[Autoimmunity and oral cavity, where are we in 2023?] / Auto-immunité et cavité orale, où en est-on en 2023 ?

Autoimmune diseases (AIDs) remain an enigma to the current understanding of immune system functioning. Identifying their etiologies remains a major challenge, despite growing knowledge. The oral cavity has a very special place in regard to AIDs. The oral mucosa, the most exposed body's natural barrier to pathogens, plays a role in both education of the immune system and the organism's daily protection. On the one hand, systemic disturbance of the immune system can impact the oral sphere with early signs which are useful diagnostic tools. On the other hand, the current research efforts on interactions between microbiota and the immune system allow an update of the old hypothesis involving an initial infection to trigger autoimmunity. Dysbiosis of our microbiota, especially in the oral sphere, could lead to a breakdown in tolerance mechanisms. Immune tolerance has to maintain the integrity of the organism but also cohabitation with commensal microbiota. The relationship between periodontitis, a chronic infectious disease, and rheumatoid arthritis, one of the most common systemic autoimmune disorders, illustrates the possible relationship between chronic infections and the etiopathogenesis of autoimmunity. Indeed, its association with oral pathogens involved in periodontal damage raises questions about a possible infectious etiology of rheumatoid arthritis (RA) which would place the management of periodontitis not only as mandatory RA's support therapy but also as a prophylactic gesture to prevent autoimmunity.

Title: Auto-immunité et cavité orale, où en est-on en 2023 ? Abstract: Les maladies auto-immunes (MAI) restent une énigme dans notre compréhension du système immunitaire. L'identification de leurs étiologies demeure un défi majeur en dépit d'une augmentation exponentielle de nos connaissances sur le fonctionnement du système immunitaire. La cavité orale a une place particulière vis-à-vis des MAI. La muqueuse buccale présente les barrières naturelles de l'organisme parmi les plus exposées à des agents pathogènes. À ce titre, elles jouent un rôle dans l'éducation du système immunitaire, puis dans la protection quotidienne de l'organisme. Les perturbations du système immunitaire se manifestent fréquemment par des conséquences au niveau de la sphère buccale, le plus souvent précocement, permettant d'initier une démarche diagnostique. L'effort de recherche actuel sur les interactions entre microbiotes et système immunitaire permet de moderniser l'hypothèse historique liant une origine infectieuse à l'apparition de l'auto-immunité, en y apportant quelques nuances.

Adherence to dietary guidelines, and the risk of developing rheumatoid arthritis: results from a nested case-control study.

OBJECTIVES: To examine the relationship between adherence to dietary guidelines and the risk of developing RA. METHODS: Participants in the Malmö Diet and Cancer Study (MDCS) cohort diagnosed with RA were identified through register linkage and validated in a structured review. Four controls per case were selected, matched for sex, year of birth, and year of inclusion in the MDCS. Diet was assessed at baseline (1991-1996) using a validated diet history method. A Diet Quality Index (DQI) based on adherence to the Swedish dietary guidelines including intakes of fibre, vegetables and fruits, fish and shellfish, saturated fat, polyunsaturated fat, and sucrose, was used. The associations between the DQI and its components and the risk of RA were assessed using conditional logistic regression analysis, adjusting for total energy intake, smoking, leisure time physical activity and alcohol consumption. RESULTS: We identified 172 validated cases of incident RA in the cohort. Overall adherence to the dietary guidelines was not associated with the risk of RA. Adherence to recommended fibre intake was associated with decreased risk of RA in crude and multivariable-adjusted analyses, with odds ratios (ORs) 0.60 (95% CI 0.39, 0.93) and 0.51 (95% CI 0.29, 0.90), respectively, compared with subjects with non-adherence. CONCLUSIONS: Reaching the recommended intake level of dietary fibre, but not overall diet quality, was independently associated with decreased risk of RA. Further studies are needed to assess the role of different food sources of dietary fibre in relation to risk of RA and the underlying mechanisms.

Pathophysiology and stratification of treatment-resistant rheumatoid arthritis.

Early diagnosis and timely therapeutic intervention are clinical challenges of rheumatoid arthritis (RA), especially for treatment-resistant or difficult-to-treat patients. Little is known about the immunological mechanisms involved in refractory RA. In this review, we summarize previous research findings on the immunological mechanisms of treatment-resistant RA. Genetic prediction of treatment-resistant RA is challenging. Patients with and without anti-cyclic citrullinated peptide autoantibodies are considered part of distinct subgroups, especially regarding long-term clinical prognosis and treatment responses. B cells, T cells and other immune cells and fibroblasts are of pathophysiological importance and are associated with treatment responses. Finally, we propose a new hypothesis that stratifies patients with RA into two subgroups with distinct immunological pathologies based on our recent immunomics analysis of RA. One RA subgroup with a favorable prognosis is characterized by increased interferon signaling. Another subgroup with a worse prognosis is characterized by enhanced acquired immune responses. Increases in dendritic cell precursors and diversified autoreactive anti-modified protein antibodies may have pathophysiological roles, especially in the latter subgroup. These findings that improve treatment response predictions might contribute to future precision medicine for RA.

The Causal Association between Alcohol, Smoking, Coffee Consumption, and the Risk of Arthritis: A Meta-Analysis of Mendelian Randomization Studies.

Objective: To evaluate the genetic causality between alcohol intake, smoking, coffee consumption, and arthritis. Methods: Mendelian randomization (MR) studies with alcohol, smoking, and coffee consumption behaviors as exposures, and osteoarthritis (OA) and rheumatoid arthritis (RA) as outcomes were retrieved from up to July 2023. Two researchers with relevant professional backgrounds independently assessed the quality and extracted data from the included studies. Meanwhile, we applied MR analyses of four lifestyle exposures and five arthritis outcomes (two for OA and three for RA) with gene-wide association study (GWAS) data that were different from the included studies, and the results were also included in the meta-analysis. Statistical analyses were performed using Stata 16.0 and R software version 4.3.1. Results: A total of 84 studies were assessed. Of these, 11 were selected for meta-analysis. As a whole, the included studies were considered to be at a low risk of bias and were of high quality. Results of the meta-analysis showed no significant genetic causality between alcohol intake and arthritis (odds ratio (OR): 1.02 (0.94-1.11)). Smoking and arthritis had a positive genetic causal association (OR: 1.44 (1.27-1.64)) with both OA (1.44 (1.22-1.71)) and RA (1.37 (1.26-1.50)). Coffee consumption and arthritis also had a positive genetic causal association (OR: 1.02 (1.01-1.03)). Results from the subgroup analysis showed a positive genetic causality between coffee consumption and both OA (OR: 1.02 (1.00-1.03)) and RA (OR: 1.56 (1.19-2.05)). Conclusion: There is positive genetic causality between smoking and coffee consumption and arthritis (OA and RA), while there is insufficient evidence for genetic causality between alcohol intake and arthritis.

Artritis reumatoide / Rheumatoid arthritis

La artritis reumatoide (AR) es una enfermedad inflamatoria crónica multisistémica de etiología desconocida y de naturaleza autoinmune que afecta predominantemente a las articulaciones periféricas de forma simétrica. Aunque se ha avanzado mucho en la comprensión de su fisiopatología, su etiología sigue siendo desconocida. El factor de necrosis tumoral (TNF)-α y la interleucina (IL)-6, juegan un papel importante en la patogénesis y la perpetuación de la inflamación en la AR. La presencia de anticuerpos antipéptidos citrulinados ayuda en el diagnóstico en pacientes con poliartritis indiferenciadas y se relaciona con una evolución más agresiva de la AR. La evolución natural de la AR causa deformidad articular y discapacidad, además de una reducción de la esperanza de vida, por aumento del riesgo cardiovascular, afectación pulmonar, infecciones, iatrogenia o tumores. El diagnóstico precoz y la utilización de fármacos dirigidos que buscan la remisión temprana han mejorado sustancialmente el pronóstico de la AR (AU)

Rheumatoid arthritis (RA) is a chronic inflammatory multisystemic disease of unknown etiology and autoimmune nature that predominantly affects peripheral joints in a symmetrical fashion. Although much progress has been made in understanding the pathophysiology of RA, its etiology remains unknown. Tumor necrosis factor (TNF)-α and interleukin (IL)-6 play the important roles in the pathogenesis and maintenance of inflammation in RA. The presence of anti-citrullinated peptide antibodies aids in the diagnosis in patients with undifferentiated polyarthritis and is associated with a more aggressive RA. The natural history of RA causes joint deformity and disability, as well as reduced life expectancy, both due to increased cardiovascular risk, pulmonary involvement, infections, iatrogenesis or tumors. Early diagnosis and the use of targeted drugs to induce early remission have improved the RA prognosis (AU)

Causal effects of time-varying body size on selected autoimmune disorders: a life course Mendelian randomisation study.

BACKGROUND: Based on Barker's hypothesis, some studies investigated the associations between birth weight and several disorders. Apart from issues with statistical power and well-known shortcomings of the observational study design, there are no studies accounting for changes in weight-related body size over the life course regarding rheumatoid arthritis, psoriasis, psoriatic arthritis and multiple sclerosis. METHODS: Using genetic information of up to 806 834 participants, this study investigated the associations between time-varying weight-related body size from birth to adulthood and the mentioned autoimmune diseases. Performing Mendelian randomisation (MR), the radial inverse-variance weighted approach was used iteratively in primary analyses. Robustness of the results was confirmed in several sensitivity analyses. Potential time-dependent mediation mechanisms were identified through network-clustering and assessed using multivariable MR. RESULTS: Genetically predicted birth weight (fetal effect) was positively associated with rheumatoid arthritis (OR 1.44; 95% CI 1.17 to 1.77; Padj =0.005) but not with psoriasis, psoriatic arthritis or multiple sclerosis. This association was found to be mediated by body mass index (BMI) in adulthood (OR 1.45; 95% CI 1.14 to 1.84; Padj =0.019) rather than childhood. The direct effect of birth weight attenuated (OR 1.19; 95% CI 0.88 to 1.62); Padj =1) after adjustment for time-varying BMI. CONCLUSION: Increased birth weight appears to be a risk factor for later manifestation of rheumatoid arthritis due to both fetal genetic components and high BMI persisting into adulthood. Approaches to prevent and minimise the risk of rheumatoid arthritis could include preventing obesity in adults with high birth weight.

The SYSCID map: a graphical and computational resource of molecular mechanisms across rheumatoid arthritis, systemic lupus erythematosus and inflammatory bowel disease.

Chronic inflammatory diseases (CIDs), including inflammatory bowel disease (IBD), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are thought to emerge from an impaired complex network of inter- and intracellular biochemical interactions among several proteins and small chemical compounds under strong influence of genetic and environmental factors. CIDs are characterised by shared and disease-specific processes, which is reflected by partially overlapping genetic risk maps and pathogenic cells (e.g., T cells). Their pathogenesis involves a plethora of intracellular pathways. The translation of the research findings on CIDs molecular mechanisms into effective treatments is challenging and may explain the low remission rates despite modern targeted therapies. Modelling CID-related causal interactions as networks allows us to tackle the complexity at a systems level and improve our understanding of the interplay of key pathways. Here we report the construction, description, and initial applications of the SYSCID map (https://syscid.elixir-luxembourg.org/), a mechanistic causal interaction network covering the molecular crosstalk between IBD, RA and SLE. We demonstrate that the map serves as an interactive, graphical review of IBD, RA and SLE molecular mechanisms, and helps to understand the complexity of omics data. Examples of such application are illustrated using transcriptome data from time-series gene expression profiles following anti-TNF treatment and data from genome-wide associations studies that enable us to suggest potential effects to altered pathways and propose possible mechanistic biomarkers of treatment response.

Causality of occupational exposure on rheumatoid arthritis and ankylosing spondylitis: a two-sample mendelian randomization study.

Objective: This study aimed to explore the potential causal link between three specific types of occupational exposure on rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Method: A Two-sample Mendelian randomization (TSMR) analysis, comprising univariate MR (UVMR) and multivariate MR (MVMR) analyses, was performed to investigate the potential causal association between three types of occupational exposures, jobs involving mainly walking or standing (JWS), jobs involving heavy manual or physical work (JMP), and jobs involving shift work(JSW) on RA and AS. Genetic variants for genome-wide association studies (GWAS) of occupational exposure and AS were obtained from the UK Biobank. GWAS summary data for RA were obtained from FinnGen Biobank analysis. For UVMR, six methods of Inverse Variance Weighted (IVW), MR-Egger, Weighted Mode, Weighted Median, Simple Mode, MR pleiotropy residual sum, and outlier (MR-PRESSO) were used for the analysis. The MVMR was analyzed using the IVW model as well as the MR-Egger model. Results: The UVMR suggested no causal relationship between the three occupational exposure and RA [IVW: P=0.59,0.21,0.63] or AS [IVW: P=0.43,0.57,0.04], as did the bidirectional MR [IVW: P=0.73,0.70,0.16], [IVW: P=0.65,0.68,0.74]. Although unadjusted MVMR suggested a causal relationship between JMP and AS [IVW: OR = 1.01, 95% CI = 1.00- 1.02, p = 0.02], the adjusted MVMR denied this relationship and concluded that there was no causal relationship between the other occupational exposure and either RA or AS. Conclusion: Our MR analysis did not establish a direct causal relationship between certain occupational exposures and either RA or AS.

[Outcome of joint replacement in patients with underlying rheumatoid disease]. / Outcome nach Gelenkersatz bei Patienten mit rheumatoider Grunderkrankung.

BACKGROUND: Artificial joint replacement is a meaningful treatment option for patients with advanced rheumatic degenerative joint diseases. The aim of this study was to investigate the influence of the underlying rheumatic diseases on postoperative complications and patient-reported outcome (PRO) after elective total joint replacement (TJR). MATERIAL AND METHODS: In a retrospective analysis of 9149 patients with elective total knee or total hip arthroplasty (TKR and THR), complication rates and PRO of patients with and without rheumatic diseases (RD) were compared. Multivariate logistic regression models were used to determine whether the underlying rheumatic disease was an independent risk factor for various complications. RESULTS: In the univariate analyses the RD patients had an increased risk of medical complications (7.1% vs. 5.2%; p = 0.028) and Clavien-Dindo grade IV complications (2.8% vs. 1.8%; p = 0.048) after TJR. This was confirmed in multivariate statistical analyses (p < 0.034). The rates for operative revisions and surgical complications were comparable (2.5% vs. 2.4%; p = 0.485). Analysis of the PRO showed a higher responder rate in patients with RD after TKR (91.9% vs. 84.5%, p = 0.039). In contrast, the responder rate in patients with RD after THR was comparable (93.4% vs. 93.2%, p = 0.584). CONCLUSION: Despite increased postoperative complication rates, patients with underlying rheumatic diseases showed a comparable outcome 1 year after TJR. After TKR the RD patients showed even higher responder rates. Although RD patients are a vulnerable patient group, they can still benefit from joint replacement.

Advances in the implications of the gut microbiota on the treatment efficacy of disease-modifying anti-rheumatic drugs in rheumatoid arthritis.

Alterations in the composition or function of the gut microbiota are associated with the etiology of human diseases. Drug-microbiota interactions can affect drug bioavailability, effectiveness, and toxicity through various routes. For instance, the direct effect of microbial enzymes on drugs can either boost or diminish their efficacy. Thus, considering its wide range of metabolic capabilities, the gut microbiota is a promising target for pharmacological modulation. Furthermore, drugs can alter the microbiota and the mechanisms by which they interact with their host. Individual variances in microbial profiles can also contribute to the different host responses to various drugs. However, the influence of interactions between the gut microbiota and drugs on treatment efficacy remains poorly elucidated. In this review, we will discuss the impact of microbiota dysbiosis in the pathogenesis of rheumatoid arthritis (RA), and we will attempt to elucidate the crosstalk between the gut microbiota and disease-modifying anti-rheumatic drugs (DMARDs), with an emphasis on how drug-microbiota interactions affect the treatment efficacy in RA. We speculate that improved knowledge of these critical interactions will facilitate the development of novel therapeutic options that use microbial markers for predicting or optimizing treatment outcomes.

Eggerthella lenta augments preclinical autoantibody production and metabolic shift mimicking senescence in arthritis.

Although the etiology of rheumatoid arthritis (RA) is unknown, a strong genetic predisposition and the presence of preclinical antibodies before the onset of symptoms is documented. An expansion of Eggerthella lenta is associated with severe disease in RA. Here, using a humanized mouse model of collagen-induced arthritis, we determined the impact of E. lenta abundance on RA severity. Naïve mice gavaged with E. lenta produce preclinical rheumatoid factor and, when induced for arthritis, develop severe disease. The augmented antibody response was much higher in female mice, and among patients with RA, women had higher average load of E. lenta. Expansion of E. lenta increased CXCL5 and CD4 T cells, and both interleukin-17- and interferon-γ-producing B cells. Further, E. lenta gavage caused gut dysbiosis and decline in amino acids and nicotinamide adenine dinucleotide with an increase in microbe-dependent bile acids and succinyl carnitine causing systemic senescent-like inflammation.

The role of TRPV1 in RA pathogenesis: worthy of attention.

Transient receptor potential cation channel subfamily V member 1 (TRPV1) is a Ca2+permeable, non-selective cation channel that is found primarily in sensory nerve fibres. Previous studies focused on pain transmission. However, recent studies have found that the TRPV1 channel, in addition to being associated with pain, also plays a role in immune regulation and their dysregulation frequently affects the development of rheumatoid arthritis (RA). A thorough understanding of the mechanism will facilitate the design of new TRPV1-targeted drugs and improve the clinical efficacy of RA. Here, we provide an updated and comprehensive overview of how the TRPV1 channel intrinsically regulates neuronal and immune cells, and how alterations in the TRPV1 channel in synoviocytes or chondrocytes extrinsically affect angiogenesis and bone destruction. Rapid progress has been made in research targeting TRPV1 for the treatment of inflammatory arthritis, but there is still much-uncharted territory regarding the therapeutic role of RA. We present a strategy for targeting the TRPV1 channel in RA therapy, summarising the difficulties and promising advances in current research, with the aim of better understanding the role of the TRPV1 channel in RA pathology, which could accelerate the development of TRPV1-targeted modulators for the design and development of more effective RA therapies.

Modifiable risk factors linked to the development of rheumatoid arthritis: evidence, immunological mechanisms and prevention.

Rheumatoid Arthritis (RA) is a common autoimmune disease that targets the synovial joints leading to arthritis. Although the etiology of RA remains largely unknown, it is clear that numerous modifiable risk factors confer increased risk to developing RA. Of these risk factors, cigarette smoking, nutrition, obesity, occupational exposures and periodontal disease all incrementally increase RA risk. However, the precise immunological mechanisms by which these risk factors lead to RA are not well understood. Basic and translational studies have provided key insights into the relationship between inflammation, antibody production and the influence in other key cellular events such as T cell polarization in RA risk. Improving our general understanding of the mechanisms which lead to RA will help identify targets for prevention trials, which are underway in at-risk populations. Herein, we review the modifiable risk factors that are linked to RA development and describe immune mechanisms that may be involved. We highlight the few studies that have sought to understand if modification of these risk factors reduces RA risk. Finally, we speculate that modification of risk factors may be an appealing avenue for prevention for some at-risk individuals, specifically those who prefer lifestyle interventions due to safety and economic reasons.

The Role of Autophagy as a Trigger of Post-Translational Modifications of Proteins and Extracellular Vesicles in the Pathogenesis of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease, characterized by persistent joint inflammation, leading to cartilage and bone destruction. Autoantibody production is directed to post-translational modified (PTM) proteins, i.e., citrullinated or carbamylated. Autophagy may be the common feature in several types of stress (smoking, joint injury, and infections) and may be involved in post-translational modifications (PTMs) in proteins and the generation of citrullinated and carbamylated peptides recognized by the immune system in RA patients, with a consequent breakage of tolerance. Interestingly, autophagy actively provides information to neighboring cells via a process called secretory autophagy. Secretory autophagy combines the autophagy machinery with the secretion of cellular content via extracellular vesicles (EVs). A role for exosomes in RA pathogenesis has been recently demonstrated. Exosomes are involved in intercellular communications, and upregulated proteins and RNAs may contribute to the development of inflammatory arthritis and the progression of RA. In RA, most of the exosomes are produced by leukocytes and synoviocytes, which are loaded with PTM proteins, mainly citrullinated proteins, inflammatory molecules, and enzymes that are implicated in RA pathogenesis. Microvesicles derived from cell plasma membrane may also be loaded with PTM proteins, playing a role in the immunopathogenesis of RA. An analysis of changes in EV profiles, including PTM proteins, could be a useful tool for the prevention of inflammation in RA patients and help in the discovery of personalized medicine.

Association between exposure to external airborne agents and autoimmune disease.

The etiology of autoimmune disease pathogeneses remains obscure, and the impact of general environmental or occupational exposure to external airborne agents (EAA) on autoimmune diseases remains understudied. This study was conducted to elucidate the association between exposure to EAA and the risk of autoimmune diseases according to exposure type. From the NHIS-NSC (2002-2019), 17,984,963 person-years were included in the data analysis. Autoimmune diseases were categorized based on the InterLymph classification. We estimated the incidence and rate ratio of autoimmune diseases according to the EAA exposure. Association between exposure and autoimmune diseases was investigated using logistic regression analysis, adjusted for potential confounders. Of the 1,082,879 participants, 86,376 (8.0%) were diagnosed with autoimmune diseases. Among these, 208 (14.1%) experienced severe exposure to EAA. Total EAA exposure was significantly associated with any autoimmune disease (OR: 1.29, 95% CI: 1.11-1.49) and organ-specific diseases (OR: 1.28, 95% CI: 1.08-1.53). Inorganic dust exposure was associated with organ-specific diseases (OR, 1.38; 95% CI: 1.01-1.81). Exposure to other dust was significantly associated with any autoimmune disease (OR: 1.35, 95% CI: 1.10-1.66), connective tissue diseases (OR: 1.43, 95% CI: 1.03-1.99), and organ-specific diseases (OR: 1.28, 95% CI: 1.00-1.65). Exposure to EAA was predominantly related to psoriasis, rheumatoid arthritis (RA), and type 1 diabetes (T1DM). We found that exposure to EAA is a potential risk factor for autoimmune diseases, especially psoriasis, RA, and T1DM. Our findings provide insight into the role of exposure to severe airborne agents in the pathogenesis of autoimmune diseases.

Autoimmune Connective Tissue Diseases: Systemic Lupus Erythematosus and Rheumatoid Arthritis.

Systemic lupus erythematosus and rheumatoid arthritis are just 2 of several autoimmune connective tissue diseases that are primarily chronic in nature but can present to the emergency department by virtue of an acute exacerbation of disease. Beyond an acute exacerbation of disease, their predilection for invading multiple organ systems lends itself to the potential for patients presenting to the emergency department with either a single or isolated symptom or a myriad of signs and/or symptoms indicative of a degree of disease complexity and severity that warrant timely recognition and resuscitation.

[The role of dietary factors and nutrients in rheumatoid arthritis]. / Étrendi tényezok és tápanyagok szerepe rheumatoid arthritisben.

Rheumatoid arthritis is the most common autoimmune inflammatory joint disease. Internal and external factors may play a role in its development. In recent years, an increasing number of studies highlighted that diet has a central role in the risk and progression of the disease. Several foods and nutrients present anti-inflammatory and antioxidant properties that have protective effects on the development and outcome of rheumatoid arthritis. The aim of this review is to summarize and describe the results of randomized clinical trials or cohorts that have investigated the effects of diet and nutrition in relation to rheumatoid arthritis and the potential role of dietary therapy in the management of rheumatoid arthritis. Certain dietary patterns and components can be used as adjunctive therapies in the treatment of rheumatoid arthritis and may contribute to the effective reduction of disease activity, the induction of remission and its long-term maintenance. At present, there is no nutrition guideline on the dietary management of rheumatoid arthritis and it is therefore important to objectively assess the potential effects and risks of dietary factors and dietary habits. Orv Hetil. 2023; 164(27): 1052-1061.