Abatacept enhances blood regulatory B cells of rheumatoid arthritis patients to a level that associates with disease remittance

AbstractAbatacept, an inhibitor of CD28 mediated T-cell activation, has been shown to be effective in controlling inflammation during rheumatoid arthritis (RA). However, its effects on immune regulatory B and T cells (Bregs and Tregs) has not been fully explored. Thirty-one RA patients treated with abatacept for ≥ 6 months along with 31 RA patients treated with other modalities as well as 30 healthy controls were recruited. Of these 62 RA patient, 49 (79%) were females with a mean age of 54 ± 12 years and disease duration of 10 ± 6 years. The blood levels of Tregs and Bregs and their production of immunosuppressive cytokines, were determined using FACS analysis and Luminex Multiplex assay. Treatment with abatacept significantly enhanced the blood level of IL-35+ IL-10+ Bregs (P = 0.0007). Their levels were higher in the blood of remitted patients (DAS28-CRP < 2.6) compared to the unremitted ones (P = 0.0173), 6 months following abatacept treatment initiation. Moreover, abatacept treatment significantly enhanced the blood levels of LAG3+ conventional and unconventional Tregs of RA patients. This increase in the blood levels of Bregs and Tregs was accompanied with an elevated serum level of IL-35 and IFN-β in abatacept-treated patients. Therefore, Abatacept efficiency to achieve remittance in RA could be attributed, in part, to its ability to enhance immune regulatory cells, especially IL-35+ IL-10+ Bregs.

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AB0234 SURVIVAL OF ABATACEPT IN RHEUMATOID ARTHRITIS PATIENTS: A REAL-LIFE STUDY

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.3689 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 1143.1-1143

Author(s):

E. Molteni ◽

F. Ceccarelli ◽

C. Castellani ◽

F. Giardina ◽

C. Alessandri ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cell Activation ◽

Cell Activation ◽

Disease Duration ◽

Retention Rate ◽

Real Life ◽

Standard Of Care ◽

Median Disease Duration ◽

Drug Survival

Background:Abatacept (ABA) is a biological drug approved for the treatment of rheumatoid arthritis (RA) patients that, by working on CTLA4, can inhibit T-cell activation. Randomized controlled trials have demonstrated both the efficacy and a good safety profile, characterized by a lower infectious risk in comparison with other biological DMARDs, in RA patients. In a real-life setting, the drug retention rate could be considered as a surrogate of drug effectiveness. Data from the literature reported a retention rate of ABA ranging from 55 to 76% at 12 months and from 54 to 64% at 24 months (1-3).Objectives:In the present longitudinal analysis, we evaluated the retention rate of ABA in a large monocentric RA cohort.Methods:We enrolled consecutive RA patients starting treatment with intravenous (IV) or subcutaneous (SC) ABA according to the standard of care. All the patients fulfilled the 2010 ACR/EULAR classification criteria for RA. For each patient, we collected demographic parameters, serological status, previous and concomitant treatments, and disease activity by DAS28 with C reactive protein (DAS28-CRP). All the patients were assessed at baseline, and after 4 and 12 months (T4 and T12, respectively). The reasons for withdrawal of treatment were registered and classified as primary or secondary inefficacy or adverse events (AEs). Kaplan-Meier statistical analysis has been done to evaluate the survival of the treatment in patients with at least 12 months follow-up.Results:We evaluated 161 patients [M/F 21/140; median age 67 years (IQR 21.7), median disease duration 180 months (IQR 161)]. RF was positive in 70.3% of patients, ACPA in 66.4%. ABA was the first biological DMARD in 66 patients (41%). At baseline, the median DAS28-CRP was 4.3 (IQR 1.6) and ABA was administered in association with MTX in 96 patients (59.6%). One hundred-eleven patients (68.9%) started SC ABA [M/F 16/95; median age 64.5 years (IQR 21.5), median disease duration 156 months (IQR 132)], the remaining 50 IV ABA [M/F 5/45, median age 71 years (IQR 60.2), median disease duration 187 months (IQR 157)]. Median age and disease duration were significantly higher in patients receiving IV in comparison with SC ABA (p=0.008 and p=0.03, respectively). We found a significant reduction of DAS28-CRP values during the follow-up in comparison with baseline [4 months: median 3.5 (IQR 1.9), p<0.0001; 12 months: median 3.2 (IQR 1.4), p<0.0001]. Seven patients were lost to follow-up, in the remaining 154 patients a median treatment duration of 33 months (IQR 49) was registered. Data on drug survival are reported in Figure 1A: at 12 months, 92% of patients persisted on treatment; this percentage decreased to 78.2% at 24 months and to 67.9% at 36 months. Furthermore, we did not find any differences in drug survival either with respect to SC vs IV administration (12 months: 93.7% versus 88.6%; 24 months 78.9% versus 72.6%; 36 months 63.7% versus 72.6%; Figure 1B) or according to the association with MTX. Concerning the withdrawal reasons, 46 patients (29.9%) stopped ABA due to inefficacy (primary in 28, secondary in 18), 11 patients (7.1%) due to AEs, and 7 for inadequate adherence (4.5%). Finally, 10 patients switched from IV to SC administration, due to patient’s preference.Conclusion:In our monocentric RA cohort, we have observed a high retention rate of ABA at both 12 and 24 months, confirming the good profile of this drug in terms of effectiveness and safety, irrespective of the route of administration and association with MTX.References:[1]Cagnotto, Arthritis Res Ther 2020; (2) Salmon, J Clin Med 2020; Westhovens, Rheumatol Int 2020.Acknowledgements:I would like to acknowledge Dr. F. Ceccarelli, for her patience.Disclosure of Interests:None declared

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Faculty Opinions recommendation of Human CD4+CD25+ regulatory cells have marked and sustained effects on CD8+ T cell activation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1016400.200702 ◽

2003 ◽

Author(s):

Matthias von Herrath

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cd8 T Cell ◽

Regulatory Cells ◽

Sustained Effects

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AB1164 A COST PER RESPONDER ANALYSIS OF ABATACEPT VERSUS ADALIMUMAB FOR THE TREATMENT OF RHEUMATOID ARTHRITIS AMONG PATIENTS WITH SHARED EPITOPE (SE) POSITIVITY FROM A UNITED STATES PAYER PERSPECTIVE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.1019 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1872.1-1873

Author(s):

S. H. Park ◽

X. Han ◽

F. Lobo ◽

S. Nanji ◽

D. Patel

Keyword(s):

Rheumatoid Arthritis ◽

United States ◽

T Cell Activation ◽

Real World ◽

Cell Activation ◽

Shared Epitope ◽

Pharmacy Cost ◽

Controlled Clinical Trial ◽

Payer Perspective ◽

Cost Per Responder

Background:The shared epitope (SE) is a significant genetic risk factor for rheumatoid arthritis (RA), and it has been proposed to be associated with T-cell activation and the production of anti-citrullinated protein antibody (ACPA).1-3The results from the Early AMPLE trial, a head-to-head trial comparing the efficacy of abatacept versus adalimumab among early moderate-to-severe RA patients with positive ACPA (ACPA+) and rheumatoid factor (RF), showed that at week 24, patients with SE positivity (SE+) responded better to abatacept compared to adalimumab across all efficacy measures evaluated (ACR20 [American College of Rheumatology], ACR50, ACR70, DAS[disease activity score]28-CRP[C-reactive protein]).4Objectives:To compare the cost per responder (CPR) between abatacept and adalimumab among RA patients with SE+ at week 24 using the Early AMPLE trial data from a United States (US) payer perspective.Methods:A CPR analysis was conducted for RA patients with SE+, ACPA+, and RF. Responders were defined as patients achieving ACR20, ACR50, ACR70, or DAS28-CRP ≤2.6 and efficacy data was sourced from the trial (Figure 1).4Approved product labels were referenced for treatment dosing regimen and wholesale acquisition cost was used to calculate pharmacy cost.5A real-world rebate scenario was considered for adalimumab (30%) to reflect the real-world pricing in the US market. The CPR was calculated as the total pharmacy cost divided by the proportion of responders.Results:The total pharmacy cost at week 24 was $26,273 per patient for abatacept and $21,731 per patient for adalimumab. With achieving ACR70 as the definition of responder, the CPR at 24-week was $46,337 for abatacept and $74,935 for adalimumab, a difference of $28,598 (Table 1). The CPR was consistently lower for abatacept compared to adalimumab across all clinical measures, with difference ranging from $7,099 to $43,609.Table 1.Overall cost per responder resultsAbataceptAdalimumabDifferenceACR20$30,303.74$37,403.06-$7,099.32ACR50$34,254.68$48,077.83-$13,823.15ACR70$46,337.46$74,935.10-$28,597.64DAS28-CRP ≤2.6$52,546.68$96,155.65-$43,608.97Conclusion:While the pharmacy cost was higher for abatacept compared to adalimumab driven by the rebate, due to its higher clinical efficacy, the CPR was consistently lower for SE+ RA patients treated with abatacept. The results may be useful for US healthcare decision makers in understanding how to optimize treatment for SE+ RA patient while minimizing costs in today’s budget constrained environment.References:[1]Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis.Arthritis and rheumatism. 1987;30(11):1205-13.[2]Holoshitz J. The rheumatoid arthritis HLA-DRB1 shared epitope.Curr Opin Rheumatol. 2010;22(3):293-8.[3]Sakkas LI, Bogdanos DP, Katsiari C, et al. Anti-citrullinated peptides as autoantigens in rheumatoid arthritis-relevance to treatment.Autoimmun Rev. 2014;13(11):1114-20.[4]Fleischmann R, Weinblatt M, Ahmad H, et al. Efficacy of abatacept and adalimumab in patientsn with early rheumatoid arthritis with multiple poor prognostic factors: post hoc analysis of a randomized controlled clinical trial (AMPLE).Rheumatol Ther. 2019;6(4): 559-571.[5]Truven Health Analytics. Redbook online. Accessed October 11, 2019.Disclosure of Interests:Sang Hee Park Consultant of: Pharmerit International, which received consultancy fees from Bristol-Myers Squibb (US), Inc. for this study, Xue Han Employee of: BMS, Francis Lobo Shareholder of: Bristol-Myers Squibb (US), Employee of: Bristol-Myers Squibb (US), Sakina Nanji Consultant of: Pharmerit International, which received consultancy fees from Bristol-Myers Squibb (US), Inc. for this study, Dipen Patel Consultant of: Pharmerit International, which received consultancy fees from Bristol-Myers Squibb (US), Inc. for this study

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Molecular signatures and new candidates to target the pathogenesis of rheumatoid arthritis

Physiological Genomics ◽

10.1152/physiolgenomics.00004.2010 ◽

2010 ◽

Vol 42A (4) ◽

pp. 267-282 ◽

Cited By ~ 61

Author(s):

U. Ungethuem ◽

T. Haeupl ◽

H. Witt ◽

D. Koczan ◽

V. Krenn ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cell Activation ◽

Gene Networks ◽

Cell Activation ◽

Joint Disease ◽

Disease Stage ◽

Unknown Etiology ◽

Coxa Vara ◽

Molecular Signatures ◽

Loss Of Function

Rheumatoid arthritis (RA) is a chronic, inflammatory joint disease of unknown etiology and pronounced interpatient heterogeneity. To characterize RA at the molecular level and to uncover pathomechanisms, we performed genome-wide gene expression analysis. We identified a set of 1,054 genes significantly deregulated in pair-wise comparisons between RA and osteoarthritis (OA) patients, RA and normal donors (ND), or OA and ND. Correlation analysis revealed gene sets regulated identically in all three groups. As a prominent example secreted phosphoprotein 1 (SPP1) was identified to be significantly upregulated in RA compared with both OA and ND. SPP1 expression was found to correlate with genes expressed during an inflammatory response, T-cell activation and apoptosis, suggesting common underlying regulatory networks. A subclassification of RA patients was achieved on the basis of proteoglycan 4 (PRG4) expression, distinguishing PRG4 high and low expressors and reflecting the heterogeneity of the disease. In addition, we found that low PRG4 expression was associated with a more aggressive disease stage, which is in accordance with PRG4 loss-of-function mutations causing camptodactyly-arthropathy-coxa vara-pericarditis syndrome. Altogether we provide evidence for molecular signatures of RA and RA subclasses, sets of new candidate genes as well as for candidate gene networks, which extend our understanding of disease mechanisms and may lead to an improved diagnosis.

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Triple DMARD treatment in early rheumatoid arthritis modulates synovial T cell activation and plasmablast/plasma cell differentiation pathways

PLoS ONE ◽

10.1371/journal.pone.0183928 ◽

2017 ◽

Vol 12 (9) ◽

pp. e0183928 ◽

Cited By ~ 12

Author(s):

Alice M. Walsh ◽

Mihir D. Wechalekar ◽

Yanxia Guo ◽

Xuefeng Yin ◽

Helen Weedon ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Cell Differentiation ◽

T Cell ◽

Plasma Cell ◽

Early Rheumatoid Arthritis ◽

T Cell Activation ◽

Cell Activation ◽

Plasma Cell Differentiation ◽

Dmard Treatment ◽

Differentiation Pathways

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Fetal–maternal HLA-C mismatch is associated with decidual T cell activation and induction of functional T regulatory cells

Journal of Reproductive Immunology ◽

10.1016/j.jri.2009.05.003 ◽

2009 ◽

Vol 82 (2) ◽

pp. 148-157 ◽

Cited By ~ 141

Author(s):

Tamara Tilburgs ◽

Sicco A. Scherjon ◽

Barbara J. van der Mast ◽

Geert W. Haasnoot ◽

Minke Versteeg-v.d.Voort-Maarschalk ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

T Regulatory Cells ◽

Regulatory Cells

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Association of CD28 IVS3 +17T/C Polymorphism with Soluble CD28 in Rheumatoid Arthritis

Disease Markers ◽

10.1155/2011/620849 ◽

2011 ◽

Vol 30 (1) ◽

pp. 25-29 ◽

Cited By ~ 11

Author(s):

I. Y. Ledezma-Lozano ◽

J. J. Padilla-Martínez ◽

S. D. Leyva-Torres ◽

I. Parra-Rojas ◽

M. G. Ramírez-Dueñas ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cell ◽

T Cell Activation ◽

Healthy Subjects ◽

Cell Activation ◽

Costimulatory Molecule ◽

Serum Levels ◽

Unknown Etiology ◽

Clinical Activity ◽

Western Mexico

Objective:Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology in which inflammatory pathology involves T cell activation and the CD28 costimulatory molecule involved in T cell presentation. The gene includes the CD28 IVS3 +17T/C polymorphism that could be associated with susceptibility to RA whereas the soluble concentrations of CD28 (sCD28) could be related to clinical activity.Methods:We investigated the CD28 IVS3 +17T/C polymorphism in 200 RA patients and 200 healthy subjects (HS). Furthermore, we quantified the sCD28 concentrations in 77 samples of each group. We applied indexes focused to determine the activity and disability (DAS28 and Spanish HAQ-DI, respectively) in RA patients.Methods:We investigated the CD28 IVS3 +17T/C polymorphism in 200 RA patients and 200 healthy subjects (HS). Furthermore, we quantified the sCD28 concentrations in 77 samples of each group. We applied indexes focused to determine the activity and disability (DAS28 and Spanish HAQ-DI, respectively) in RA patients.Results:RA patients had significantly higher frequencies of the CD28 T allele compared to HS (p= 0.032 OR = 1.59, C.I. 1.02–2.49). In addition, the IVS3 +17 T/T genotype frequency was also increased in RA vs. HS (p= 0.026). The RA patients showed higher sCD28 serum levels than HS (p= 0.001). Carriers of the T/T genotype in RA patients showed higher sCD28 levels than C/C carriers (p= 0.047). In addition, a correlation between sCD28 and Spanish HAQ-DI (correlation, 0.272;p= 0.016), was found.Conclusion:The T allele in CD28 IVS3 +17T/C polymorphism is associated with a susceptibility to RA in Western Mexico. In addition, increased sCD28 levels are related to T/T genotype in RA patients.

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