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Objectives: Periodontitis and underlying bacteria have been linked to the development of rheumatoid arthritis (RA). One suggested pathogen is Aggregatibacter actinomycetemcomitans ( A.a .), which expresses leukotoxin A (LtxA) that can citrullinate human proteins, providing a possible trigger for the production of anti-citrullinated protein antibodies (ACPA). In this study, we seek to determine the presence of antibodies toward LtxA in patients at risk of developing RA., Methods: Two prospective observational patient cohorts (one Swedish and one British) with symptomatic at-risk patients were studied. Anti-LtxA antibodies were analyzed by a cell-based neutralization assay in baseline serum and compared to 100 Swedish blood donors that served as controls., Results: Serum anti-LtxA levels or positivity did not differ between patients and blood donors. In the British cohort, anti-LtxA was more prevalent among ACPA-positive arthralgia patients compared with ACPA-negative arthralgia cases (24% vs. 13%, p < 0.0001). In the Swedish at-risk cohort, anti-LtxA positive patients were at increased risk of progression to arthritis (hazard ratio (HR) 2.10, 95% CI 1.04-4.20), but this was not confirmed in the UK at-risk cohort (HR 0.99, CI 0.60-1.65)., Conclusion: Serum anti-LtxA is not elevated before RA diagnosis, and associations with disease progression and ACPA levels differ between populations. Other features of the oral microbiome should be explored in upcoming periodontitis-related RA research., Competing Interests: KMan reports personal fees from AbbVie, Lilly, and UCB AbbVie, outside the submitted work and research grants from Gilead and Lilly. PE reports consultant fees from BMS, AbbVie, MSD, Pfizer, Novartis, and Roche and personal fees from Abbvie, Gilead, Lilly, and Novartis, outside the submitted work and also reports research grants from AbbVie, BMS, Lilly, and Samsung. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Martinsson, Di Matteo, Öhman, Johansson, Svärd, Mankia, Emery and Kastbom.)

In recent years rheumatologists have begun to shift focus from early rheumatoid arthritis (RA) to studying individuals at risk of developing the disease. It is now possible to use blood, clinical and imaging biomarkers to identify those at risk of progression before the onset of clinical synovitis. The use of imaging, in particular ultrasound (US) and magnetic resonance imaging (MRI), has become much more widespread in individuals at-risk of RA. Numerous studies have demonstrated that imaging can help us understand RA pathogenesis as well as identifying individuals at high risk of progression. In addition, imaging techniques are becoming more sophisticated with newer imaging modalities such as high-resolution peripheral quantitative computed tomography (HR-pQRCT), nuclear imaging and whole body-MRI (WB-MRI) starting to emerge. Imaging studies in at risk individuals are heterogeneous in nature due to the different at-risk populations, imaging modalities and protocols used. This review will explore the available imaging modalities and the rationale for their use in the main populations at risk of RA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Harnden, Di Matteo and Mankia.)

In individuals at-risk of developing inflammatory arthritis, the value of an ultrasound (US) scan assessment to predict progression has been demonstrated repeatedly. However, depending on recruitment criteria, these individuals may be at different stages in the arthritis development continuum, therefore representing a heterogeneous population. As a consequence, the predictive value of ultrasound results may differ between cohorts. As other reviews have focused on the challenges in population recruitment or have combined biomarkers predicting value according to one recruitment pathway, we wanted to focus on the sole use of ultrasound assessment and its variation according to population recruitment criteria. In this review, we discuss the use of ultrasound in the different at-risk populations across the inflammatory arthritis disease continuum. This review demonstrates that although some sub-population data is scarce, ultrasound is best predictive in three at-risk populations: those with a positive ACPA test in the context of non-specific MSK symptoms, those with clinically suspect arthralgia and those with palindromic rheumatism. We consider that ultrasound assessment will be a cornerstone in prediction risk modeling and prevention studies of the preclinical phases of IA in the future., (Copyright © 2020 Duquenne, Chowdhury, Mankia and Emery.)

Once referred to as "normal commensal flora" the human microbiome plays an integral role between health and disease. The host mucosal surface replete with a multitude of immune cells is a vast arena constantly sensing and responding to antigen presentation and microbial by-products. It is this key role that may allow the microbiome to prime or protect the host from autoimmune disease. Rheumatoid arthritis (RA) is a chronic, disabling inflammatory condition characterized by a complex multifactorial etiology. The presence of certain genetic markers has been proven to increase susceptibility to RA however it does not guarantee disease development. Given low concordance rates demonstrated in monozygotic twin studies there is a clear implication for the involvement of external players in RA pathogenesis. Since the historical description of rheumatoid factor, numerous additional autoantibodies have been described in the sera of RA patients. The presence of anti-cyclic citrullinated protein antibody is now a standard test, and is associated with a more severe disease course. Interestingly these antibodies are detectable in patient's sera long before the clinical signs of RA occur. The production of autoantibodies is driven by the lack of tolerance of the immune system, and how tolerance is broken is a crucial question for understanding RA development. Here we review current literature on the role of the microbiome in RA development including periodontal, gut and lung mucosa, with particular focus on proposed mechanisms of host microbiome interactions. We discuss the use of Mendelian randomization to assign causality to the microbiome and present considerations for future studies., (Copyright © 2020 Rooney, Mankia and Emery.)

Objectives: To compare comorbidities in a cohort of cyclic citrullinated peptide (CCP) antibody positive patients without or prior to onset of inflammatory arthritis (IA) to those in patients with early IA., Methods: Baseline data from two established cohorts were used. The first recruited people at risk of IA: CCP antibody positive cases without IA (CCP Cohort, n  = 296). The second cohort [the Inflammatory Arthritis CONtinuum study (IACON)] recruited patients with early IA ( n  = 725). Proportions of patients with given comorbidities were compared between cohorts and then logistic regression was used to determine odds ratios (OR) for the CCP cohort having specific comorbidities, compared to IACON patients. Analyses adjusted for gender, age, smoking status, and body mass index., Results: Patients from the CCP cohort were younger (mean age 50, compared to 53 years). The proportion of patients with at least one comorbidity was higher in the IACON than the CCP cohort: (40% compared to 24%, respectively). Results of logistic regression analyses suggested the odds of hypertension, taking a lipid-lowering agent, ischemic heart disease, cerebrovascular disease, lung disease, and diabetes were not increased in either cohort. However, patients in the CCP cohort were more likely to be taking an antidepressant (OR = 1.62, 95% CI 1.03, 2.56, p  = 0.037)., Conclusion: There was no significant difference in comorbidities among people with CCP antibodies but without IA, compared to those of patients with established IA.