Less Plaque Progression in TNF Inhibitor Users

Demyelinating peripheral neuropathy has been described in association with tumor necrosis factor (TNF) inhibitors. It is rarely developed after treatment discontinuation. We present the case of a child with juvenile idiopathic arthritis who developed peripheral neuropathy few months after TNF inhibitor withdrawal with clinical worsening of the neurological sequelae while undergoing treatment with abatacept.

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POS1002 BASELINE CALPROTECTIN AND VISFATIN LEVELS PREDICT RADIOGRAPHIC SPINAL PROGRESSION AFTER 2 YEARS IN ANKYLOSING SPONDYLITIS PATIENTS ON TNF INHIBITOR THERAPY

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.3059 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 769.2-770

Author(s):

J. Rademacher ◽

M. Siderius ◽

L. Gellert ◽

F. Wink ◽

M. Verba ◽

...

Keyword(s):

Risk Factors ◽

Logistic Regression ◽

Ankylosing Spondylitis ◽

Bone Formation ◽

Bone Turnover ◽

Radiographic Progression ◽

Serum Levels ◽

Tnf Inhibitor ◽

Research Support

Background:Radiographic spinal progression determinates functional status and mobility in ankylosing spondylitis (AS)1.Objectives:To analyse whether biomarker of inflammation, bone turnover and adipokines at baseline or their change after 3 months or 2 years can predict spinal radiographic progression after 2 years in AS patients treated with TNF-α inhibitors (TNFi).Methods:Consecutive AS patients from the Groningen Leeuwarden Axial Spondyloarthritis (GLAS) cohort2 starting TNFi between 2004 and 2012 were included. The following serum biomarkers were measured at baseline, 3 months and 2 years of follow-up with ELISA: - Markers of inflammation: calprotectin, matrix metalloproteinase-3 (MMP-3), vascular endothelial growth factor (VEGF) - Markers of bone turnover: bone-specific alkaline phosphatase (BALP), serum C-terminal telopeptide (sCTX), osteocalcin (OC), osteoprotegerin (OPG), procollagen typ I and II N-terminal propeptide (PINP; PIINP), sclerostin. - Adipokines: high molecular weight (HMW) adiponectin, leptin, visfatinTwo independent readers assessed spinal radiographs at baseline and 2 years of follow-up according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Radiographic spinal progression was defined as mSASSS change ≥2 units or the formation of ≥1 new syndesmophyte over 2 years. Logistic regression was performed to examine the association between biomarker values at baseline, their change after 3 months and 2 years and radiographic spinal progression. Multivariable models for each biomarker were adjusted for mSASSS or syndesmophytes at baseline, elevated CRP (≥5mg/l), smoking status, male gender, symptom duration, BMI, and baseline biomarker level (the latter only in models with biomarker change).Results:Of the 137 included AS patients, 72% were male, 79% HLAB27+; mean age at baseline was 42 years (SD 10.8), ASDAScrp 3.8 (0.8) and mSASSS 10.6 (16.1). After 2 years of follow-up, 33% showed mSASSS change ≥2 units and 24% had developed ≥1 new syndesmophyte. Serum levels of biomarkers of inflammation and bone formation showed significant changes under TNFi therapy, whereas adipokine levels were not altered from baseline (Figure 1).Univariable logistic regression revealed a significant association of baseline visfatin (odds ratio OR [95% confidence interval] 1.106 [1.007-1.215]) and sclerostin serum levels (OR 1.006 [1.001-1.011]) with mSASSS progression after 2 years. Baseline sclerostin levels were also associated with syndesmophyte progression (OR 1.007 [1.001-1.013]). In multivariable logistic analysis, only baseline visfatin level remained significantly associated (OR 1.465 [1.137-1.889]) with mSASSS progression. Furthermore, baseline calprotectin showed a positive association with both, mSASSS (OR 1.195 [1.055-1.355]) and syndesmophyte progression (OR 1.107 [1.001-1.225]) when adjusting for known risk factors for radiographic progression.Univariable logistic regression showed that change of sclerostin after 3 months was associated with syndesmophytes progression (OR 1.007 [1.000-1.015), change of PINP level after 2 years was associated with mSASSS progression (OR 1.027 [1.003-1.052]) and change of visfatin after 2 years was associated with both measures of radiographic progression – mSASSS (OR 1.108 [1.004-1.224]) and syndesmophyte formation (OR 1.115; [1.002-1.24]). However, those associations were lost in multivariable analysis.Conclusion:Independent of known risk factors, baseline calprotectin and visfatin levels were associated with radiographic spinal progression after 2 years of TNFi. Although biomarkers of inflammation and bone formation showed significant changes under TNFi therapy, these changes were not significantly related to radiographic spinal progression in our cohort of AS patients.References:[1]Poddubnyy et al 2018[2]Maas et al 2019Acknowledgements:Dr. Judith Rademacher is participant in the BIH-Charité Clinician Scientist Program funded by the Charité –Universitätsmedizin Berlin and the Berlin Institute of Health.Disclosure of Interests:Judith Rademacher: None declared, Mark Siderius: None declared, Laura Gellert: None declared, Freke Wink Consultant of: AbbVie, Maryna Verba: None declared, Fiona Maas: None declared, Lorraine M Tietz: None declared, Denis Poddubnyy: None declared, Anneke Spoorenberg Consultant of: Abbvie, Pfizer, MSD, UCB, Lilly and Novartis, Grant/research support from: Abbvie, Pfizer, UCB, Novartis, Suzanne Arends Grant/research support from: Pfizer.

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Bone marrow-derived NGFR+ cells regulate arterial remodeling and those poor mobilizations in peripheral blood in acute coronary syndrome predicts plaque progression at the non-targeted lesion

European Heart Journal ◽

10.1093/ehjci/ehaa946.1679 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

S Takashima ◽

S Usui ◽

S Matsuura ◽

C Goten ◽

O Inoue ◽

...

Keyword(s):

Bone Marrow ◽

Acute Coronary Syndrome ◽

Peripheral Blood ◽

Funding Source ◽

Arterial Remodeling ◽

Plaque Progression ◽

Wild Type ◽

Plaque Volume ◽

Coronary Syndrome

Abstract Background In our previous 5-year cohort study, we demonstrated that low gene expression of nerve growth factor receptor (NGFR) in peripheral leucocytes in acute coronary syndrome (ACS) predicted repetitive coronary interventions at the de novo lesions. An NGFR-positive cell has been demonstrated to reside in bone marrow (BM) stromal fraction and to be increased in peripheral blood mononuclear cell (MNCs) fraction in patients with ischemic heart disease. Purpose To investigate whether the BM-NGFR+ cell is associated with arterial remodeling and the relationship between the levels of peripheral NGFR+ cells after ACS and coronary plaque progression in an experimental and prospective clinical study. Methods and results In an experimental study, 8-week-old C57B6/J wild type male mice were subjected to irradiation with 9.6 Gy and transplantation with BM (BMT) isolated from GFP-transgenic NGFR wild type (WT) or knock-out (KO) mice at day 1. Four weeks after BMT, the right carotid artery was ligated for 4 weeks. Induced neointimal area was increased (p<0.05), where cells under apoptosis were decreased (p<0.05) in NGFR-KO-BMT group compared to WT-BMT group (n=4). NGFR+ cells were not detected in wild type sham-operated artery, whereas in the ligated artery in WT-BMT group NGFR+ cells assembled in the developed neointima and exclusively presented double positive with GFP, but absent in NGFR-KO-BMT group (p<0.05, n=4). In a clinical study, thirty patients with ACS who underwent primary percutaneous coronary intervention (PCI) were enrolled. The peripheral blood sample was collected on days 0, 3 and 7, and 9 months follow-up and the number of NGFR+MNCs were measured by flowcytometric analysis. The plaque volume at non-targeted coronary lesion (non-TL:>5 mm proximal or distal to the implanted stents) were quantitatively analysed using gray-scale intravascular ultrasound (IVUS) and Q-IVUS™ software at the acute phase and 9 months follow-up. The number of NGFR+MNCs in peripheral blood was 1.5-fold increased at day 3 (0.064±0.056%) compared to day 0 (0.042±0.030%) (p<0.05). The change in normalized total plaque volume (TAVN) at non-TL at 9 months was negatively correlated with the number of NGFR+MNCs at day 0 (r=−0.51), day 3 (r=−0.51) and 9 months (r=−0.59) after ACS (p<0.05). Multiple regression analysis showed that NGFR+MNCs at day 0 (β=−0.48, p=0.01) and CRP (β=−0.53, P<0.01) are independent factors associating with TAVN change at non-TL at 9 months, regardless of LDL-cholesterol control level. ROC analysis revealed that NGFR+MNCs <0.049 at day 0 predicted the increase of TAVN with AUC 0.78; sensitivity 0.82 and specificity 0.67. Conclusions Bone marrow-derived peripheral NGFR+ cells negatively regulate arterial remodeling through appropriate apoptosis of neointimal cells and the peripheral level of NGFR+ cells in ACS predicts plaque progression at the non-targeted lesion. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): KAKENHI

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AB1267 ONLINE CASE-BASED EDUCATION SIGNIFICANTLY IMPROVED RHEUMATOLOGISTS’ KNOWLEDGE AND CONFIDENCE IN MANAGING PATIENTS WITH RA

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.2297 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1925.2-1925

Author(s):

E. Bell ◽

A. Sendaydiego ◽

P. C. Taylor

Keyword(s):

Rapid Evolution ◽

Safety Data ◽

Treatment Strategies ◽

Further Education ◽

Learning Activity ◽

Tnf Inhibitor ◽

Jak Inhibitors ◽

Significance Level ◽

Average Percentage ◽

Post Assessment

Background:With the rapid evolution in treatment strategies and the increasing range of available therapeutics for rheumatoid arthritis (RA), keeping pace with advances can be a challenge for busy physicians.Objectives:We assessed whether online CME can improve rheumatologists’ knowledge of RA management focusing on the assessment and monitoring of RA, the selection of appropriate treatments and the clinical efficacy and safety data for JAK inhibitors.Methods:Rheumatologists participated in a text-based activity featuring two patient cases with questions that “tested” knowledge and discussion of the main “teaching” points. Educational effect was assessed using a repeated-pair design, pre-/post-assessment. A Chi-square test of independence determined if a statistically significant improvement (5% significance level,P<.05) existed in the number of correct responses between the pretest and posttest scores. Cramer’s V estimated the effect size of the education. The activity launched on 15 December 2018 with data collection through 27 February 2019.Results:•Significant improvement in average percentage of correct responses, rising from 47% at baseline to 92% post-activity (P<.001) and extensive educational impact (Cramer’s V=0.496)•Significant increase in percentage of rheumatologists (n=111) answering all 3 questions correctly (9% at baseline rising to 78% post assessment)•Significant improvements in knowledge of EULAR/ACR assessment criteria (86% improvement,P<.001), EULAR treatment recommendations for a patient failing on MTX and a TNF inhibitor (100% improvement,P<.001), and the VTE risk associated with having RA or receiving RA treatments (108% improvement,P<.001)•46% of rheumatologists reported greater confidence in their ability to appropriately incorporate JAK inhibitors into the treatment of patients with RA (average confidence shift 20%)Conclusion:Overall, this learning activity was highly successful in improving rheumatologists’knowledge and confidence in managing patients with RA, particularly with regard to the appropriate use of JAK inhibitors in patients for whom such treatment is suitable. The extensive impact of this interactive ‘test then teach’ activity is likely to directly translate into patient benefit. Further education on this topic would be useful to enhance and reinforce this knowledge and to support physician confidence in the use of JAK inhibitors in clinical practice.References:[1]https://www.medscape.org/viewarticle/906202Disclosure of Interests:Elaine Bell: None declared, Anne Sendaydiego: None declared, Peter C. Taylor Grant/research support from: Celgene, Eli Lilly and Company, Galapagos, and Gilead, Consultant of: AbbVie, Biogen, Eli Lilly and Company, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer Roche, and UCB

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AB0499 PHYSICAL ACTIVITY ASSESSMENT IN TUNISIAN PATIENTS WITH SPONDYLOARTHRITIS: THE IPAQ EVALUATION

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.2053 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 1277.1-1277

Author(s):

F. Majdoub ◽

M. Sellami ◽

S. Miladi ◽

A. Fazaa ◽

L. Souabni ◽

...

Keyword(s):

Physical Activity ◽

Disease Activity ◽

Axial Spondyloarthritis ◽

Cross Sectional Study ◽

Urban Setting ◽

Tnf Inhibitor ◽

Sectional Study ◽

Cross Sectional ◽

Tunisian Patients ◽

Different Levels

Background:The occurrence of Spondyloarthritis (SpA) often conditions patients’ quality of life and hinders their well-being. Physical activity (PA) is associated with various health-related benefits among adults with chronic inflammatory rheumatism but may be insufficiently performed.Objectives:This study aimed to assess PA in patients with SpA and explore its associated factors.Methods:This is a single-center cross-sectional study, involving patients with SpA, visiting our outpatient hospital over eight weeks. Patients responded to the International Physical Activity Questionnaire-Short form (IPAQ-S).Results:Sixty patients were included (39 M/21 F) with an average age of 45.8 years [25-78]. The mean duration of SpA was 13.2 years [1-25]. About 80% of patients were from an urban setting. Sixty-three percent of patients had a professional activity, while 13.3% were retired. Twenty-nine patients (48.3%) had axial and peripheral form, 18 patients (30%) had SpA with enteropathic arthritis, 8 (13.3%) with psoriatic arthritis, 3 patients (5%) had axial spondyloarthritis, and only 2 patients (3.3%) with SAPHO-Syndrom. About 23% of patients had hip arthritis and only 5% had uveitis. Fifty-eight patients were on TNF-inhibitor (21/58 Adalimumab, 15/58 Infliximab, 14/58 Etanercept, 8/58 Golimumab). The average BASDAI was 2.7/10. The average ASDASCRP was 2.1/10. The average BASFI was 3.3/10. IPAQ results were distributed as follows: 78.3% of patients were in the « low physical activity » category, 21.7% were in the « moderate physical activity » while none of the patients were in the « high physical activity ». Patients without employment had lower levels of physical activity (29.7%) but no association was observed between those two items (p=0.082). Disease activity objectified with BASDAI was related to low physical activity (p=0.045) whereas no association was observed with ASDASCRP (p=0.870) or BASFI (p=0.056). Otherwise, TNF-inhibitor treatment was not related to different levels of PA (p=0.09).Conclusion:Tunisian patients with SpA don’t perform enough physical activity. Except for high disease activity, the different levels of PA did not appear to be explained by other disease-related variables. Thereby, physical activity should be encouraged in SpA.References:[1]Fabre, S., Molto, A., Dadoun, S. et al. Physical activity in patients with axial spondyloarthritis: a cross-sectional study of 203 patients. Rheumatol Int 36, 1711–1718 (2016).Disclosure of Interests:None declared.

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OP0229 GUSELKUMAB INDUCES SUSTAINED REDUCTION IN ACUTE PHASE PROTEINS AND TH17 EFFECTOR CYTOKINES IN ACTIVE PSORIATIC ARTHRITIS IN TWO PHASE-3 CLINICAL TRIALS (DISCOVER-1 AND DISCOVER-2)

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.1240 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 144-145

Author(s):

S. Siebert ◽

I. Mcinnes ◽

M. J. Loza ◽

K. MA ◽

K. Leander ◽

...

Keyword(s):

Acute Phase ◽

Acute Phase Proteins ◽

Geometric Mean ◽

Tnf Inhibitor ◽

Healthy Controls ◽

Phase 3 ◽

Two Phase ◽

Protein Levels ◽

Disease Characteristics ◽

Effector Cytokines

Background:Guselkumab (GUS), an IL-23 inhibitor monoclonal antibody (Mab) that specifically binds to the IL-23p19 subunit, demonstrated efficacy compared to placebo (PBO) in reducing skin and musculoskeletal signs and symptoms in patients (pts) with active psoriatic arthritis (PsA) in two phase-3 studies, DISCOVER 1 & 2.1,2Previous results from a GUS PsA Phase-2 trial3and Ustekinumab (UST, anti-IL12/23p40 MAb) PsA Phase-3 trials (PSUMMIT 1 & 2)4showed associations of baseline IL-17A, IL-17F, and CRP with baseline disease characteristics, and associations of GUS-induced cytokine reductions with clinical responses.Objectives:To investigate plausible cytokine expression in PsA and alterations after exposure to GUS therapy.Methods:In DISCOVER 1 & 2, pts were treated with GUS 100 mg at Wk 0, 4, then every 8Wks (q8w); GUS 100mg q4w; or matching PBO. 21 serum biomarkers were measured in a random subset of 300 PsA pts from the DISCOVER program at Weeks (Wks) 0, 4, & 24 and in 34 healthy controls matched for age, sex, and ethnicity. Serum proteins measured were acute phase reactants CRP & SAA (Meso Scale Discovery (MSD) Platform) and inflammatory cytokines/chemokines: Th17 effector cytokines IL-17A, IL-17F, & IL-22 (Single Molecule Counting Erenna® Immunoassay Platform) and soluble ICAM-1, soluble VCAM-1, IL-6, CXCL-8, IL-10, IL-13, IL-12p70, CCL22, IFN-γ, CCL2, CCL4, TNFα, IL-1β, IL-2, IL-4 (MSD), & YKL-40 (Quantikine Immunoassay). Serum IL-17A, IL-17B, & CRP measured in the Phase-3 PSUMMIT trials of UST for PsA4were included for comparison with GUS.Results:At baseline, serum levels of acute phase proteins CRP, SAA, & IL-6, and Th17-effector cytokines IL-17A & IL-17F were elevated in pts with PsA compared with healthy controls (p<0.05, geometric mean ≥ 40% higher, FIG 1). There was no significant dysregulation in the other cytokines measured in PsA pts compared to healthy controls. Baseline IL-17A, IL-17F, IL-22, & CCL22 were significantly associated with baseline psoriasis disease activity (Body Surface Area & Psoriatic Area and Severity Index, Spearman Signed Rank p<0.05, r>0.25). Baseline CRP, SAA, IL-6, & YKL40 were significantly associated with baseline joint disease (Disease Activity Score 28-CRP, Spearman p<0.05, r>0.25). Baseline SAA, IL-6, IL-17A, & IL-17F were higher in pts with prior TNF inhibitor exposure than without (p<0.05, geometric mean ≥ 40% higher), although pts with PsA both with and without prior TNF inhibitor had higher levels than the healthy control set.GUS treatment resulted in decreases in serum CRP, SAA, IL-6, IL-17A, IL-17F, & IL-22 that were significantly greater than PBO as early as Week 4 (FIG 1). These protein levels continued to decrease through Wk 24 in GUS-treated pts with both dosing regimens (p<0.05, geometric mean decrease from baseline ≥ 33%). Further, Wk 24 IL-17A & IL-17F levels for pts treated with either dose of GUS were not significantly different from healthy controls, suggesting a normalization of peripheral effector cytokines associated with the IL-23/Th17 axis following treatment with GUS. Effects on IL-17A/IL-17F were greater in GUS treated pts than UST treated pts, while CRP levels were similar in both programs (FIG 2).Conclusion:Comprising a strong pharmacodynamic effect, GUS treatment reduced serum protein levels of acute phase and Th17-effector cytokines (whose elevations at baseline were associated with PsA disease characteristics) and achieved comparable levels to those in healthy controls. In pts with PsA, reductions of IL-17A and IL-17F by GUS were of greater magnitude than those by UST.References:[1]Deodhar et al. ACR 2019, abs #807. Arth Rheumatol. 2019;71 S10: 1386[2]Mease et al. ACR 2019, abs #L13. Arth Rheumatol. 2019;71 S10:5247[3]Siebert et al. EULAR 2019, abs #479. Ann Rheum Dis. 2019;78 S2:293[4]Siebert et al. Arth Rheumatol. 2019;71:1660Acknowledgments:NoneDisclosure of Interests:Stefan Siebert Grant/research support from: BMS, Boehringer Ingelheim, Celgene, GlaxoSmithKline, Janssen, Novartis, Pfizer, UCB, Consultant of: AbbVie, Boehringer Ingelheim, Janssen, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, Celgene, Janssen, Novartis, 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, Matthew J Loza Employee of: Janssen Research & Development, LLC, Keying Ma Employee of: Janssen Research & Development, LLC, Karen Leander, Employee of: Janssen Research & Development, LLC, Vani Lakshminarayanan Employee of: Janssen Research & Development, LLC, Carol Franks Employee of: Janssen Research & Development, LLC, Philip Cooper Employee of: Janssen Research & Development, LLC, Kristen Sweet Employee of: Janssen Research & Development, LLC

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