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HLA-DRB1 shared epitope risk alleles are the strongest genetic risk factors for rheumatoid arthritis (RA) and potential biomarkers for treatment response to biological disease-modifying antirheumatic drugs (bDMARDs). This study aimed to investigate the association between treatment response and individual HLA-DRB1 alleles in RA patients receiving different bDMARDs. We recruited 106 patients with active RA who had started abatacept, tocilizumab, or TNF inhibitors as a first-line bDMARDs. We examined the relationship between Simplified Disease Activity Index (SDAI) improvement at 3 months and HLA-DRB1 allele carriage. The results revealed that the HLA-DRB1*04:05 allele, a shared-epitope allele, was significantly associated with better SDAI improvement only after abatacept treatment (SDAI improvement 28.5% without the allele vs 59.8% with allele, p = 0.003). However, no significant association was found with other treatments. Both multivariate linear regression and mediation analysis confirmed that the HLA-DRB1*04:05 allele was independently associated with abatacept treatment response, regardless of anti-CCP antibody titers. The study concluded that in patients with RA receiving their first-line bDMARD treatment, carrying the HLA-DRB1*04:05 allele was associated with better SDAI improvement specifically in abatacept-treated patients. These disease-risk HLA alleles have the potential to serve as genomic biomarkers for predicting treatment response with co-stimulation blockage therapy., (© 2023. Springer Nature Limited.)

Objectives: Interstitial lung disease sometimes occurs in rheumatoid arthritis patients. Although the underlying immunological mechanisms responsible for interstitial lung disease associated with rheumatoid arthritis have not yet been clarified, some reports have suggested possible roles of B cells. To examine the role of B-cell subsets in interstitial lung disease in rheumatoid arthritis patients, we analyzed peripheral blood B-cell subsets., Methods: We analyzed the frequencies of the peripheral blood B-cell subsets by flow cytometry in rheumatoid arthritis patients with and without interstitial lung disease ( n  = 16 and 81, respectively) and in healthy donors ( n  = 110) by high-resolution computed tomography., Results: Compared with healthy donors, rheumatoid arthritis patients showed statistically higher frequencies of naive B cells and lower frequencies of memory B cells. Moreover, the frequencies of memory B cells were lower in rheumatoid arthritis patients with interstitial lung disease than in those without. Multivariate analysis showed that the frequency of memory B cells, particularly switched memory B cells, was significantly decreased in rheumatoid arthritis patients with interstitial lung disease, even after adjusting for prednisolone dose., Conclusions: We suspect memory B cells play important roles in interstitial lung disease associated with rheumatoid arthritis.

Objective: Biologic disease-modifying antirheumatic drugs (bDMARDs) used for rheumatoid arthritis (RA) treatment have several mechanisms of action. Interleukin-6 inhibitors (IL-6i) block the production of acute-phase reactants (APRs), which are some of the composite measures of disease activity. We undertook this study to examine the agreement between the European League Against Rheumatism (EULAR) response based on the erythrocyte sedimentation rate (ESR) or C-reactive protein level, the Simplified Disease Activity Index 50% response measure (SDAI50), and the Clinical Disease Activity Index 50% response measure (CDAI50) in patients treated with IL-6i and other bDMARDs., Methods: We enrolled 306 patients with RA who started or switched bDMARDs. Treatment response at 6 months was analyzed. Kappa statistics were used to evaluate the agreement between different response measures. The contribution of APRs to improvement in disease activity scores was examined. The change of Health Assessment Questionnaire (HAQ) score was analyzed in IL-6i-treated patients., Results: Good agreement was achieved between response measures, with κ >0.6 in patients treated with tumor necrosis factor inhibitors or cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin fusion protein. In IL-6i-treated patients, the agreement was low between the EULAR response (ESR) and the SDAI50 or the CDAI50 (κ = 0.43 and 0.37, respectively). Under IL-6i treatment, APR improvement accounted for 56.0% of total improvement of the Disease Activity Score in 28 joints (DAS28) using the ESR. When discordance was found between the CDAI50 and EULAR response in IL-6i-treated patients, all patients were classified as EULAR-only responders; there was no HAQ improvement in EULAR-only responders., Conclusion: EULAR response criteria overestimate the response under IL-6i treatment because the APR improvement largely contributes to the DAS28 improvement., (© 2019, American College of Rheumatology.)

Objectives: Glucocorticoids (GCs) are effective treatments for rheumatoid arthritis (RA) but long-term use has adverse effects. This study aimed to elucidate whether GCs can be discontinued by introducing biological disease-modifying antirheumatic drugs (bDMARDs) and the factors influencing the outcome. Method: We included RA patients who had been orally taking GCs at the initiation of bDMARDs. The changes in GC dose after starting bDMARDs were evaluated and the GC discontinuation rate was analyzed using Kaplan-Meier analysis. The factors associated with discontinuation of GCs were assessed by Cox hazard models. Results: Eighty RA patients were included in the study. The dosage of oral prednisolone (PSL) was significantly reduced from 5.0 to 3.0 mg/day by 3 months ( p =  .013). GCs were discontinued in 31.3% of patients and the median time until GC discontinuation was 10.1 months. The GC discontinuation rate was significantly higher in patients with Class 1 and 2 ( p  = .024), with an initial PSL dose <5 mg/day ( p  = .040), and with low DAS28(ESR) ( p  = .038). In multivariate analyses, higher DAS28(ESR) (odds ratio, 0.200; p  = .039), and higher PSL dose (odds ratio, 0.748; p  = .029) were significantly associated with less frequent GC discontinuation. Conclusion: DAS28(ESR) high and PSL dose were factors associated with discontinuation of GC use after starting bDMARDs.

Objectives: The characteristics of lymphoproliferative disorders (LPD) in patients with rheumatoid arthritis (RA) remain unclear. Therefore, we retrospectively analyzed the clinical characteristics of these patients in our department., Methods: Twenty RA patients who developed LPD between April 2003 and August 2016 in our department were analyzed., Results: All of the RA patients who developed LPD had been treated with methotrexate (MTX). The median weekly and total dosages of MTX were 6.8 mg/week and 2530 mg, respectively. The median duration of MTX administration was eight years. Nineteen patients (95%) achieved complete remission (CR) and 15 (75%) achieved CR with MTX cessation alone. Based on the pathological findings, we divided MTX-associated LPD patients into two groups (n = 16); polymorphic LPD (31%) and other groups. CR with MTX cessation alone was achieved in 5 (100%) and 6 (54.5%) patients in the polymorphic LPD and other groups, respectively (p = .12). Moreover, the duration from the cessation of MTX to CR was significantly shorter in the polymorphic LPD group than in the other group (5.3 months vs 12.6 months, p = .01, respectively)., Conclusion: Polymorphic LPD, which was the most frequent pathological diagnosis in this cohort, was associated with a higher incidence of CR and a significantly shorter duration to CR.

We analyzed the transcriptome of detailed CD4 + T cell subsets including them after abatacept treatment, and examined the difference among CD4 + T cell subsets and identified gene sets that are closely associated disease activity and abatacept treatment. Seven CD4 + T cell subsets (naive, Th1, Th17, Th1/17, nonTh1/17, Tfh and Treg) were sorted from PBMCs taken from 10 RA patients and 10 healthy controls, and three RA patients donated samples before and 6 months after abatacept treatment. Paired-end RNA sequencing was performed using HiSeq 2500. A total of 149 samples except for 12 outliers were analyzed. Overview of expression pattern of RA revealed that administration of abatacept exerts a large shift toward the expression pattern of HC. Most of differentially expressed gene (DEG) upregulated in RA (n = 1776) were downregulated with abatacept treatment (n = 1349). Inversely, most of DEG downregulated in RA (n = 1860) were upregulated with abatacept treatment (n = 1294). This DEG-based analysis revealed shared pathway changes in RA CD4 + T cell subsets. Knowledge-based pathway analysis revealed the upregulation of activation-related pathways in RA that was substantially ameliorated by abatacept. Weighted gene co-expression network analysis (WGCNA) evaluated CD4 + T cells collectively and identified a gene module that consisted of 227 genes and was correlated with DAS28-CRP (Spearman's rho = 0.46, p = 4 × 10 -9 ) and abatacept administration (Spearman's rho = -0.91, p = 5 × 10 -57 ). The most highly connected 30 genes of this module included ZAP70 and JAK3, and pathway analysis of this module revealed dysregulation of the TCR signaling pathway network, which was ameliorated by abatacept., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Regulatory T cells (Tregs) play a role in the suppression of inflammation in autoimmune diseases, and lymphocyte activation gene 3 (LAG3) was reported as a marker of interleukin (IL)-10-producing Tregs. We aimed to clarify the function of human IL-10-producing CD4 + CD25 - LAG3 + T cells (LAG3 + Tregs) and their association with rheumatoid arthritis (RA)., Methods: LAG3 + Tregs of human peripheral blood mononuclear cells (PBMCs) were cultured with B cells and follicular helper T cells to examine antibody suppression effects. The frequency of LAG3 + Tregs was evaluated in peripheral blood samples from 101 healthy donors and 85 patients with RA. In patients treated with abatacept, PBMC samples were analyzed before and after treatment. Naive CD4 + T cells were sorted and cultured in the presence of abatacept, followed by flow cytometric analysis and function assays., Results: LAG3 + Tregs produced high amounts of IL-10 and interferon-γ, and they suppressed B-cell antibody production more strongly than CD25 + Tregs. Cell-to-cell contact was required for the suppressive function of LAG3 + Tregs. The frequency of LAG3 + Tregs was lower in patients with RA, especially those with higher Clinical Disease Activity Index scores. LAG3 + Tregs significantly increased after 6 months of abatacept treatment, whereas CD25 + Tregs generally decreased. Abatacept treatment in vitro conferred LAG3 and EGR2 expression on naive CD4 + T cells, and abatacept-treated CD4 + T cells exhibited suppressive activity., Conclusions: IL-10-producing LAG3 + Tregs are associated with the immunopathology and therapeutic response in RA. LAG3 + Tregs may participate in a mechanism for the anti-inflammatory and immune-modulating effects of targeted therapy for costimulation.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that leads to destructive arthritis. Although the HLA class II locus is the strongest genetic risk factor for rheumatoid arthritis, the relationship between HLA class II alleles and lymphocyte activation remains unclear. We performed immunophenotyping of peripheral blood mononuclear cells on 91 HLA-DRB1-genotyped RA patients and 110 healthy donors. The frequency of memory CXCR4(+)CD4(+) T cells, and not Th1 and Th17 cells, was significantly associated with disease severity by multiple linear regression analysis. RA patients with one or more susceptible HLA-DR haplotypes (shared epitope: SE) displayed a significantly higher frequency of memory CXCR4(+)CD4(+) T cells. Moreover, the frequency of memory CXCR4(+)CD4(+) T cells significantly correlated with the expression level of HLA-DR on B cells, which was elevated in RA patients with SE. In vitro analysis and transcriptomic pathway analysis suggested that the interaction between HLA-DR and T cell receptors is an important regulator of memory CXCR4(+)CD4(+) T cells. Clinically, a higher frequency of memory CXCR4(+)CD4(+) T cells predicted a better response to CTLA4-Ig. Memory CXCR4(+)CD4(+) T cells may serve as a powerful biomarker for unraveling the linkage between HLA-DRB1 genotype and disease activity in RA.