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The Pathogenesis of Rheumatoid Arthritis—Breakthroughs in Molecular Mechanisms 2.0
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The Pathogenesis of Rheumatoid Arthritis—Breakthroughs in Molecular Mechanisms 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (15 March 2023) | Viewed by 12829

Special Issue Editors

Prof. Dr. Yuki Nanke

E-Mail Website
Guest Editor
Institute of Rheumatology, Tokyo Women's Medical University, Tokyo 162-8666, Japan
Interests: osteoclastology; osteoimmunology; rheumatoid arthritis; osteoporosis; Behcet's diseases
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Shigeru Kotake

E-Mail Website
Guest Editor
Division of Rheumatology, First Department of Comprehensive Medicine, Jichi Medical University Saitama Medical Center, Saitama 330-0834, Japan
Interests: medicine; immunology; microbiology; Behcet’s disease; arthritis

Special Issue Information

Dear Colleagues, 

The pathogenesis of rheumatoid arthritis (RA) consists of the formation of synovial villi, inflammation, immune abnormalities, and bone–cartilage destruction. According to these pathogenesis findings, conventional therapy was empirically performed using conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). However, since the 1990s, pathogenesis investigations have advanced to include the cloning of IL-6, clarifying the role of IL-17・Th17 in bone destruction; the cloning of RANKL; anti-RANKL Ab in the therapy of RA in Japan; and the introduction of “Osteoimmunology”. In addition, therapies using biological DMARDs have resulted in breakthroughs in pathogenesis investigations; the inhibition of the function of a specific molecule by an antibody has clarified its function in vivo, such as “knock-out in vivo in human”. Recently, inflammatory cell states have been clarified in RA joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. In this Special Issue, both original and review papers present important advances in molecular investigations of RA pathogenesis.

Dr. Yuki Nanke
Prof. Dr. Shigeru Kotake
Guest Editors

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Published Papers (6 papers)

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Editorial

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5 pages, 179 KiB  
Editorial
The Pathogenesis of Rheumatoid Arthritis Breakthroughs in Molecular Mechanisms 1 and 2
by Yuki Nanke
Int. J. Mol. Sci. 2023, 24(13), 11060; https://doi.org/10.3390/ijms241311060 - 04 Jul 2023
Cited by 1 | Viewed by 1752
Abstract
The pathogenesis of rheumatoid arthritis (RA) consists of the formation of synovial villi, inflammation, immune abnormalities, and bone–cartilage destruction [...] Full article
(This article belongs to the Special Issue The Pathogenesis of Rheumatoid Arthritis—Breakthroughs in Molecular Mechanisms 2.0)

Research

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13 pages, 1572 KiB  
Communication
Serum Levels of IFABP2 and Differences in Lactobacillus and Porphyromonas gingivalis Abundance on Gut Microbiota Are Associated with Poor Therapeutic Response in Rheumatoid Arthritis: A Pilot Study
by Oscar Zaragoza-García, Natividad Castro-Alarcón, Gloria Pérez-Rubio, Ramcés Falfán-Valencia, Olivia Briceño, José Eduardo Navarro-Zarza, Isela Parra-Rojas, Mario Tello and Iris Paola Guzmán-Guzmán
Int. J. Mol. Sci. 2023, 24(3), 1958; https://doi.org/10.3390/ijms24031958 - 19 Jan 2023
Cited by 4 | Viewed by 1727
Abstract
Intestinal dysbiosis is related to the physiopathology and clinical manifestation of rheumatoid arthritis (RA) and the response to pharmacologic treatment. The objectives of this study were (1) to analyze the effect of conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) on the abundance of [...] Read more.
Intestinal dysbiosis is related to the physiopathology and clinical manifestation of rheumatoid arthritis (RA) and the response to pharmacologic treatment. The objectives of this study were (1) to analyze the effect of conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) on the abundance of gut microbiota’s bacteria; (2) to evaluate the relationship between the differences in microbial abundance with the serum levels of intestinal fatty-acid binding protein 2 (IFABP2), cytokines, and the response phenotype to csDMARDs therapy in RA. A cross-sectional study was conducted on 23 women diagnosed with RA. The abundance of bacteria in gut microbiota was determined with qPCR. The ELISA technique determined serum levels of IFABP2, TNF-α, IL-10, and IL-17A. We found that the accumulated dose of methotrexate or prednisone is negatively associated with the abundance of Lactobacillus but positively associated with the abundance of Bacteroides fragilis. The Lactobacillus/Porphyromonas gingivalis ratio was associated with the Disease Activity Score-28 for RA with Erythrocyte Sedimentation Rate (DAS28-ESR) (r = 0.778, p = 0.030) and with the levels of IL-17A (r = 0.785, p = 0.027) in the group treated with csDMARD. Moreover, a relation between the serum levels of IFABP2 and TNF-α (r = 0.593, p = 0.035) was observed in the group treated with csDMARD. The serum levels of IFABP2 were higher in patients with secondary non-response to csDMARDs therapy. In conclusion, our results suggest that the ratios of gut microbiota’s bacteria and intestinal permeability seems to establish the preamble for therapeutic secondary non-response in RA. Full article
(This article belongs to the Special Issue The Pathogenesis of Rheumatoid Arthritis—Breakthroughs in Molecular Mechanisms 2.0)
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13 pages, 1312 KiB  
Article
Anti-Citrullinated Peptide Antibodies Control Oral Porphyromonas and Aggregatibacter species in Patients with Rheumatoid Arthritis
by Marina I. Arleevskaya, Eugenia A. Boulygina, Regina Larionova, Shamil Validov, Olga Kravtsova, Elena I. Shagimardanova, Lourdes Velo, Geneviève Hery-Arnaud, Caroline Carlé and Yves Renaudineau
Int. J. Mol. Sci. 2022, 23(20), 12599; https://doi.org/10.3390/ijms232012599 - 20 Oct 2022
Cited by 5 | Viewed by 1456
Abstract
Oral microbiome changes take place at the initiation of rheumatoid arthritis (RA); however, questions remain regarding the oral microbiome at pre-RA stages in individuals with clinically suspect arthralgia (CSA). Two cross-sectional cohorts were selected including 84 Tatarstan women (15 early-RA as compared to [...] Read more.
Oral microbiome changes take place at the initiation of rheumatoid arthritis (RA); however, questions remain regarding the oral microbiome at pre-RA stages in individuals with clinically suspect arthralgia (CSA). Two cross-sectional cohorts were selected including 84 Tatarstan women (15 early-RA as compared to individuals with CSA ranging from CSA = 0 [n = 22], CSA = 1 [n = 19], CSA = 2 [n = 11], and CSA ≥ 3 [n = 17]) and 42 women with established RA (median: 5 years from diagnosis [IQ: 2–11]). Amplicon sequence variants (ASVs) obtained from oral samples (16S rRNA) were analyzed for alpha and beta diversity along with the abundance at the genus level. A decrease in oral Porphyromonas sp. is observed in ACPA-positive individuals, and this predominates in early-RA patients as compared to non-RA individuals irrespective of their CSA score. In the RA-established cohort, Porphyromonas sp. and Aggregatibacter sp. reductions were associated with elevated ACPA levels. In contrast, no associations were reported when considering individual, genetic and clinical RA-associated factors. Oral microbiome changes related to the genera implicated in post-translational citrullination (Porphyromonas sp. and Aggregatibacter sp.) characterized RA patients with elevated ACPA levels, which supports that the role of ACPA in controlling the oral microbiome needs further evaluation. Full article
(This article belongs to the Special Issue The Pathogenesis of Rheumatoid Arthritis—Breakthroughs in Molecular Mechanisms 2.0)
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12 pages, 1632 KiB  
Article
Subgingival Microbiome in Rheumatoid Arthritis Patients with Periodontitis
by Yi-Jing Chen, Wei-Chun Hung, Yu-Hsiang Chou, Chern-Hsiung Lai, Po Peng, Pei-Syuan Jhou, Min-Ru Tsai, Jim Jinn-Chyuan Sheu and Jeng-Hsien Yen
Int. J. Mol. Sci. 2022, 23(17), 9883; https://doi.org/10.3390/ijms23179883 - 31 Aug 2022
Cited by 5 | Viewed by 1723
Abstract
Rheumatoid arthritis (RA) and periodontitis are suggested to be closely linked based on microbial dysbiosis, but limited subgingival bacteria have been proven in the pathogenesis of RA. We enrolled 30 RA patients and 25 controls and divided them into three groups with matched [...] Read more.
Rheumatoid arthritis (RA) and periodontitis are suggested to be closely linked based on microbial dysbiosis, but limited subgingival bacteria have been proven in the pathogenesis of RA. We enrolled 30 RA patients and 25 controls and divided them into three groups with matched age, gender, and diabetes statuses: group AM (all of the matched participants), group PD (periodontally diseased), and group PH (periodontally healthy). Their subgingival microbial composition was determined by V3–V4 16S rRNA gene sequencing. Significant differences in subgingival microbial clustering between the RA patients and controls were observed in groups AM and PD. Among the taxa enriched in RA, Aminipila butyrica and Peptococcus simiae were the only two species displaying positive correlation to the level of anti-citrullinated protein antibodies (ACPAs) in both of the groups. Surprisingly, the median of relative abundances of A. butyrica and P. simiae were 0% in the controls of group PD. Furthermore, a gene encoding arginine deiminase with the capability to produce citrulline was addressed in the complete genome sequence of A. butyrica. This is the first study to elucidate the important roles of A. butyrica and P. simiae as periodontal bacteria leading to RA possibly through the induction of ACPA production. Full article
(This article belongs to the Special Issue The Pathogenesis of Rheumatoid Arthritis—Breakthroughs in Molecular Mechanisms 2.0)
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Review

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17 pages, 2501 KiB  
Review
New Insights into the Role of Synovial Fibroblasts Leading to Joint Destruction in Rheumatoid Arthritis
by Kotaro Matsuda, Naoto Shiba and Koji Hiraoka
Int. J. Mol. Sci. 2023, 24(6), 5173; https://doi.org/10.3390/ijms24065173 - 08 Mar 2023
Cited by 8 | Viewed by 2307
Abstract
Rheumatoid arthritis (RA), one of the most common autoimmune diseases, is characterized by multiple-joint synovitis with subsequent destruction of bone and cartilage. The excessive autoimmune responses cause an imbalance in bone metabolism, promoting bone resorption and inhibiting bone formation. Preliminary studies have revealed [...] Read more.
Rheumatoid arthritis (RA), one of the most common autoimmune diseases, is characterized by multiple-joint synovitis with subsequent destruction of bone and cartilage. The excessive autoimmune responses cause an imbalance in bone metabolism, promoting bone resorption and inhibiting bone formation. Preliminary studies have revealed that receptor activator of NF-κB ligand (RANKL)-mediated osteoclast induction is an important component of bone destruction in RA. Synovial fibroblasts are the crucial producers of RANKL in the RA synovium; novel analytical techniques, primarily, single-cell RNA sequencing, have confirmed that synovial fibroblasts include heterogeneous subsets of both pro-inflammatory and tissue-destructive cell types. The heterogeneity of immune cells in the RA synovium and the interaction of synovial fibroblasts with immune cells have recently received considerable attention. The current review focused on the latest findings regarding the crosstalk between synovial fibroblasts and immune cells, and the pivotal role played by synovial fibroblasts in joint destruction in RA. Full article
(This article belongs to the Special Issue The Pathogenesis of Rheumatoid Arthritis—Breakthroughs in Molecular Mechanisms 2.0)
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38 pages, 3334 KiB  
Review
Organokines in Rheumatoid Arthritis: A Critical Review
by Lucas Fornari Laurindo, Mariana Canevari de Maio, Sandra Maria Barbalho, Elen Landgraf Guiguer, Adriano Cressoni Araújo, Ricardo de Alvares Goulart, Uri Adrian Prync Flato, Edgar Baldi Júnior, Cláudia Rucco Penteado Detregiachi, Jesselina Francisco dos Santos Haber, Patrícia C. Santos Bueno, Raul S. J. Girio, Rachel Gomes Eleutério and Marcelo Dib Bechara
Int. J. Mol. Sci. 2022, 23(11), 6193; https://doi.org/10.3390/ijms23116193 - 31 May 2022
Cited by 13 | Viewed by 3051
Abstract
Rheumatoid arthritis (RA) is a systemic autoimmune disease that primarily affects the joints. Organokines can produce beneficial or harmful effects in this condition. Among RA patients, organokines have been associated with increased inflammation and cartilage degradation due to augmented cytokines and metalloproteinases production, [...] Read more.
Rheumatoid arthritis (RA) is a systemic autoimmune disease that primarily affects the joints. Organokines can produce beneficial or harmful effects in this condition. Among RA patients, organokines have been associated with increased inflammation and cartilage degradation due to augmented cytokines and metalloproteinases production, respectively. This study aimed to perform a review to investigate the role of adipokines, osteokines, myokines, and hepatokines on RA progression. PubMed, Embase, Google Scholar, and Cochrane were searched, and 18 studies were selected, comprising more than 17,000 RA patients. Changes in the pattern of organokines secretion were identified, and these could directly or indirectly contribute to aggravating RA, promoting articular alterations, and predicting the disease activity. In addition, organokines have been implicated in higher radiographic damage, immune dysregulation, and angiogenesis. These can also act as RA potent regulators of cells proliferation, differentiation, and apoptosis, controlling osteoclasts, chondrocytes, and fibroblasts as well as immune cells chemotaxis to RA sites. Although much is already known, much more is still unknown, principally about the roles of organokines in the occurrence of RA extra-articular manifestations. Full article
(This article belongs to the Special Issue The Pathogenesis of Rheumatoid Arthritis—Breakthroughs in Molecular Mechanisms 2.0)
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