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Background:Interstitial lung disease (ILD) is a common extra-articular manifestation of rheumatoid arthritis (RA) and also the most common non-musculoskeletal manifestation of idiopathic inflammatory myopathies (IIM), including polymyositis, dermatomyositis and clinically amyopathic dermatomyositis. Previous studies have suggested that alveolar macrophages (AMs) and T cells are associated with the pathogenesis of ILD. Recently, it is reported that coinhibitory molecules are expressed at the site of inflammation such as RA synovium; however, detailed lung immunophenotyping has not been reported.Objectives:To identify immunologic factors in the lungs of patients with RA-associated ILD (RA-ILD) and IIM-associated ILD (IIM-ILD) and to examine their pathological mechanisms.Methods:A total of 11 patients with RA-ILD, 16 with IIM-ILD, and 6 with drug-induced ILD (DI-ILD) and 8 healthy controls were enrolled. Peripheral blood and bronchoalveolar lavage fluid (BALF) were immunophenotyped by flow cytometry. AMs were analyzed by RNA-sequence and coculture assay with peripheral naïve CD4+ T cells of healthy individuals.Results:Several coinhibitory molecules were coexpressed on BALF T cells in the order of CTLA-4, PD-1, Tim-3, and LAG-3 from most to least, whereas only PD-1 was expressed on peripheral T cells among them. In RA-ILD, PD-1+ and Tim-3+ CD4+ T cells in the BALF were increased. PD-1+CD4+ T cells populations correlated differentiated B cells and Tim-3+CD4+ T cells populations correlated with ILD severity and RF titer. In contrast, in IIM-ILD, activated CD8+ T cells were increased and they coexpressed CTLA-4, PD-1 and Tim-3. BALF PD-1+CD4+ T cells rarely expressed CXCR5, and they positively correlated with plasmablasts and plasma cells, indicating most of them are considered Tph cells. In the coculture experiments, AMs of RA-ILD and IIM-ILD induced more PD-1 and Tim-3 on CD4+ T cells, suggesting that coinhibitory molecule expression on BALF T cells was partly due to AMs. In RNA-sequence, PD-ligand (PD-L) 1 and PD-L2 genes were significantly downregulated in AMs from RA-lLD compared with DI-ILD.Conclusion:We identified T cell subsets that play a central role in the pathogenesis of RA-ILD and IIM-ILD; PD-1 on T cells in RA-ILD and Tim-3 on CD8+ T cells in IIM-ILD might be key factors in the disease process. The evaluation of coinhibitory molecules on BALF T cells could be clinically useful.Disclosure of Interests:Maho Nakazawa: None declared, Katsuya Suzuki: None declared, Masaru Takeshita: None declared, Jun Inamo: None declared, Hirofumi Kamata: None declared, Makoto Ishii: None declared, Yoshitaka Oyamada: None declared, Hisaji Oshima: None declared, Tsutomu Takeuchi Grant/research support from: Eisai Co., Ltd, Astellas Pharma Inc., AbbVie GK, Asahi Kasei Pharma Corporation, Nippon Kayaku Co., Ltd, Takeda Pharmaceutical Company Ltd, UCB Pharma, Shionogi & Co., Ltd., Mitsubishi-Tanabe Pharma Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co. Ltd., Consultant of: Chugai Pharmaceutical Co Ltd, Astellas Pharma Inc., Eli Lilly Japan KK, Speakers bureau: AbbVie GK, Eisai Co., Ltd, Mitsubishi-Tanabe Pharma Corporation, Chugai Pharmaceutical Co Ltd, Bristol-Myers Squibb Company, AYUMI Pharmaceutical Corp., Eisai Co., Ltd, Daiichi Sankyo Co., Ltd., Gilead Sciences, Inc., Novartis Pharma K.K., Pfizer Japan Inc., Sanofi K.K., Dainippon Sumitomo Co., Ltd.

Background:Residual synovitis can be detected by sensitive modalities such as ultrasonography in patients with rheumatoid arthritis in clinical remission. On the other hand, a previous study has shown that ultrasound-guided treatment provides modest benefit compared to a conventional strategy aiming clinical remission in early patients. It is still unclear how discordant clinical remission is from imaging remission by ultrasonography in patients treated with biologic agentsObjectives:To clarify the discordance between clinical remission and imaging remission in patients with rheumatoid arthritis treated with biologic agents.Methods:Patients with rheumatoid arthritis who were treated with biologic agents and in clinical remission defined as disease activity score for 28 joints (DAS28)Results:A total of 41 patients were enrolled with 22 patients treated with tumor necrosis factor (TNF)-α inhibitors and 19 with interleukin (IL)-6 inhibitors. The mean age, female ratio, the mean disease duration, and the mean duration of clinical remission were 60 years old, 87%, 5.1 years and 11.5 years. The imaging remission by ultrasonography was observed only in 51.2 %. When patients were divided according to biologic agents, baseline characteristics including median age, disease duration and clinically remission duration were comparable between both groups, while the rates of seropositivity and the stage of radiological progression was higher in IL-6 group (seropositivity, p=0.04; radiological progression, p=0.02). The mean DAS28 was 1.93 in the TNFα group and 1.02 in the IL-6 group. The discordance of clinical remission and imaging remission was observed in 28.6% of the TNFα group and 71.4% of the IL-6 group (p=0.03). The residual synovitis scores of GS and PD in 44 joints were significantly lower in the TNFα than the IL-6 group (GS, 1.1±1.8 vs 4.7 ± 4.6, pConclusion:Our results showed that there was substantial discordance between clinical remission and imaging remission, especially in the patients treated with IL-6 inhibitors. In patients treated with biologic agents, clinical remission should be assessed more stringently than the usual 2.6, and ulltrasound-guided management may be useful.References:[1]Smolen JS, et al. Ann Rheum Dis 2020;0:1–15.[2]Iwamoto T, et al. Arthritis Care Res (Hoboken). 2014;66(10):1576-81[3]Tanaka Y. Ann Rheum Dis 2010;69:1286 –91[4]Kaneko Y, et al. Ann Rheum Dis 2018;77:1268–1275[5]Brown AK, et al. Arthritis Rheum 2008;58: 2958 – 67.Acknowledgments:We would like to thank Harumi Kondo for their assistance.Disclosure of Interests:Yasushi Kondo: None declared, Yuko Kaneko Speakers bureau: Dr. Kaneko reports personal fees from AbbVie, personal fees from Astellas, personal fees from Ayumi, personal fees from Bristol-Myers Squibb, personal fees from Chugai, personal fees from Eisai, personal fees from Eli Lilly, personal fees from Hisamitsu, personal fees from Jansen, personal fees from Kissei, personal fees from Pfizer, personal fees from Sanofi, personal fees from Takeda, personal fees from Tanabe-Mitsubishi, personal fees from UCB, Shuntaro Saito: None declared, Yuichiro Ohta: None declared, Komei Sakata: None declared, Yumiko Inoue: None declared, Chihiro Takahashi: None declared, Kazuoto Hiramoto: None declared, Jun Inamo: None declared, Tsutomu Takeuchi Grant/research support from: Eisai Co., Ltd, Astellas Pharma Inc., AbbVie GK, Asahi Kasei Pharma Corporation, Nippon Kayaku Co., Ltd, Takeda Pharmaceutical Company Ltd, UCB Pharma, Shionogi & Co., Ltd., Mitsubishi-Tanabe Pharma Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co. Ltd., Consultant of: Chugai Pharmaceutical Co Ltd, Astellas Pharma Inc., Eli Lilly Japan KK, Speakers bureau: AbbVie GK, Eisai Co., Ltd, Mitsubishi-Tanabe Pharma Corporation, Chugai Pharmaceutical Co Ltd, Bristol-Myers Squibb Company, AYUMI Pharmaceutical Corp., Eisai Co., Ltd, Daiichi Sankyo Co., Ltd., Gilead Sciences, Inc., Novartis Pharma K.K., Pfizer Japan Inc., Sanofi K.K., Dainippon Sumitomo Co., Ltd.

I am grateful to Dr Young Ho Lee1 for response to my article.2 Although my study demonstrated non-causal association between gut microbiome and the risk of rheumatoid arthritis (RA), the author demonstrated significant association between them. First, the reason why different conclusions were drawn from two studies is that I extracted only ‘Gut microbiota (bacterial taxa) (unit decrease)’ from variables of exposures in harmonised dataset before conducting Mendelian randomisation (MR) (R script is …

I read with great interest the article by Alpizar-Rodriguez et al regarding the risk of intestinal dysbiosis, particularly Prevotella spp enrichment, in preclinical rheumatoid arthritis (RA).1 Immune response in gut is assumed to be one of the triggers of development of RA.2 However, it is hard to assess causal association by case–control study due to limitations such as latent confounding factors; dysbiosis first or RA first . Therefore, to investigate causal effect of gut microbiome on the development of RA, I conducted Mendelian randomisation (MR) analysis.3 MR is useful to investigate causal association among phenotypes and/or biomarkers because it is based on genetic variation to mimic the design of randomised controlled trials. In MR, single nucleotide polymorphisms (SNP) are expected to be random and causally upstream of the exposure; thus, SNP are used as instrumental variables (IVs) in MR. I used the publicly available two data sets of genome-wide association studies (GWASs) for gut microbiome (totally 3326 individuals) of European ancestry as the exposure4 5 and one data set …