The present study aimed to determine the association of HLA-DRB1/-DQB1 alleles with response to treatment and anti-citrullinated peptide antibody (ACPA) status in Iranian rheumatoid arthritis (RA) patients. A total of 167 RA patients, including 114 good responders (GRs) and 53 poor responders (PRs) as well as 330 ethnic-matched healthy controls, participated in this study. Disease activity and treatment response were assessed using the Disease Activity Score 28-joint (DAS28) scores during the 9-month post-treatment. HLA-DRB1/-DQB1 alleles were identified using polymerase chain reaction with a sequence-specific primers (PCR-SSP) method and compared between the study groups. Of the patients, 106 (63.5%) were ACPA-positive, 88 (52.7%) human leucocyte antigen (HLA)-shared epitope (SE)-positive, 64 (38.3%) ACPA+SE+ and 37 (22.2%) ACPA-SE-. HLA-SE alleles were significantly more frequent in patients (p = 3.2e - 05), in PR versus GR patients (p = 0.01) and in ACPA+ versus ACPA- patients (p = 0.009). PR patients had a higher prevalence of ACPA+SE+ compared to GR patients (p = 0.02). Higher frequencies of DRB1*04:02 (pc = 0.03), *04:04 (pc = 0.007), *04:05 (pc = 5.0e - 05), *10:01 (pc = 1.0e - 04), DQB1*03:02 (pc = 0.002) and *05:01 (pc = 0.002) alleles, and lower frequencies of DRB1*04:01 (pc = 0.007), *11:01 (pc = 0.03), *13:01 (pc = 0.03) and DQB1*06:03 (pc = 0.03) alleles were observed in patients compared to healthy controls. These findings suggest a relationship between HLA-SE alleles and ACPA development and a potential link between HLA-SE/non-SE alleles and therapeutic responses in RA patients.

Autoimmune rheumatic diseases (ARDs) are a heterogeneous group of conditions characterized by excessive and misdirected immune responses against the body's own musculoskeletal tissues. Their exact aetiology remains unclear, with genetic, demographic, behavioural and environmental factors implicated in disease onset. One prominent hypothesis for the initial breach of immune tolerance (leading to autoimmunity) is molecular mimicry, which describes structural or sequence similarities between human and microbial proteins (mimotopes). This similarity can lead to cross-reactive antibodies and T-cell receptors, resulting in an immune response against autoantigens. Both commensal microbes in the human microbiome and pathogens can trigger molecular mimicry, thereby potentially contributing to the onset of ARDs. In this review, we focus on the role of molecular mimicry in the onset of rheumatoid arthritis and systemic lupus erythematosus. Moreover, implications of molecular mimicry are also briefly discussed for ankylosing spondylitis, systemic sclerosis and myositis.

Noncoding variants are critical to our understanding of the genetic basis of diseases and disorders such as rheumatoid arthritis (RA). While genome-wide association studies have identified regions of the genome associated with disease, functional studies are still lagging that can identify potentially causative variants.

In order to functionally fine-map RA-associated variants, we identified variants at enhancers marked in primary activated T helper cells and conducted massively parallel reporter assay in these cells.

We found that combinations of functional variant genotypes are often exclusive to patients with RA. We leveraged 3-dimensional genome architecture and expression quantitative trait loci data to identify target genes of enhancers exhibiting allelic differences in activity. We confirmed enhancer activity and target gene interactions by Clustered Regularly Interpaced Short Palindromic Repeats Cas9 (CRISPR-Cas9) deletion in primary T cells.

The identification of functional enhancer variants suggests possible causal variants, and their target genes reveal known and novel genes as likely drivers of RA, as well as a means for therapeutic intervention.

Nephrotic syndrome is the most common glomerular disease in children, and various hypotheses regarding its etiology have been proposed, primarily focusing on immune-related mechanisms. Nephrotic syndrome can manifest as a monogenic disease caused by deleterious variants in genes such as NPHS1, which encodes nephrin. In steroid-sensitive nephrotic syndrome, HLA class II and immune-related genes have been identified as susceptibility genes. Moreover, NPHS1 is a susceptibility gene for steroid-sensitive nephrotic syndrome in patients from East Asian populations. Anti-nephrin antibodies have been identified as a significant factor in the pathogenesis of nephrotic syndrome. These discoveries have substantially advanced our understanding of nephrotic syndrome. However, the mechanisms underlying the production of anti-nephrin antibodies and their association with genetic backgrounds have remained unclear and warrant further investigation.

The DRB1 locus is strongly associated with both susceptibility and resistance to rheumatoid arthritis (RA). DRB1 alleles encoding the VKA or VRA epitope in positions 11, 71, and 74 confer the highest risk of developing RA, whereas the allele encoding VEA is protective. We therefore investigated the feasibility of creating antigen-specific tolerance without inducing alloreactivity by replacing lysine with glutamic acid at position 71 in DRβ1*04:01.

Individual DRB1 alleles and the DRB1*04:01K71E allele were cloned into T2 cell lines to measure binding of biotinylated peptides. Transgenic animals expressing DRB1*04:01, DRB1*01:01, or DRB1*04:01K71E were injected with collagen to measure T cell proliferation. Skin and bone marrow transplants between DRB1*04:01K71E and DRB1*04:01 mice were performed to determine if the single amino acid change at position 71 would be recognized as foreign. DRB1*04:01 mice transplanted with DRB1*04:01K71E bone marrow were injected with collagen to test if resistance to collagen sensitization could be transferred.

Replacing lysine (K) at position 71 in DRβ1*04:01 with glutamic acid (E) blocked collagen peptide binding and rendered the DRB1*04:01K71E mice resistant to collagen sensitization. Skin and bone marrow transplants from DRB1*04:01K71E mice were not rejected by DRB1*04:01 mice, suggesting the single E71 difference was not recognized as allogeneic. Bone marrow from DRB1*04:01K71E mice adoptively transferred antigen-specific tolerance to collagen to DRB1*04:01 mice.

These studies demonstrate that editing a single amino acid in DRβ1*04:01 blocks collagen peptide binding without inducing alloreactivity and could therefore represent a gene therapy approach to induce antigen-specific passive tolerance.

Rheumatoid arthritis (RA) has been considered an independent risk factor for cardiovascular disease (CVD), where RA and CVD later manifest following genetic predisposition and an extended preclinical phase.TheHLA-DRB1Shared Epitope (SE)allelespredispose for RA andare associated withhigherrisk of CV mortality in RA patients, but have not been evaluated in a community-living population.Thus, we evaluated whetherHLA-DRB1 (SE) alleleswereassociated with subclinical CVD, CV events, and mortality in the Multi-Ethnic Study of Atherosclerosis (MESA).

We performed HLA typing in 955 MESA participants and evaluated associations of SE alleles with coronary artery calcium (CAC) and abdominal aortic calcium (AAC); risk difference for CAC, AAC severity, and carotid intima media thickness (cIMT); and associations of SE with all-cause mortality, CVD and non-CVD death, and CV events.

Among 955 participants, 30 % were HLA-DRB1 SE positive. SE positivity was not significantly associated with higher risk of CAC, AAC, cIMT, CV events, or mortality. DRB1*10:01 demonstrated 2.63-fold higher risk for CAC (95 % CI 1.17-5.99); DRB1*14:02 demonstrated 42 % higher risk for AAC (95 % CI 1.17-1.74); and DRB1*04:05 demonstrated 24 % lower risk for AAC (95 % CI 0.58-0.99).

In a multi-ethnic community-living population, HLA-DRB1 SE alleles were not associated with subclinical CVD, CV events, or mortality. However, individual allele-associations with subclinical CVD suggested variability in risk.

Inflammation of the joints, bone erosion, and cartilage destruction are the main characteristics of rheumatoid arthritis (RA) which causes joint malfunction, structural distortion, and long-term impairment of function. According to various studies, RA affects 0.1-2.0% of people globally. It is unclear what causes RA, but multiple pathways have been associated with its pathophysiology. Non-steroidal anti-inflammatory drugs; NSAIDs (diclofenac, celecoxib, and ibuprofen), disease-modifying antirheumatic drugs; DMARDs (methotrexate, azathioprine, and cyclosporine), immunological compounds (rituximab, anakinra, and infliximab), and immune suppressants are the currently available options. However, they are associated with major side effects, like hypertension, hepatotoxicity, gastric ulcers, and kidney dysfunction which results in their limited use. To treat RA effectively, there is an urgent need for treatment options that offer minimal side effects. The dietary polyphenols have therapeutic effects on RA based on their antioxidant, apoptotic, anti-inflammatory, immunosuppressive, and immunomodulatory characteristics. At the molecular level, interleukin (IL)-6, mitogen-activated protein kinase (MAPK), tumor necrosis factor-alpha (TNF-alpha), interleukin 1b, c-Jun N-terminal kinase (JNK), and nuclear factor k light-chain-enhancer of activated B-cell (NF-kB) pathways play a critical role in modulation. Various polyphenolic compounds have been studied for their potential efficacy against RA, including genistein, resveratrol, carnosol, curcumin, epigallocatechin gallate, kaempferol, and hydroxyl tyrosol. However, it is noted that most of the studies are investigated on animal models of RA. The present review article discusses the underlying mechanisms that lead to RA and explores the promising role of polyphenols as potential therapeutic agents.

Cytomegalovirus (CMV) is a common β-herpes virus worldwide with an estimated seroprevalence among the general population of 83%. Primary infection is usually benign; however, CMV can cause severe morbidity in newborns in whom it is acquired congenitally, as well as immunocompromised individuals. Understanding the role of immunogenetic variation in risk for CMV infection can provide insight into the immune control of this ubiquitous pathogen. Here, we evaluated the association of human leukocyte antigen (HLA) genetic variation with CMV seropositivity in more than 518,000 individuals from two independent cohorts. We found three HLA class II alleles (HLA-DRB1∗04:03 with risk; HLA-DRB1∗01:03 and HLA-DRB1∗07:01 with protection) to be significantly associated with CMV serostatus across both cohorts and in multiple population subgroups. Interestingly, HLA-DRB1∗04:03 and HLA-DRB1∗01:03, the alleles with the strongest observed effect, are relatively rare, while common homologous alleles show no association with CMV. We show that these differences are mediated by changes in charge and volume to two key pockets in the peptide-binding groove of the HLA molecule, providing a structural basis for the observed association. Our results provide population-scale evidence for the role of HLA in mediating infection with this ubiquitous human virus and a framework for understanding immunological conditions necessary for efficient viral control.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterized by the disruption of the alveolar and interstitial architecture due to extracellular matrix deposition. Emerging evidence suggests that genetic susceptibility plays a crucial role in IPF development. This study explores the role of human leukocyte antigen (HLA) alleles and haplotypes in IPF susceptibility and progression within the genetically distinct Sardinian population. Genotypic data were analyzed for associations with disease onset and progression, focusing on allele and haplotype frequencies in patients exhibiting slow (S) or rapid (R) progression. While no significant differences in HLA allele frequencies were observed between IPF patients and controls, the HLA-DRB1*04:05 allele and the extended haplotype (HLA-A*30:02, B*18:01, C*05:01, DQA1*05:01, DQB1*02:01, DRB1*03:01) were associated with a slower disease progression and improved survival (log-rank = 0.032 and 0.01, respectively). At 36 months, carriers of these variants demonstrated significantly better pulmonary function, measured with single-breath carbon monoxide diffusing capacity (DLCO%p) (p = 0.005 and 0.02, respectively). Multivariate analysis confirmed these findings as being independent of confounding factors. These results highlight the impact of HLA alleles and haplotypes on IPF outcomes and underscore the potential of the Sardinian genetic landscape to illuminate immunological mechanisms, paving the way for predictive biomarkers and personalized therapies.

Cell death contributes to the pathogenesis of rheumatoid arthritis (RA) through various pathways. Disulfidptosis is a recently discovered novel form of cell death characterized by the abnormal accumulation of intracellular disulfide bonds. It remains unclear for the association between RA and disulfidptosis.

A comprehensive analysis of three GEO datasets was presented in this study. First, the analysis involved the use of weighted gene co-expression network analysis (WGCNA) and differential analysis and were employed to identify the key module genes related to RA and disulfidptosis-related genes. The machine learning algorithms were used to identify the hub genes. Second, a diagnostic model was constructed for RA based on the hub genes. The nomogram and receiver operating characteristic (ROC) curves were utilized to evaluate the diagnostic value of the model. Third, two RA subtypes were identified based on hub genes by using consensus clustering analysis. Then, the disease activity scores, clinical markers, and immune cells were compared between the two RA subgroups. Finally, the differential expression of hub genes was validated between healthy controls and RA patients by qPCR.

Four hub genes (KLHL2, POLK, CLEC4D, NXT2) were identified. The expression of the four hub genes was verified to be significantly higher in RA patients compared with healthy controls. The superior diagnostic value of the model was validated, which demonstrated that the model outperforms each hub gene individually. Two subtypes of RA were determined. Patients in cluster A exhibited relatively lower levels of DAS28-CRP, DAS28-ESR, CDAI, SDAI, RF, CRP, and MMP3. In contrast, patients in cluster B had significantly higher levels of the above markers.

Four hub genes were identified to provide unique insights into the role of disulfidptosis in RA. Additionally, a promising diagnosis model and patient stratification were established based on the hub genes to assess the risk of RA onset and RA disease activity.

Rheumatic diseases encompass a wide range of autoimmune and inflammatory disorders, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriatic arthritis (PsA), and systemic sclerosis (SSc). These conditions often result in chronic pain, disability, and reduced quality of life, with unpredictable disease courses that may lead to joint destruction, organ damage, or systemic complications. Biomarkers, defined as measurable indicators of biological processes or conditions, have the potential to transform clinical practice by improving disease diagnosis, monitoring, prognosis, and treatment decisions. While significant strides have been made in identifying and validating biomarkers in rheumatic diseases, challenges remain in their standardization, clinical utility, and integration into routine practice. This review provides an overview of the current state of biomarkers in rheumatic diseases, their roles in clinical settings, and the emerging advancements in the field.

To evaluate erosive pathological lesions on a skeleton from medieval Transylvania.

A skeleton from a Székely archaeological site in Transylvania was examined and radiocarbon dated to Cal 1300 CE - 1415 CE.

The skeletal remains were examined macroscopically and with radiographic imaging. A differential diagnosis was conducted following established protocols.

The individual was estimated to be a probable adult female. Periarticular erosive lesions involving multiple synovial joints, particularly on the small joints of the hands and feet, were observed.

A differential diagnosis identifies lesions characteristic of rheumatoid arthritis dating prior to the mid-15th century.

The significance of this diagnosis is great since researchers debate the antiquity and spread of rheumatoid arthritis. Some researchers hypothesize that RA originated in the Americas and spread to Europe after the mid-15th century. However, this study asserts that RA existed in Europe prior to European colonization of the Americas.

Only 30-40 % of the skeletal material was excavated, potentially impacting the differential diagnosis.

This case encourages researchers to explore the presence of RA in other medieval groups within and beyond Transylvania as a means to reconstruct the antiquity and geographical distribution of the condition.

Rheumatoid arthritis (RA) is an autoimmune disorder that impacts around 1% of the global population. Up to 20% of people become disabled within a year, which has a severely negative impact on their health and quality of life. RA has a complicated pathogenic mechanism, which initially affects small joints and progresses to larger ones over time. It can damage the skin, eyes, heart, kidney, and lung. Oral medications, intra-articular injections, and other treatments are being used; nevertheless, they have drawbacks, including low bioavailability, numerous adverse effects, and poor patient compliance. Dissolving microneedles (DMNs) are a safe and painless method for transdermal drug delivery, achieved through their ability to physically penetrate the epidermal barrier. They enable targeted drug delivery, significantly enhancing the bioavailability of medications and improving patient compliance. DMNs are particularly effective in delivering both lipophilic and high molecular weight biomolecules. The superior bioavailability of DMNs is demonstrated by the fact that low-dose DMN administration can achieve up to 25.8 times higher bioavailability compared to oral administration. This paper provides a comprehensive review of recent advancements in the use of DMNs for RA treatment, encompassing various materials (such as hyaluronic acid, chitosan, etc.), fabrication techniques (such as the two-step casting method, photopolymerization), and performance evaluations (including morphology, mechanical properties, skin penetration capability, solubility, and pharmacodynamics). Additionally, a thorough safety assessment has been conducted, revealing that DMNs cause minimal skin irritation and exhibit low cytotoxicity, ensuring their safety for clinical application. DMNs provide a highly effective and promising alternative to oral and injectable drug delivery systems, offering a novel therapeutic approach for RA patients that significantly improves treatment outcomes and enhances their quality of life.

Rheumatoid arthritis (RA) is a prevalent autoimmune disorder marked by chronic inflammatory arthritis and systemic effects. The etiology of RA is complex, involving genetic factors like HLA-DR4 and HLA-DR1, as well as environmental influences, particularly smoking, which heightens disease risk. Affecting approximately 1% of the global population, RA is associated with considerable morbidity and mortality, with its prevalence expected to increase due to demographic shifts, especially in certain regions. RA symptoms commonly manifest between ages 35 and 60 but can also affect children under 16 in cases of juvenile RA. Symptoms include prolonged joint stiffness, pain, fatigue, and, in advanced cases, joint deformities. Current treatment approaches involve disease-modifying antirheumatic drugs, biologics, and glucocorticoids to manage symptoms and slow disease progression, though these treatments often present limitations due to adverse effects and varied patient response. The identification of genetic markers, such as HLA-DRB1 and PTPN22, supports the growing emphasis on personalized treatment strategies that account for genetic and lifestyle factors. Non-pharmacological approaches - diet adjustments, physical activity, and stress management - are increasingly valued for their complementary role in RA management. Lifestyle interventions, including whole-food, plant-based diets and physical therapy, show promise in reducing inflammation and improving joint function. Technological advancements, like telemedicine, mobile health applications, and artificial intelligence, are enhancing RA diagnosis and treatment, making care more precise and accessible. Despite these advancements, RA remains incurable, necessitating continued research into novel therapeutic targets and approaches. A comprehensive, patient-centered approach that integrates lifestyle modifications, preventive strategies, and innovative treatments is essential for improving RA management and patient outcomes.

Rheumatoid arthritis (RA) is an autoimmune condition that predominantly affects synovial joints, manifesting with joint swelling, pain, and stiffness. In advanced stages, unchecked inflammation can inflict damage on bone and cartilage, resulting in disabilities and deformities of the joints. Additionally, systemic and extra-articular complications may arise due to the consequences of uncontrolled inflammation. Helicobacter pylori (H. pylori) is one of the most prevalent chronic bacterial infections in humans. This microorganism is a spiral-shaped, flagellated, microaerophilic gram-negative bacterium. Prolonged exposure leads to the activation of the immune system, with infected gastric mucosa epithelial cells continuously producing cytokines. This production, in turn, triggers the generation of antibodies as well as T Helper 1 and T Helper 2 effector T cells. The persistent antigenic stimulation resulting from H. pylori infection could lead to the progression of autoimmune diseases. Numerous clinical and pharmacological trials have illustrated the efficacy of traditional Chinese medicine against H. pylori. This review aims to delve into the connection between H. pylori and rheumatoid arthritis so as understand the pathogenesis. The concluding section of this review explores the interplay of Chinese medicine and Helicobacter pylori concerning rheumatoid arthritis.

Rheumatoid arthritis (RA) is associated with high-risk HLA class II alleles known as the "RA shared epitope." Among prevalent shared epitope alleles, study of DRB1*04:04 has been limited. To define relevant epitopes, we identified citrullinated peptide sequences from synovial antigens that were predicted to bind to HLA-DRB1*04:04 and utilized a systematic approach to confirm their binding and assess their recognition by CD4 T cells. After confirming the immunogenicity of 13 peptides derived from aggrecan, cartilage intermediate layer protein (CILP), α-enolase, vimentin, and fibrinogen, we assessed their recognition by T cells from a synovial tissue sample, observing measurable responses to 8 of the 13 peptides. We then implemented a multicolor tetramer panel to evaluate the frequency and phenotype of antigen-specific CD4 T cells in individuals with anti-citrullinated protein antibody-positive RA and controls. In subjects with RA, CILP-specific T-cell frequencies were significantly higher than those of other antigens. The surface phenotypes exhibited by antigen-specific T cells were heterogeneous, but Th1-like and Th2-like cells predominated. Stratifying based on disease status and activity, antigen-specific T cells were more frequent and most strongly polarized in RA subjects with high disease activity. In total, these findings identify novel citrullinated epitopes that can be used to interrogate antigen-specific CD4 T cells and show that antigen-specific T-cell frequency is elevated in subjects with high disease activity.

Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. Although RA is chiefly associated with HLA class II, nevertheless some HLA class I associations have also been observed. These molecules present antigenic peptides to CD8+ T lymphocytes and natural killer cells. HLA-I molecules bind their peptide cargo (8-10 amino acids long) in the endoplasmic reticulum. Peptides longer than 10 amino acids are trimmed by the endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 to fit the peptide binding groove of the HLA-I molecule. Here, we investigated the possible association of ERAP1 and ERAP2 polymorphisms with RA, and also any possible correlation between serum levels of the ERAP2 protein with disease severity.

We used Real-Time PCR to genotype ERAP1 and ERAP2 and ELISA test to detect ERAP2 protein.

We found significant associations of ERAP1 rs30187, rs27044, and rs26618, as well as ERAP2 rs2248374, with susceptibility to RA. ERAP1 rs26653 and ERAP2 rs2248374 were also associated with the Disease Activity Score (DAS28), and some polymorphisms were also associated with anti-citrullinated protein or anti-mutated citrullinated vimentin antibodies. RA patients secreted higher concentrations of ERAP2 than controls. Patients with mild disease activity (DAS28 < 3.2) released a concentration of ERAP2 four times lower than that of patients with severe disease activity (DAS28 > 5.1). We detected a higher level of ERAP2 in rheumatoid factor (RF)-positive patients than in RF-negative patients. ERAP2 concentration above 5.85 ng/mL indicated a severe phase of RA.

Some ERAP1 and ERAP2 polymorphisms seem to be related to susceptibility to RA or the severity of the disease. The ERAP2 protein tested in serum could be a valuable biomarker of RA severity.

The mucosal origin hypothesis in rheumatoid arthritis (RA) posits that inhalant exposures, such as cigarette smoke and crystalline silica (c-silica), trigger immune responses contributing to disease onset. Despite the established risk posed by these exposures, the mechanistic link between inhalants, lung inflammation, and inflammatory arthritis remains poorly understood, partly from the lack of a suitable experimental model. As c-silica accelerates autoimmune phenotypes in lupus models and is a recognized risk factor for several autoimmune diseases, we investigated whether c-silica exposure could induce RA-like inflammatory arthritis in mice.

Two arthritis-prone mouse strains, BXD2/TyJ and HLA-DR4 transgenic (DR4-Tg), were exposed to c-silica or PBS via oropharyngeal instillation. Arthritis was evaluated by clinical signs and histopathology. Autoimmunity was further evaluated by serological analysis, including autoantibodies and cytokines and chemokines. Lung pathology was evaluated by histopathology and immunofluorescent staining for lymphocyte and macrophages.

C-silica exposure induced chronic pulmonary silicosis in all mice. In BXD2 mice, this was associated with rapid arthritis development, marked by synovitis, bone erosion, and elevated serum autoantibody levels targeting various antigens, including snRNP and citrullinated protein. Additionally, BXD2 mice exhibited inducible bronchus-associated lymphoid tissue (iBALT) formation and elevated autoantibodies in bronchoalveolar lavage fluid (BALF). Conversely, DR4-Tg mice had no significant arthritis, negligible autoantibody responses, and milder lung inflammation lacking iBALT.

We introduce a novel model of c-silica-mediated inflammatory arthritis, creating a novel platform to unravel the molecular and cellular underpinnings of RA and advance understanding of the mucosal origin hypothesis.

Polymorphism and mutations of human leukocyte antigens (HLAs) and calreticulin are risk factors for uveitis. Here, we sought to determine the therapeutic effects of Clarstatin, a cyclic peptide antagonist of the HLA shared-epitope-calreticulin interaction, in experimental autoimmune uveitis (EAU) models.

Mice were injected with Clarstatin intraperitoneally and its effect was compared to that of corticosteroid. EAU was evaluated clinically and histologically. Ocular infiltration of CD45+ hematopoietic cells and splenocyte CD4+ expression were determined using immunofluorescence and flow cytometry (fluorescence-activated cell sorting [FACS]). ELISA was used to measure the ocular level of the proinflammatory cytokines.

Clarstatin significantly ameliorated the severity of EAU in the C57BL/6J mild and the B10.RIII severe mice models. There was a significant dose and time-dependent decrease, in the range of 30% to 80%, in the clinical score (P < 0.05), histological score (P < 0.05), and number of retinal and spleen CD45+ cells (P < 0.05 and P < 0.001, respectively), a comparable effect to corticosteroid. Clarstatin reduced the intraocular levels of interleukin 6 (IL-6; P < 0.05) and monocyte chemoattractant protein-1 (MCP-1; P < 0.01) by 41% and 59%, respectively.

Systemic delivery of Clarstatin significantly improved mild and severe EAU. Its potential anti-inflammatory therapeutic effects represent a novel mode of treatment in ocular inflammation. It may also be a relevant treatment modality in systemic autoimmune conditions in which calreticulin plays a role in their pathogenesis.

Autoantibodies serve as essential clinical biomarkers and may indicate etiological mechanisms in rheumatic diseases. In light of the increasing knowledge concerning the diversity and biologic implications of anti-citrullinated peptide/protein antibodies (ACPAs), we have re-evaluated the association between the ACPA response and the HLA-DRB1 allelic groups, known to represent a major genetic risk factor for rheumatoid arthritis (RA).

We explored a collection of 4,392 well-characterized incident patients with RA of White European descent from the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) new-onset RA study, as well as 1,199 cases of patients with RA of Southeast Asian origin from the Malaysian EIRA study. We focused on a quantitative analysis of the levels of anti-cyclic citrullinated peptide IgG antibodies, including those falling below the diagnostic threshold.

Our data show that non-shared epitope alleles HLA-DRB1*09 and *15 exhibit significant associations with ACPA levels. Notably, these novel associations were independent of ethnicity. To validate our findings, we conducted an additional replication study in an independent pool of 4,109 patients with RA of White European origin.

These results indicate a new, previously overlooked, role for the HLA locus in the regulation of the levels of ACPA RA-specific autoantibodies that goes beyond the shared epitope-defined gene variants.

Rheumatoid arthritis (RA) is a prevalent and currently incurable autoimmune disease. Existing conventional medical treatments are limited in their efficacy, prolonged disease may lead to bone destruction, joint deformity, and loss of related functions, which places a huge burden on RA patients and their families. For millennia, the use of traditional Chinese medicine (TCM), exemplified by the Gui-Zhi-Shao-Yao-Zhi-Mu decoction (GZSYZM), has been demonstrated to offer distinct therapeutic advantages in the management of RA. Exploring the potential mechanism of GZSYZM in the treatment of RA is a hot topic in the field of TCM.

High-throughput sequencing data of RA at bulk level and single cell level and Chinese Materia Medica target-related databases were used as data sources. Ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry was employed for the identification of the most relevant compounds to the active ingredients present in the GZSYZM granules. Potential disease genes were identified using a combination of differential expression analysis and weighted gene co-expression network analysis, and the "Chinese Materia Medica-Ingredient-Target" network was constructed to obtain candidate drug target genes. The GZSYZM-RA hub genes were then identified based on Molecular Complex Detection algorithm. To explore the associations and potential mechanisms between the GZSYZM-RA hub gene set and RA, Mendelian randomization (MR) analysis and Bayesian co-localization analysis were used to further identify the GZSYZM-RA core genes that were causally associated with RA. A nomogram was constructed based on a multifactorial logistic regression model using the GZSYZM-RA core genes as predictors of RA. To evaluate its diagnostic value, receiver operating characteristic (ROC) curves, calibration curves, and decision curves were plotted. The potential downstream regulatory mechanisms of the gene of interest in GZSYZM in RA therapy were finally investigated using single- gene set enrichment analysis and molecular docking. The aim was to model the optimal conformation of its target protein receptor binding to the small molecule ligand in GZSYZM to identify the key constituents.

Functional enrichment analysis revealed that the GZSYZM-RA hub gene set is enriched in several autoimmune-related mechanistic pathways, with a particular emphasis on the phosphoinositide 3 kinase (PI3K)‑serine/threonine kinase (AKT) signaling pathway. AUCell scores demonstrated active expression of the GZSYZM-RA hub gene set with the PI3K-AKT signaling pathway on monocytes, especially non-classical monocytes. Immunol infiltration analysis based on the CIBERSORT algorithm also showed a strong correlation between several genes in the GZSYZM-RA hub gene set and monocytes by calculating Spearman's rank correlation coefficients. MR analysis with co-localization analysis further identified seven core genes (CASP8, PPARG, IKBKB, PPARA, IFNG, MYC, and STAT3) causally associated with RA. Diagnostic value for clinical decision making was demonstrated by a multivariable logistic regression model constructed with GZSYZM-RA core genes. Molecular docking analysis indicates that CASP8 and GZSYZM have high docking scores, with three key constituents (quercetin, kaempferol, and diosmetin) exhibiting strong binding affinities.

GZSYZM may regulate the abnormal over-proliferation and apoptotic imbalance of fibroblast-like synoviocytes in RA patients by inhibiting signaling of the PI3K-AKT signaling pathway while activating CASP8-mediated pro-apoptotic effects. And it may be effective in directly or indirectly inhibiting monocyte-to-osteoclast differentiation, ultimately improving the poor prognosis of joint destruction in RA patients.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that primarily affects the synovial joint linings, resulting in progressive disability, increased mortality, and considerable economic costs. Early treatment with disease-modifying antirheumatic medications (DMARDs) can significantly improve the overall outlook for people with RA. Contemporary pharmaceutical interventions, encompassing standard, biological, and emerging small molecule disease- modifying anti-rheumatic medications continue to be the cornerstone of RA management, with substantial advancements made in the pursuit of achieving remission from the disease and preventing joint deformities. Nevertheless, a substantial segment of individuals with RA do not experience a satisfactory response to existing treatments, underscoring the pressing need for novel therapeutic options. Biologic DMARDs are among the therapy choices. Non-tumor necrosis factor inhibitors (Non-TNFi) such as abatacept, rituximab, tocilizumab, and sarilumab are examples, as are anti-tumor necrosis factor (TNF) medications such as infliximab, adalimumab, etanercept, golimumab, and certolizumab pegol. More recent biomarkers have emerged and showed usefulness in the early detection of RA. These biomarkers, often referred to simply as "biomarkers", are quantifiable indicators of normal or pathologic processes, and they can also gauge treatment response. The assessment of RA treatment response typically combines patient-reported outcomes, physical evaluations, and laboratory findings, as there isn't a single biomarker that has proven sufficient for measuring disease activity. This review explores the usage of biologic DMARDs as a therapeutic approach for RA, as well as the biomarkers typically used for RA early diagnosis, prognosis prediction, and disease activity evaluation.

Citrullination, a post-translational modification (PTM), plays a critical role in rheumatoid arthritis (RA) by triggering immune responses to citrullinated self-antigens. Some HLA-DRB1 genes encode molecules with the shared epitope (QKRAA/QRRAA) sequence in the peptide-binding groove which preferentially presents citrulline-modified peptides, like vimentin, that intensifies the immune response in RA. In this study, we used computational approaches to evaluate intermolecular interactions between vimentin peptide-ligands (with/without PTM) and HLA-DRB1 alleles associated with a significantly increased risk for RA development. Crystal structures for HLA-DRB1*04:01, *04:04, and *04:05 bound to citrullinated peptides (PDB ID: 4MCY, 4MD5, 6BIR) were retrieved from the Protein Data Bank and non-citrullinated 3D structures were generated by mutating citrulline to arginine. The pHLA complexes were submitted to four rounds (50 ns each) of molecular dynamic simulations (MD) with Gromacs v.2022. Our results show that citrulline strengthens the interaction between vimentin and the HLA-DRB1 molecules, therefore impacting both the peptide affinity to the HLAs and pHLA stability; it also induces more intermolecular hydrogen bond formation during MD in the pHLA. Citrulline prevents repulsion between amino acid 71β and the P4-residue of native vimentin. Thus, vimentin citrullination seems to affect pHLA binding and dynamics, which may influence RA-related immune responses.

Rheumatoid arthritis (RA) is characterized by chronic inflammation in the synovial membrane, leading to matrix destruction of cartilage and bone. While various types of immune cell are found in inflamed synovium in RA, macrophages and osteoclasts also play important roles in joint destruction. Peripheral blood monocytes migrate to synovial tissue and differentiate into macrophages and osteoclasts in RA. Synovial macrophages are classified into two subsets: M1 (proinflammatory macrophages) or M2 (anti-proinflammatory macrophages). Human circulating monocytes have also been divided into three subsets according expression level of CD14 and CD16: CD14+CD16- (classical); CD14brightCD16+ (intermediate); or CD14dimCD16+ (non-classical). Many recent studies have investigated the involvement of each subset of synovial macrophages and circulating monocytes in the pathophysiology of RA. On the other hand, several distinct human cell populations originating in circulating monocytes have the capacity to differentiate into non-phagocytic cells, including endothelial cells and adipocytes. This review summarizes the role of circulating monocytes in the pathophysiology of RA as precursor cells of not only phagocytes, such as macrophages and osteoclasts, but also non-phagocytes, such as endothelial cells and adipocytes. Furthermore, there is a growing body of evidence showing a significantly positive association between periodontopathic bacterial infection and the pathophysiology of RA. Therefore, the role of periodontopathic bacteria in the development of RA is also discussed.

In the past four decades, a plethora of genetic association studies have been carried out in cohorts of patients with rheumatoid arthritis. These studies have highlighted key aspects of disease pathogenesis and suggested causal mechanisms. In this review, we discuss major advances in our understanding of the genetic architecture of rheumatoid arthritis susceptibility, severity and treatment response and explain how genetics supports current models of disease pathogenesis and outcome. We outline future research directions, like Mendelian randomisation, and present a number of potential avenues for clinical translation, including risk and outcome prediction, patient stratification into treatment response groups and pharmacological applications.

Rheumatoid arthritis (RA) is an autoimmune inflammatory condition that primarily affects the joints and periarticular soft tissue. The development of joint swelling is traditionally regarded as the starting point of the disease. Emerging evidence indicates that RA patients often experience a preclinical stage characterized by immunological and inflammatory changes before developing the disease. The review discusses ongoing efforts to predict the transition from this preclinical phase to clinical RA and describes studies aimed at preventing the onset of RA in individuals at risk. Over the past two decades, there have been significant advancements in RA management and outcomes. An increasing number of patients can now achieve disease remission, and in some cases, this remission persists without ongoing treatment, which is effectively a cure. As new therapies and evolving scientific evidence emerge, recommendations for RA management are continuously evolving. Despite these improvements in the management of RA, many patients still do not respond to multiple conventional or more advanced therapies, including biologic and targeted synthetic disease modifying anti-rheumatic drugs, or experience disease flares when treatments are tapered or discontinued. This situation underscores the need for reliable biomarkers to guide therapy more effectively, improve personalized treatment approaches and monitoring strategies (i.e. precision medicine). In conclusion, this review provides a comprehensive overview of RA, covering new research on the 'pre-clinical' phase of the disease, as well as its epidemiology, pathogenesis, clinical manifestations, diagnosis, imaging, and management strategies. It highlights key clinical aspects of RA and addresses ongoing challenges in disease management, particularly in the areas of prevention and treatment.

Rheumatic diseases (RDs) are characterized by autoimmunity and autoinflammation and are recognized as complex due to the interplay of multiple genetic, environmental, and lifestyle factors in their pathogenesis. The rapid advancement of genome-wide association studies (GWASs) has enabled the identification of numerous single nucleotide polymorphisms (SNPs) associated with RD susceptibility. Based on these SNPs, polygenic risk scores (PRSs) have emerged as promising tools for quantifying genetic risk in this disease group. This chapter reviews the current status of PRSs in assessing the risk of RDs and discusses their potential to improve the accuracy of the diagnosis of these complex diseases through their ability to discriminate among different RDs. PRSs demonstrate a high discriminatory capacity for various RDs and show potential clinical utility. As GWASs continue to evolve, PRSs are expected to enable more precise risk stratification by integrating genetic, environmental, and lifestyle factors, thereby refining individual risk predictions and advancing disease management strategies.

Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy over the past decade. Unfortunately, immune related adverse events (irAEs) are common, including rheumatologic adverse events. These rheumatologic irAEs include de novo rheumatoid arthritis-like presentations or flares of pre-existing rheumatoid arthritis, collectively called ICI-associated rheumatoid arthritis. In this article we review the different mechanisms of disease activity and management approaches including use of conventional (cs) DMARDs and biologic (b) DMARDs in this patient population. Other forms of ICI-induced inflammatory arthritis e.g., PMR-like or Spondylarthritis-type IA, are beyond the scope of this review.

The heterogeneous presentations of inflammatory arthritis in patients receiving immune checkpoint inhibitors has made this a challenging area to study. Nonetheless, recent studies are providing better understanding on the mechanisms of de novo disease and flares in patients with rheumatoid arthritis. About half of patients with pre-existing rheumatoid arthritis flare after receiving checkpoint inhibitors. Persistent arthritis is often encountered in patients receiving combination immune checkpoint inhibitors. Outcomes on overall survival do not differ in rheumatoid arthritis patients receiving checkpoint inhibitors compared to their non-arthritis counterparts. Rheumatologist play a critical role in the management of active rheumatoid arthritis induced by checkpoint inhibitors. Collaboration with oncology colleagues will continue to be a crucial component in providing quality care to these patients. While the use of glucocorticoids is often the first line therapy for active inflammatory arthritic disease, we recommend earlier consideration of DMARDs just as we inverted the treatment pyramid several decades ago, for rheumatoid arthritis.

Rheumatoid arthritis (RA) has been implicated in interstitial lung disease (ILD) as majority of studies have been comprised of patients with known RA. However, it remains unclear whether an underlying risk for RA in combination with genetic risk for pulmonary fibrosis is associated with radiological markers of early lung injury and fibrosis in broader population samples.

Determine whether genetic and serological biomarkers of RA risk in combination with the MUC5B (rs35705950) risk allele (T) are associated with interstitial lung abnormalities (ILA) on computed tomography (CT) scans.

Associations of RA-risk HLA-DRB1 alleles (*04:01, *04:08, *04:05, *04:04, *10:01) and serum RA autoantibodies with ILA in the Multi-Ethnic Study of Atherosclerosis (MESA, n=4,018) and COPDGene (n=5,963) cohorts were modeled using logistic regression and adjusted for age, sex, self-reported race and ethnicity, smoking history, body mass index, and principal components of genetic ancestry.

The prevalence of an RA risk HLA-DRB1 allele was 16.5% and 21.9% in MESA and COPDGene, respectively. ILA was present in 3.9% and 11% in MESA and COPDGene, respectively. An RA risk HLA-DRB1 allele was not significantly associated with ILA in MESA and COPDGene. In MESA, higher serum levels of IgA rheumatoid factor (RF) and anti-cyclic citrullinated peptide were associated with an odds ratio (OR) for ILA of 1.20 (95% CI 1.07-1.35) and 1.19 (95% CI 1.04-1.37), respectively. Among smokers without baseline ILA, per doubling of IgM RF was associated with an OR for ILA 10 years later of 1.25 (95% CI 1.08-1.43). Associations were not significantly different by MUC5B risk allele status.

RA-related HLA-DRB1 alleles were not associated with ILA, whereas higher serum levels of IgM RF among smokers without baseline ILA were associated with subsequent ILA.

Autoimmune disorders are characterized by aberrant T cell and B cell reactivity to the body's own components, resulting in tissue destruction and organ dysfunction. Autoimmune diseases affect a wide range of people in many parts of the world and have become one of the major concerns in public health. In recent years, there have been substantial progress in our understanding of the epidemiology, risk factors, pathogenesis and mechanisms of autoimmune diseases. Current approved therapeutic interventions for autoimmune diseases are mainly non-specific immunomodulators and may cause broad immunosuppression that leads to serious adverse effects. To overcome the limitations of immunosuppressive drugs in treating autoimmune diseases, precise and target-specific strategies are urgently needed. To date, significant advances have been made in our understanding of the mechanisms of immune tolerance, offering a new avenue for developing antigen-specific immunotherapies for autoimmune diseases. These antigen-specific approaches have shown great potential in various preclinical animal models and recently been evaluated in clinical trials. This review describes the common epidemiology, clinical manifestation and mechanisms of autoimmune diseases, with a focus on typical autoimmune diseases including multiple sclerosis, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, and sjögren's syndrome. We discuss the current therapeutics developed in this field, highlight the recent advances in the use of nanomaterials and mRNA vaccine techniques to induce antigen-specific immune tolerance.

Systemic lupus erythematosus (SLE) is a prime example of how the interplay between genetic and environmental factors can trigger systemic autoimmunity, particularly in young women. Although clinical disease can take years to manifest, risk is established by the unique genetic makeup of an individual. Genome-wide association studies have identified almost 200 SLE-associated risk loci, yet unravelling the functional effect of these loci remains a challenge. New analytic tools have enabled researchers to delve deeper, leveraging DNA sequencing and cell-specific and immune pathway analysis to elucidate the immunopathogenic mechanisms. Both common genetic variants and rare non-synonymous mutations can interact to increase SLE risk. Notably, variants strongly associated with SLE are often located in genome super-enhancers that regulate MHC class II gene expression. Additionally, the 3D conformations of DNA and RNA contribute to genome regulation and innate immune system activation. Improved therapies for SLE are urgently needed and current and future knowledge from genetic and genomic research should provide new tools to facilitate patient diagnosis, enhance the identification of therapeutic targets and optimize testing of agents.

Rheumatoid arthritis (RA) is a potentially devastating autoimmune disease. The great majority of patients with RA are seropositive for anti-citrullinated protein antibodies (ACPAs), rheumatoid factors, or other autoantibodies. The onset of clinically apparent inflammatory arthritis meeting classification criteria (clinical RA) is preceded by ACPA seropositivity for an average of 3-5 years, a period that is designated as 'at-risk' of RA for ACPA-positive individuals who do not display signs of arthritis, or 'pre-RA' for individuals who are known to have progressed to developing clinical RA. Prior studies of individuals at-risk of RA have associated pulmonary mucosal inflammation with local production of ACPAs and rheumatoid factors, leading to development of the 'mucosal origins hypothesis'. Recent work now suggests the presence of multiple distinct mucosal site-specific mechanisms that drive RA evolution. Indicatively, subsets of individuals at-risk of RA and patients with RA harbour a faecal bacterial strain that has exhibited arthritogenic activity in animal models and that favours T helper 17 (TH17) cell responses in patients. Periodontal inflammation and oral microbiota have also been suggested to promote the development of arthritis through breaches in the mucosal barrier. Herein, we argue that mucosal sites and their associated microbial strains can contribute to RA evolution via distinct pathogenic mechanisms, which can be considered causal mucosal endotypes. Future therapies instituted for prevention in the at-risk period, or, perhaps, during clinical RA as therapeutics for active arthritis, will possibly have to address these individual mechanisms as part of precision medicine approaches.

Emerging research has investigated the potential impact of several modifiable risk factors on the risks of rheumatoid arthritis (RA), but the findings did not yield consistent results. This study aimed to comprehensively explore the genetic causality between modifiable risk factors and the susceptibility of RA risk using the Mendelian randomization (MR) approach.

Genetic instruments for modifiable risk factors were selected from several genome-wide association studies at the genome-wide significance level (p < 5 × 10-8), respectively. Summary-level data for RA were sourced from a comprehensive meta-analysis. The causal estimates linking modifiable risk factors to RA risk were assessed using MR analysis with inverse variance weighting (IVW), MR-Egger, weighted, and weighted median methods.

After Bonferroni correction for multiple tests, we found the presence of causality between educational attainment and RA, where there were protective effects of educational attainment (college completion) (odds ratio [OR] = 0.50, 95% CI = 0.36, 0.69, p = 2.87E-05) and educational attainment (years of education) (OR = 0.93, 95% CI = 0.90, 0.96, p = 4.18E-06) on the lower RA risks. Nevertheless, smoking initiation was observed to be associated with increased RA risks (OR = 1.27, 95% CI = 1.09, 1.47, p = .002). Moreover, there was no indication of horizontal pleiotropy of genetic variants during causal inference between modifiable risk factors and RA.

Our study reveals the genetic causal impacts of educational attainment and smoking on RA risks, suggesting that the early monitoring and recognition of modifiable risk factors would be beneficial for the preventive counseling/treatment strategies for RA.

The aim of this study was to investigate whether a shared genetic susceptibility exists between individuals with rheumatoid arthritis (RA) and individuals with myocardial infarction (MI)-including major MI risk factors-and to quantify the degree of any such overlap.

Genome-wide association study (GWAS) data for individuals with RA were constructed from a sample of 26,637 Swedish patients with RA and controls without RA. For patients with MI, GWAS data were obtained from a previously published meta-analysis. Genome-wide genetic correlation was estimated via linkage disequilibrium score regression. LAVA was employed to estimate local genetic correlations in ~2,500 nonoverlapping loci, including the major histocompatibility complex. The controls without RA were used for reference panel data. We also assessed stratified estimates of both genome-wide and local genetic correlation based on subsamples of individuals with seropositive RA and those with seronegative RA. Furthermore, genome-wide genetic correlation was estimated between RA and selected cardiovascular risk factors to elucidate pleiotropic relationships.

Following quality control, our GWAS of patients with RA consisted of 25,826 individuas. Genome-wide genetic correlation between patients with RA and MI was estimated to 0.13 (95% confidence interval -0.03 to 0.29). Six regions exhibited significant local genetic correlation, though none harbored any known risk single-nucleotide polymorphisms for either of the two traits. Estimates were similar in both individuals with seropositive RA and those with seronegative RA. No statistically significant genetic correlations were observed between RA risk factors and any of the MI risk factors.

Our findings indicate that genetic overlap between patients with RA and MI is minor. Furthermore, genetic overlap between RA and MI risk factors seem unlikely to provide a major contribution to the increased risk of MI observed in patients with RA.

The relationship between microbiota and the immune system is complex and characterized by the ways in which microbiota directs immune function interactions, both innate and acquired and also keeps activating the immune system throughout an individual's life. In this respect, the human Major Histocompatibility Complex (MHC, referred to as HLA in humans) plays a crucial role and is also established in self-defense against microbes by presenting microbial-derived peptides to the immune cells. However, this assumption has some unclear aspects that should be investigated. For example, how is the microbiota shaped by microbe species diversity, quantity and functions of the immune system, as well as the role and molecular mechanisms of the HLA complex during this process. There are autoimmune diseases related to both HLA and specific microbiota changes or alterations, many of which are mentioned in the present review. In addition, the HLA peptide presenting function should be put in a framework together with its linkage to diseases and also with HLA compatibility necessary for transplants to be successful. These are still quite an enigmatically statistical and phenomenological approach, but no firm pathogenic mechanisms have been described; thus, HLA's real functioning is still to be fully unveiled. After many years of HLA single-genes studies, firm pathogenesis mechanisms underlying disease linkage have been discovered. Finally, microbiota has been defined as conformed by bacteria, protozoa, archaea, fungi, and viruses; notwithstanding, endogenous viral sequences integrated into the human genome and other viral particles (obelisks) recently found in the digestive mucosa should be taken into account because they may influence both the microbiome and the immune system and their interactions. In this context, we propose to integrate these microbial-genetic particle components into the microbiome concept and designate it as "microgenobiota".

Autoimmune autonomic ganglionopathy (AAG) is characterized by various autonomic and extra-autonomic symptoms and is caused by autoantibodies against nicotinic acetylcholine receptors present in the autonomic ganglia (ganglionic acetylcholine receptor, gAChR), requiring immediate and aggressive intervention to prevent the exacerbation of symptoms. However, there is currently no internationally accepted standard of care for the immunotherapy of AAG, including apheresis. Although the rationale for the use of plasma exchange (PLEX) in AAG is strong, whereby pathogenic gAChR antibodies are removed, its overall impact on patient outcomes is not well-established. Based on previous case reports and small case series studies, we provide a comprehensive overview of the challenges and uncertainties surrounding the use of PLEX for the management of AAG and provide current practice recommendations to guide treatment decisions.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints. Although much remains unknown about the pathogenesis of RA, there is evidence that impaired immune tolerance and the development of RA are related. And it is precisely the restoration of immune tolerance at the site of the inflammation that is the ultimate goal of the treatment of RA. Over the past few decades, significant progress has been made in the treatment of RA, with higher rates of disease remission and improved long-term outcomes. Unfortunately, despite these successes, the proportion of patients with persistent, difficult-to-treat disease remains high, and the task of improving our understanding of the basic mechanisms of disease development and developing new ways to treat RA remains relevant. This review focuses on describing new treatments for RA, including cell therapies and gene editing technologies that have shown potential in preclinical and early clinical trials. In addition, we discuss the opportunities and limitations associated with the use of these new approaches in the treatment of RA.

CD4+ T cells recognising citrullinated self-epitopes presented by HLA-DRB1 bearing the shared susceptibility epitope (SE) are implicated in rheumatoid arthritis (RA). However, the underlying T cell receptor (TCR) determinants of epitope specificity towards distinct citrullinated peptide antigens, including vimentin-64cit59-71 and α-enolase-15cit10-22 remain unclear. Using HLA-DR4-tetramers, we examine the T cell repertoire in HLA-DR4 transgenic mice and observe biased TRAV6 TCR gene usage across these two citrullinated epitopes which matches with TCR bias previously observed towards the fibrinogen β-74cit69-81 epitope. Moreover, shared TRAV26-1 gene usage is evident in four α-enolase-15cit10-22 reactive T cells in three human samples. Crystal structures of mouse TRAV6+ and human TRAV26-1+ TCR-HLA-DR4 complexes presenting vimentin-64cit59-71 and α-enolase-15cit10-22, respectively, show three-way interactions between the TCR, SE, citrulline, and the basis for the biased selection of TRAV genes. Position 2 of the citrullinated epitope is a key determinant underpinning TCR specificity. Accordingly, we provide a molecular basis of TCR specificity towards citrullinated epitopes.

Since entering the stage 25 years ago as a highly specific serological biomarker for rheumatoid arthritis, anti-citrullinated protein antibodies (ACPAs) have been a topic of extensive research. This hallmark B cell response arises years before disease onset, displays interpatient autoantigen variability, and is associated with poor clinical outcomes. Technological and scientific advances have revealed broad clonal diversity and intriguing features including high levels of somatic hypermutation, variable-domain N-linked glycosylation, hapten-like peptide interactions, and clone-specific multireactivity to citrullinated, carbamylated and acetylated epitopes. ACPAs have been found in different isotypes and subclasses, in both circulation and tissue, and are secreted by both plasmablasts and long-lived plasma cells. Notably, although some disease-promoting features have been reported, results now demonstrate that certain monoclonal ACPAs therapeutically block arthritis and inflammation in mouse models. A wealth of functional studies using patient-derived polyclonal and monoclonal antibodies have provided evidence for pathogenic and protective effects of ACPAs in the context of arthritis. To understand the roles of ACPAs, one needs to consider their immunological properties by incorporating different facets such as rheumatoid arthritis B cell biology, environmental triggers and chronic antigen exposure. The emerging picture points to a complex role of citrulline-reactive autoantibodies, in which the diversity and dynamics of antibody clones could determine clinical progression and manifestations.