The positivity of anti-citrullinated protein/peptide antibodies (ACPAs) is a clinically useful diagnostic and prognostic marker in rheumatoid arthritis (RA). However, the significance of ACPA titer and its fluctuation remain unclear. This study aimed to assess the role of ACPA titer and its fluctuation on disease activity and the prognosis of RA.Data obtained from the Kyoto University Rheumatoid Arthritis Management Alliance (KURAMA) cohort was analyzed. Patients whose ACPA was measured at least twice between 2011 and 2019 and whose ACPA was positive at least once were included in this study. The association between the clinical variable and ACPA titer or its change was investigated.ACPA titer was measured in a total of 3286 patients, 1806 of whom were ACPA-positive at least once. Among them, the ACPA titer level was measured more than once in 1355 patients. Very weak correlation was observed between the ACPA titer level and disease activity. Additionally, there was no trend in the fluctuation of ACPA titer level in each patient; ACPA titer level fluctuated in some patients, but not in others. Patients with high variable levels of ACPA titer were more likely to relapse from remission. In the analysis of two consecutive ACPA measurements, the titer changes predicted the relapse from remission within a year of the second measurement.The ACPA titer level fluctuated in some patients. Very weak correlation was observed between the ACPA titer level and disease activity. Fluctuation in ACPA titer level predicted relapse from remission in patients with RA.
The factors contributing to the efficacy of abatacept in patients with rheumatoid arthritis (RA) remain unknown.
Objectives
We aimed to identify cellular, transcriptomic, and proteomic features that predict responses or resistance to abatacept.
Methods
Blood samples were collected from 22 RA patients treated with abatacept at the initiation and after three months of treatment. Response to treatment was defined based on the EULAR response criteria, and seven patients were classified as responders and the others as non-responders. We quantified gene expression levels in peripheral blood mononuclear cells (PBMCs) by RNA-Seq, 67 plasma protein levels by multiplexed immunoassay, and the expression of surface molecules (CD3, 19, and 56) by flow cytometry, in addition to collecting clinical characteristics. Additionally, three gene expression data sets concerning the efficacy of abatacept[1–3], comprising 37 responders and 50 non-responders in total, were used to replicate the current study. We compared the gene expression of responders versus non-responders in each set and meta-analyzed the results.
Results
Among the clinical characteristics, the number of monocytes was significantly higher in the non-responders before treatment (p = 0.01). Regarding the transcriptome data, we found 952 differentially expressed genes (DEGs) between the responders and the non-responders before treatment initiation. A cell-type enrichment analysis showed that the DEGs were enriched in monocytes (p = 8.7 × 10-212, Figure 1A). Additionally, gene set enrichment analysis showed enrichment in the gene module, including MYD88 and TIRAP, with the strongest significance among all of the pathways tested. When we estimated the expression of MYD88 and TIRAP in monocytes by deconvolution analysis, the non-responders had higher expression before treatment initiation (p = 0.04 and 0.03, respectively). Among the 67 protein levels, two exhibited a correlation with the expression of the module (p < 0.05). Of these, hepatocyte growth factor (HGF), which is produced by monocytes, was present at significantly higher concentrations in non-responders before treatment (p = 0.02). The analysis of the replication sets identified 1,695 DEGs. These were also enriched for the genes expressed in monocytes (p = 2.9 × 10-90, Figure 1B) but not for the module detected in the current study. Among the DEGs, those expressed in monocytes were enriched for the genes involved in the aerobic electron transport system in mitochondria based on gene set enrichment analysis.
Conclusion
Monocyte-derived transcriptomic features before treatment underlay the differences in abatacept efficacy. The pathway activated in monocytes was the MYD88/TIRAP-HGF axis in the current study, but that pathway in the replication set was the aerobic electron transport system. Overall, our results highlight the contribution of monocytes as the cells responsible for abatacept-treatment resistance and the heterogeneity of activated pathways within them.
References
[1]Nakamura, S. et al. Identification of baseline gene expression signatures predicting therapeutic responses to three biologic agents in rheumatoid arthritis: a retrospective observational study. Arthritis Res. Ther. 18, (2016). [2]Triaille, C. et al. Common Transcriptomic Effects of Abatacept and Other DMARDs on Rheumatoid Arthritis Synovial Tissue. Front. Immunol. 12, (2021). [3]Derambure, C. et al. Pre-silencing of genes involved in the electron transport chain (ETC) pathway is associated with responsiveness to abatacept in rheumatoid arthritis. Arthritis Res. Ther. 19, (2017).
Acknowledgements
This study received funding from Astellas Pharma Inc.
Disclosure of Interests
Takeshi Iwasaki: None declared, Ryu Watanabe Speakers bureau: Asahi Kasei, Chugai, Eli Lilly, GSK, and Sanofi, Grant/research support from: AbbVie, Hiromu Ito Grant/research support from: Bristol Myers, Takayuki Fujii Speakers bureau: Asahi Kasei Pharma, Abbvie, Jansen, Tanabe Mitsubishi Pharma, and Eisai Co LTD, Koichiro Ohmura: None declared, Hiroyuki Yoshitomi: None declared, Koichi Murata Speakers bureau: AbbVie GK, Eisai Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Inc., Bristol-Myers Squibb, Daiichi Sankyo Co. Ltd., and Asahi Kasei Pharma Corp., Grant/research support from: Daiichi Sankyo Co. Ltd, Kosaku Murakami Speakers bureau: Bristol Myers, Ono Pharmaceutical, Akira Onishi Speakers bureau: Pfizer Inc., Bristol-Myers Squibb., Asahi Kasei Pharma Corp., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K, Ono Pharmaceutical Co., UCB Japan Co., Mitsubishi Tanabe Pharma Co., Eisai Co. Ltd., Abbvie Inc., Takeda Pharmaceutical Co. Ltd., and Daiichi Sankyo Co. Ltd., Grant/research support from: Pfizer Inc., Bristol-Myers Squibb., Advantest, Ayumi, and the Health Care Science Institute., Employee of: Department of Advanced Medicine for Rheumatic Diseases is supported by Nagahama City, Shiga, Japan, Toyooka City, Hyogo, Japan, and five pharmaceutical companies (Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co. Ltd, UCB Japan Co. Ltd, AYUMI Pharmaceutical Co., and Asahi Kasei Pharma Corp.). It is also supported by grants from Daiichi Sankyo Co. Ltd. Above-mentioned pharmaceutical companies were not involved in the study design, data collection and analysis, manuscript writing, and manuscript submission., Masao Tanaka Speakers bureau: AbbVie GK, Asahi Kasei Pharma Corp., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., Pfizer Inc., Tanabe Mitsubishi Pharma Corp., UCB Japan Co., Ltd.., Grant/research support from: AbbVie GK, Eisai Co., Ltd., Kyowa Kirin Co., Ltd. Taisho Pharmaceutical Co., Ltd. Teijin Pharma, Ltd.., Employee of: M.T. belongs to the department financially supported by two local governments in Japan (Nagahama City, Shiga and Toyooka City, Hyogo) and five pharmaceutical companies (Tanabe Mitsubishi Pharma Corp., Chugai Pharmaceutical Co., Ltd., Ayumi Pharmaceutical Corp., Asahi Kasei Pharma Corp. and UCB Japan Co., Ltd.)., Shuichi Matsuda: None declared, Fumihiko Matsuda: None declared, Akio Morinobu Speakers bureau: AbbVie G.K., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Eisai Co. Ltd., Pfizer Inc., Bristol-Myers Squibb., Mitsubishi Tanabe Pharma Co., Astellas Pharma Inc., and Gilead Sciences Japan., Grant/research support from: AbbVie G.K., Asahi Kasei Pharma Corp., Chugai Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Co. Taisho Pharmaceutical Co., Ltd.,and Eisai Co. Ltd. outside the work., Motomu Hashimoto Speakers bureau: Eli Lilly, Chugai, Mitsubishi Tanabe, Bristol Myers, Eisai, Grant/research support from: AbbVie, Asahi Kasei, Astellas, Bristol Myers, Eisai, Daiichi Sankyo, Eli Lilly, Novartis.
ABSTRACT Objectives To determine the current retention rate of mepolizumab (MPZ) and identify factors associated with drug retention in patients with eosinophilic granulomatosis with polyangiitis (EGPA) in the Kansai multicentre cohort (REVEAL cohort). Methods Sixty patients diagnosed with EGPA and treated with MPZ between December 2016 and June 2023 were enrolled. The clinical characteristics, including laboratory data, treatments administered, and disease course outcomes, were collected retrospectively. The patients were stratified into MPZ continuation (n = 53) and discontinuation (n = 7) groups, and drug retention was statistically compared using the log-rank test. Results The median age of patients was 54.5 years, with 55% females, and 33% antineutrophil cytoplasmic antibody-positive at disease onset. MPZ exhibited a retention rate of 78.7% after 5 years. The reasons for discontinuation included treatment of coexisting diseases, inadequate response, and remission. Patient characteristics at disease onset were comparable between the groups. Patients receiving immunosuppressants (IS) before MPZ introduction demonstrated significantly higher retention rates (P = 0.038). During the final observation, the MPZ continuation group had a lower vasculitis damage index score (P = 0.027). Conclusions MPZ exhibited a high 5-year retention rate, particularly in patients requiring IS. This study implies that long-term use of MPZ may mitigate irreversible organ damage.
Abstract We read with great interest the article by Hein et al., which described the meta-analysis study on the impact of disease-modifying anti-rheumatic drugs (DMARDs) therapy on skeletal muscle mass in rheumatoid arthritis (RA) patients. While the data presented are impressive, we add some remarks about methodological issues that should be considered. First, this meta-analysis does not include several necessary studies that have provided data on the relationship between anti-tumor necrosis factor (anti-TNF) therapy and body composition. To make the meta-analysis more comprehensive, it could be necessary to incorporate these studies into this analysis. Second, this study did not employ a representative measure of skeletal muscle mass that was adjusted for body size, such as skeletal muscle mass index (SMI). It is well recognized that skeletal muscle mass varies with body size, particularly height and body mass index. Given the heterogeneity background of body size in the studies included in this meta-analysis, it may be worthwhile to conduct an additional analysis regarding the associations between DMARDs and the adjusted measure of skeletal muscle mass such as SMI, which is recommended in several guidelines when determining and contrasting the quantity of skeletal muscle mass. Third, when determining body composition, several reports show variances between bioelectrical impedance analysis (BIA) and dual-energy X-ray absorptiometry (DEXA) in RA as well as in general. In this regard, it may not be appropriate to simultaneously perform a meta-analysis of skeletal muscle mass determined by DEXA and BIA. With the issues described above, we conclude by recommending additional investigations to strengthen the arguments presented by this valuable meta-analysis.
T cells that mediate autoimmune diseases such as rheumatoid arthritis (RA) are difficult to characterize because they are likely to be deleted or inactivated in the thymus if the self antigens they recognize are ubiquitously expressed. One way to obtain and analyze these autoimmune T cells is to alter T cell receptor (TCR) signaling in developing T cells to change their sensitivity to thymic negative selection, thereby allowing their thymic production. From mice thus engineered to generate T cells mediating autoimmune arthritis, we isolated arthritogenic TCRs and characterized the self antigens they recognized. One of them was the ubiquitously expressed 60 S ribosomal protein L23a (RPL23A), with which T cells and autoantibodies from RA patients reacted. This strategy may improve our understanding of the underlying drivers of autoimmunity.
Abstract Sarcopenia is an age-related disease with an increased risk of mortality. It is emerging that low serum vitamin D (25(OH)D) affects the sarcopenic state in general, but in rheumatoid arthritis (RA), these associations are not understood although the prevalence of vitamin D insufficiency is high in RA. We conducted a cross-sectional study of older female outpatients from our cohort (KURAMA) database. We measured skeletal muscle mass, handgrip strength, and gait-speed to diagnose severe sarcopenia. The serum 25(OH)D concentration was measured using electrochemiluminescence immunoassay. A total of 156 Patients (sarcopenia:44.9%, severe sarcopenia: 29.5%, and without sarcopenia: 25.6%) were enrolled. Classification of vitamin D status at a cutoff point of median 25(OH)D concentration revealed that low 25(OH)D status was associated with a high prevalence of severe sarcopenia and with low measured values of muscle mass, handgrip, and gait-speed. Furthermore, multiple regression analysis identified that low 25(OH)D status was associated with a high prevalence of severe sarcopenia (OR 6.00; 95% CI 1.99–18.08). In components of sarcopenia, both low physical performance and muscle mass were associated with low 25(OH) status. In conclusion, vitamin D levels are associated with severe sarcopenia and its components, and modification of vitamin D status including vitamin D supplementation may play a role in improving sarcopenia in RA.
Secondary non-response to infliximab (IFX) occurs in some patients with rheumatoid arthritis (RA). Although therapeutic drug monitoring (TDM) is a useful tool to optimize IFX therapy, it is unclear whether it can help to identify the risk of secondary non-response. This study aimed to explore the utility of serum levels of IFX or other biomarkers to predict IFX discontinuation owing to secondary non-response. A single-center, retrospective study was conducted using the Kyoto University Rheumatoid Arthritis Management Alliance cohort database between 2011 and 2020. Serum IFX levels were measured using liquid chromatography-tandem mass spectrometry. An electrochemiluminescence assay was used to quantify serum levels of tumor necrosis factor-α and interleukin-6 and detect anti-drug antibodies. Eighty-four out of 310 patients were eligible for this study. The cutoff levels of biomarkers were determined by receiver operating characteristic analysis. IFX persistence was similar between groups stratified using IFX levels, tumor necrosis factor-α levels, interleukin-6 levels, and anti-drug antibodies positivity. The group with lower IFX and higher interleukin-6 levels had the worst therapy persistence (p = 0.017) and the most frequent disease worsening (90.0%, p < 0.001). Evaluating both interleukin-6 and IFX levels, not just IFX alone, enabled us to identify patients at risk of discontinuing IFX treatment. These findings support the utility of measuring IFX and interleukin-6 levels for successful maintenance therapy for RA.
ABSTRACT Objectives Late-onset rheumatoid arthritis (LORA), which has been increasing in recent years, lacks evidence for initial treatment. Japanese rheumatology experts recognized this gap and addressed it by developing consensus statements on the first clinical application of LORA. Methods These statements were created following an introductory discussion about treatment fundamentals, which included a review of existing literature and cohort data. The steering committee created a draft, which was refined using a modified Delphi method that involved panel members reaching a consensus. The panel made decisions based on input from geriatric experts, clinical epidemiologists, guideline developers, patient groups, and the LORA Research Subcommittee of the Japan College of Rheumatology. Results The consensus identified four established facts, three basic approaches, and six expert opinions for managing LORA. Methotrexate was recommended as the primary treatment, with molecular-targeted agents being considered if treatment goals cannot be achieved. An emphasis was placed on assessing the lives of older patients due to challenges in risk management and methotrexate accessibility caused by comorbidities or cognitive decline. Conclusions The experts substantiated and refined 13 statements for the initial treatment of LORA. To validate these claims, the next is to conduct a registry study focusing on new LORA cases.
A hypomorphic mutation of the gene encoding zeta‐associated protein‐70 (ZAP‐70), a signaling molecule in T cells, produces autoimmune arthritis in mice under a microbially conventional condition but not in a clean environment. The genetic anomaly alters thymic selection of self‐reactive T cells as well as natural regulatory T cells and their respective functions. Highly self‐reactive polyclonal T cells, including arthritogenic ones, thus produced by the thymus strongly recognize self‐antigens presented by antigen‐presenting cells, stimulate them to up‐regulate co‐stimulatory molecules and secrete cytokines that drive naïve self‐reactive T cells to differentiate into autoimmune effector Th17 cells. Administration of microbial products and activation of complement can facilitate the differentiation, evoking clinically overt arthritis in a microbially clean environment. Furthermore, mutation‐dependent graded attenuation of T cell receptor signaling alters disease phenotypes and the dependency of disease occurrence on the environment. These findings provide a model of how genetic and environmental factors, in association, cause autoimmune diseases such as rheumatoid arthritis.
