Key Points Question What is the prevalence of periodontal disease and citrullinating periodontopathic bacteria in anti–cyclic citrullinated protein–positive at-risk individuals (CCP+ at-risk) compared with a healthy control group and patients with early rheumatoid arthritis (RA)? Findings This cross-sectional study identified an increased prevalence of periodontal disease sites, clinical periodontitis, and periodontal inflamed surface area in CCP+ at-risk individuals and those with early RA compared with a control group. Results showed that CCP+ at-risk individuals had increased abundance of Porphyromonas gingivalis at healthy periodontal sites compared with the control group and patients with early RA. Meaning In individuals at risk of RA, periodontitis and P gingivalis were increased before joint disease and may be a target for prevention.

ObjectivesAn increased prevalence of periodontitis and perturbation of the oral microbiome has been identified in patients with rheumatoid arthritis (RA). The periodontal pathogen Porphyromonas gingivalis may cause local citrullination of proteins, potentially triggering anti-citrullinated protein antibody production. However, it is not known if oral dysbiosis precedes the onset of clinical arthritis. This study comprehensively characterised the oral microbiome in anti-cyclic citrullinated peptide (anti-CCP) positive at-risk individuals without clinical synovitis (CCP+at risk).MethodsSubgingival plaque was collected from periodontally healthy and diseased sites in 48 CCP+at risk, 26 early RA and 32 asymptomatic healthy control (HC) individuals. DNA libraries were sequenced on the Illumina HiSeq 3000 platform. Taxonomic profile and functional capability of the subgingival microbiome were compared between groups.ResultsAt periodontally healthy sites, CCP+at risk individuals had significantly lower microbial richness compared with HC and early RA groups (p=0.004 and 0.021). Microbial community alterations were found at phylum, genus and species levels. A large proportion of the community differed significantly in membership (523 species; 35.6%) and structure (575 species; 39.1%) comparing CCP+at risk and HC groups. Certain core species, including P. gingivalis, had higher relative abundance in the CCP+at risk group. Seventeen clusters of orthologous gene functional units were significantly over-represented in the CCP+at risk group compared with HC (adjusted p value <0.05).ConclusionAnti-CCP positive at-risk individuals have dysbiotic subgingival microbiomes and increased abundance of P. gingivalis compared with controls. This supports the hypothesis that the oral microbiome and specifically P. gingivalis are important in RA initiation.

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.

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Rationale and ObjectiveVascular cell adhesion molecule-1 (VCAM-1) is upregulated in ischemia reperfusion injury (IRI), persisting after restoration of blood flow. We hypothesized that microparticles of iron oxide targeting VCAM-1 (VCAM-MPIO) would depict “ischemic memory” and enable in vivo assessment of VCAM-1 expression.Methodology and FindingsMice subject to unilateral, transient (30 minutes) renal ischemia and subsequent reperfusion received intravenous VCAM-MPIO (4.5 mg iron/kg body weight). Contrast agent bound rapidly (<30 minutes) in IRI-kidneys and appeared as intensely low signal areas by MRI in vivo. Automated segmentation and quantification yielded MPIO contrast volumes of 5991±354×106 µm3 in IRI vs. 87±7×106 µm3 in kidneys with no surgical intervention (P<0.001); 90±8×106 µm3 in IRI kidneys exposed to control (IgG-MPIO) and 625±80×106 µm3, in IRI kidneys pre-treated with a blocking dose of VCAM-1 antibody (P<0.001). In keeping with quantitative MRI data, VCAM-1 mRNA expression in IRI was 65-fold higher than in kidneys without surgical intervention (3.06±0.63 vs. 0.05±0.02, P<0.001). Indeed VCAM-1 mRNA expression and VCAM-MPIO contrast volume were highly correlated (R2 = 0.901, P<0.01), indicating that quantification of contrast volume reflected renal VCAM-1 transcription. Serial imaging showed VCAM-MPIO accumulation at target within 30 minutes, persisting for ≥90 minutes, while unbound VCAM-MPIO was cleared rapidly from blood, with sequestration by mac-3 positive Kupffer cells in the liver and monocyte/macrophages in the spleen.Conclusions(1) VCAM-MPIO detected VCAM-1 expression and defined its 3-dimensional distribution, revealing “ischemic memory” in renal IRI; (2) automated volumetric quantification of VCAM-MPIO accurately reflected tissue levels of VCAM-1 mRNA; and (3) VCAM-MPIO bound rapidly to target with active sequestration of unbound MPIO in the liver and spleen.

Objective Endothelial cell activation is an important mediator of monocyte recruitment to sites of vascular inflammation. We hypothesised that high-affinity dual-ligand microparticles of iron oxide, targeted to P-selectin and vascular cell adhesion molecule-1 (VCAM-1) (PV-MPIO), would identify activated endothelial cells during atherosclerosis progression. Methods and Results In vivo MRI in apolipoprotein E-deficient mice showed rapid binding of PV-MPIO to the aortic root, which was maximal 30 minutes post-MPIO injection and maintained at 60 minutes. Minimal binding was observed for control IgG-MPIO. Intensely low MR signal areas, corresponding to PV-MPIO binding, were detected early (14 weeks), during foam cell formation. Contrast effects increased at 20 weeks during fibrofatty lesion development (P < 0.05), but reduced by 30 weeks (P < 0.01). Across all lesion severities, MRI contrast effects correlated with lesion macrophage area quantified by immunohistochemistry (R = 0.53; P < 0.01). Near-infrared fluorescently labeled PV-MPIO were shown, by flow cytometry, to bind only activated endothelial cells, and not to macrophages. Using en face immunofluorescence, we further demonstrate selective PV-MPIO accumulation at atherosclerosis-susceptible sites, with minimal binding to atherosclerosis-spared regions. Conclusions This high affinity leukocyte mimetic MRI agent reveals endothelial activation. PV-MPIO demonstrate exceptionally rapid in vivo steady state accumulation, providing conspicuous MR contrast effects that can be objectively quantified. In atherosclerosis progression, PV-MPIO tracked closely with the burden and distribution of plaque macrophages, not merely plaque size. On a biocompatible platform, this approach has potential for quantitative MRI of inflammatory disease activity.

ObjectivesTo use high-resolution imaging to characterise palindromic rheumatism (PR) and to compare the imaging pattern observed to that seen in new-onset rheumatoid arthritis (NORA).MethodsUltrasound (US) assessment of synovitis, tenosynovitis and non-synovial extracapsular inflammation (ECI) was performed during and between flares in a prospective treatment-naive PR cohort. MRI of the flaring region was performed where possible. For comparison, the same US assessment was also performed in anticyclic citrullinated peptide (CCP) positive individuals with musculoskeletal symptoms (CCP+ at risk) and patients with NORA.ResultsThirty-one of 79 patients with PR recruited were assessed during a flare. A high frequency of ECI was identified on US; 19/31 (61%) of patients had ECI including 12/19 (63%) in whom ECI was identified in the absence of synovitis. Only 7/31 (23%) patients with PR had synovitis (greyscale ≥1 and power Doppler ≥1) during flare. In the hands/wrists, ECI was more prevalent in PR compared with NORA and CCP+ at risk (65% vs 29 % vs 6%, p<0.05). Furthermore, ECI without synovitis was specific for PR (42% PR vs 4% NORA (p=0.003) and 6% CCP+ at risk (p=0.0012)). Eleven PR flares were captured by MRI, which was more sensitive than US for synovitis and ECI. 8/31 (26%) patients with PR developed RA and had a similar US phenotype to NORA at progression.ConclusionPR has a distinct US pattern characterised by reversible ECI, often without synovitis. In patients presenting with new joint swelling, US may refine management by distinguishing relapsing from persistent arthritis.

BackgroundDespite 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).MethodsAn 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.ResultsEpidemiological 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.ConclusionThese consensus statements provide data-driven guidance for rheumatologists, health professionals and investigators conducting clinical trials and observational studies in individuals at risk of RA.