The role of the microbiome in driving RA-related autoimmunity

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

The Role of Ultrasound Across the Inflammatory Arthritis Continuum: Focus on “At-Risk” Individuals

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

The Role of Musculoskeletal Ultrasound in the Rheumatoid Arthritis Continuum

Purpose of Review: Rheumatoid arthritis (RA) is no longer considered a fixed phenotype but rather a disease continuum. This review outlines the current and potential value of applying ultrasound (US) along this continuum: from the prediction of progression to RA in at-risk individuals, to confirmation of the early diagnosis of RA, as well as the consideration of differential diagnoses, and the use in disease monitoring and defining remission. Recent Findings: In individuals at-risk of RA (i.e., positive autoantibodies with symptoms but without synovitis), US has shown a promising predictive value for the development of clinical arthritis, providing the opportunity to improve risk stratification (and disease prevention) of these individuals. The detection of inflammation on US in patients with early undifferentiated arthritis, in which a definite diagnosis cannot be reached, could predict evolution to persistent arthritis, mostly RA. This, in addition to the US potential ability to identify disease specific patterns for different rheumatic conditions, might facilitate early diagnosis and, therefore, improve the management of patients with RA, or other types of inflammatory arthritides. US has also demonstrated the capability to predict radiographic progression, and relapse risk after treatment discontinuation, in RA patients in remission according to the clinical instruments, raising implications in the management, including therapy discontinuation, of these patients. Summary: US has an undeniable value in the management of patients at different stages along the RA continuum. Further research is needed to identify which groups of patients benefit the most from US imaging

Periodontal disease and periodontal bacteria as triggers for rheumatoid arthritis

There is an epidemiological association between periodontitis and rheumatoid arthritis (RA), which is hypothesised to lead to enhanced generation of RA-related autoantibodies that can be detected years before the onset of RA symptoms. Periodontitis is a common dysbiotic disease; tissue damage occurs because the immune system fails to limit both the resident microbial community and the associated local immune response. Certain periodontal bacteria, including Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, may contribute to RA autoantibody production through direct post-translational modification of proteins or, indirectly, by influencing neutrophil-mediated neo-epitope generation. Oral bacteria that invade the blood may also contribute to chronic inflammatory responses and generation of autoantibodies. The putative association between periodontitis and the development of RA raises the potential of finding novel predictive markers of disease and disease progression and for periodontitis treatment to be included in the future as an adjunct to conventional RA immunotherapy or as part of a preventive strategy

Should We Be Screening for and Treating Periodontal Disease in Individuals Who Are at Risk of Rheumatoid Arthritis?

There is increasing evidence supporting an association between periodontal disease (PD) and rheumatoid arthritis (RA), both mechanistically and clinically. Trials have shown that treating PD in people with RA may improve RA disease activity. Patients with musculoskeletal symptoms without arthritis, who test positive for cyclic-citrullinated protein antibodies, are at risk of RA (CCP+ at-risk), with seropositivity preceding arthritis onset by months or years. Importantly, there is evidence to suggest that periodontal inflammation may precede joint inflammation in CCP+ at-risk and, therefore, this could be a trigger for RA. There has been increased research interest in RA prevention and the phenotyping of the pre-RA disease phase. This review will examine the merits of identifying individuals who are CCP+ at-risk and performing screening for PD. In addition, we discuss how PD should be treated once identified. Finally, the review will consider future research needed to advance our understanding of this disease association

Ultrasound erosions in the feet best predict progression to inflammatory arthritis in anti-CCP positive at-risk individuals without clinical synovitis

Objectives To investigate, in anti-cyclic citrullinated peptide antibody positive (CCP+) at-risk individuals without clinical synovitis, the prevalence and distribution of ultrasound (US) bone erosions (BE), their correlation with subclinical synovitis and their association with the development of inflammatory arthritis (IA). Methods Baseline US scans of 419 CCP+ at-risk individuals were analysed. BE were evaluated in the classical sites for rheumatoid arthritis damage: the second and fifth metacarpophalangeal (MCP2 and MCP5) joints, and the fifth metatarsophalangeal (MTP5) joints. US synovitis was defined as synovial hypertrophy (SH) ≥2 or SH ≥1+power Doppler signal ≥1. Subjects with ≥1 follow-up visit were included in the progression analysis (n=400). Results BE were found in ≥1 joint in 41/419 subjects (9.8%), and in 55/2514 joints (2.2%). The prevalence of BE was significantly higher in the MTP5 joints than in the MCP joints (p1 joint 10.6 (95% CI 1.9 to 60.4, p<0.01) and BE and synovitis in ≥1 MTP5 joint 5.1 (95% CI 1.4 to 18.9, p=0.02). In high titre CCP+ at-risk individuals, with positive rheumatoid factor and BE in ≥1 joint, the OR increased to 16.9 (95% CI 2.1–132.8, p<0.01). Conclusions In CCP+ at-risk individuals, BE in the feet appear to precede the onset of clinical synovitis. BE in >1 joint, and BE in combination with US synovitis in the MTP5 joints, are the most predictive for the development of clinical arthritis

To stop or not to stop: what should we be doing with biologic DMARDs when patients undergo orthopaedic surgery?

Management of biologic DMARDs in patients undergoing orthopaedic surgery is variable; flare avoidance is a priority

Predicting Flare in Patients With Rheumatoid Arthritis in Biologic Induced Remission, on Tapering, and on Stable Therapy

Objective The tapering of biologic disease-modifying antirheumatic drug (b-DMARD) therapy for patients with rheumatoid arthritis (RA) in stable remission is frequently undertaken, but specific guidance on how to successfully taper is lacking. The objective of this study is to identify predictors of flare in patients in stable b-DMARD–induced clinical remission, who did or did not follow structured b-DMARD tapering. Methods Patients with RA receiving b-DMARD treatment who had achieved sustained remission according to a Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) <2.6 for ≥6 months were offered tapering. Clinical, ultrasound (US) (total power Doppler [PD]/grayscale abnormalities), CD4+ T cell subsets, and patient-reported outcomes (PROs) were collected at inclusion. The primary endpoint was the occurrence of flare (loss of DAS28-CRP remission) over 12 months. Logistic regression analyses identified predictors of flare. Dichotomization into high/low-risk groups was based on 80% specificity using the area under the receiving operator curve (AUROC). Results Of 63 patients choosing tapering, 23 (37%) flared compared with 12 of 60 (20%) on stable treatment (P = 0.043). All patients who flared regained remission upon reinstating treatment. In the tapering group, flare was associated with lower regulatory T cell (Treg) (P < 0.0001) and higher CRP levels (P < 0.0001), erythrocyte sedimentation rate (P < 0.035), and inflammation-related cells (IRCs) (P = 0.054); stepwise modeling selected Tregs (odds ratio [OR] = 0.350, P = 0.004), IRCs (OR = 1.871, P = 0.007), and CRP level (OR = 1.577, P = 0.004) with 81.7% accuracy and AUROC = 0.890. In the continued therapy group, modeling retained the tender joint count, total PD, and visual analog scale pain score, with 82.1% accuracy and AUROC = 0.899. Most patients in the study were considered low risk of flare (80 of 123 patients [65%]). Only 5 of 37 (13.5%) of the low-risk patients who tapered flared, which was notable compared with the continued therapy group (20% flare). Conclusion Flare on tapering b-DMARDs was predicted by lower Tregs and elevated inflammation biomarkers (IRCs/CRP level); flare on continued b-DMARDs was associated with raised pain parameters and US inflammation. Knowledge of these biomarkers should improve outcomes by targeted selection for tapering, and by increased monitoring of those on continued therapy predicted to flare

Comorbidities in Anti-Cyclic Citrullinated Peptide Positive At-Risk Individuals Do Not Differ from Those Patients with Early Inflammatory Arthritis

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