Reducing cardiovascular risk with immunomodulators: a randomised active comparator trial among patients with rheumatoid arthritis.

OBJECTIVE: Recent large-scale randomised trials demonstrate that immunomodulators reduce cardiovascular (CV) events among the general population. However, it is uncertain whether these effects apply to rheumatoid arthritis (RA) and if certain treatment strategies in RA reduce CV risk to a greater extent. METHODS: Patients with active RA despite use of methotrexate were randomly assigned to addition of a tumour necrosis factor (TNF) inhibitor (TNFi) or addition of sulfasalazine and hydroxychloroquine (triple therapy) for 24 weeks. Baseline and follow-up 18F-fluorodeoxyglucose-positron emission tomography/CT scans were assessed for change in arterial inflammation, an index of CV risk, measured as an arterial target-to-background ratio (TBR) in the carotid arteries and aorta. RESULTS: 115 patients completed the protocol. The two treatment groups were well balanced with a median age of 58 years, 71% women, 57% seropositive and a baseline disease activity score in 28 joints of 4.8 (IQR 4.0, 5.6). Baseline TBR was similar across the two groups. Significant TBR reductions were observed in both groups-ΔTNFi: -0.24 (SD=0.51), Δtriple therapy: -0.19 (SD=0.51)-without difference between groups (difference in Δs: -0.02, 95% CI -0.19 to 0.15, p=0.79). While disease activity was significantly reduced across both treatment groups, there was no association with change in TBR (ß=0.04, 95% CI -0.03 to 0.10). CONCLUSION: We found that addition of either a TNFi or triple therapy resulted in clinically important improvements in vascular inflammation. However, the addition of a TNFi did not reduce arterial inflammation more than triple therapy. TRIAL REGISTRATION NUMBER: NCT02374021.

Testing the Effects of Disease-Modifying Antirheumatic Drugs on Vascular Inflammation in Rheumatoid Arthritis: Rationale and Design of the TARGET Trial.

Individuals with rheumatoid arthritis (RA) are at increased risk for atherosclerotic cardiovascular disease (ASCVD) events relative to the general population, potentially mediated by atherosclerotic plaques that are more inflamed and rupture prone. We sought to address whether RA immunomodulators reduce vascular inflammation, thereby reducing ASCVD risk, and whether such reduction depends on the type of immunomodulator. The TARGET (Treatments Against RA and Effect on 18-Fluorodeoxyglucose [18 F-FDG] Positron Emission Tomography [PET]/Computed Tomography [CT]) trial (NCT02374021) will enroll 150 patients with RA with active disease and an inadequate response to methotrexate. Participants will be randomized to add either a tumor necrosis factor (TNF) inhibitor (etanercept or adalimumab) or sulfasalazine and hydroxychloroquine to their background methotrexate. Participants will undergo full-body 18 F-FDG-labelled PET scanning at baseline and after 6 months. Efficacy and safety evaluations will occur every 6 weeks, with therapy modified in a treat-to-target approach. The primary outcome is the comparison of change in arterial inflammation in the wall of the aorta and carotid arteries between the randomized treatment groups, specifically, the change in the mean of the maximum target-to-background ratio of arterial 18 F-FDG uptake in the most diseased segment of either the aorta and carotid arteries. A secondary analysis will compare the effects of achieving low disease activity or remission with those of moderate to high disease activity on vascular inflammation. The TARGET trial will test, for the first time, whether RA treatments reduce arterial inflammation and whether such reduction differs according to treatment strategy with either TNF inhibitors or a combination of nonbiologic disease-modifying antirheumatic drugs.

Performance Characteristics of Pulmonary Function Tests for the Detection of Interstitial Lung Disease in Adults With Early Diffuse Cutaneous Systemic Sclerosis.

OBJECTIVE: Interstitial lung disease (ILD) is the leading cause of death in patients with systemic sclerosis (SSc). Although pulmonary function tests (PFTs) are commonly used to screen for ILD in patients with SSc, studies have shown that they lack sensitivity for the detection of ILD in general SSc cohorts. This study was undertaken to assess the performance characteristics of PFTs for the detection of ILD in patients with early diffuse cutaneous SSc (dcSSc), a population at high risk for the development of ILD. METHODS: We performed a retrospective cohort study of patients enrolled in the Prospective Registry of Early Systemic Sclerosis at 11 sites in the US between April 2012 and January 2019. Patients were included if they underwent spirometry and high-resolution computed tomography (HRCT) of the chest. We calculated the performance characteristics of PFTs for the detection of ILD on HRCT. RESULTS: The study included 212 patients, 54% of whom had radiographic ILD. For the detection of ILD on HRCT imaging, a forced vital capacity (FVC) <80% predicted had a sensitivity of 63%. The combination of FVC <80% predicted or diffusing capacity for carbon monoxide (DLco) <80% predicted improved the sensitivity to 85%. An FVC <80% predicted had a negative predictive value (NPV) of 61%, while the combination of FVC <80% predicted or DLco <80% predicted had an NPV of 70%. CONCLUSION: PFTs alone are an inadequate screening tool for the diagnosis of ILD in patients with early dcSSc. HRCT should be part of the ILD screening algorithm in patients with dcSSc.

Reducing Missed Opportunities for Influenza Vaccination in Patients with Rheumatoid Arthritis: Evaluation of a Multisystem Intervention.

OBJECTIVE: To assess a multimodal intervention for reducing missed opportunities for outpatient influenza vaccination in individuals with rheumatoid arthritis (RA). METHODS: Patients with RA were enrolled from a single center and each rheumatology outpatient visit was tracked for missed opportunities for influenza vaccination, defined as a visit in which an unvaccinated patient without contraindications remained unvaccinated or lacked documentation of vaccine recommendation in the electronic medical record (EMR). Providers then received a multimodal intervention consisting of an education session, EMR alerts, and weekly provider-specific e-mail reminders. Missed opportunities before and after the intervention were compared, and the determinants of missed opportunities were analyzed. RESULTS: A total of 228 patients with RA were enrolled (904 preintervention visits) and 197 returned for at least 1 postintervention visit (721 postintervention visits). The preintervention frequency of any missed opportunities for influenza vaccination was 47%. This was reduced to 23% postintervention (p < 0.001). Among those vaccinated, the relative hazard for influenza vaccination post- versus preintervention period was 1.24 (p = 0.038). Younger age, less frequent office visits, higher erythrocyte sedimentation rate, and negative attitudes about vaccines were each independently associated with missed opportunities preintervention. Postintervention, these factors were no longer associated with missed opportunities; however, the intervention was not as effective in non-Hispanic black patients, non-English speakers, those residing outside of the New York City metropolitan area, and those reporting prior adverse reactions to vaccines. CONCLUSION: Improved uptake of influenza vaccination in patients with RA is possible using a multimodal approach. Certain subgroups may need a more potent intervention for equivalent efficacy.

Adipose Tissue Macrophages in Rheumatoid Arthritis: Prevalence, Disease-Related Indicators, and Associations With Cardiometabolic Risk Factors.

OBJECTIVE: Adipose tissue macrophages (ATMs) are a potent source of inflammatory cytokines, with profound effects on adipose tissue function, yet their potential role in rheumatoid arthritis (RA) pathobiology is largely unstudied. METHODS: Periumbilical subcutaneous adipose tissue was obtained from 36 RA patients and 22 non-RA controls frequency matched on demographics and body mass index. Samples were stained for the macrophage marker CD68, and the average proportions of ATMs, crown-like structures (periadipocyte aggregates of 3 or more ATMs), and fibrosis were compared between groups. RESULTS: The adjusted proportion of ATMs among all nucleated cells was 76% higher in RA than in non-RA samples (37.7 versus 21.3%, respectively; P < 0.001), and the adjusted average number of crown-like structures was more than 1.5-fold higher in the RA group than in controls (0.58 versus 0.23 crown-like structure/high-power field, respectively; P = 0.001). ATMs were significantly more abundant in early RA and in those with anti-cyclic citrullinated peptide seropositivity. Users of methotrexate, leflunomide, and tumor necrosis factor inhibitors had a significantly lower proportion of ATMs compared with nonusers. Crown-like structures were significantly higher in patients with rheumatoid factor seropositivity and in those with C-reactive protein levels ≥10 mg/liter, and significantly lower among those treated with statins. Linear ATMs were significantly associated with whole-body insulin resistance, but not with serum lipids. CONCLUSIONS: ATMs and crown-like structures were more abundant in RA patients and were associated with systemic inflammation, autoimmunity, and whole-body insulin resistance, suggesting possible contributions to the RA disease process. Lower levels of ATMs and crown-like structures associated with specific RA treatments suggest that adipose tissue inflammation may be ameliorated by immunomodulation.