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.

Factors Associated With Mortality in Patients With Immune-Mediated Rheumatic Diseases and COVID-19 From Latin America: Data From Argentina, Mexico, and Brazil.

OBJECTIVE: To describe characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with rheumatic immune-mediated inflammatory diseases (IMIDs) from Argentina, Mexico and Brazil, and to assess factors associated with mortality in this population. METHODS: Data from 3 national registries, SAR-COVID (Argentina), CMR-COVID (Mexico), and ReumaCoV-Brasil (Brazil), were combined. Adult patients with IMIDs and SARS-CoV-2 infection were recruited. Sociodemographic data, comorbidities, IMID clinical characteristics and treatment, and SARS-CoV-2 infection presentation and outcomes were recorded. RESULTS: A total of 4827 individuals were included: 2542 (52.7%) from SAR-COVID, 1167 (24.2%) from CMR-COVID, and 1118 (23.1%) from ReumaCoV-Brasil. Overall, 82.1% were female with a mean age of 49.7 (SD, 14.3) years; 22.7% of the patients were hospitalized, and 5.3% died because of COVID-19 (coronavirus disease 2019). Argentina and Brazil had both 4% of mortality and Mexico 9.4%. In the multivariable analysis, older age (≥60 years; odds ratio [OR], 7.4; 95% confidence interval [CI], 4.6-12.4), male sex (OR, 1.5; 95% CI, 1.1-2.1), living in Mexico (OR, 3.0; 95% CI, 2.0-4.4), comorbidity count (1 comorbidity: OR, 1.5; 95% CI, 1.0-2.1), diagnosis of connective tissue disease or vasculitis (OR, 1.8; 95% CI, 1.3-2.4), and other diseases (OR, 2.6; 95% CI, 1.6-4.1) compared with inflammatory joint disease, high disease activity (OR, 4.2; 95% CI, 2.5-7.0), and treatment with glucocorticoids (OR, 1.9; 95% CI, 1.4-2.5) or rituximab (OR, 4.2; 95% CI, 2.7-6.6) were associated with mortality. CONCLUSIONS: Mortality in patients with IMIDs was particularly high in Mexicans. Ethnic, environmental, societal factors, and different COVID-19 mitigation measures adopted have probably influenced these results.

Characteristics associated with poor COVID-19 outcomes in people with psoriasis, psoriatic arthritis and axial spondyloarthritis: data from the COVID-19 PsoProtect and Global Rheumatology Alliance physician-reported registries.

OBJECTIVES: To investigate factors associated with severe COVID-19 in people with psoriasis (PsO), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). METHODS: Demographic data, clinical characteristics and COVID-19 outcome severity of adults with PsO, PsA and axSpA were obtained from two international physician-reported registries. A three-point ordinal COVID-19 severity scale was defined: no hospitalisation, hospitalisation (and no death) and death. ORs were estimated using multivariable ordinal logistic regression. RESULTS: Of 5045 cases, 18.3% had PsO, 45.5% PsA and 36.3% axSpA. Most (83.6%) were not hospitalised, 14.6% were hospitalised and 1.8% died. Older age was non-linearly associated with COVID-19 severity. Male sex (OR 1.54, 95% CI 1.30 to 1.83), cardiovascular, respiratory, renal, metabolic and cancer comorbidities (ORs 1.25-2.89), moderate/high disease activity and/or glucocorticoid use (ORs 1.39-2.23, vs remission/low disease activity and no glucocorticoids) were associated with increased odds of severe COVID-19. Later pandemic time periods (ORs 0.42-0.52, vs until 15 June 2020), PsO (OR 0.49, 95% CI 0.37 to 0.65, vs PsA) and baseline exposure to TNFi, IL17i and IL-23i/IL-12+23i (OR 0.57, 95% CI 0.44 to 0.73; OR 0.62, 95% CI 0.45 to 0.87; OR 0.67, 95% CI 0.45 to 0.98; respectively; vs no disease-modifying antirheumatic drug) were associated with reduced odds of severe COVID-19. CONCLUSION: Older age, male sex, comorbidity burden, higher disease activity and glucocorticoid intake were associated with more severe COVID-19. Later pandemic time periods, PsO and exposure to TNFi, IL17i and IL-23i/IL-12+23i were associated with less severe COVID-19. These findings will enable risk stratification and inform management decisions for patients with PsO, PsA and axSpA during COVID-19 waves or similar future respiratory pandemics.

A Mixed-Methods Systematic Review on Syndemics in Rheumatology.

OBJECTIVE: We aimed to assess the use of framework and corresponding methodology to document syndemics and its impact in rheumatic and musculoskeletal diseases (RMDs). METHODS: Using a mixed-methods systematic review, studies using the syndemic framework approach for RMDs were identified and published from January 2003 to January 2021. The Joanna Briggs Institute, Cochrane Collaboration, and PRISMA guidelines were followed to search, retrieve, revise, and analyze. RESULTS: A total of 658 potential articles were identified, but only 10 were initially eligible. After a full-text review, 4 were included. Following a full-text review, 2 quantitative, 1 qualitative, and 1 mixed-methods study were included. In the first, network analysis found that RMDs were associated with comorbidities, unhealthy habits, low educational level, living in rural areas, socioeconomic conditions, and health inequality in indigenous communities. In the second, SSEM and cluster analysis demonstrated an association between low back pain and factors, such as comorbidities and indigenous status, among others, in urban/rural communities. The qualitative study examined 3 fishing family generations and reported less syndemic vulnerability. The mixed-methods study focused on osteoarthritis with multimorbidities in African American population, where lack of education added to worsening outcomes. CONCLUSIONS: Even though the insights syndemic studies have given to other areas, its use in rheumatology is scarce. The complexity of the clinical and social determinants related to RMDs makes it necessary to conduct further studies from a syndemic perspective.

An Analysis COVID-19 in Mexico: a Prediction of Severity.

BACKGROUND: Coronavirus disease 2019 (COVID-19) causes a mild illness in most cases; forecasting COVID-19-associated mortality and the demand for hospital beds and ventilators are crucial for rationing countries' resources. OBJECTIVE: To evaluate factors associated with the severity of COVID-19 in Mexico and to develop and validate a score to predict severity in patients with COVID-19 infection in Mexico. DESIGN: Retrospective cohort. PARTICIPANTS: We included 1,435,316 patients with COVID-19 included before the first vaccine application in Mexico; 725,289 (50.5%) were men; patient's mean age (standard deviation (SD)) was 43.9 (16.9) years; 21.7% of patients were considered severe COVID-19 because they were hospitalized, died or both. MAIN MEASURES: We assessed demographic variables, smoking status, pregnancy, and comorbidities. Backward selection of variables was used to derive and validate a model to predict the severity of COVID-19. KEY RESULTS: We developed a logistic regression model with 14 main variables, splines, and interactions that may predict the probability of COVID-19 severity (area under the curve for the validation cohort = 82.4%). CONCLUSIONS: We developed a new model able to predict the severity of COVID-19 in Mexican patients. This model could be helpful in epidemiology and medical decisions.

EULAR points to consider for conducting clinical trials and observational studies in individuals at risk of rheumatoid arthritis.

BACKGROUND: Despite growing interest, there is no guidance or consensus on how to conduct clinical trials and observational studies in populations at risk of rheumatoid arthritis (RA). METHODS: An European League Against Rheumatism (EULAR) task force formulated four research questions to be addressed by systematic literature review (SLR). The SLR results informed consensus statements. One overarching principle, 10 points to consider (PTC) and a research agenda were proposed. Task force members rated their level of agreement (1-10) for each PTC. RESULTS: Epidemiological and demographic characteristics should be measured in all clinical trials and studies in at-risk individuals. Different at-risk populations, identified according to clinical presentation, were defined: asymptomatic, musculoskeletal symptoms without arthritis and early clinical arthritis. Study end-points should include the development of subclinical inflammation on imaging, clinical arthritis, RA and subsequent achievement of arthritis remission. Risk factors should be assessed at baseline and re-evaluated where appropriate; they include genetic markers and autoantibody profiling and additionally clinical symptoms and subclinical inflammation on imaging in those with symptoms and/or clinical arthritis. Trials should address the effect of the intervention on risk factors, as well as progression to clinical arthritis or RA. In patients with early clinical arthritis, pharmacological intervention has the potential to prevent RA development. Participants' knowledge of their RA risk may inform their decision to participate; information should be provided using an individually tailored approach. CONCLUSION: These consensus statements provide data-driven guidance for rheumatologists, health professionals and investigators conducting clinical trials and observational studies in individuals at risk of RA.

Syndemics & syndemogenesis in COVID-19 and rheumatic and musculoskeletal diseases: old challenges, new era.

People with rheumatic and musculoskeletal diseases (RMDs) are facing several challenges during the COVID-19 pandemic, such as poor access to regular health services and drug shortages, particularly in developing countries. COVID-19 represents a syndemic, synergistic condition that interacts with and exacerbates pre-existing diseases such as RMDs, other co-morbidities and social conditions. The emerging evidence on both biological and non-biological factors implicated in worse outcomes in people with RMDs affected by the COVID-19 pandemic, whether infected by the virus or not, calls for the need to use more novel and holistic frameworks for studying disease. In this context, the use of a syndemic framework becomes particularly relevant. We appeal for a focus on the identification of barriers and facilitators to optimal care of RMDs in the context of the COVID-19 pandemic, in order to tackle both the pandemic itself and the health inequities inherent to it.

Identification of biological pathways specific to phases preceding rheumatoid arthritis development through gene expression profiling.

The etiopathogenesis of rheumatoid arthritis is partially understood; however, it is believed to result from a multi-step process. The immune onset followed by pre-clinical phases will eventually lead to the development of symptomatic disease. We aim at identifying differentially expressed genes in order to highlight pathways involved in the pre-clinical stages of rheumatoid arthritis development. The study population consisted of first-degree relatives of patients with rheumatoid arthritis, known to have an increased risk of developing disease as compared to the general population. Whole transcriptome analysis was performed in four groups: asymptomatic without autoantibodies or symptoms associated with possible rheumatoid arthritis (controls); having either clinically suspect arthralgias, undifferentiated arthritis or autoimmunity associated with RA (pre-clinical stages of RA: Pcs-RA); having subsequently developed classifiable RA (pre-RA); and early untreated rheumatoid arthritis patients (RA). Differentially expressed genes were determined, and enrichment analysis was performed. Functional enrichment analysis revealed 31 pathways significantly enriched in differentially expressed genes for Pcs-RA, pre-RA and RA compared to the controls. Osteoclast pathway is among the seven pathways specific for RA. In Pcs-RA and in pre-RA, several enriched pathways include TP53 gene connections, such as P53 and Wnt signalling pathways. Analysis of whole transcriptome for phenotypes related to rheumatoid arthritis allows highlighting which pathways are requested in the pre-clinical stages of disease development. After validation in replication studies, molecules belonging to some of these pathways could be used to identify new specific biomarkers for individuals with impending rheumatoid arthritis.

Prevotella copri in individuals at risk for rheumatoid arthritis.

OBJECTIVES: Rheumatoid arthritis (RA) has been associated with a relative expansion of faecal Prevotellaceae. To determine the microbiome composition and prevalence of Prevotella spp. in a group of individuals at increased risk for RA, but prior to the development of the disease. METHODS: In an ongoing cohort study of first-degree relatives (FDRs) of patients with RA, we identified 'FDR controls', asymptomatic and without autoantibodies, and individuals in pre-clinical RA stages, who had either developed anticitrullinated peptide antibodies or rheumatoid factor positivity and/or symptoms and signs associated with possible RA. Stool sampling and culture-independent microbiota analyses were performed followed by descriptive statistics and statistical analyses of community structures. RESULTS: A total of 133 participants were included, of which 50 were categorised as 'FDR controls' and 83 in 'pre-clinical RA stages'. The microbiota of individuals in 'pre-clinical RA stages' was significantly altered compared with FDR controls. We found a significant enrichment of the bacterial family Prevotellaceae, particularly Prevotella spp., in the 'pre-clinical RA' group (p=0.04). CONCLUSIONS: Prevotella spp. enrichment in individuals in pre-clinical stages of RA, before the onset of RA, suggests a role of intestinal dysbiosis in the development of RA.

Role of reproductive and menopausal factors in functional and structural progression of rheumatoid arthritis: results from the SCQM cohort.

OBJECTIVES: To study the relationship between female reproductive and menopausal factors on functional and structural joint damage progression in women with RA. METHODS: This is an observational cohort study of RA patients enrolled in the Swiss Clinical Quality Management Program for Rheumatoid Arthritis. Information about female hormonal factors, such as pregnancies, menopause and hormonal therapy, were retrospectively retrieved using a specific questionnaire. The primary outcome was functional disability progression (HAQ) and the secondary outcome radiographic joint damage progression. We compared the functional progression between pre- and post-menopausal women using a multilevel regression model for longitudinal data, adjusting for potential confounders, such as baseline age, years of education, disease duration, seropositivity, DAS28 and treatment. RESULTS: A total of 1667 women were analysed, of whom 1025 (61%) were post-menopausal. Participants had a median of 6 HAQ assessments (interquartile range 3-10) during 5.1 (interquartile range 2.2-9.8) years of follow-up. At baseline, post-menopausal women had higher HAQ and erosion scores than pre-menopausal women. The evolution of HAQ scores over time differed between pre- and post-menopausal women (P < 0.001), with a less favourable evolution in post-menopausal women, particularly with earlier age at menopause. Erosion progression did not differ between pre- and post-menopausal women. CONCLUSION: In women with RA, functional disability progression differed between pre- and post-menopausal women. The more favourable evolution of function in pre-menopausal women was not explained by disease duration, age or radiographic damage.

Drug retention of biological DMARD in rheumatoid arthritis patients: the role of baseline characteristics and disease evolution.

OBJECTIVE: To examine the association of the evolution in physician-reported and patient-reported outcomes with decision to stop biological DMARDs (bDMARDs) in RA. The contribution of baseline characteristics is well established, but little is known about how the disease evolution influences the decision to discontinue therapy. METHODS: RA patients who initiated a bDMARD treatment from 2009 and with information on date of visit were pooled from seven European RA registers. Each outcome was divided into baseline assessments (capturing the inter-individual differences at drug initiation) and changes from baseline at subsequent visits (capturing the individual evolution). Cox regression models were used to examine their association with drug discontinuation, adjusting for baseline patient and co-therapy characteristics and stratifying by register and calendar year of drug initiation. RESULTS: A total of 25 077 patients initiated a bDMARDs (18 507 a TNF-inhibitor, 3863 tocilizumab and 2707 abatacept) contributing an amount of 46 456.8 patient-years. Overall, drug discontinuation was most strongly associated with a poor evolution of the DAS28, with a hazard ratio of 1.34 (95% CI 1.29, 1.40), followed by its baseline value. A change of Physician Global Assessment was the next strongest predictor of discontinuation, then the Patient Global Assessment. CONCLUSIONS: The decision to discontinue treatments appears to be mostly influenced by DAS28 and particularly its evolution over time, followed by Physician Global Assessment evolution, suggesting that the decision to stop bDMARDs relies more on the physician's than on the patient's global assessment.

Periodontal status correlates with anti-citrullinated protein antibodies in first-degree relatives of individuals with rheumatoid arthritis.

AIM: To evaluate periodontal status in first-degree relatives of patients with rheumatoid arthritis (FDR-RA) and detect correlation with the presence of anti-citrullinated protein antibodies (ACPAs). MATERIALS AND METHODS: Rheumatologic status and periodontal status were evaluated in a nested case-control study of FDR-RA with no diagnosis of RA at enrolment. The following parameters were assessed in 34 ACPA-positive (ACPA+) and 65 ACPA-negative (ACPA-) subjects: gingival index (GI), plaque index (PI), probing depth (PD), bleeding on probing (BOP) and clinical attachment level (CAL). We compared the two groups using conditional logistic regression. RESULTS: In ACPA+ individuals, the mean, PD, BOP, CAL and number of sites per person with PD > 4 mm and BOP were significantly higher compared to the ACPA- group. All ACPA+ subjects had periodontitis: 44.1% presenting moderate and 47.1% severe periodontitis. ACPA- subjects had mainly mild (30.8%) and moderate (27%) periodontitis, differences being significantly different for both moderate periodontitis (p = 0.001) and severe periodontitis (p < 0.001). In multivariable analyses, ACPA status (p = 0.04) and age (p = 0.002) were significantly and independently associated with periodontal conditions. CONCLUSION: High prevalence and severity of periodontitis in FDR-RA was associated with seropositivity to ACPAs. This further strengthens the hypothesis that periodontitis may be a risk factor in the development of RA.

[Microbiota and inflammatory rheumatisms]. / Microbiotes et rhumatismes inflammatoires.

The microbiota and dysbiosis are involved in various diseases. Many studies in mice and humans demonstrate its influence on inflammatory rheumatisms. In rheumatoid arthritis (RA), Prevotella copri, a Gram-negative bacteria of the intestinal flora, is found to be more prevalent in the early stages of the disease. Specific antibodies against this germ have been identified in RA patients, suggesting a role of this bacteria in the initiation of the disease. Oral microorganisms involved in periodontitis have also been associated with the development and the activity of RA. These discoveries imply new targets in the management of inflammatory rheumatisms.

Le microbiote et son dysfonctionnement sont impliqués dans de nombreuses maladies. Beaucoup d'études chez la souris et l'homme tendent à démontrer leur rôle dans les rhumatismes inflammatoires. Dans la polyarthrite rhumatoïde (PR), Prevotella copri, une bactérie Gram négatif de la flore intestinale, se retrouve de façon prépondérante aux stades précoces de la maladie. Des anticorps spécifiques contre ce germe ont pu être mis en évidence chez les patients avec une PR, suggérant une implication dans l'initiation de la maladie. Les micro-organismes oraux impliqués dans la parodontite ont également été associés au développement et à l'activité de la PR. Ces découvertes permettent d'envisager de nouvelles pistes thérapeutiques.

The role of female hormonal factors in the development of rheumatoid arthritis.

RA is the most common chronic systemic autoimmune disease, with a higher prevalence in women, suggesting female hormonal factors play a role in the development of the disease. However, many controversies still exist. The aim of this review was to appraise data from recent research concerning female hormonal factors and their association with RA disease development. The study of female hormonal factors is challenging because serum levels may differ throughout a woman's lifetime and interact with various environmental, immunological, genetic and endocrine factors influencing the development of autoimmunity. As some female hormonal factors may be potentially modifiable, understanding their impact on RA development is clinically relevant and may result in specific preventive interventions in high-risk populations.

Female hormonal factors and the development of anti-citrullinated protein antibodies in women at risk of rheumatoid arthritis.

Objectives: To analyse the association between female hormonal factors and the development of systemic autoimmunity associated with RA in women at increased risk for RA, namely first-degree relatives of patients with RA (RA-FDRs). Methods: In an ongoing cohort study of RA-FDRs, we analysed all women with available ACPA status. The primary outcome was ACPA positivity. The predictors of interest were female hormonal factors, such as oral contraceptives, breastfeeding, post-menopausal status, early post-menopausal period and total number of ovulatory years. Results: A total of 768 female RA-FDRs were analysed, of which 42 (5%) had developed ACPA positivity. ACPA-positive women were older (52 vs 44 years, P = 0.001). Hormonal factors significantly and independently associated with the presence of ACPA were the post-menopausal (P < 0.001) and the early post-menopausal periods (P = 0.040). Conclusions: In women at increased risk of RA, characteristic systemic autoimmunity was associated with menopause, suggesting that the acute decline in ovarian function might contribute to the development of autoimmunity associated with RA and potentially to the increased risk of RA in women.

Differential impact of systemic lupus erythematosus and rheumatoid arthritis on health-related quality of life.

PURPOSE: This study examined and compared health-related quality of life (QoL) in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). METHODS: We included patients from two multicentric cohorts, the Swiss SLE cohort study (SSCS) and the Swiss Clinical Quality Management Program for RA (SCQM-RA). Patients were matched by age, sex and disease duration using the propensity score. Disease activity was assessed by SELENA-SLEDAI in SLE and by DAS-28 in RA. QoL was captured by the short-form 36 (SF-36). The primary outcomes were physical component summary (PCS) and mental component summary (MCS) of the SF-36. Generalized estimating equation models were used to assess evolution over time. RESULTS: We analyzed 267 SLE patients and 267 matched RA patients. More patients with RA had active disease and more patients with SLE had immunosuppressant therapies at baseline. The median [interquartile range (IQR)] MCS and PCS scores were 45.1 [33.7-52.6] and 45.6 [38.0-53.0] in SLE and 48.8 [37.6-56.7] and 34.7 [26.8-43.0] in RA, respectively (ps < 0.001). Over one year the differences persisted, although PCS and MCS increased in RA (ps < 0.001) but not in SLE in the univariate analysis. The differences in MCS and PCS scores between RA and SLE remained qualitatively similar after adjustment for patient characteristics, treatment, and activity disease. CONCLUSIONS: SLE and RA both affect QoL. Patients with SLE have lower MCS, whereas patients with RA have lower PCS. These differences remained over 1 year of follow up, suggesting fundamental dissimilarities between SLE and RA in their impact on QoL.