Submit to Special Issue Submit Abstract to Special Issue Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

Molecular and Therapeutic Research in Rheumatoid Arthritis

Special Issue Editors
Special Issue Information
Keywords
Published Papers

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: 30 April 2024 | Viewed by 8986

Share This Special Issue

Special Issue Editor

Dr. Joan Carles Vallvé

E-Mail Website
Guest Editor

Department of Medicine and Surgery, Rovira i Virgili University, Sant Llorenç 21, 43201 Reus, Tarragona, Spain
Interests: Rheumatoid arthritis; Cardiovascular risk; microRNAs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects approximately 1% of the world's population. It is characterized by inflammation and damage of the joints, which causes pain, stiffness, and loss of function. Over the last few decades, researchers have made great advances in understanding the mechanisms behind this condition and how can they be targeted to treat it. However, the exact etiology of the disease is not yet fully understood.

RA is a complex disease that involves a multitude of factors, such as environmental, genetic, and epigenetic factors. Additionally, molecular research has revealed multiple molecular factors that contribute to the disease’s pathogenesis, including a variety of immune cells, such as T-cells, B-cells, macrophages, and neutrophils, and has provided better molecular insights into the various cytokines and chemokines involved in the immune response. Targeting these cytokines with biologic drugs has revolutionized RA treatment, but researchers continue to search for new drug targets to address the underlying immune dysfunction. New research has also showed promise in identifying other molecular targets for RA therapy, including molecules that impact the activation and differentiation of immune cells, enzymes that regulate cellular signaling pathways, as well as small non-coding RNAs and microRNAs that can regulate gene expression in the RA pathogenesis process. Overall, these molecular advances in RA research hold promise for more precise and personalized treatment approaches, allowing for earlier intervention and improved patient outcomes.

This Special Issue aims to showcase the recent advances in research related to RA, with the goal of identifying novel effective molecular targets for the development of preventive and therapeutic strategies. We encourage investigators to submit original research focused on the molecular mechanisms underlying the development, progression, or treatment of RA. Manuscripts should focus on cutting-edge research to provide new insights into the physiological and pathophysiological processes involved in the development and progression of rheumatoid arthritis. The scope of this Special Issue includes experimental medical approaches and human studies that provide opportunities for "back translation" into basic research. We welcome proposals aimed at improving our understanding of the molecular mechanisms underlying RA at the cellular, systemic, and whole-body levels, in humans or model systems. Clinical papers that focus on the molecular pathways or intermediates involved in the development and progression of rheumatoid arthritis are also welcome in this Special Issue and manuscripts that examine the relationship between clinical outcomes and molecular targets, biomarkers, or pathways are particularly encouraged. Additionally, review articles that critically and systematically cover related research, with concluding remarks and an outlook, will be considered for inclusion in this Special Issue.

Dr. Joan Carles Vallvé
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

rheumatoid arthritis
inflammation
cytokines
autoimmunity
microRNAs

Published Papers (9 papers)

Download All Papers

Order results

Result details

Show export options Show export options

Select all

Export citation of selected articles as:

Research

Jump to: Review

14 pages, 928 KiB

Open AccessArticle

Natural Autoantibodies in Biologic-Treated Rheumatoid Arthritis and Ankylosing Spondylitis Patients: Associations with Vascular Pathophysiology

by Diána Simon, Dorottya Kacsándi, Anita Pusztai, Boglárka Soós, Edit Végh, György Kerekes, Monika Bodoki, Szilvia Szamosi, Gabriella Szűcs, Zoltán Prohászka, Péter Németh, Tímea Berki and Zoltán Szekanecz

Int. J. Mol. Sci. 2024, 25(6), 3429; https://doi.org/10.3390/ijms25063429 - 18 Mar 2024

Viewed by 710

Abstract

Cardiovascular (CV) morbidity and mortality have been associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Natural autoantibodies (nAAb) are involved in innate immunity, as well as autoimmunity, inflammation, and atherosclerosis. There have not been any studies assessing the effects of biologics on nAAbs in RA and AS, also in relation to vascular pathophysiology. Fifty-three anti-TNF-treated RA and AS patients were included in a 12-month follow-up study. Anti-citrate synthase (CS) and anti-topoisomerase I fragment 4 (TOPO-F4) IgM and IgG levels were determined by ELISA. Ultrasonography was performed to assess brachial artery flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT), and arterial pulse-wave velocity (PWV). Other variables were also evaluated at baseline and 6 and 12 months after treatment initiation. Anti-TNF therapy improved FMD in RA and PWV in AS and stabilized ccIMT. TNF inhibition increased anti-CS IgM and IgG, and possibly also anti-TOPO-F4 IgG levels. Various correlation analyses revealed that nAAbs might be independently involved in autoimmunity as well as changes in inflammation and vascular pathology over time in biologic-treated patients (p < 0.05). We also found associations between anti-TOPO-F4 IgG and anti-Hsp60 IgG (p < 0.05). Baseline nAAb levels or nAAb level changes might determine changes in CRP, disease activity, FMD, PWV, and ccIMT over time (p < 0.05). The interplay between arthritis and inflammatory atherosclerosis, as well as the effects of anti-TNF biologics on these pathologies, might independently involve nAAbs. Full article

(This article belongs to the Special Issue Molecular and Therapeutic Research in Rheumatoid Arthritis)

► Show Figures

Figure 1

13 pages, 1927 KiB

Open AccessArticle

PIM Kinases as Potential Biomarkers and Therapeutic Targets in Inflammatory Arthritides

by Elisa Assirelli, Jacopo Ciaffi, Valentina Scorcu, Susanna Naldi, Veronica Brusi, Luana Mancarella, Lucia Lisi, Federica Pignatti, Francesco Ursini and Simona Neri

Int. J. Mol. Sci. 2024, 25(6), 3123; https://doi.org/10.3390/ijms25063123 - 08 Mar 2024

Viewed by 602

Abstract

The Proviral Integration site for the Moloney murine leukemia virus (PIM)-1 kinase and its family members (PIM-2 and PIM-3) regulate several cellular functions including survival, proliferation, and apoptosis. Recent studies showed their involvement in the pathogenesis of rheumatoid arthritis RA, while no studies are available on psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). The main objective of this study is to assess the expression of PIM kinases in inflammatory arthritides, their correlation with proinflammatory cytokines, and their variation after treatment with biologic disease-modifying anti-rheumatic drugs or JAK inhibitors. We evaluated PIM-1, -2, and -3 expression at the gene and protein level, respectively, in the peripheral blood mononuclear cells and serum of patients with RA, PsA, axSpA, and healthy individuals (CTR). All the samples showed expression of PIM-1, -2, and -3 kinases both at the gene and protein level. PIM-1 was the most expressed protein, PIM-3 the least. PIM kinase levels differed between controls and disease groups, with reduced PIM-1 protein and increased PIM-3 protein in all disease samples compared to controls. No difference was found in the expression of these molecules between the three different pathologies. PIM levels were not modified after 6 months of therapy. In conclusion, our preliminary data suggest a deregulation of the PIM pathway in inflammatory arthritides. In-depth studies on the role of PIM kinases in this field are warranted. Full article

(This article belongs to the Special Issue Molecular and Therapeutic Research in Rheumatoid Arthritis)

► Show Figures

Figure 1

13 pages, 1859 KiB

Open AccessArticle

Functional MICA Variants Are Differentially Associated with Immune-Mediated Inflammatory Diseases

by Chin-Man Wang, Keng-Poo Tan, Yeong-Jian Jan Wu, Jian-Wen Zheng, Jianming Wu and Ji-Yih Chen

Int. J. Mol. Sci. 2024, 25(5), 3036; https://doi.org/10.3390/ijms25053036 - 06 Mar 2024

Viewed by 555

Abstract

As the principal ligand for NKG2D, MICA elicits the recruitment of subsets of T cells and NK cells in innate immunity. MICA gene variants greatly impact the functionality and expression of MICA in humans. The current study evaluated whether MICA polymorphisms distinctively influence the pathogenesis of psoriasis (PSO), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) in Taiwanese subjects. The distributions of MICA alleles and levels of serum soluble NKG2D were compared between healthy controls and patients with PSO, RA, and SLE, respectively. The binding capacities and cell surface densities of MICA alleles were assessed by utilizing stable cell lines expressing four prominent Taiwanese MICA alleles. Our data revealed that MICA*010 was significantly associated with risks for PSO and RA (P_FDR = 1.93 × 10⁻¹⁵ and 0.00112, respectively), while MICA*045 was significantly associated with predisposition to SLE (P_FDR = 0.0002). On the other hand, MICA*002 was associated with protection against RA development (P_FDR = 4.16 × 10⁻⁶), while MICA*009 was associated with a low risk for PSO (P_FDR = 0.0058). MICA*002 exhibited the highest binding affinity for NKG2D compared to the other MICA alleles. Serum concentrations of soluble MICA were significantly elevated in SLE patients compared to healthy controls (p = 0.01). The lack of cell surface expression of the MICA*010 was caused by its entrapment in the endoplasmic reticulum. As a prevalent risk factor for PSO and RA, MICA*010 is deficient in cell surface expression and is unable to interact with NKG2D. Our study suggests that MICA alleles distinctively contribute to the pathogenesis of PSO, RA, and SLE in Taiwanese people. Full article

(This article belongs to the Special Issue Molecular and Therapeutic Research in Rheumatoid Arthritis)

► Show Figures

Figure 1

15 pages, 1874 KiB

Open AccessArticle

The Association between Inefficient Repair of DNA Double-Strand Breaks and Common Polymorphisms of the HRR and NHEJ Repair Genes in Patients with Rheumatoid Arthritis

by Grzegorz Galita, Joanna Sarnik, Olga Brzezinska, Tomasz Budlewski, Marta Poplawska, Sebastian Sakowski, Grzegorz Dudek, Ireneusz Majsterek, Joanna Makowska and Tomasz Poplawski

Int. J. Mol. Sci. 2024, 25(5), 2619; https://doi.org/10.3390/ijms25052619 - 23 Feb 2024

Viewed by 615

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation affecting up to 2.0% of adults around the world. The molecular background of RA has not yet been fully elucidated, but RA is classified as a disease in which the genetic background is one of the most significant risk factors. One hallmark of RA is impaired DNA repair observed in patient-derived peripheral blood mononuclear cells (PBMCs). The aim of this study was to correlate the phenotype defined as the efficiency of DNA double-strand break (DSB) repair with the genotype limited to a single-nucleotide polymorphism (SNP) of DSB repair genes. We also analyzed the expression level of key DSB repair genes. The study population contained 45 RA patients and 45 healthy controls. We used a comet assay to study DSB repair after in vitro exposure to bleomycin in PBMCs from patients with rheumatoid arthritis. TaqMan SNP Genotyping Assays were used to determine the distribution of SNPs and the Taq Man gene expression assay was used to assess the RNA expression of DSB repair-related genes. PBMCs from patients with RA had significantly lower bleomycin-induced DNA lesion repair efficiency and we identified more subjects with inefficient DNA repair in RA compared with the control (84.5% vs. 24.4%; OR 41.4, 95% CI, 4.8–355.01). Furthermore, SNPs located within the RAD50 gene (rs1801321 and rs1801320) increased the OR to 53.5 (95% CI, 4.7–613.21) while rs963917 and rs3784099 (RAD51B) to 73.4 (95% CI, 5.3–1011.05). These results were confirmed by decision tree (DT) analysis (accuracy 0.84; precision 0.87, and specificity 0.86). We also found elevated expression of RAD51B, BRCA1, and BRCA2 in PBMCs isolated from RA patients. The findings indicated that impaired DSB repair in RA may be related to genetic variations in DSB repair genes as well as their expression levels. However, the mechanism of this relation, and whether it is direct or indirect, needs to be elucidated. Full article

(This article belongs to the Special Issue Molecular and Therapeutic Research in Rheumatoid Arthritis)

► Show Figures

Figure 1

16 pages, 2510 KiB

Open AccessArticle

Plasma Expression of Carotid Plaque Presence-Related MicroRNAs Is Associated with Inflammation in Patients with Rheumatoid Arthritis

by Dídac Llop, Silvia Paredes, Daiana Ibarretxe, Delia Taverner, Núria Plana, Roser Rosales, Lluís Masana and Joan Carles Vallvé

Int. J. Mol. Sci. 2023, 24(20), 15347; https://doi.org/10.3390/ijms242015347 - 19 Oct 2023

Viewed by 760

Abstract

Rheumatoid arthritis (RA) is associated with problems beyond the joints such as cardiovascular (CV) disease. MicroRNA-24, -146 and -Let7a are associated with carotid plaque presence in RA patients. We evaluated whether these microRNAs were involved in the inflammatory state of RA, and we studied their gene targets to understand their role in inflammation and atherosclerosis. A total of 199 patients with RA were included. Inflammatory variables such as disease activity score 28 (DAS28) and erythrocyte sedimentation rate (ESR) were quantified. MicroRNAs were extracted from plasma and quantified with qPCR. Multivariate models and classification methods were used for analysis. The multivariate models showed that diminished expression of microRNA-146 was associated with inferior levels of DAS28-ESR, and the decreased expression of microRNA-24, -146 and -Let7a were associated with lowered ESR in the overall cohort. When microRNAs were evaluated globally, a global increase was associated with increased DAS28-ESR and ESR in the overall cohort. Sex-stratified analyses showed different associations of these microRNAs with the inflammatory variables. Finally, random forest models showed that microRNAs have a pivotal role in classifying patients with high and low inflammation. Plasmatic expressions of microRNA-24, -146 and -Let7a were associated with inflammatory markers of RA. These microRNAs are associated with both inflammation and atherosclerosis and are potential therapeutic targets for RA. Full article

(This article belongs to the Special Issue Molecular and Therapeutic Research in Rheumatoid Arthritis)

► Show Figures

Figure 1

16 pages, 3012 KiB

Open AccessArticle

Effects of Tofacitinib on Muscle Remodeling in Experimental Rheumatoid Sarcopenia

by Ismael Bermejo-Álvarez, Sandra Pérez-Baos, Paula Gratal, Juan Pablo Medina, Raquel Largo, Gabriel Herrero-Beaumont and Aránzazu Mediero

Int. J. Mol. Sci. 2023, 24(17), 13181; https://doi.org/10.3390/ijms241713181 - 24 Aug 2023

Cited by 2 | Viewed by 1379

Abstract

Sarcopenia is a frequent comorbidity of rheumatoid arthritis (RA). Clinical trials have shown that JAK inhibitors (JAKi) produce an asymptomatic increase in serum creatine kinase (CK) in RA, suggesting an impact on muscle. We evaluated the effect of JAKi in muscle remodeling in an experimental RA model. Antigen-induced arthritis (experimental RA, e-RA) was performed in 14 rabbits. Seven rabbits received tofacitinib (TOFA, orally 10 mg/kg/day). Animals were euthanized one day after the last ovalbumin injection, and muscles were prepared for histology, RT-PCR, and WB. C-reactive protein (CRP) and Myostatin (MSTN) serum concentration were determined by ELISA. Creatine and creatine kinase (CK) were analyzed. An increase in body weight as well as tibialis anterior cross-sectional area and diameter was observed in e-RA+TOFA vs. e-RA. e-RA decreased type II fibers and increased the myonuclei number, with all reverted by TOFA. TOFA did not modify CRP levels, neither did MSTN. TOFA significantly reduced IL-6, atrogin-1, and MuRF-1 compared with e-RA. e-RA+TOFA showed higher CK and lower creatine levels compared with e-RA. No differences in PAX-7 were found, while TOFA prevented the increase in MyoD1 in e-RA. Our model reflects the features of rheumatoid sarcopenia in RA. JAKi increased muscle mass through attenuating IL-6/JAK/STAT activation, decreasing atrogenes, and restoring muscle differentiation markers. These data together with an increase in CK support the role of CK as a valuable marker of muscle gain following JAKi treatment. Full article

(This article belongs to the Special Issue Molecular and Therapeutic Research in Rheumatoid Arthritis)

► Show Figures

Figure 1

18 pages, 3157 KiB

Open AccessArticle

Analysis of Novel Immunological Biomarkers Related to Rheumatoid Arthritis Disease Severity

by Sandra Pascual-García, Pascual Martínez-Peinado, Ana B. López-Jaén, Francisco J. Navarro-Blasco, Yoel G. Montoyo-Pujol, Enrique Roche, Gloria Peiró and José M. Sempere-Ortells

Int. J. Mol. Sci. 2023, 24(15), 12351; https://doi.org/10.3390/ijms241512351 - 02 Aug 2023

Cited by 3 | Viewed by 1426

Abstract

Rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs) are the most frequently used rheumatoid arthritis (RA) diagnostic markers, but they are unable to anticipate the patient’s evolution or response to treatment. The aim of this study was to identify possible severity biomarkers to predict an upcoming flare-up or remission period. To address this objective, sera and anticoagulated blood samples were collected from healthy controls (HCs; n = 39) and from early RA (n = 10), flare-up (n = 5), and remission (n = 16) patients. We analyzed leukocyte phenotype markers, regulatory T cells, cell proliferation, and cytokine profiles. Flare-up patients showed increased percentages of cluster of differentiation (CD)3⁺CD4⁻ lymphocytes (p < 0.01) and granulocytes (p < 0.05) but a decreased natural killer (NK)/T lymphocyte ratio (p < 0.05). Analysis of leukocyte markers by principal component analysis (PCA) and receiver operating characteristic (ROC) curves showed that CD45RO⁺ (p < 0.0001) and CD45RA⁺ (p < 0.0001) B lymphocyte expression can discriminate between HCs and early RA patients, while CD3⁺CD4⁻ lymphocyte percentage (p < 0.0424) and CD45RA⁺ (p < 0.0424), CD62L⁺ (p < 0.0284), and CD11a⁺ (p < 0.0185) B lymphocyte expression can differentiate between flare-up and RA remission subjects. Thus, the combined study of these leukocyte surface markers could have potential as disease severity biomarkers for RA, whose fluctuations could be related to the development of the characteristic pro-inflammatory environment. Full article

(This article belongs to the Special Issue Molecular and Therapeutic Research in Rheumatoid Arthritis)

► Show Figures

Figure 1

Review

Jump to: Research

23 pages, 1485 KiB

Open AccessReview

Potential Rheumatoid Arthritis-Associated Interstitial Lung Disease Treatment and Computational Approach for Future Drug Development

by Eunji Jeong, Hyunseok Hong, Yeon-Ah Lee and Kyoung-Soo Kim

Int. J. Mol. Sci. 2024, 25(5), 2682; https://doi.org/10.3390/ijms25052682 - 26 Feb 2024

Viewed by 973

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by swelling in at least one joint. Owing to an overactive immune response, extra-articular manifestations are observed in certain cases, with interstitial lung disease (ILD) being the most common. Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is characterized by chronic inflammation of the interstitial space, which causes fibrosis and the scarring of lung tissue. Controlling inflammation and pulmonary fibrosis in RA-ILD is important because they are associated with high morbidity and mortality. Pirfenidone and nintedanib are specific drugs against idiopathic pulmonary fibrosis and showed efficacy against RA-ILD in several clinical trials. Immunosuppressants and disease-modifying antirheumatic drugs (DMARDs) with anti-fibrotic effects have also been used to treat RA-ILD. Immunosuppressants moderate the overexpression of cytokines and immune cells to reduce pulmonary damage and slow the progression of fibrosis. DMARDs with mild anti-fibrotic effects target specific fibrotic pathways to regulate fibrogenic cellular activity, extracellular matrix homeostasis, and oxidative stress levels. Therefore, specific medications are required to effectively treat RA-ILD. In this review, the commonly used RA-ILD treatments are discussed based on their molecular mechanisms and clinical trial results. In addition, a computational approach is proposed to develop specific drugs for RA-ILD. Full article

(This article belongs to the Special Issue Molecular and Therapeutic Research in Rheumatoid Arthritis)

► Show Figures

Figure 1

20 pages, 1614 KiB

Open AccessReview

Exosomal Osteoclast-Derived miRNA in Rheumatoid Arthritis: From Their Pathogenesis in Bone Erosion to New Therapeutic Approaches

by Sandra Pascual-García, Pascual Martínez-Peinado, Carolina Pujalte-Satorre, Alicia Navarro-Sempere, Jorge Esteve-Girbés, Ana B. López-Jaén, Juan Javaloyes-Antón, Raúl Cobo-Velacoracho, Francisco J. Navarro-Blasco and José M. Sempere-Ortells

Int. J. Mol. Sci. 2024, 25(3), 1506; https://doi.org/10.3390/ijms25031506 - 25 Jan 2024

Viewed by 1026

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease that causes inflammation, pain, and ultimately, bone erosion of the joints. The causes of this disease are multifactorial, including genetic factors, such as the presence of the human leukocyte antigen (HLA)-DRB1*04 variant, alterations in the microbiota, or immune factors including increased cytotoxic T lymphocytes (CTLs), neutrophils, or elevated M1 macrophages which, taken together, produce high levels of pro-inflammatory cytokines. In this review, we focused on the function exerted by osteoclasts on osteoblasts and other osteoclasts by means of the release of exosomal microRNAs (miRNAs). Based on a thorough revision, we classified these molecules into three categories according to their function: osteoclast inhibitors (miR-23a, miR-29b, and miR-214), osteoblast inhibitors (miR-22-3p, miR-26a, miR-27a, miR-29a, miR-125b, and miR-146a), and osteoblast enhancers (miR-20a, miR-34a, miR-96, miR-106a, miR-142, miR-199a, miR-324, and miR-486b). Finally, we analyzed potential therapeutic targets of these exosomal miRNAs, such as the use of antagomiRs, blockmiRs, agomiRs and competitive endogenous RNAs (ceRNAs), which are already being tested in murine and ex vivo models of RA. These strategies might have an important role in reestablishing the regulation of osteoclast and osteoblast differentiation making progress in the development of personalized medicine. Full article

(This article belongs to the Special Issue Molecular and Therapeutic Research in Rheumatoid Arthritis)

► Show Figures

Journal Menu

Journal Browser

Molecular and Therapeutic Research in Rheumatoid Arthritis

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Published Papers (9 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI