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Journal of Autoimmunity Jun 2020Rheumatoid arthritis is a heterogeneous disease, which can be, based on data combining genetic risk factors and autoantibodies, sub-classified into ACPA-positive and... (Review)
Review
Rheumatoid arthritis is a heterogeneous disease, which can be, based on data combining genetic risk factors and autoantibodies, sub-classified into ACPA-positive and -negative RA. Presence of ACPA and RF as well as rising CRP-levels in some patients years before onset of clinical symptoms indicate that relevant immune responses for RA development are initiated very early. ACPA are highly specific for RA, whereas RF can also be found among healthy (elderly) individuals and patients with other autoimmune diseases or infection. The most important genetic risk factor for RA development, the shared epitope alleles, resides in the MHC class II region. Shared epitope alleles, however, only predispose to the development of ACPA-positive RA. Smoking is thus far the most important environmental risk factor associated with the development of RA. Studies on synovitis have shown the importance not only of adaptive but also of innate immune responses. In summary of the various results from immunological changes in blood and synovial tissue, the extension of the immune response from a diffuse myeloid to a lympho-myeloid inflammation appears to be associated with a more successful therapeutic response to biologics. With respect to advances in synovitis research, new targets for treatment against pathological subsets of immune cells or fibroblasts are already on the horizon. However, alternative strategies involving the microbiome may play an important role as well and research in this field is growing rapidly.
Topics: Animals; Arthritis, Rheumatoid; Autoantibodies; Autoantigens; Autoimmunity; Biomarkers; Disease Susceptibility; Environment; Genetic Predisposition to Disease; Humans; Microbiota; Prognosis; Rheumatoid Factor; Risk Factors
PubMed: 31980337
DOI: 10.1016/j.jaut.2019.102400 -
Clinical and Experimental Rheumatology Mar 2023In the past 20 years, earlier diagnosis and more intensive management have considerably improved the prognosis of rheumatoid arthritis (RA), with milder disease course... (Review)
Review
In the past 20 years, earlier diagnosis and more intensive management have considerably improved the prognosis of rheumatoid arthritis (RA), with milder disease course achieved in particular in seropositive patients. In contrast, seronegative RA has remained largely neglected, and continues to be surrounded by uncertainties regarding its correct diagnosis, clinical phenotype, optimal treatment strategies and relevant outcomes.The purpose of this review is to summarise new insights about the pathogenic, clinical and prognostic peculiarities of seronegative RA that emerged during 2022, and that make this disease subset at least partially different from its seropositive counterpart.
Topics: Humans; Rheumatoid Factor; Arthritis, Rheumatoid; Prognosis; Disease Progression
PubMed: 36971084
DOI: 10.55563/clinexprheumatol/go7g26 -
Current Opinion in Rheumatology May 2020This review is to provide an update on the current understanding of rheumatoid arthritis (RA) development related to disease development prior to the onset clinically... (Review)
Review
PURPOSE OF REVIEW
This review is to provide an update on the current understanding of rheumatoid arthritis (RA) development related to disease development prior to the onset clinically apparent synovitis (i.e. Pre-RA), and opportunities for disease prevention.
RECENT FINDINGS
A growing number of studies have demonstrated that serum elevations of autoantibodies rheumatoid factor, antibodies to citrullinated protein/peptide antigens (ACPAs) and antibodies to other posttranslationally modified proteins (e.g. carbamylated proteins) are highly predictive of future development of inflammatory arthritis/RA during a period that can be termed Pre-RA. Other factors including genetic, environmental, symptoms and imaging findings can also enhance prediction. Moreover, several novel biomarkers and changes in autoantibodies (e.g. glycosylation of variable domains) have been identified in Pre-RA. There has also been growing evidence that initiation and propagation of RA-related autoimmunity during the Pre-RA phase may be related to mucosal processes. The discovery of Pre-RA has also underpinned the development of several clinical prevention trials in RA; specifically, the PRAIRI study demonstrated that a single dose of rituximab can delay the onset of clinically apparent IA in at-risk individuals. Additional studies are evaluating the ability of drugs including abatacept, hydroxychloroquine and methotrexate to prevent or delay future RA.
SUMMARY
The results from ongoing natural history and prevention trials in RA should further inform several critical issues in RA prevention including identification and enrolment of individuals at high-risk of imminent RA, the efficacy, safety and cost-effectiveness of prevention, and potentially the identification of new targets for prevention.
Topics: Arthritis, Rheumatoid; Autoantibodies; Autoimmunity; Biomarkers; Humans; Peptides, Cyclic; Rheumatoid Factor
PubMed: 32205569
DOI: 10.1097/BOR.0000000000000708 -
PloS One 2019Antibodies are important for immunity and exist in several classes (IgM, IgD, IgA, IgG, IgE). They are composed of symmetric dimeric molecules with two antigen binding...
Antibodies are important for immunity and exist in several classes (IgM, IgD, IgA, IgG, IgE). They are composed of symmetric dimeric molecules with two antigen binding regions (Fab) and a constant part (Fc), usually depicted as Y-shaped molecules. Rheumatoid factors found in patients with rheumatoid arthritis are autoantibodies binding to IgG and paradoxically appear to circulate in blood alongside with their antigen (IgG) without reacting with it. Here, it is shown that rheumatoid factors do not react with native IgG in solution, and that their epitopes only become accessible upon certain physico-chemical treatments (e.g. heat treatment at 57 °C), by physical adsorption on a hydrophobic surface or by antigen binding. Moreover, chemical cross-linking in combination with mass spectrometry showed that the native state of IgG is a compact (closed) form and that the Fab parts of IgG shield the Fc region and thereby control access of rheumatoid factors and presumably also some effector functions. It can be inferred that antibody binding to pathogen surfaces induces a conformational change, which exposes the Fc part with its effector sites and rheumatoid factor epitopes. This has strong implications for understanding antibody structure and physiology and necessitates a conceptual reformulation of IgG models.
Topics: Arthritis, Rheumatoid; Epitopes; Humans; Immunoglobulin Fc Fragments; Immunoglobulin G; Protein Structure, Quaternary; Rheumatoid Factor; Structure-Activity Relationship
PubMed: 31199818
DOI: 10.1371/journal.pone.0217624 -
Frontiers in Immunology 2021Measurement of two groups of autoantibodies, rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA) have gained increasing significance in the... (Review)
Review
Measurement of two groups of autoantibodies, rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA) have gained increasing significance in the diagnosis and classification of rheumatoid arthritis (RA) over the last 65 years. Despite this rising importance of autoimmune serology in RA, there is a palpable lack of harmonization between different commercial RF and ACPA tests. While a minimal diagnostic specificity has been defined for RF tests, which almost always are related to an international reference preparation, neither of this applies to ACPA. Especially assays with low diagnostic specificity are associated with very low positive predictive values or post-test probabilities in real world settings. In this review we focus on issues of practical bearing for the clinical physician diagnosing patients who potentially have RA, or treating patients diagnosed with RA. We advocate that all clinically used assays for RF and ACPA should be aligned to a common diagnostic specificity of 98-99% compared to healthy controls. This high and rather narrow interval corresponds to the diagnostic specificity seen for many commercial ACPA tests, and represents a specificity that is higher than what is customary for most RF assays. Data on antibody occurrence harmonized in this way should be accompanied by test result-specific likelihood ratios for the target diagnosis RA on an ordinal or interval scale, which will provide the clinical physician with more granular and richer information than merely relating numerical values to a single cut-off point. As many physicians today are used to evaluate autoantibodies as positive or negative on a nominal scale, the introduction of test result-specific likelihood ratios will require a change in clinical mindset. We also discuss the use of autoantibodies to prognosticate future arthritis development in at-risk patients as well as predict severe disease course and outcome of pharmacological treatment.
Topics: Anti-Citrullinated Protein Antibodies; Arthritis, Rheumatoid; Disease Progression; Humans; Immunoassay; Likelihood Functions; Predictive Value of Tests; Randomized Controlled Trials as Topic; Reproducibility of Results; Rheumatoid Factor
PubMed: 34054878
DOI: 10.3389/fimmu.2021.685312 -
Clinical Reviews in Allergy & Immunology Oct 2022Autoantibodies represent a hallmark of rheumatoid arthritis (RA), with the rheumatoid factor (RF) and antibodies against citrullinated proteins (ACPA) being the most... (Review)
Review
Autoantibodies represent a hallmark of rheumatoid arthritis (RA), with the rheumatoid factor (RF) and antibodies against citrullinated proteins (ACPA) being the most acknowledged ones. RA patients who are positive for RF and/or ACPA ("seropositive") in general display a different etiology and disease course compared to so-called "seronegative" patients. Still, the seronegative patient population is very heterogeneous and not well characterized. Due to the identification of new autoantibodies and advancements in the diagnosis of rheumatic diseases in the last years, the group of seronegative patients is constantly shrinking. Aside from antibodies towards various post-translational modifications, recent studies describe autoantibodies targeting some native proteins, further broadening the spectrum of recognized antigens. Next to the detection of new autoantibody groups, much research has been done to answer the question if and how autoantibodies contribute to the pathogenesis of RA. Since autoantibodies can be detected years prior to RA onset, it is a matter of debate whether their presence alone is sufficient to trigger the disease. Nevertheless, there is gathering evidence of direct autoantibody effector functions, such as stimulation of osteoclastogenesis and synovial fibroblast migration in in vitro experiments. In addition, autoantibody positive patients display a worse clinical course and stronger radiographic progression. In this review, we discuss current findings regarding different autoantibody types, the underlying disease-driving mechanisms, the role of Fab and Fc glycosylation and clinical implications.
Topics: Arthritis, Rheumatoid; Autoantibodies; Humans; Rheumatoid Factor
PubMed: 34495490
DOI: 10.1007/s12016-021-08890-1 -
International Journal of Molecular... Sep 2023Interstitial lung disease (ILD) is one of the most serious extra-articular complications of rheumatoid arthritis (RA), which increases the mortality of RA. Because the... (Review)
Review
Interstitial lung disease (ILD) is one of the most serious extra-articular complications of rheumatoid arthritis (RA), which increases the mortality of RA. Because the pathogenesis of RA-ILD remains poorly understood, appropriate therapeutic strategies and biomarkers have not yet been identified. Thus, the goal of this review was to summarize and analyze the reported data on the etiology and pathogenesis of RA-ILD. The incidence of RA-ILD increases with age, and is also generally higher in men than in women and in patients with specific genetic variations and ethnicity. Lifestyle factors associated with an increased risk of RA-ILD include smoking and exposure to pollutants. The presence of an anti-cyclic citrullinated peptide antibody, high RA disease activity, and rheumatoid factor positivity also increase the risk of RA-ILD. We also explored the roles of biological processes (e.g., fibroblast-myofibroblast transition, epithelial-mesenchymal transition, and immunological processes), signaling pathways (e.g., JAK/STAT and PI3K/Akt), and the histopathology of RA involved in RA-ILD pathogenesis based on published preclinical and clinical models of RA-ILD in animal and human studies.
Topics: Male; Animals; Humans; Female; Phosphatidylinositol 3-Kinases; Arthritis, Rheumatoid; Lung Diseases, Interstitial; Risk Factors; Rheumatoid Factor
PubMed: 37833957
DOI: 10.3390/ijms241914509 -
American Family Physician Apr 2018Rheumatoid arthritis is the most commonly diagnosed systemic inflammatory arthritis, with a lifetime prevalence of up to 1% worldwide. Women, smokers, and those with a...
Rheumatoid arthritis is the most commonly diagnosed systemic inflammatory arthritis, with a lifetime prevalence of up to 1% worldwide. Women, smokers, and those with a family history of the disease are most often affected. Rheumatoid arthritis should be considered if there is at least one joint with definite swelling that is not better explained by another disease. In a patient with inflammatory arthritis, the presence of a rheumatoid factor and/or anti-citrullinated protein antibody, elevated C-reactive protein level, or elevated erythrocyte sedimentation rate is consistent with a diagnosis of rheumatoid arthritis. Rheumatoid arthritis may impact organs other than the joints, including lungs, skin, and eyes. Rapid diagnosis of rheumatoid arthritis allows for earlier treatment with disease-modifying antirheumatic drugs, which is associated with better outcomes. The goal of therapy is to initiate early medical treatment to achieve disease remission or the lowest disease activity possible. Methotrexate is typically the first-line agent for rheumatoid arthritis. Additional disease-modifying antirheumatic drugs or biologic agents should be added if disease activity persists. Comorbid conditions, including hepatitis B or C or tuberculosis infections, must be considered when choosing medical treatments. Although rheumatoid arthritis is often a chronic disease, some patients can taper and discontinue medications and remain in long-term remission.
Topics: Anti-Citrullinated Protein Antibodies; Antirheumatic Agents; Arthritis, Rheumatoid; Blood Sedimentation; C-Reactive Protein; Diagnosis, Differential; Early Diagnosis; Early Medical Intervention; Humans; Patient Acuity; Prevalence; Prognosis; Rheumatoid Factor; Risk Factors
PubMed: 29671563
DOI: No ID Found -
International Journal of Molecular... Jan 2021Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease mainly involving synovial inflammation and articular bone destruction. RA is a heterogeneous disease... (Review)
Review
From Rheumatoid Factor to Anti-Citrullinated Protein Antibodies and Anti-Carbamylated Protein Antibodies for Diagnosis and Prognosis Prediction in Patients with Rheumatoid Arthritis.
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease mainly involving synovial inflammation and articular bone destruction. RA is a heterogeneous disease with diverse clinical presentations, prognoses and therapeutic responses. Following the first discovery of rheumatoid factors (RFs) 80 years ago, the identification of both anti-citrullinated protein antibodies (ACPAs) and anti-carbamylated protein antibodies (anti-CarP Abs) has greatly facilitated approaches toward RA, especially in the fields of early diagnosis and prognosis prediction of the disease. Although these antibodies share many common features and can function synergistically to promote disease progression, they differ mechanistically and have unique clinical relevance. Specifically, these three RA associating auto-antibodies (autoAbs) all precede the development of RA by years. However, while the current evidence suggests a synergic effect of RF and ACPA in predicting the development of RA and an erosive phenotype, controversies exist regarding the additive value of anti-CarP Abs. In the present review, we critically summarize the characteristics of these autoantibodies and focus on their distinct clinical applications in the early identification, clinical manifestations and prognosis prediction of RA. With the advancement of treatment options in the era of biologics, we also discuss the relevance of these autoantibodies in association with RA patient response to therapy.
Topics: Anti-Citrullinated Protein Antibodies; Arthritis, Rheumatoid; Autoantibodies; Autoantigens; Autoimmunity; Biomarkers; Disease Progression; Humans; Immunologic Tests; Prognosis; Rheumatoid Factor
PubMed: 33445768
DOI: 10.3390/ijms22020686 -
Frontiers in Immunology 2023The aim of this study is to evaluate the effectiveness and safety of curcumin in rheumatoid arthritis patients. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The aim of this study is to evaluate the effectiveness and safety of curcumin in rheumatoid arthritis patients.
METHODS
A computerized search from PubMed, Embase, Cochrane Library, and Web of Science databases was performed until 3 March 2023. Literature screening, basic data extraction and risk of bias evaluation were independently performed by two researchers each. The quality evaluation of the literature was performed according to the Cochrane Handbook for Risk of Bias Assessment tool for treatment evaluation.
RESULTS
The current study includes six publications covering 539 rheumatoid arthritis patients. The activity of rheumatoid arthritis was assessed using erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), protein, disease activity score (DAS), rheumatoid factor (RF), Visual Analogue Scale (VAS) pain, tender joint count (TJC) and swollen joint count (SJC). ESR (MD = -29.47, 95% CI [-54.05, -4.88], Z=2.35, P = 0.02), DAS28 (MD = -1.20, 95% CI [-1.85, -0.55], Z=3.62, P = 0.0003), SJC (MD = -5.33, 95% CI [-9.90, -0.76], Z = 2.29, P = 0.02) and TJC (MD = -6.33, 95% CI [-10.86, -1.81], Z = 2.74, P = 0.006) showed significantly change in experimental patients compared with controls.
CONCLUSION
Curcumin is beneficial for rheumatoid arthritis treatment. Inflammation levels and clinical symptoms in patients with rheumatoid arthritis can be improved by curcumin supplementation. Large sample randomized controlled trials on the effects of curcumin on patients with rheumatoid arthritis are needed in the future.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/PROSPERO/, identifier (CRD42022361992).
Topics: Humans; Curcumin; Arthritis, Rheumatoid; Rheumatoid Factor; Inflammation; C-Reactive Protein
PubMed: 37325651
DOI: 10.3389/fimmu.2023.1121655