Rheumatoid Arthritis: The Continuum of Disease and Strategies for Prediction, Early Intervention, and Prevention.

Rheumatoid arthritis (RA) is known to include a pre-RA stage that can be defined as the presence of familial or genetic risk factors, biomarker abnormalities (eg, anticitrullinated protein antibodies [ACPA]), symptoms, and even abnormal imaging findings prior to the development of the onset of clinical RA with inflammatory arthritis that is apparent on physical examination. Indeed, there are multiple completed or ongoing retrospective case-control as well as prospective observational studies to identify the key biologic drivers of disease. Further, building on the predictive ability of combinations of biomarkers, symptoms, and imaging for future RA, there are multiple clinical trials completed, underway, or in development to identify approaches that may prevent, delay, or ameliorate future clinical RA in at-risk individuals. Importantly, however, although an effective preventive intervention has not yet been identified, at-risk individuals are being increasingly identified in clinical care; this presents a challenge of how to manage these individuals in clinical practice. This review will discuss the current understanding of the biology and natural history of RA development, nomenclature, and current models for prediction of future RA, as well as evaluate the current and ongoing clinical prevention trials with the overall goal to provide insights into the challenges and opportunities in the field of RA prevention. Moreover, this review will provide up-to-date options for clinical management of individuals at risk for RA.

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.

Prevention of Collagen-Induced Arthritis by an Anti-Glycan Monoclonal Antibody Reactive with 6-Sulfo Sialyl Lewis x in DBA/1 Mice.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial tissue inflammation, substantially impacting the quality of life of patients. The interaction between L-selectin and its glycoprotein ligands modified with 6-sulfo sialyl Lewis x (6-sulfo sLex) is known to mediate lymphocyte homing to initiate immune responses. Thus, this process could be a potential therapeutic target for RA. Herein, we explored the preventive effects of an anti-6-sulfo sLex monoclonal antibody (mAb), SF1, on collagen-induced arthritis (CIA) in DBA/1 mice. Mice were administered SF1 from day 21 postfirst immunization with type II collagen (CII), and the effects of SF1 on both clinical and histopathological disease progression evoked by the second immunization were examined. SF1 significantly suppressed clinical features and histological levels associated with arthritis severity. Enzyme-linked immunosorbent assay consistently indicated that SF1 inhibited the production of CII-specific IgG2a. Based on the reverse transcription-quantitative PCR analysis, SF1 suppressed the expression of interferon-γ, a T helper 1 cytokine, as well as that of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1ß, in draining lymph nodes. Collectively, these results indicate that SF1, an anti-sulfated glycan mAb, could be beneficial in preventing CIA in mice and may afford as a novel agent to treat RA.

Recomendaciones SER sobre la gestión de riesgo del tratamiento con FAME biológicos o sintéticos dirigidos en pacientes con artritis reumatoide / Recommendations by the Spanish Society of Rheumatology on risk management of biological treatment and JAK inhibitors in patients with rheumatoid arthritis

Objetivo: Elaborar recomendaciones basadas en la evidencia disponible y el consenso de expertos, para la gestión del riesgo del tratamiento biológico y los inhibidores de las JAK en pacientes con artritis reumatoide. Métodos: Se identificaron preguntas clínicas de investigación relevantes para el objetivo del documento. Estas preguntas fueron reformuladas en formato PICO (paciente, intervención, comparación, outcome o desenlace) por un panel de expertos, seleccionados en base a su experiencia en el área. Se realizó una revisión sistemática de la evidencia, graduándose de acuerdo a los criterios GRADE (Grading of Recommendations Assessment, Development, and Evaluation). A continuación, se formularon las recomendaciones específicas. Resultados: Se propusieron por el panel de expertos 6preguntas PICO en base a su relevancia clínica y a la existencia de información reciente referentes al riesgo de aparición de infecciones graves, el riesgo de reactivación del virus de la hepatitisB, el riesgo de reactivación del virus varicela-zoster, el riesgo de aparición de cáncer de piel (melanoma y no melanoma) o hematológico, el riesgo de aparición de enfermedad tromboembólica y el riesgo de progresión del virus del papiloma humano. Se formularon un total de 29 recomendaciones, estructuradas por pregunta, basadas en la evidencia encontrada y el consenso de los expertos. Conclusiones: Se presentan las recomendaciones SER sobre la gestión del riesgo del tratamiento con terapias biológicas e inhibidores de las JAK en la artritis reumatoide.(AU)

Objective: To present recommendations based on the available evidence and the consensus of experts, for risk management of biological treatment and JAK inhibitors in patients with rheumatoid arthritis. Methods: Clinical research questions relevant to the purpose of the document were identified. These questions were reformulated in PICO format (patient, intervention, comparison, outcome) by a panel of experts, selected based on their experience in the area. A systematic review of the evidence was carried out, grading according to the GRADE criteria (Grading of Recommendations Assessment, Development, and Evaluation). Specific recommendations were then formulated. Results: Six PICO questions were proposed by the panel of experts based on their clinical relevance and the existence of recent information regarding the risk of occurrence of serious infections, the risk of reactivation of the hepatitisB virus, the risk of reactivation of the virus varicella-zoster, the risk of appearance of skin (melanoma and non-melanoma) or hematological cancer, the risk of appearance of thromboembolic disease and the risk of progression of the human papilloma virus. A total of 29 recommendations were formulated, structured by question, based on the evidence found and the consensus of the experts. Conclusions: The SER recommendations on risk management of treatment with biologic therapies and JAK inhibitors in rheumatoid arthritis are presented.(AU)

Rheumatoid arthritis prevention in arthralgia: fantasy or reality?

The concept of a 'window of opportunity' in treating a disease assumes the existence of a time frame during which the trajectory of the disease can be effectively and permanently modified. In rheumatoid arthritis (RA), optimal timing of this period is presumed to be during the phase before arthritis is clinically apparent and disease is diagnosed. Several proof-of-concept trials of treatment during the 'arthralgia' phase of RA have been completed in the past 4 years, with the underlying notion that temporary treatment at this stage could prevent the development of RA or induce a sustained reduction in the burden of disease. This Review summarizes the results of these trials and reflects on the outcomes in relation to the patients' perspectives. Overall, the majority of symptomatic at-risk individuals could benefit from a fixed period treatment, even if RA does not develop. Various factors must be taken into consideration when translating these findings into clinical practice. More evidence is needed to target the individuals at highest risk, and additional tools are needed to monitor treatment and guide decisions about whether treatment can be discontinued. Without these tools, there is a paradoxical risk of seemingly increasing the incidence of the disease and prolonging disease duration, which is the opposite of what the concept of intervening in the window of opportunity entails.

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.

Nutrition and its role in prevention and management of rheumatoid arthritis.

Accumulating research evidence suggests that nutrition might be implicated in the risk of development and in the management of autoimmune disease, including rheumatoid arthritis (RA), characterized by immune-inflammatory response. Nutrition can have direct roles through the provision of pro- or anti-inflammatory foods, and indirect roles through management of co-morbidity management. The review updates on the evidence relating RA risk and management with focus on specific foods such as fish and diets/dietary patterns such as the Mediterranean diet, fasting and elimination diets and oral nutritional supplements including omega-3 polyunsaturated fatty acids (PUFA). Evidence on herbs and spices, beverages, Vitamin D, and probiotics is also reviewed. Diet has been shown to improve disease activity through reducing inflammation and oxidation and through its beneficial effects on the gut microbiota. Based on the existing evidence, it is recommended that as an adjunct to medical treatment, nutrition therapy for RA should be based on an anti-inflammatory Mediterranean diet (MD) supplemented with at least twice a week consumption of oily fish and/or omega-3 PUFA supplements at 2 g/day. The need for rheumatologists to work more closely with registered dietitians in the management of patients particularly in supporting a well-balanced diet according to individual needs, is highlighted.

[Can we prevent the occurrence of Rheumatoid Arthritis in 2023?] / Peut-on prévenir la survenue de la polyarthrite rhumatoïde en 2023 ?

The improvement of our knowledge about the pathogenic mechanisms, the identification of the risks factors and the development of new antirheumatic drugs have enabled significant progress in the management of patients suffering of Rheumatoid Arthritis (RA). We know now that the disease develops long before the first clinical signs appear (immunological onset of the disease or asymptomatic period). One of the current lines of research is the prevention of the disease using early interventions during the asymptomatic stage. In this article, we will summarize the current knowledge concerning the risk factors, the identification of asymptomatic patients at high risk developing rheumatoid arthritis, as well as potential interventions that would allow prevention of the disease.

L'amélioration de nos connaissances sur les mécanismes pathogéniques, l'identification des facteurs de risque, ainsi que le développement de nouveaux traitements antirhumatismaux, ont permis un progrès significatif dans la prise en charge des patients souffrant d'une polyarthrite rhumatoïde (PR). On sait maintenant que la maladie se développe bien avant l'apparition des premiers signes de la maladie (début immunologique de la maladie ou période asymptomatique). Un des axes de recherche actuel est de prévenir la maladie par une intervention précoce, au stade asymptomatique. Dans cet article, nous allons résumer les connaissances actuelles sur les facteurs de risque, l'identification des patients asymptomatiques à haut risque de développer une PR, ainsi que sur les mesures étudiées qui permettraient la prévention de cette maladie.

[Methotrexate to prevent progression to rheumatoid arthritis?] / Methotrexaat om reumatoïde artritis te voorkomen?

The TREAT EARLIER was aimed at testing whether methotrexate could prevent the evolution from clinically suspect arthralgia to Rheumatoid Arthritis. Although the primary outcome was negative, symptoms did improve during and after use of methotrexate. Here we discuss how to interpret these findings, and place the study in the existing evidence.

Preventive interventions in individuals at risk for Rheumatoid Arthritis: State of the art and perspectives.

During the last decade, the outlook for patients with rheumatoid arthritis (RA) has improved greatly, especially for patients with autoantibody-positive RA. To further improve long-term disease outcomes, the field has turned to investigating the efficacy of treatment initiated in the pre-arthritic phase of RA, based on the adage "the sooner the better." In this review, the concept of prevention is evaluated and different risk stages are being examined for their pre-test risks of RA development. These risks affect the post-test risk of biomarkers used at these stages and, consequently, the accuracy with which the risk of RA can be estimated. Furthermore, through their effect on accurate risk stratification, these pre-test risks ultimately also associate with the likelihood of false-negative trial results (the so-called "clinicostatistical tragedy"). Outcome measures to assess preventive effects are evaluated and relate to either the occurrence of disease itself or to the severity of risk factors for RA development. Results of recently completed prevention studies are discussed in the light of these theoretical considerations. The results vary, but clear prevention of RA has not been demonstrated. While some treatments (e.g. methotrexate) persistently reduced symptom severity, physical disability, and the severity of imaging joint inflammation, other treatments were not reported to produce long-lasting effects (hydroxychloroquine, rituximab, atorvastatin). The review concludes with future perspectives regarding the design of new prevention studies and considerations and requirements before findings can be implemented in daily practice in individuals at risk of RA attending rheumatology practices.

Dasatinib, a selective tyrosine kinase inhibitor, prevents joint destruction in rheumatoid arthritis animal model.

AIM: We aimed to evaluate the preventive role of the tyrosine kinase inhibitor dasatinib in an animal model of rheumatoid arthritis (RA). METHODS: DBA/1J mice were injected with bovine type II collagen to induce arthritis (collagen-induced arthritis [CIA]). There were four experimental groups of mice, namely negative control (non-CIA), vehicle-treated CIA, dasatinib-pretreated CIA, and dasatinib-treated CIA. After collagen immunization, arthritis progression in the mice was clinically scored twice weekly for 5 weeks. Flow cytometry was used to evaluate in vitro CD4+ T-cell differentiation and ex vivo mast cell/CD4+ T-cell differentiation. Osteoclast formation was evaluated using tartrate-resistant acid phosphatase (TRAP) staining and by estimating the resorption pit area. RESULTS: We found that the clinical arthritis histological scores were lower in the dasatinib pretreatment group than in the vehicle and dasatinib post-treatment groups. Flow cytometry showed that FcεR1+ cells were downregulated and regulatory T cells were upregulated in splenocytes of the dasatinib pretreatment group compared with those in the vehicle group. Additionally, there was a decline in IL-17+ CD4+ T-cell differentiation and an increase in CD4+ CD24high Foxp3+ T-cell differentiation with in vitro dasatinib treatment of human CD4+ T cells. The number of TRAP+ osteoclasts and the area of the resorption were decreased in the bone marrow cells derived from dasatinib-pretreated mice compared with those derived from vehicle group. CONCLUSION: Dasatinib protected against arthritis in an animal model of RA by regulating the differentiation of regulatory T cells and IL-17+ CD4+ T cells and inhibiting osteoclastogenesis, indicating the therapeutic potential of dasatinib in the treatment of early RA.

Omega 3 Fatty Acids Intake Does Not Decrease the Risk of Rheumatoid Arthritis Occurrence: A Meta-Analysis. Comment on Tanski et al. The Relationship between Fatty Acids and the Development, Course and Treatment of Rheumatoid Arthritis. Nutrients 2022, 14, 1030.

In an article published in Nutrients, Tanski et al. performed a systematic review and concluded that omega-3 fatty acids might contribute to a reduced incidence of rheumatoid arthritis (RA) [...].

Bifidobacterium pseudocatenulatum-Mediated Bile Acid Metabolism to Prevent Rheumatoid Arthritis via the Gut-Joint Axis.

Early intervention in rheumatoid arthritis (RA) is critical for optimal treatment, but initiation of pharmacotherapy to prevent damage remains unsatisfactory currently. Manipulation of the gut microbiome and microbial metabolites can be effective in protecting against RA. Thus, probiotics can be utilized to explore new strategies for preventing joint damage. The aim of this study was to explore the metabolites and mechanisms by which Bifidobacterium pseudocatenulatum affects RA. Based on 16S rRNA sequencing and UPLC-MS/MS assays, we focused on bile acid (BA) metabolism. In a collagen-induced arthritis (CIA) mouse model, B. pseudocatenulatum prevented joint damage by protecting the intestinal barrier and reshaped gut microbial composition, thereby elevating bile salt hydrolase (BSH) enzyme activity and increasing the levels of unconjugated secondary BAs to suppress aberrant T-helper 1/17-type immune responses; however, these benefits were eliminated by the Takeda G protein-coupled receptor 5 (TGR5) antagonist SBI-115. The results suggested that a single bacterium, B. pseudocatenulatum, can prevent RA, indicating that prophylactic administration of probiotics may be an effective therapy.

Prevention of rheumatoid arthritis: A systematic literature review of preventive strategies in at-risk individuals.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease characterized by symmetrical peripheral polyarthritis in the hands and/or feet, leading to long-term disability if not treated effectively. RA is preceded by a preclinical phase, in which genetically predisposed individuals accumulate environmental risk factors, and during which autoimmunity develops, followed by the emergence of non-specific signs and symptoms before arthritis becomes manifest. Early treatment in at-risk individuals - i.e. before the disease is fully established - has the theoretical potential to delay or prevent disease onset, with a positive impact on both patients' life and society. OBJECTIVES: We aimed to understand the feasibility of preventive treatment in at-risk individuals, taking into account recently performed studies and ongoing clinical trials, as well as patient perspectives. METHODS: We performed a systematic literature review (SLR) on Medline and Embase, searching articles published between 2010 and 2021 with the following key-words: "Rheumatoid arthritis", "arthralgia", "pre-treatment" or "prevent". RESULTS: Our SLR identified a total of 1821 articles. Articles were independently screened by two researchers. A total of 14 articles were included after screening, and an additional 8 reports were manually included. We identified ten relevant clinical trials performed in at-risk individuals, or in individuals with undifferentiated inflammatory arthritis. Although no treatment was shown to prevent RA onset, early treatment with rituximab and abatacept delayed onset of full-blown RA, and both conventional and biological disease-modifying anti-rheumatic drugs (DMARDs) decreased disease-related physical limitations and increased DAS28-defined remission, at least temporarily. CONCLUSIONS: This SLR demonstrates that early treatment of at-risk individuals may be effective in delaying RA onset, thereby decreasing disease-related limitations in individuals in the pre-clinical phase of RA. Whether this may ultimately lead to prevention of RA remains to be determined.

Exploring preferences of at-risk individuals for preventive treatments for rheumatoid arthritis.

OBJECTIVE: Some immunomodulatory drugs have been shown to delay the onset of, or lower the risk of developing, rheumatoid arthritis (RA), if given to individuals at risk. Several trials are ongoing in this area; however, little evidence is currently available about the views of those at risk of RA regarding preventive treatment. METHOD: Three focus groups and three interviews explored factors that are relevant to first degree relatives (FDRs) of RA patients and members of the general public when considering taking preventive treatment for RA. The semi-structured qualitative interview prompts explored participant responses to hypothetical attributes of preventive RA medicines. Transcripts of focus group/interview proceedings were inductively coded and analysed using a framework approach. RESULTS: Twenty-one individuals (five FDRs, 16 members of the general public) took part in the study. Ten broad themes were identified describing factors that participants felt would influence their decisions about whether to take preventive treatment if they were at increased risk of RA. These related either directly to features of the specific treatment or to other factors, including personal characteristics, attitude towards taking medication, and an individual's actual risk of developing RA. CONCLUSION: This research highlights the importance of non-treatment factors in the decision-making process around preventive treatments, and will inform recruitment to clinical trials as well as information to support shared decision making by those considering preventive treatment. Studies of treatment preferences in individuals with a confirmed high risk of RA would further inform clinical trial design.

Lifestyle, Hormonal, and Metabolic Environmental Risks for Rheumatoid Arthritis.

Although there is a substantial body of literature focused on understanding noninhalational risk-factors for rheumatoid arthritis, the data are mixed and often conflicting. Given the other health benefits for certain lifestyle modifications, it seems reasonable for clinicians to promote healthy lifestyle habits related to diet, exercise, maintenance of health weight, and maintenance of good dental hygiene. Overall, however, these lifestyle modifications may be expected to have modest benefit, and other strategies to prevent rheumatoid arthritis in high-risk patients are needed.

Where traditional Chinese medicine meets Western medicine in the prevention of rheumatoid arthritis.

Chinese medicine has a long tradition of use against rheumatoid arthritis (RA). The formulations are based on combinations of typically 5-10 plants, which are usually boiled and administered as a decoction or tea. There are few clinical trials performed so the clinical evidence is sparse. One fundamental of traditional medicine is to prevent disease. RA is an autoimmune, inflammatory and chronic disease that primarily affects the joints of 0.5%-1% of the population. In two out of three of the cases, the patients are characterised by the presence of autoantibodies such as the rheumatoid factor and the more disease-specific autoantibody against citrullinated proteins, so-called 'ACPA' (anticitrullinated protein/peptide antibodies). ACPA positivity is also strongly associated with specific variations in the HLA-DRB1 gene, the shared epitope alleles. Together with smoking, these factors account for the major risks of developing RA. In this review, we will summarise the background using certain plant-based formulations based on Chinese traditional medicine for the treatment and prevention of RA and the strategy we have taken to explore the mechanisms of action. We also summarise the major pathophysiological pathways related to RA and how these could be analysed. Finally, we summarise our ideas on how a clinical trial using Chinese herbal medicine to prevent RA could be conducted.