. Overall effects of UPA on single pBMs were broadly similar between DMARD-IR and bio-IR patients. However, analysis of pBMs differentially modulated by UPA in R vs NR indicated that favorable clinical response (achievement of ACR50, PASDAS MDA, and PASI75) in DMARD-IR patients was associated with the down modulation of pBMs predicted to be linked to IFN, IL10, IL17, IL22, and IL27 pathways; while favorable clinical response in bio-IR patients was associated with the down modulation of multiple pBM predicted to be linked to the IL17, IL23, and IL1 pathways.Conclusion:UPA effects in both DMARD-IR and bio-IR PsA patients likely stem from the direct and indirect inhibition of multiple biological pathways belonging to the adaptive and innate immune systems. Responder/Non-Responder analysis suggests a possible shift from a TH1 biased biology in DMARD-IR PsA patients to a more TH17 biased biology in bio-IR PsA patients. This apparent change in the disease biology of PsA patients after inadequate response to prior therapy could be attributed to the actual alteration of the disease biology, treatment outcome-based patient selection, or both. Considering the clinical efficacy of UPA in both DMARD-IR and bio-IR PsA patients, this observation highlights the importance of targeting multiple pathways with drugs such as UPA for the treatment of a broad range of PsA patients.References:[1]McInnes, I. et al. Annals of the Rheumatic Diseases 79, 16-17 (2020).[2]Mease, P.J. et al.Annals of the Rheumatic Diseases, annrheumdis-2020-218870 (2020).Acknowledgements:AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship.Disclosure of Interests:Thierry Sornasse Shareholder of: AbbVie, Employee of: AbbVie, Jaclyn Anderson Shareholder of: AbbVie, Employee of: AbbVie, Koji Kato Shareholder of: AbbVie, Employee of: AbbVie, Apinya Lertratanakul Shareholder of: AbbVie, Employee of: AbbVie, Iain McInnes Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Sanofi Regeneron, UCB Pharma, Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Sanofi Regeneron, UCB Pharma, Christopher T. Ritchlin Consultant of: AbbVie, Amgen, Celgene, Janssen, Lilly, Novartis, Pfizer, Sun, UCB Pharma, Grant/research support from: AbbVie, Amgen, UCB

scholarly journals THU0207 SUSTAINABILITY OF RESPONSE TO UPADACITINIB AS MONOTHERAPY OR IN COMBINATION AMONG PATIENTS WITH RHEUMATOID ARTHRITIS AND PRIOR INADEQUATE RESPONSE TO CONVENTIONAL SYNTHETIC DMARDS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 327.1-328
Author(s):  
A. Kavanaugh ◽  
M. H. Buch ◽  
B. Combe ◽  
L. Bessette ◽  
I. H. Song ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Inadequate Response ◽  
Research Support ◽  
Two Phase ◽  
First Occurrence ◽  
Activity Measures ◽  
Disease Activity Measures

Background:The primary treatment goal for patients (pts) with rheumatoid arthritis (RA) is a state of sustained clinical remission (REM) or low disease activity (LDA).1,2Objectives:To assess the long-term sustainability of responses to upadacitinib (UPA), a JAK inhibitor, with or without background csDMARD(s) in pts with RA.Methods:Data are from two phase 3 randomized, controlled trials of UPA in RA pts with roughly similar baseline disease characteristics: SELECT-NEXT enrolled pts with an inadequate response (IR) to csDMARD(s) on background stable csDMARD(s) receiving UPA 15 mg or 30 mg once daily or placebo for 12 weeks (wks); SELECT-MONOTHERAPY enrolled methotrexate (MTX)-IR pts receiving UPA 15 mg or 30 mg monotherapy or blinded MTX for 14 wks. After 12/14 wks, pts could enter a blinded long-term extension and receive UPA 15 mg or 30 mg for up to 5 years. This post hoc analysis evaluated clinical REM (CDAI ≤2.8; SDAI ≤3.3), LDA (CDAI≤10; SDAI≤11), and DAS28(CRP) <2.6/≤3.2 at first occurrence before Wk 84; additionally, these measures were evaluated at 3, 6, and 12 months after the first occurrence for the total number of pts randomized to UPA 15 mg. Sustainability of response was evaluated by Kaplan-Meier only for those pts who achieved REM/LDA and was defined as time to the earliest date of losing response at two consecutive visits or discontinuation of study drug. The predictive ability of time to clinical REM/LDA was assessed using Harrell’s concordance (c)-index (for reference, an index ~ 0.5, indicates no ability to predict; an index of 1 or -1 would be a perfect prediction). The last follow up dates were 22 March, 2018 (SELECT-NEXT) and 25 May, 2019 (SELECT-MONOTHERAPY), when all pts had reached the Wk 84 visit.Results:Through Wk 84, the percent of treated pts achieving CDAI REM/LDA was 43%/79% for those receiving UPA 15 mg with background csDMARD(s) (SELECT-NEXT) and 37%/76% for those receiving UPA 15 mg without background csDMARD(s) (SELECT-MONOTHERAPY). 35%/25% of pts randomized to UPA 15 mg with background csDMARD(s) and 27%/23% of pts randomized to UPA 15 mg without background csDMARD(s) achieved sustained CDAI REM through 6/12 months after the first occurrence. 64%/56% of pts randomized to UPA 15 mg with background csDMARD(s) and 61%/56% of pts randomized to UPA 15 mg without background csDMARD(s) achieved sustained CDAI LDA through 6/12 months after the first occurrence (Figure 1). Time to initial clinical REM/LDA did not appear to be associated with sustained disease control. The c-indices (95%CI) for CDAI REM in the UPA 15 mg with background csDMARD(s) and UPA 15 mg without background csDMARD(s) groups were 0.541 (0.47, 0.62) and 0.568 (0.49, 0.65) and that of LDA were 0.521 (0.46, 0.58) and 0.498 (0.43, 0.56), respectively. Through last follow-up visit, 55% of pts receiving UPA 15 mg with background csDMARD(s) and 62% of pts receiving UPA 15 mg without background csDMARD(s) remained in CDAI REM while 72% and 70% of pts remained in CDAI LDA, respectively (Figure 2). Similar results were observed across other disease activity measures (SDAI REM/LDA and DAS28(CRP) <2.6/≤3.2).Conclusion:More than a quarter and more than a half of pts with RA and prior IR to csDMARD(s) receiving UPA with or without background csDMARD therapy achieved sustained clinical REM and LDA, respectively, across disease activity measures. Sustainability of responses appeared comparable among pts receiving UPA with or without background csDMARDs through up to 84 wks.References:[1]EULAR: Smolen JS, et al. Ann Rheum Dis 2017;76:960–977.[2]ACR: Singh et al. Arthritis & Rheumatology Vol. 68, No. 1, January 2016, pp 1–26.Disclosure of Interests: :Arthur Kavanaugh Grant/research support from: Abbott, Amgen, AstraZeneca, BMS, Celgene Corporation, Centocor-Janssen, Pfizer, Roche, UCB – grant/research support, Maya H Buch Grant/research support from: Pfizer, Roche, and UCB, Consultant of: Pfizer; AbbVie; Eli Lilly; Gilead Sciences, Inc.; Merck-Serono; Sandoz; and Sanofi, Bernard Combe Grant/research support from: Novartis, Pfizer, Roche-Chugai, Consultant of: AbbVie; Gilead Sciences, Inc.; Janssen; Eli Lilly and Company; Pfizer; Roche-Chugai; Sanofi, Speakers bureau: Bristol-Myers Squibb; Gilead Sciences, Inc.; Eli Lilly and Company; Merck Sharp & Dohme; Pfizer; Roche-Chugai; UCB, Louis Bessette Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, UCB Pharma, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, UCB Pharma, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Sanofi, In-Ho Song Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Yanna Song Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Jessica Suboticki Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Peter Nash Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB

scholarly journals POS0492 A MOLECULAR SIGNATURE RESPONSE CLASSIFIER PREDICTS THE LIKELIHOOD OF EULAR NON-RESPONSE TO TNF INHIBITOR THERAPIES IN RA: RESULTS FROM A RETROSPECTIVE COHORT ANALYSIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 478.2-479
Author(s):  
L. Zhang ◽  
C. van der Tog ◽  
A. den Broeder ◽  
T. Mellors ◽  
E. Connolly-Strong ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Predictive Value ◽  
Molecular Signature ◽  
Response Criteria ◽  
Treat To Target ◽  
Inadequate Response ◽  
Tnf Inhibitor ◽  
Target Setting ◽  
The Impact

Background:Following RA treatment recommendations, most people with rheumatoid arthritis (RA) begin targeted therapy with TNF inhibitors (TNFi), even though inadequate response to TNFi therapies is widespread. Treatment changes from one medication to the next are currently fueled by disease-activity measures and eventually result in disease control for most patients; however, this “trial-and-error” approach wastes precious time on ineffective treatments. A delay in reaching treat-to-target goals has a negative effect on patient burden and, possibly, disease progression.1 Useful predictors for TNFi response have been challenging to identify but a specific molecular signature response classifier (MSRC) test was shown to be predictive for inadequate response to TNFi therapies.2 The impact of such identification has the potential to result in improved patient outcomes, but further validation would be welcome, especially for response criteria other than ACR50, and in a stringent treat-to-target setting with lower baseline disease activity.Objectives:To validate the predictive value of the MSRC test in identifying those patients who do not meet EULAR good response criteria after 6 months of TNFi treatment.Methods:Data from a prospective cohort study conducted in the Sint Maartenskliniek (Nijmegen, the Netherlands) of RA patients who started adalimumab or etanercept TNFi as their first biologic were included.3 Baseline RNA samples and clinical assessments were used to identify patients who had a molecular signature1 of non-response to TNFi therapy. Outcomes were calculated at six months using DAS28-CRP-based EULAR good response, and high and low confidence responders and non-responders were identified using Monte Carlo simulation with 2,000 repeats and 70% precision cut off. Outcome measurements were blinded for test results. Treatment switch before 6 months was imputed as non-response. Odds ratios and area under the ROC curve (AUC) assessments were used to evaluate the ability of the MSRC test to predict inadequate response at 6 months against EULAR good response criteria.Results:A total of 68 out of 88 RA patients were identified to have a high-confidence response status and were included in analyses (Table 1). EULAR good response was observed in 45.5% (31/68) of patients. Patients were stratified according to detection of a molecular signature of non-response with an AUC of 0.61. The odds that a patient with the molecular signature of non-response at baseline failed to achieve a EULAR good response at 6 months was four times greater than that of a patient lacking the molecular signature (odds ratio 4.0, 95% confidence interval 1.2-13.3).Table 1.Patient demographicsCharacteristicRA patients (N = 68)Age, median (SD)57 (11)Female, n (%)43 (63.2)CCP positive, n (%)34 (50.0)RF positive, n (%)38 (55.9)Prescribed adalimumab at baseline, n (%)11 (16.2)Prescribed etanercept at baseline, n (%)57 (83.8)Conclusion:In this validation study, the molecular signature of non-response identified patients who did not fulfill the EULAR good response criteria to TNFi therapies. The patient selection process for this study had limitations; additional analysis in an alternative cohort would further verify the performance of the MSRC test. Nevertheless, the test, previously validated for ACR50, now has been validated using EULAR good response in a treat-to-target setting.References:[1]Schipper LG et al, Time to achieve remission determines time to be in remission. Arthritis Res Ther 201[2]Mellors T, et al. Clinical Validation of a Blood-Based Predictive Test for Stratification of Response to Tumor Necrosis Factor Inhibitor Therapies in Rheumatoid Arthritis Patients. Network and Systems Medicine 2020[3]Tweehuysen L et al. Predictive value of ex-vivo drug-inhibited cytokine production for clinical response to biologic DMARD therapy in rheumatoid arthritis. Clin Exp Rheumatol 2019Disclosure of Interests:Lixia Zhang Shareholder of: Scipher Medicine Corporation, Employee of: Scipher Medicine Corporation, Celeste van der Tog: None declared, Alfons den Broeder Consultant of: Abbvie, Amgen, Cellgene, Roche, Biogen, Lilly, Novartis, Celltrion Sanofi, Gilead., Grant/research support from: Abbvie, Amgen, Cellgene, Roche, Biogen, Lilly, Novartis, Celltrion Sanofi, Gilead., Ted Mellors Shareholder of: Scipher Medicine Corporation, Employee of: Scipher Medicine Corporation, Erin Connolly-Strong Shareholder of: Scipher Medicine Corporation, Employee of: Scipher Medicine Corporation, Johanna Withers Shareholder of: Scipher Medicine Corporation, Employee of: Scipher Medicine Corporation, Alex Jones Shareholder of: Scipher Medicine Corporation, Employee of: Scipher Medicine Corporation, Viatcheslav Akmaev Shareholder of: Scipher Medicine Corporation, Employee of: Scipher Medicine Corporation

scholarly journals SAT0033 USING CHROMOSOME CONFORMATION FOR INSIGHT INTO PATHOGENESIS OF EARLY RHEUMATOID ARTHRITIS ENDOTYPES

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 946.2-947
Author(s):  
C. Duncan ◽  
E. Hunter ◽  
C. Koutsothanasi ◽  
M. Salter ◽  
A. Akoulitchev ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Early Rheumatoid Arthritis ◽  
Inadequate Response ◽  
Loss Of Function ◽  
Inception Cohort ◽  
Chromosome Conformation ◽  
Patient Response ◽  
Early Ra ◽  
Longitudinal Response

Background:Rheumatoid arthritis (RA) is a chronic autoimmune disease with substantial immunopathogenic heterogeneity. It is well established that early diagnosis and initiation of effective therapy is crucial to prevent loss of function. Previously, various RA treatment trajectories have been identified, however there are currently no clinically validated biomarkers that can identify these trajectories at the start of treatment. Evaluation of the structural epigenome has revealed that chromosome conformation signatures (CCS) offer great potential as binary, informative biomarkers, and have been previously shown to predict early RA patient response to Methotrexate with 90% sensitivity (1). These signatures can also reveal highly regulated areas of the genome, which may be underpinning disease endotypes.Objectives:The objective of this study was to evaluate the structural epigenome in early RA over longitudinal samples to determine whether it is associated with treatment trajectories.Methods:Patient data and samples were from the Scottish Early Rheumatoid Arthritis (SERA) cohort; a pan-Scotland inception cohort. CDAI, DAS28 ESR and DAS28 CRP measurements were calculated at baseline, 6 months and 12 months to determine longitudinal treatment response. From 3 principal longitudinal response trajectories, 18 patients (who had equivalent disease activity at baseline) were chosen to investigate the structural epigenome. These 18 comprised of responders (R), non-responders (NR) and initial responders (IR; low disease activity/remission at 6 months but moderate/high disease activity at 12 months) with 6 patients per group at each time point. 20 pooled healthy samples were used as a comparator population. EpiSwitch libraries were probed on 180K Agilent SureSelect custom arrays that were designed using EpiSwitch propriety information and publicly available data from Walshet al(2). Microarray data was analysed using the Limma package within R studio.Results:EpiSwitch array analysis showed that there were >10,000 statistically significant differential chromosomal loops between R, NR and IR. Evaluation of the 3 trajectory groups (R, NR and IR), taking into account the healthy chromosomal conformation, revealed an RA-associated structural epigenome that comprised of 10,445 chromosomal loops that were stable, over the three time points. Subsequent analysis of the distinct treatment trajectories demonstrated that 3683 of the stable, disease-associated chromosomal loops were shared by all 3. However, 4496 were associated with distinct response trajectories, with 1221, 2574 and 701 loops unique to R, NR and IR respectively.Conclusion:The stable chromosomal architecture unique to each treatment trajectory suggests that various underlying molecular endotypes may exist. Moreover, the stable loops common to all groups allude to a baseline level of dysregulation in RA and offers the potential to discover novel drivers of disease. This work provides the foundation to further our understanding of RA pathogenesis and the potential of finding a biomarker that would be of significant value in a clinical setting.References:[1] Carini, C., Hunter, E., Scottish Early Rheumatoid Arthritis Inception cohort Investigators, Ramadass, A. S., Green, J., Akoulitchev, A., et al. (2018). Chromosome conformation signatures define predictive markers of inadequate response to methotrexate in early rheumatoid arthritis.Journal of Translational Medicine,16(1), 18–11[2] Walsh, A. M., Whitaker, J. W., Huang, C. C., Cherkas, Y., Lamberth, S. L., Brodmerkel, C., et al. (2016). Integrative genomic deconvolution of rheumatoid arthritis GWAS loci into gene and cell type associations.Genome Biology,17(1), 2205Disclosure of Interests:Caitlin Duncan: None declared, Ewan Hunter: None declared, Christina Koutsothanasi: None declared, Matthew Salter: None declared, Alexandre Akoulitchev: None declared, Iain McInnes Grant/research support from: Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Janssen, and UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, Novartis, Pfizer, and UCB, Carl Goodyear: None declared

scholarly journals Radiographic changes in TMJ in relation to serology and disease activity in RA patients

2020 ◽  
Vol 49 (1) ◽  
pp. 20190186
Author(s):  
Mostafa Mahmoud Youssef Mohamed ◽  
Mushira M. Dahaba ◽  
Mary Medhat Farid ◽  
Adel Mahmoud Ali Elsayed
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Joint Damage ◽  
Inverse Correlation ◽  
Rheumatoid Arthritis Group ◽  
Control Group ◽  
Significant Inverse Correlation ◽  
Moderate Disease ◽  
Condylar Head ◽  
Radiographic Changes

Objectives: This study was undertaken as an attempt to assess radiographic temporomandibular joint (TMJ) changes in relation to rheumatoid factor (RF), anticitrullinated protein (ACCP) antibodies and disease activity score 28 (DAS28) in rheumatoid arthritis (RA) patients to find the best predictor of rheumatoid affection of the TMJ with the ultimate goal of maintaining TMJ function and preventing joint damage. Methods: 20 Rheumatoid Arthritis patients as well as 20 volunteers were included in this study. RA group were assessed for RF, ACCP, DAS28. Both groups were assessed by CBCT for TMJ dimensions and radiographic osteoarthritic changes. All data were statistically analyzed. Results: Rheumatoid Arthritis group showed significantly less condylar height and more radiographic osteoarthritic changes than the control group. RF showed no significant correlation with either TMJ measurements or TMJ radiographic osteoarthritic changes. ACCP showed significant inverse correlation with condylar height and anteroposterior (AP) dimensions, but non-significant relation with mediolateral dimension and radiographic osteoarthritic changes. DAS28 showed significant inverse correlation with condylar AP and mediolateral dimensions. It also showed significant correlation with flattening of the TMJ condylar head and flattening of the articular fossa. Patients with high and moderate disease activity showed significantly smaller AP TMJ dimension than patients with low disease activity. Disease activity showed statistically significant direct correlation with all osteoarthritic changes except for erosions of the glenoid fossa and condyle. Conclusion: Disease Activity Score28 score and disease activity are strong indicators of TMJ affection in RA patients when compared to RF and ACCP. ACCP is a better indicator of changes in condylar measurements than TMJ osteoarthritic changes. While RF is the least efficient indicator of TMJ involvement in RA patients.

scholarly journals Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial

2016 ◽  
Vol 76 (5) ◽  
pp. 840-847 ◽  
Author(s):  
Gerd R Burmester ◽  
Yong Lin ◽  
Rahul Patel ◽  
Janet van Adelsberg ◽  
Erin K Mangan ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Active Rheumatoid Arthritis ◽  
Activity Index ◽  
Joint Disease ◽  
Phase Iii ◽  
Inadequate Response ◽  
Efficacy And Safety ◽  
Double Blind ◽  
End Point

ObjectivesTo compare efficacy and safety of sarilumab monotherapy with adalimumab monotherapy in patients with active rheumatoid arthritis (RA) who should not continue treatment with methotrexate (MTX) due to intolerance or inadequate response.MethodsMONARCH was a randomised, active-controlled, double-blind, double-dummy, phase III superiority trial. Patients received sarilumab (200 mg every 2 weeks (q2w)) or adalimumab (40 mg q2w) monotherapy for 24 weeks. The primary end point was change from baseline in 28-joint disease activity score using erythrocyte sedimentation rate (DAS28-ESR) at week 24.ResultsSarilumab was superior to adalimumab in the primary end point of change from baseline in DAS28-ESR (−3.28 vs −2.20; p<0.0001). Sarilumab-treated patients achieved significantly higher American College of Rheumatology 20/50/70 response rates (sarilumab: 71.7%/45.7%/23.4%; adalimumab: 58.4%/29.7%/11.9%; all p≤0.0074) and had significantly greater improvement in Health Assessment Questionnaire-Disability Index (p=0.0037). Importantly, at week 24, more patients receiving sarilumab compared with adalimumab achieved Clinical Disease Activity Index remission (7.1% vs 2.7%; nominal p=0.0468) and low disease activity (41.8% vs 24.9%; nominal p=0.0005, supplemental analysis). Adverse events occurred in 63.6% (adalimumab) and 64.1% (sarilumab) of patients, the most common being neutropenia and injection site reactions (sarilumab) and headache and worsening RA (adalimumab). Incidences of infections (sarilumab: 28.8%; adalimumab: 27.7%) and serious infections (1.1%, both groups) were similar, despite neutropenia differences.ConclusionsSarilumab monotherapy demonstrated superiority to adalimumab monotherapy by improving the signs and symptoms and physical functions in patients with RA who were unable to continue MTX treatment. The safety profiles of both therapies were consistent with anticipated class effects.Trial registration numberNCT02332590.

Anti carbamylated protein antibodies as a diagnostic marker in patients with rheumatoid arthritis and its association with disease activity

QJM ◽  
2021 ◽  
Vol 114 (Supplement_1) ◽  
Author(s):  
Magda Medhat Awad El debsy ◽  
Mervat Mohammed Abdul Hakim ◽  
Henaz Farouk Khaled ◽  
Hala Mohamed Abd El Sabour Sabbah
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Plasma Levels ◽  
Significant Positive Correlation ◽  
Diagnostic Marker ◽  
Complete Blood Count ◽  
Control Group ◽  
Positive Correlation ◽  
Larsen Score ◽  
Function Tests

Abstract Background Despite the diagnostic contribution of anti-citrullinated protein( anti-CCP) antibody and rheumatoid factor (RF), approximately one-third of patients with rheumatoid arthritis (RA) remain seronegative .Anti-carbamylated protein (Anti-Carp) antibodies have been attracting increasing attention as a new diagnostic marker of RA. Objective evaluate levels of anti-carp antibodies in RA patients in order to detect its role as a diagnostic marker and its possible association with disease activity and severity. Methods This study included thirty adult patients with clinical evidence of rheumatoid arthritis and thirty healthy matched age and sex as controls. All underwent history taking, clinical examination, assessment of disease activity with modified Disease Activity28 (DAS28), Laboratory investigations including Complete blood count (CBC), erythrocytes sedimentation rate (ESR), C-Reactive Protein (CRP), Liver function tests, Kidney function tests, Serum uric acid, RF, anti CCP Ab, anti-Carp Ab and radiographic Assessment with Larsen score. Results Plasma levels of anti-Carp Ab were significantly higher in patients than control group (p &gt; 0,001) with sensitivity of 73.33% and specificity of 100%.it showed significant positive correlation with CRP (r = 0.37 )(p &lt; 0.05) as a marker of activity of RA and also there was significant positive correlation with RF and ACPA (r = 0.45)(r = 0.48) (p &lt; 0.05) respectively as a diagnostic marker for RA. Plasma levels of anti-Carp Ab were higher in patients with more joints damage and erosions as assessed by Larsen radiological score as there was a highly significant correlation between Larsen score and serum Anti-Carp(r = 0.61)(p &lt; 0.001).. Conclusion serum Anti–Carp antibody level was higher in RA patients which serve as a diagnostic marker for RA, also its significant correlation with CRP and Larsen score may serve as a marker for disease progression and severity.

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