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ObjectiveTraditional nondigital methods of participant recruitment for clinical research studies in rheumatology can be costly and inefficient, particularly for recruitment of underserved populations. We aimed to address this need by evaluating two methods of online recruitment to an observational cohort of individuals at risk for rheumatoid arthritis, namely web and Facebook advertisements.MethodsA 3-month countywide web-based recruitment campaign was conducted consisting of text and image-based advertisements. Similar advertisements were subsequently displayed on Facebook, initially in English for 5 months and later in Spanish for an additional 3 months. Individuals who clicked on advertisements were directed to a website landing page containing study information and could contact study personnel to schedule testing for anti-cyclic citrullinated peptide-3 (CCP3). The primary outcome measure for each campaign was the click-through rate.ResultsDuring the web campaign, 413,289 advertisement impressions were displayed, resulting in 428 clicks (click-through rate 0.10%) and only one screened participant. During the English Facebook campaign, 724,815 advertisements were displayed with 6765 clicks (click-through rate 0.93%) and 43 screened participants, significantly greater than the web campaign (P

ObjectiveTo develop updated guidelines for the pharmacologic management of rheumatoid arthritis.MethodsWe developed clinically relevant population, intervention, comparator, and outcomes (PICO) questions. After conducting a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the certainty of evidence. A voting panel comprising clinicians and patients achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations.ResultsThe guideline addresses treatment with disease-modifying antirheumatic drugs (DMARDs), including conventional synthetic DMARDs, biologic DMARDs, and targeted synthetic DMARDs, use of glucocorticoids, and use of DMARDs in certain high-risk populations (i.e., those with liver disease, heart failure, lymphoproliferative disorders, previous serious infections, and nontuberculous mycobacterial lung disease). The guideline includes 44 recommendations (7 strong and 37 conditional).ConclusionThis clinical practice guideline is intended to serve as a tool to support clinician and patient decision-making. Recommendations are not prescriptive, and individual treatment decisions should be made through a shared decision-making process based on patients' values, goals, preferences, and comorbidities.

OBJECTIVE:Pulmonary disease is a leading cause of morbidity and mortality in rheumatoid arthritis (RA). In this study, we investigated the prevalence and progression of interstitial lung abnormalities (ILA) in a prospective cohort study of 18 subjects with early RA. METHODS:Eighteen adults diagnosed with anti-citrullinated protein-antibody-positive RA within the prior year underwent baseline high-resolution computed tomography (HRCT), symptom assessment, and pulmonary function and laboratory testing. The follow-up HRCT and clinical assessment were completed after 1 year. RESULTS:Seven of the 18 patients (39%) had baseline HRCT abnormalities including septal thickening, honeycombing, ground glass opacities, and/or traction bronchiectasis. At follow-up, 6 out of the 7 subjects (86%) with ILAs at baseline exhibited progression, while 10 out of 11 (91%) without ILAs at baseline remained stable. A higher Clinical Chronic Obstructive Pulmonary Disease Questionnaire score was associated with both the presence and progression of HRCT abnormalities (10 vs 2, p=0.045; 10 vs 2, p=0.009, respectively). C-reactive protein (CRP) trended higher in patients with radiologic abnormalities (3.5 mg/L vs 1.1 mg/L, p=0.08) and was significantly higher in those with progression (3.5 mg/L vs 1 mg/L, p=0.024). Smoking, pulmonary function, and autoantibodies were not associated with HRCT abnormalities. CONCLUSION:ILAs are prevalent in patients with early RA. If identified at baseline, radiographic progression of ILAs after 1 year is likely, while those without ILAs at baseline are unlikely to develop new ILAs. In addition, early respiratory symptoms and higher CRP levels may correlate with the presence and progression of underlying ILAs.

OBJECTIVE:Pulmonary disease is a leading cause of morbidity and mortality in rheumatoid arthritis (RA). In this study, we investigated the prevalence and progression of interstitial lung abnormalities (ILA) in a prospective cohort study of 18 subjects with early RA. METHODS:Eighteen adults diagnosed with anti-citrullinated protein-antibody-positive RA within the prior year underwent baseline high-resolution computed tomography (HRCT), symptom assessment, and pulmonary function and laboratory testing. The follow-up HRCT and clinical assessment were completed after 1 year. RESULTS:Seven of the 18 patients (39%) had baseline HRCT abnormalities including septal thickening, honeycombing, ground glass opacities, and/or traction bronchiectasis. At follow-up, 6 out of the 7 subjects (86%) with ILAs at baseline exhibited progression, while 10 out of 11 (91%) without ILAs at baseline remained stable. A higher Clinical Chronic Obstructive Pulmonary Disease Questionnaire score was associated with both the presence and progression of HRCT abnormalities (10 vs 2, p=0.045; 10 vs 2, p=0.009, respectively). C-reactive protein (CRP) trended higher in patients with radiologic abnormalities (3.5 mg/L vs 1.1 mg/L, p=0.08) and was significantly higher in those with progression (3.5 mg/L vs 1 mg/L, p=0.024). Smoking, pulmonary function, and autoantibodies were not associated with HRCT abnormalities. CONCLUSION:ILAs are prevalent in patients with early RA. If identified at baseline, radiographic progression of ILAs after 1 year is likely, while those without ILAs at baseline are unlikely to develop new ILAs. In addition, early respiratory symptoms and higher CRP levels may correlate with the presence and progression of underlying ILAs.

BACKGROUND:Extra-articular manifestations of rheumatoid arthritis (RA), potentially due to systemic inflammation, include cardiovascular disease and sarcopenic obesity. Adiponectin, an adipose-derived cytokine, has been implicated in inflammatory processes in RA, but little is known regarding its association with inflammation in a pre-clinical period. Therefore, we investigated whether adiponectin was associated with inflammatory markers in individuals at risk for RA, and whether RA-related autoimmunity modifies these associations. METHODS:We analyzed samples from 144 first-degree relatives (FDRs) of RA probands, of whom 23 were positive for anti-cyclic citrullinated peptide antibody and/or ≥ 2 rheumatoid factor isotypes (IgM, IgG or IgA). We called this phenotype the 'high risk autoantibody profile (HRP)' as it has been shown in prior work to be >96% specific for future RA. We measured adiponectin, cytokines, and high-sensitivity C-reactive protein (hsCRP). Using linear mixed effects models, we evaluated interaction between HRP positivity and adiponectin on inflammatory markers, adjusting for age, sex, ethnicity, body mass index, pack-years smoking, and use of cholesterol-lowering medications. RESULTS:In everyone, adiponectin concentration was inversely associated with hsCRP and IL-1β in adjusted models, where a 1% higher adiponectin was associated with a 26% lower hsCRP (p = 0.04) and a 26% lower IL-1β (p = 0.04). Significant interactions between HRP and adiponectin for associations with GM-CSF, IL-6, and IL-9 were detected in fully adjusted models (p = 0.0006, p = 0.006, p = 0.01, respectively). In HRP positive FDRs but not HRP negative FDRs, a 1% higher adiponectin was associated with 97% higher GM-CSF, 73% higher IL-6, and 54% higher IL-9 concentrations. CONCLUSIONS:Adiponectin associates with inflammatory markers, and these associations differ in individuals with a high-risk autoantibody profile compared with those without. The interaction between adiponectin and autoimmunity warrants further investigation into the potential systemic effects of RA-related autoantibodies and adiponectin on inflammation in the absence of clinically apparent RA.

BackgroundHypertension is more common in patients with rheumatoid arthritis (RA) than in the general population. It is unknown whether hypertension is due to RA-related medications or the disease itself. Therefore, we sought to investigate associations between RA-related autoantibodies, specifically antibodies to citrullinated protein antigens (ACPA) and systolic blood pressure (SBP) and diastolic blood pressure (DBP) in first-degree relatives of RA patients, who were free of RA and RA-related medications. We hypothesized that a greater number of detectable ACPA would be associated with high SBP and DBP, independent of other risk factors in these first-degree relatives.MethodsWe evaluated associations between ACPA and SBP and DBP in a cross-sectional study of 72 first-degree relatives (defined as parent, child, or sibling) of RA patients. Fifteen ACPA were measured using a Bio-Plex bead-based assay; each was dichotomized as positive/negative based on pre-specified cut-points. Analysis of covariance was used to evaluate associations between ACPA positivity and SBP and DBP, adjusting for age, sex, race, body mass index (BMI), pack-years of smoking, high sensitivity C-reactive protein (hsCRP), and current use of anti-hypertensive medications.ResultsAverage age was 51 and 69% were women. Mean SBP was 119 ± 18 and DBP was 74 ± 9 mm Hg. Thirty-three (46%) first-degree relatives were positive for ≥1 ACPA; and were younger, had lower BMI, more pack-years of smoking, and higher hsCRP concentrations compared to ACPA negative first-degree relatives. For each additional positive ACPA, SBP was 0.98 ± 0.5 mm Hg (p = 0.05) higher, and DBP was 0.66 ± 0.3 mm Hg (p = 0.04) higher. Anti-cit-fibrinogen A (211-230) positive and anti-cit-filaggrin positive first-degree relatives had 11.5 and 13.9 mm Hg higher SBP (p = 0.02) respectively. Anti-cit-clusterin, cit-filaggrin, and cit-vimentin positive first-degree relatives had 7-8 mm Hg higher DBP (p = 0.03, 0.05, 0.05 respectively), compared to being negative for these individual ACPA. Consistent with associations between ACPA, SBP, and DBP, anti-cyclic citrullinated peptides (anti-CCP2) positive first-degree relatives had 16.4± (p = 0.03) higher SBP and 12.1± mm Hg (p = 0.01) higher DBP than anti-CCP2 negative first-degree relatives.ConclusionIn first-degree relatives without RA, ACPA positivity is associated with higher SBP and DBP. Subclinical autoimmune processes and ACPA may play a role in the vascular changes potentially leading to hypertension prior to RA onset.

Objective: Rheumatoid arthritis (RA) has a "pre‐RA" period in which multiple autoantibodies, including antibodies to citrullinated (cit) proteins (ACPA), rheumatoid factor (RF), anti–peptidyl arginine deiminase (anti‐PAD), among others, have been described; however, few studies have tested all autoantibodies in a single pre‐RA cohort. This study aims to evaluate the prevalence of multiple autoantibodies in pre‐RA and potentially identify an autoantibody profile in pre‐RA that indicates imminent onset of clinical RA. Methods: We evaluated 148 individuals with two pre‐ and one post‐RA diagnosis samples available from the Department of Defense Serum Repository and matched controls. Samples were tested for immuglobulin (Ig) G anti–cyclic cit peptide‐3 (anti‐CCP3), five ACPA fine specificities, five anti‐PAD isoforms, as well as RF IgA and RF IgM using commercial platforms; cutoffs were determined using levels present in <1% of controls. Results: Positivity of anti‐CCP3, RF IgA and RF IgM, anti‐PAD1, anti–cit‐vimentin 2, anti–cit‐fibrinogen, and anti–cit‐histone 1 increased over time in pre‐RA, although anti‐PAD and ACPA fine specificities were predominately present within anti‐CCP3–positive individuals. Within anti‐CCP3–positive samples from the pre‐RA period, positivity for RFs as well as anti‐PAD and ACPA fine specificities classified samples as being closer to the time of RA diagnosis. Conclusion: Multiple autoantibodies are present in pre‐RA and increase in positivity as the time of RA diagnosis approaches. These results confirm previous findings predicting imminent RA and provide a pathway using commercial‐grade assays to assess the risk for and timing of development of clinical RA. [ABSTRACT FROM AUTHOR]

Objective: To investigate immune dysregulation in the peripheral blood that contributes to the pre‐rheumatoid arthritis (RA) stage of RA development in anticitrullinated protein antibody (ACPA)+ individuals. Methods: Using 37 markers by mass cytometry, we investigated peripheral blood mononuclear cells (PBMCs) from ACPA+ at‐risk individuals, ACPA+ early untreated patients with RA, and ACPA− controls in the Tokyo Women's Medical University cohort (n = 17 in each group). Computational algorithms, FlowSOM and Optimized t‐Distributed Stochastic Neighbor Embedding, were employed to explore specific immunologic differences between study groups. These findings were further evaluated, and longitudinal changes were explored, using flow cytometry and PBMCs from the US‐based Targeting Immune Responses for Prevention of RA cohort that included 11 ACPA+ individuals who later developed RA (pre‐RA), of which 9 had post‐RA diagnosis PBMCs (post‐RA), and 11 ACPA− controls. Results: HLA‐DR+ peripheral helper T (Tph) cells, activated regulatory T cells, PD‐1hi CD8+ T cells, and CXCR5−CD11c−CD38+ naive B cells were significantly expanded in PBMCs from at‐risk individuals and patients with early RA from the Tokyo Women's Medical University cohort. Expansion of HLA‐DR+ Tph cells and CXCR5−CD11c−CD38+ naive B cells was likewise found in both pre‐RA and post‐RA time points in the Targeting Immune Responses for Prevention of RA cohort. Conclusion: The expansion of HLA‐DR+ Tph cells and CXCR5−CD11c−CD38+ naive B cells in ACPA+ individuals, including those who developed inflammatory arthritis and classified RA, supports a key role of these cells in transition from pre‐RA to classified RA. These findings may identify a new mechanistic target for treatment and prevention in RA. [ABSTRACT FROM AUTHOR]