Rethink about the role of rheumatoid factor and anti-citrullinated protein antibody in rheumatoid arthritis

Abstract Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by joint inflammation and extra-articular manifestations. Many questions in the pathogenesis, clinical manifestation, and disease spectrum are answered after the discovery of the first autoantibody namely rheumatoid factor (RF). The finding of the second autoantibody named anti-citrullinated protein antibody (ACPA), which unearths the importance of protein citrullination process. It further provides the insight how immune cells and complement interact to perpetuate the inflammatory response. These two autoantibodies pave the way for our better understanding of RA. This review article focuses on the history, pathophysiology, and clinical association of these two autoantibodies in RA.

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Familial Risks and Heritability of Rheumatoid Arthritis: Role of Rheumatoid Factor/Anti-Citrullinated Protein Antibody Status, Number and Type of Affected Relatives, Sex, and Age

Arthritis & Rheumatism ◽

10.1002/art.38097 ◽

2013 ◽

Vol 65 (11) ◽

pp. 2773-2782 ◽

Cited By ~ 81

Author(s):

Thomas Frisell ◽

Marie Holmqvist ◽

Henrik Källberg ◽

Lars Klareskog ◽

Lars Alfredsson ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Rheumatoid Factor ◽

Status Number ◽

Citrullinated Protein

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Pathogenic Role of Immune Cells in Rheumatoid Arthritis: Implications in Clinical Treatment and Biomarker Development

Cells ◽

10.3390/cells7100161 ◽

2018 ◽

Vol 7 (10) ◽

pp. 161 ◽

Cited By ~ 49

Author(s):

Hooi-Yeen Yap ◽

Sabrina Tee ◽

Magdelyn Wong ◽

Sook-Khuan Chow ◽

Suat-Cheng Peh ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Immune Cells ◽

Joint Damage ◽

Joint Inflammation ◽

Inflammatory Disorder ◽

Pathogenic Role ◽

Early Detection Of Disease ◽

Symmetric Pattern ◽

Severity Of The Disease

Rheumatoid arthritis (RA) is a chronic, autoimmune, systemic, inflammatory disorder that affects synovial joints, both small and large joints, in a symmetric pattern. This disorder usually does not directly cause death but significantly reduces the quality of life and life expectancy of patients if left untreated. There is no cure for RA but, patients are usually on long-term disease modifying anti-rheumatic drugs (DMARDs) to suppress the joint inflammation, to minimize joint damage, to preserve joint function, and to keep the disease in remission. RA is strongly associated with various immune cells and each of the cell type contributes differently to the disease pathogenesis. Several types of immunomodulatory molecules mainly cytokines secreted from immune cells mediate pathogenesis of RA, hence complicating the disease treatment and management. There are various treatments for RA depending on the severity of the disease and more importantly, the patient’s response towards the given drugs. Early diagnosis of RA and treatment with (DMARDs) are known to significantly improve the treatment outcome of patients. Sensitive biomarkers are crucial in early detection of disease as well as to monitor the disease activity and progress. This review aims to discuss the pathogenic role of various immune cells and immunological molecules in RA. This review also highlights the importance of understanding the immune cells in treating RA and in exploring novel biomarkers.

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A Tale of Two Immune Cells in Rheumatoid Arthritis: The Crosstalk Between Macrophages and T Cells in the Synovium

Frontiers in Immunology ◽

10.3389/fimmu.2021.655477 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jiajie Tu ◽

Wei Huang ◽

Weiwei Zhang ◽

Jiawei Mei ◽

Chen Zhu

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

Immune Cells ◽

Bone Erosion ◽

Joint Inflammation ◽

Cartilage Degradation ◽

Inflammatory Phenotypes ◽

Inflammatory Autoimmune Disease ◽

Cellular Components ◽

Cellular Types

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. Joint inflammation of RA is closely related to infiltration of immune cells, synovium hyperplasia, and superfluous secretion of proinflammatory cytokines, which lead to cartilage degradation and bone erosion. The joint synovium of RA patients contains a variety of immune cellular types, among which monocytes/macrophages and T cells are two essential cellular components. Monocytes/macrophages can recruit and promote the differentiation of T cells into inflammatory phenotypes in RA synovium. Similarly, different subtypes of T cells can recruit monocytes/macrophages and promote osteoblast differentiation and production of inflammatory cytokines. In this review, we will discuss how T cell-monocyte/macrophage interactions promote the development of RA, which will provide new perspectives on RA pathogenesis and the development of targeted therapy.

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POS0441 DEVELOPMENT OF RHEUMATOID ARTHRITIS AMONG ANTI-CITRULLINATED PROTEIN ANTIBODIES POSITIVE ASYMPTOMATIC INDIVIDUALS: A PROSPECTIVE OBSERVATIONAL STUDY

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.344 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 449.1-449

Author(s):

S. Mizuki ◽

K. Horie ◽

K. Imabayashi ◽

K. Mishima ◽

K. Oryoji

Keyword(s):

Rheumatoid Arthritis ◽

Risk Factors ◽

Observational Study ◽

Rheumatoid Factor ◽

Prospective Observational Study ◽

Enzyme Linked Immunosorbent Assay ◽

P Value ◽

Healthy Population ◽

Asymptomatic Individuals ◽

Citrullinated Protein

Background:In the idividuals with genetic and enviromental risk factors, immune events at mucosal surfaces occur and may precede systemic autoimmunity. Anti-citrullinated protein antibodies (ACPA) are present in the serum for an average of 3-5 years prior to the onset of rheumatoid arthritis (RA) during an asymptomatic period. In ACPA-positivite individuals, the additional presence of RA-related risk factors appears to add significant power for the development of RA. To date, there have been few reports in which clinical courses of ACPA-positive asymptomatic individuals were investigated prospectively.Objectives:To observe the clinical time course of ACPA-positive healthy population for the development of RA.Methods:Healthy volunteers without joint pain or stiffness, who attended the comprehensive health screening of our hospital, were enrolled in this prospective observational study. The serum ACPA levels were quantified by Ig-G anti-cyclic citrullinated peptide enzyme-linked immunosorbent assay with levels > 4.4 U/mL considered positive. ACPA-positive subjects were followed by rheumatologists of our department clinically or a questionnaire sent by mail for screening to detect arthritis.Results:5,971 healthy individuals without joint symptons were included. Ninty-two (1.5%) were positive for ACPA. Of these, 19 (20.7%) developed RA and two were suspected as RA by mail questionnaire. Their average age were 58-years, and women were 68%. The average duration between the date of serum sampling and diagnosis was 10.7 months. ACPA-positive individuals who developed to RA had higher serum ACPA and Ig-M rheumatoid factor levels than ACPA-positive individuals who did not (P value by Mann-Whitney U test: 0.002, 0.005, respectively).Conclusion:Among ACPA-positive asymptomatic individuals, 20% developed RA. The higher titer of ACPA and Ig-M rheumatoid factor levels are risk factors for devoloping RA.Disclosure of Interests:None declared

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Insights in the Role of Lipids, Oxidative Stress and Inflammation in Rheumatoid Arthritis Unveiled by New Trends in Lipidomic Investigations

Antioxidants ◽

10.3390/antiox10010045 ◽

2021 ◽

Vol 10 (1) ◽

pp. 45

Author(s):

Helena Beatriz Ferreira ◽

Tânia Melo ◽

Artur Paiva ◽

Maria do Rosário Domingues

Keyword(s):

Rheumatoid Arthritis ◽

Oxidative Stress ◽

Lipid Peroxidation ◽

Lipid Profile ◽

Inflammatory Responses ◽

Molecular Level ◽

Lipid Hydroperoxides ◽

Lipid Species ◽

Inflammatory Autoimmune Disease

Rheumatoid arthritis (RA) is a highly debilitating chronic inflammatory autoimmune disease most prevalent in women. The true etiology of this disease is complex, multifactorial, and is yet to be completely elucidated. However, oxidative stress and lipid peroxidation are associated with the development and pathogenesis of RA. In this case, oxidative damage biomarkers have been found to be significantly higher in RA patients, associated with the oxidation of biomolecules and the stimulation of inflammatory responses. Lipid peroxidation is one of the major consequences of oxidative stress, with the formation of deleterious lipid hydroperoxides and electrophilic reactive lipid species. Additionally, changes in the lipoprotein profile seem to be common in RA, contributing to cardiovascular diseases and a chronic inflammatory environment. Nevertheless, changes in the lipid profile at a molecular level in RA are still poorly understood. Therefore, the goal of this review was to gather all the information regarding lipid alterations in RA analyzed by mass spectrometry. Studies on the variation of lipid profile in RA using lipidomics showed that fatty acid and phospholipid metabolisms, especially in phosphatidylcholine and phosphatidylethanolamine, are affected in this disease. These promising results could lead to the discovery of new diagnostic lipid biomarkers for early diagnosis of RA and targets for personalized medicine.

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Prostacyclin-IP signaling and prostaglandin E2-EP2/EP4 signaling both mediate joint inflammation in mouse collagen-induced arthritis

Journal of Experimental Medicine ◽

10.1084/jem.20051310 ◽

2006 ◽

Vol 203 (2) ◽

pp. 325-335 ◽

Cited By ~ 142

Author(s):

Tetsuya Honda ◽

Eri Segi-Nishida ◽

Yoshiki Miyachi ◽

Shuh Narumiya

Keyword(s):

Rheumatoid Arthritis ◽

Synovial Fluid ◽

Joint Inflammation ◽

Synovial Fibroblasts ◽

The Other ◽

Receptor Subtype ◽

Significant Suppression ◽

Wild Type ◽

Collagen Induced Arthritis

Prostaglandin (PG)I2 (prostacyclin [PGI]) and PGE2 are abundantly present in the synovial fluid of rheumatoid arthritis (RA) patients. Although the role of PGE2 in RA has been well studied, how much PGI2 contributes to RA is little known. To examine this issue, we backcrossed mice lacking the PGI receptor (IP) to the DBA/1J strain and subjected them to collagen-induced arthritis (CIA). IP-deficient (IP−/−) mice exhibited significant reduction in arthritic scores compared with wild-type (WT) mice, despite anti-collagen antibody production and complement activation similar to WT mice. IP−/− mice also showed significant reduction in contents of proinflammatory cytokines, such as interleukin (IL)-6 in arthritic paws. Consistently, the addition of an IP agonist to cultured synovial fibroblasts significantly enhanced IL-6 production and induced expression of other arthritis-related genes. On the other hand, loss or inhibition of each PGE receptor subtype alone did not affect elicitation of inflammation in CIA. However, a partial but significant suppression of CIA was achieved by the combined inhibition of EP2 and EP4. Our results show significant roles of both PGI2-IP and PGE2-EP2/EP4 signaling in the development of CIA, and suggest that inhibition of PGE2 synthesis alone may not be sufficient for suppression of RA symptoms.

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Comparative Utility of Anti-Citrullinated Protein Antibodies Verses Rheumatoid Factor in the Management of Rheumatoid Arthritis

MOJ Orthopedics & Rheumatology ◽

10.15406/mojor.2017.08.00323 ◽

2017 ◽

Vol 8 (4) ◽

Author(s):

Anjali Patwardhan

Keyword(s):

Rheumatoid Arthritis ◽

Rheumatoid Factor ◽

Citrullinated Protein

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A spontaneous rheumatoid arthritis-like disease in MRL/l mice.

Journal of Experimental Medicine ◽

10.1084/jem.155.6.1690 ◽

1982 ◽

Vol 155 (6) ◽

pp. 1690-1701 ◽

Cited By ~ 224

Author(s):

L Hang ◽

A N Theofilopoulos ◽

F J Dixon

Keyword(s):

Rheumatoid Arthritis ◽

Rheumatoid Factor ◽

Joint Inflammation ◽

Close Correlation ◽

Human Rheumatoid Arthritis ◽

Igm Rheumatoid Factor ◽

Joint Pathology ◽

Old Females

MRL/l mice spontaneously develop an arthritis very similar in many respects to human rheumatoid arthritis. A detailed morphologic and serologic analysis of this disease revealed the following: (a) a 75% incidence of synovial and periarticular inflammation, very similar to human rheumatoid arthritis, in 5-6 mo-old females, (b) close associations between presence of joint inflammation and subsynovial and/or periarticular vasculitis, and (c) a close correlation between presence of circulating IgM rheumatoid factor (RF) and demonstrable synovial and/or joint pathology, i.e., 95% of mice with significant levels of IgMRF had synovitis and/or arthritis.

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