Immunopathogenesis and Immunotherapeutic Strategies in Rheumatoid Arthritis

2021 ◽  
Vol 16 (8) ◽  
pp. 141-150
Author(s):  
Tooba Qamar ◽  
Sayali Mukherjee
Keyword(s):  
Rheumatoid Arthritis ◽  
Dendritic Cell ◽  
Genetic Risk ◽  
Review Article ◽  
Systemic Autoimmune Disease ◽  
Targeted Therapeutics ◽  
Cell Based Therapy ◽  
Joint Tenderness ◽  
Citrullinated Protein ◽  
Mhc Alleles

Rheumatoid Arthritis (RA) is a systemic autoimmune disease which results from failure of immune tolerance. Autoantibodies like Rheumatoid factor, Anti-Carbamylated Antibodies, Anti-Acetylated and Anti- Citrullinated Protein Antibodies keep on circulating in blood which target self-tissues. The major symptoms of RA are polyarticular inflammation of the synovial membrane, wrists and feet along with the joint tenderness and formation of nodules in the joints. There are many MHC alleles as well as non-MHC immunoregulatory genes which confer the genetic risk in Rheumatoid Arthritis. Immunotherapeutic strategies involved are dendritic cell targeted therapeutics, cell-based therapy and autoantibody-mediated refractoriness. The increase in the mortality rate of RA is recognized widely but different aspects of immunopathogenesis are not explained fully. The aim of the review article is to discuss all the factors that can contribute towards the immunopathogenesis of this disease and to screen out the most prominent immunotherapeutic strategies.

scholarly journals Sequencing of the MHC region defines HLA-DQA1 as the major independent risk for anti-citrullinated protein antibodies (ACPA)-positive rheumatoid arthritis in Han population

2018 ◽  
Author(s):  
Jianping Guo ◽  
Tao Zhang ◽  
Hongzhi Cao ◽  
Xiaowei Li ◽  
Hao Liang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell Activation ◽  
Genetic Risk ◽  
Cell Activation ◽  
Disease Risk ◽  
Interaction Analysis ◽  
Hla Typing ◽  
Han Population ◽  
Hla Dqa1 ◽  
Citrullinated Protein

ABSTRACTThe strong genetic contribution of the major histocompatibility complex (MHC) to rheumatoid arthritis (RA) susceptibility has been generally attributed to HLA-DRB1. However, due to the high linkage disequilibrium in the MHC region, it is difficult to define the ‘real’ or/and additional independent genetic risks using the conventional HLA genotyping or chip-based microarray technology. By the capture sequencing of entire MHC region for discovery and HLA-typing for validation in 2,773 subjects of Han ancestry, we identified HLA-DQα1:160D as the strongest independent genetic risk for anti-citrullinated protein antibodies (ACPA)-positive RA in Han population (P = 6.16 × 10−36, OR=2.29). Further stepwise conditional analysis revealed that DRβ1:37N has an independent protective effect on ACPA–positive RA (P = 5.81 × 10−16, OR=0.49). The DQα1:160 coding allele DQA1*0303 displayed high impact on joint radiographic severity, especially in patients with early disease and smoking (P = 3.02 × 10−5). Interaction analysis by comparative molecular modeling revealed that the negative charge of DQα1:160D stabilizes the dimer of dimers, leading to an increased T cell activation. The electrostatic potential surface analysis indicated that the negative charged DRβ1:37N encoding alleles could bind with epitope P9 arginine, thus may result in a decreased RA susceptibility.In this study, we provide the first evidence that HLA-DQA1, instead of HLA-DRB1, is the strongest and independent genetic risk for ACPA-positive RA in Chinese Han population. Our study also illustrates the value of MHC deep sequencing for fine mapping disease risk variants in the MHC region.

scholarly journals A NEVER-ENDING STORY OF RHEUMATOID ARTHRITIS

2020 ◽  
pp. 10-17
Author(s):  
BALJIT K. ◽  
QADRIE Z. L. ◽  
AMIT B. ◽  
GAUTAM S. P.
Keyword(s):  
Rheumatoid Arthritis ◽  
Early Diagnosis ◽  
Clinical Manifestations ◽  
Joint Stiffness ◽  
Review Article ◽  
Diagnosis And Treatment ◽  
Treat To Target ◽  
The Novel ◽  
Joint Tenderness ◽  
Loss Of Motion

There are distinct Rheumatic disorders, still Rheumatoid arthritis (RA) is believed to be very prevailing. RA is an empathic disorder described over integral redness, constant inflammation, and the existence of auto-antibodies. In RA, inflammation in joints, loss of motion of joint stiffness, joint tenderness are most common in patients. Deformity of joints can be prevented by early diagnosis and treatment. The extremity of the disease can be reduced by combining the drugs and improved weight more profiled than single medication. Treat-to-target progress results in a superior-conclusion in RA, and the ACR, EULAR, and other specialized systems have supported treat-to-target as a basic curative strategy for RA. The novel methods used in RA have upgraded the development of the disorder and maximum people helpful in cancellation of clinical manifestations if the identification of disorder takes place before time. This review article is written after studying most of the journal’s articles, which were published between 1997-2019.

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

2021 ◽  
Vol 2 (1) ◽  
pp. 19-25
Author(s):  
Wang Yu Sung ◽  
Wen Chan Tsai
Keyword(s):  
Rheumatoid Arthritis ◽  
Rheumatoid Factor ◽  
Immune Cells ◽  
Joint Inflammation ◽  
Review Article ◽  
Disease Spectrum ◽  
Inflammatory Autoimmune Disease ◽  
Citrullinated Protein ◽  
Chronic Inflammatory Autoimmune Disease

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.

Helenalin: An Anti-Inflammatory and Anti-Neoplastic Agent: A Review

2020 ◽  
Vol 16 (8) ◽  
pp. 1134-1146
Author(s):  
Priyanka Kriplani ◽  
Kumar Guarve ◽  
Uttam S. Baghel
Keyword(s):  
Rheumatoid Arthritis ◽  
Adverse Effects ◽  
Chronic Conditions ◽  
Review Article ◽  
Google Scholar ◽  
Medical Community ◽  
Inflammatory Agent ◽  
Skin Cancers ◽  
Medicinal Properties ◽  
Anti Inflammatory

Objective: Helenalin is a natural anti-inflammatory agent that is proving its efficacy to treat various medical conditions. Though many plants are proving their effectiveness but their mechanisms are still not well understood. The objective of the review is to summarize various mechanisms of helenalin to treat inflammatory disorders and cancers, adverse effects, and avenues of further research. Methods: Structured research was carried out including Pub med, Science direct Medline, Research Gate and Google Scholar to find all articles published on helenalin. Various keywords used were “helenalin”, “Arnica”, “cancer”, “anti-inflammatory”, “cardiovascular”, “IBD”, “pharmacokinetics” etc. The aim of the review was to find out the problem prevailing in the data published to date which will help the researchers to investigate the molecule clinically. Results: Seventy articles are included in the review. Helenalin is found to cure chronic conditions like rheumatoid arthritis, ulcers and malignancies like stomach, colon, breast, larynx, lung and skin cancers via multiple mechanisms. These diseases do not proceed via a unilateral pathway. So, it can be a useful molecule to treat numerous diseases. Conclusion: This review article will help us to systemically analyze the wealth of information concerning the medicinal properties of helenalin and to recognize the gaps which have vetoed its pervasive application in the medical community.

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

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

ASSOCIATIONS BETWEEN SERUM ANTIBODIES TO PERIODONTAL PATHOGENS AND PRECLINICAL PHASES OF RHEUMATOID ARTHRITIS

Rheumatology ◽  
2021 ◽  
Author(s):  
Daniel Manoil ◽  
Delphine S Courvoisier ◽  
Benoit Gilbert ◽  
Burkhard Möller ◽  
Ulrich A Walker ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Primary Outcome ◽  
Signs And Symptoms ◽  
Serum Levels ◽  
Study Cohort ◽  
Periodontal Pathogens ◽  
Serum Antibodies ◽  
Current Smoking ◽  
Clinical Arthritis ◽  
Citrullinated Protein

Abstract Objectives To examine whether serum antibodies against selected periodontal pathogens are associated with early symptoms of rheumatoid arthritis (RA) development in healthy individuals at risk of developing the disease. Methods Within an ongoing study cohort of first-degree relatives of patients with RA (RA-FDRs), we selected four groups corresponding to specific preclinical phases of RA development (n = 201). (1) RA-FDR controls without signs and symptoms of arthritis nor RA-related autoimmunity (n = 51); (2) RA-FDRs with RA-related autoimmunity (n = 51); (3) RA-FDRs with inflammatory arthralgias without clinical arthritis (n = 51); (4) RA-FDRs who have presented at least one swollen joint (“unclassified arthritis”) (n = 48). Groups were matched for smoking, age, sex and shared epitope status. The primary outcome was IgG serum levels against five selected periodontal pathogens and one commensal oral species assessed using validated-in-house ELISA assays. Associations between IgG measurements and preclinical phases of RA development were examined using Kruskal-Wallis or Mann-Whitney tests (α = 0.05). Results None of the IgGs directed against individual periodontal pathogens significantly differed between the four groups of RA-FDRs. Further analyses of cumulated IgG levels into bacterial clusters representative of periodontal infections, revealed significantly higher IgG titers against periodontopathogens in anti-citrullinated protein antibodies (ACPA)-positive RA-FDRs (p = 0.015). Current smoking displayed a marked trend towards reduced IgG titers against periodontopathogens. Conclusion Our results do not suggest an association between serum IgG titers against individual periodontal pathogens and specific preclinical phases of RA development. However, associations between cumulative IgG titers against periodontopathogens and the presence of ACPAs suggest a synergistic contribution of periodontopathogens to ACPA development.

scholarly journals Association analysis of juvenile idiopathic arthritis genetic susceptibility factors in Estonian patients

2021 ◽  
Author(s):  
Tiit Nikopensius ◽  
Priit Niibo ◽  
Toomas Haller ◽  
Triin Jagomägi ◽  
Ülle Voog-Oras ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Juvenile Idiopathic Arthritis ◽  
Autoimmune Diseases ◽  
Genetic Risk ◽  
Association Studies ◽  
Control Sample ◽  
Case Control ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

Abstract Background Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition of childhood. Genetic association studies have revealed several JIA susceptibility loci with the strongest effect size observed in the human leukocyte antigen (HLA) region. Genome-wide association studies have augmented the number of JIA-associated loci, particularly for non-HLA genes. The aim of this study was to identify new associations at non-HLA loci predisposing to the risk of JIA development in Estonian patients. Methods We performed genome-wide association analyses in an entire JIA case–control sample (All-JIA) and in a case–control sample for oligoarticular JIA, the most prevalent JIA subtype. The entire cohort was genotyped using the Illumina HumanOmniExpress BeadChip arrays. After imputation, 16,583,468 variants were analyzed in 263 cases and 6956 controls. Results We demonstrated nominal evidence of association for 12 novel non-HLA loci not previously implicated in JIA predisposition. We replicated known JIA associations in CLEC16A and VCTN1 regions in the oligoarticular JIA sample. The strongest associations in the All-JIA analysis were identified at PRKG1 (P = 2,54 × 10−6), LTBP1 (P = 9,45 × 10−6), and ELMO1 (P = 1,05 × 10−5). In the oligoarticular JIA analysis, the strongest associations were identified at NFIA (P = 5,05 × 10−6), LTBP1 (P = 9,95 × 10−6), MX1 (P = 1,65 × 10−5), and CD200R1 (P = 2,59 × 10−5). Conclusion This study increases the number of known JIA risk loci and provides additional evidence for the existence of overlapping genetic risk loci between JIA and other autoimmune diseases, particularly rheumatoid arthritis. The reported loci are involved in molecular pathways of immunological relevance and likely represent genomic regions that confer susceptibility to JIA in Estonian patients. Key Points• Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease with heterogeneous presentation and genetic predisposition.• Present genome-wide association study for Estonian JIA patients is first of its kind in Northern and Northeastern Europe.• The results of the present study increase the knowledge about JIA risk loci replicating some previously described associations, so adding weight to their relevance and describing novel loci.• The study provides additional evidence for the existence of overlapping genetic risk loci between JIA and other autoimmune diseases, particularly rheumatoid arthritis.

scholarly journals Blastic plasmacytoid dendritic cell neoplasm with genetic mutations in multiple epigenetic modifiers: a case report

2021 ◽  
Vol 49 (2) ◽  
pp. 030006052098266
Author(s):  
Xinmei Dang ◽  
Di Zhou ◽  
Lingjun Meng ◽  
Lintao Bi
Keyword(s):  
Dendritic Cell ◽  
Plasmacytoid Dendritic Cell ◽  
Genetic Mutations ◽  
Cell Surface Markers ◽  
Targeted Therapeutics ◽  
Genetic Studies ◽  
Clinical Prognosis ◽  
Epigenetic Modifiers ◽  
Cell Neoplasm ◽  
Underlying Pathogenesis

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematodermic malignancy derived from plasmacytoid dendritic cell precursors. Despite advances in our understanding of tumor cell surface markers, the pathogenesis of BPDCN remains largely unknown. No standard or optimal treatments are available for BPDCN, and the prognosis is usually poor. We report herein a case of BPDCN that harbored multiple genetic mutations in epigenetic modifiers such as TET2 and ZRSR2. Genetic studies in patients with BPDCN may provide insights into the underlying pathogenesis, prediction of clinical prognosis, and development of better targeted therapeutics for this rare clinical entity.

scholarly journals AB0006 GENETIC RISK PROFILE FOR PSORIATIC ARTHRITIS PREDISPOSITION IN ITALIAN PATIENTS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1038.1-1038
Author(s):  
M. S. Chimenti ◽  
C. Ciccacci ◽  
G. De Benedittis ◽  
A. Latini ◽  
P. Conigliaro ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Psoriatic Arthritis ◽  
Candidate Genes ◽  
Genetic Risk ◽  
Protective Role ◽  
Risk Profile ◽  
Joint Disease ◽  
Taqman Assay ◽  
Allelic Discrimination ◽  
Risk Alleles

Background:Psoriatic arthritis (PsA) is a chronic inflammatory joint disease typically associated with psoriasis and classified in the group of spondyloarthritis (1). The pathogenesis is based on an interplay of different genes interacting with several environmental factors including stress, trauma, infections, triggering an inflammatory response related to the activation of innate and acquired immunity in different tissues and organs (2). However, the risk for the development of PsA is not clearly understood.Objectives:The aim of this study was to evaluate, in a cohort of Italian PsA out-patients of the Rheumatology Unit of the University of Rome Tor Vergata, the association of genetic variants in candidate genes for PSA susceptibility and their possible contribute in the modulation of clinical and laboratory features.Methods:The genes were selected according to previous studies describing these genes as involved in susceptibility to rheumatoid arthritis (RA) (3), since a common genetic background can be shared between these diseases. Nine SNPs (single nucleotide polymorphism) in eight candidate genes were analysed: STAT4 (rs7574865), TRAF3IP2 (rs33980500), TNFAIP3 (rs6920220 and rs2230926), MIR146A (rs2910164), PSORS1C1 (rs2233945), IL-10 (rs1800872), HCP5 (rs3099844) and ERAP1 (rs27524). Polymorphisms were analysed in 163 consecutive PsA out-patients and 198 healthy controls (HC). Genotyping was performed by allelic discrimination by TaqMan assay. Alleles frequencies differences between cases and controls or between phenotypic groups were compared using Pearson’s χ 2 test.Results:We have observed an association between PSA susceptibility and the variant alleles of STAT4 [OR= 1.60 (1.15-2.21), P= 0.005], TRAF3IP2 [OR= 1.65 (1.01-2.65), P= 0.04], ERAP1 [OR= 1.40 (1.05-1.85), P= 0.02] and TNFAIP3 (rs6920220) [OR= 1.75 (1.19-2.57), P= 0.004]. On the contrary, the variant allele of IL-10 polymorphism seems to play a protective role [OR= 0.74 (1.05-1.85), P= 0.05]. Moreover, in order to define a genetic risk profile, we have counted the total number of risk alleles in each subject, considering as risk alleles the allelic variant of rs7574865 (STAT4), rs33980500 (TRAF3IP2), rs6920220 (TNFAIP3) and rs27524 (ERAP1) SNPs. Then, we have compared the risk allele number distribution between patients and HC (Fig.1). Classes with 3 or more risk alleles are significantly more represented in patients than in HC (OR= 2.03, P=0.004). The risk to develop the disease increases significantly in subjects with at least four risk alleles (OR= 2.96, P=0.002).Figure 1.Number of risk alleles in patients and controls: rs7574865 (STAT4), rs33980500 (TRAF3IP2), rs6920220 (TNFAIP3) and rs27524 (ERAP1) SNPs.Conclusion:We confirm the associations between five SNPs, already studied in RA, and PSA susceptibility, suggesting a common inflammatory pathway in chronic inflammatory rheumatological diseases. Moreover, we show how the genotyping of only few associated SNPs could help to define a genetic risk profile for PSA development.References:[1]Calabresi E, et al. One year in review 2019: psoriatic arthritis. Clin Exp Rheumatol. 2020;38:1046-55.[2]Chimenti MS, Triggianese P, De Martino E, Conigliaro P, Fonti GL, Sunzini F, Caso F, Perricone C, Costa L, Perricone R. An update on pathogenesis of psoriatic arthritis and potential therapeutic targets. Expert Rev Clin Immunol. 2019 Aug;15(8):823-836.[3]Ciccacci C, et al. Polymorphisms in STAT-4, IL-10, PSORS1C1, PTPN2 and MIR146A genes are associated differently with prognostic factors in Italian patients affected by rheumatoid arthritis. Clin Exp Immunol. 2016;186:157-63.Disclosure of Interests:None declared

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