OBJECTIVE: We determined associations between adipokines and abnormal body composition in patients with rheumatoid arthritis (RA). METHODS: Combining data from three RA cohorts, whole-body dual-energy absorptiometry measures of appendicular lean mass and fat mass indices were converted to age-, sex-, and race- and ethnicity-specific Z scores. Lean mass relative to fat mass was determined based on prior methods. Independent associations between body composition profiles and circulating levels of adiponectin, leptin, and fibroblast growth factor (FGF)-21 were assessed using linear and logistic regression models adjusting for demographic characteristics and study cohort. We also determined the improvement in the area under the curve (AUC) for prediction of low lean mass when adipokines were added to predictive models that included clinical factors such as demographic characteristics, study, and body mass index (BMI). RESULTS: Among 419 participants, older age was associated with higher levels of all adipokines, whereas higher C-reactive protein level was associated with lower adiponectin levels and higher FGF-21 levels. Greater fat mass was strongly associated with lower adiponectin levels and higher leptin and FGF-21 levels. Higher levels of adiponectin, leptin, and FGF-21 were independently associated with low lean mass. The addition of adiponectin and leptin levels to regression models improved prediction of low lean mass when combined with demographic characteristics, study, and BMI (AUC 0.75 vs. 0.66). CONCLUSION: Adipokines are associated with both excess adiposity and low lean mass in patients with RA. Improvements in the prediction of body composition abnormalities suggest that laboratory screening could help identify patients with altered body composition who may be at greater risk of adverse outcomes.

Background

Obesity is associated with restrictive ventilatory defects and a faster rate of decline in FVC. This association is not exclusively mediated by mechanical factors and may reflect direct pulmonary injury by adipose-derived mediators.

Research question

Is adipose tissue involved in the pathogenesis of interstitial lung disease (ILD)?

Study design and methods

We evaluated the association of CT measures of pericardial, abdominal visceral, and abdominal subcutaneous adipose tissue with high-attenuation areas (HAAs) and interstitial lung abnormalities (ILAs) in a large multicenter cohort study of community-dwelling adults, using multivariable-adjusted models. We secondarily evaluated the association of adipose depot size with FVC and biomarkers of obesity and inflammation.

Results

In fully adjusted models, every doubling in pericardial adipose tissue volume was associated with a 63.4-unit increase in HAA (95% CI, 55.5-71.3), 20% increased odds of ILA (95% CI, -2% to 50%), and a 5.5% decrease in percent predicted FVC (95% CI, -6.8% to -4.3%). IL-6 levels accounted for 8% of the association between pericardial adipose tissue and HAA. Every doubling in visceral adipose tissue area was associated with a 41.5-unit increase in HAA (95% CI, 28.3-54.7), 30% increased odds of ILA (95% CI, -10% to 80%), and a 5.4% decrease in percent predicted FVC (95% CI, -6.6% to -4.3%). IL-6 and leptin accounted for 17% and 18%, respectively, of the association between visceral adipose tissue and HAA.

Interpretation

Greater amounts of pericardial and abdominal visceral adipose tissue were associated with CT measures of early lung injury and lower FVC in a cohort of community-dwelling adults. Adipose tissue may represent a modifiable risk factor for ILD.

Objective

Systemic inflammation and insulin resistance (IR) are linked, yet the determinants of IR and its impact on atherosclerosis in rheumatoid arthritis (RA) are incompletely understood. The aim of this study was to explore the prevalence of IR in RA and non-RA populations and investigate whether the associations of IR with measures of atherosclerosis differ between these groups.

Methods

IR was quantified using the homeostatic model assessment of IR (HOMA-IR), and was compared between RA patients and demographically matched non-RA controls. Differences in the associations between the HOMA-IR index and the Agatston coronary artery calcium (CAC) score, ultrasound-determined intima-media thickness (IMT) of the common carotid artery (CCA) and internal carotid artery (ICA), and focal plaque in the ICA/carotid bulb were compared according to RA status.

Results

Among the 195 RA patients and 198 controls studied, average HOMA-IR levels were higher in the RA group by 31%, and were consistently higher in the RA group regardless of stratification by demographic or cardiometabolic risk factors. While the HOMA-IR index was strongly and significantly associated with C-reactive protein (CRP) and interleukin-6 (IL-6) levels in the control group, the association was weaker in the RA group. Among RA patients, higher HOMA-IR levels were associated with rheumatoid factor (RF) seropositivity in men and women, and prednisone use in women only. Before adjustment, higher HOMA-IR levels were associated with all assessed measures of subclinical atherosclerosis in the control group only; associations were diminished and lost statistical significance after adjustment for cardiovascular risk factors. Among the RA patients, neither baseline nor average HOMA-IR levels were significantly associated with change in any of the atherosclerosis measures over an average of 3.2 years of followup.

Conclusion

Although IR was higher in RA patients than in non-RA controls, higher levels may not independently impart additional risk of atherosclerosis.

Objectives

To determine whether a novel measure of appendicular lean mass relative to fat mass is associated with physical functioning in RA.

Methods

In a cross-sectional design, three independent RA cohorts were retrospectively analysed. Whole-body DXA measures of appendicular lean mass index (ALMI, kg/m 2 ) and fat mass index (FMI, kg/m 2 ) were converted to age, sex and race-specific Z-scores using published National Health and Nutrition Examination Survey reference ranges. Adiposity-adjusted ALMI Z-scores (ALMI FMI ) were determined using a published method to adjust for normal associations between ALMI and FMI Z-scores. Associations between ALMI Z-scores, ALMI FMI Z-scores and physical functioning were assessed after adjusting for age, sex and study. Functional outcomes assessed included the HAQ, Valued Life Activities assessment and Short Physical Performance Battery. Low lean for age was defined as a Z-score of -1 or less.

Results

Our sample consisted of 442 patients with RA. The combined cohort had a mean ALMI Z-score of - 0.51 (1.08) and a mean ALMI FMI Z-score of - 0.58 (1.53), suggesting muscle mass deficits compared with a nationally representative sample. Greater ALMI FMI Z-scores demonstrated stronger associations with better functional outcomes compared with ALMI Z-scores. Associations were not attenuated with adjustment for systemic inflammation or pain. The FMI Z-score was independently associated with physical functioning, with a stronger association seen among patients with greater FMI Z-score. Adiposity-adjusted definitions of low lean mass more clearly identified those with functional impairment.

Conclusion

Estimates of appendicular lean mass that are adjusted for adiposity demonstrate stronger positive associations with functional outcomes compared with unadjusted estimates.

Objective

Citrullinated proteins have been found within atherosclerotic plaque. However, studies evaluating the association between anti-citrullinated protein antibodies (ACPAs) and imaging measures of atherosclerosis in patients with rheumatoid arthritis (RA) have been limited to seroreactive citrullinated fibrinogen or citrullinated vimentin and have rendered contradictory results. Therefore, our objective was to evaluate this association using an extended panel of ACPAs in a larger sample of RA patients without clinical cardiovascular disease (CVD).

Methods

ACPAs were identified using a custom Bio-Plex bead assay in 270 patients from 2 independent RA cohorts without clinical CVD, with the first one consisting of 195 patients and the other of 75 patients. Coronary artery calcium (CAC) was assessed by computed tomography as a measure of coronary artery disease.

Results

High levels of anti-citrullinated histone H2B antibodies were strongly associated with higher CAC scores, compared with lower antibody levels (P = 0.001); this remained significant after adjustment for traditional CV and RA-specific risk factors (P = 0.03). No association between levels of ACPAs and CAC progression at 3 years was seen (P = 0.09); however, the number of progressors was small (n = 92).

Conclusion

Higher levels of ACPAs targeting Cit-histone H2B were associated with higher CAC scores when compared to lower antibody levels, suggesting a potential role for histone citrullination seroreactivity in atherosclerosis.

INTRODUCTION: Upadacitinib (UPA) is a Janus kinase inhibitor that has demonstrated efficacy in moderate-to-severe rheumatoid arthritis (RA) with an acceptable safety profile. We investigated laboratory parameter changes in UPA RA clinical trials. METHODS: Pooled data from six randomized trials in the SELECT phase 3 program were included. Key laboratory parameters and safety data were measured for UPA 15 and 30 mg once daily (QD), adalimumab (ADA) 40 mg every other week + methotrexate (MTX), and MTX monotherapy. Exposure-adjusted event rates (EAERs) of adverse events were calculated. RESULTS: A total of 3209 patients receiving UPA 15 mg QD (10 782.7 patient-years [PY]), 1204 patients receiving UPA 30 mg QD (3162.5 PY), 579 patients receiving ADA + MTX (1573.2 PY), and 314 patients receiving MTX monotherapy (865.1 PY) were included, representing up to 6.5 years of total exposure. Decreases in mean levels of hemoglobin, neutrophils, and lymphocytes, and increases in mean levels of liver enzymes and creatinine phosphokinase were observed with UPA, with grade 3 or 4 changes observed in some patients. Mean low- and high-density lipoprotein cholesterol ratios remained stable for patients receiving UPA 15 mg QD. EAERs of anemia and neutropenia occurred at generally consistent rates between UPA and active comparators (3.1-4.3 and 1.7-5.0 events [E]/100 PY across treatment groups, respectively). Rates of hepatic disorder were higher with MTX monotherapy, UPA 15 mg and UPA 30 mg (10.8, 9.7, and 11.0 E/100 PY, respectively) versus ADA + MTX (6.4 E/100 PY). Rates of lymphopenia were highest with MTX monotherapy (3.2 E/100 PY). Treatment discontinuations due to laboratory-related events were rare, occurring in 1.1% and 2.2% of patients treated with UPA 15 and 30 mg QD, respectively. CONCLUSIONS: The results of this integrated long-term analysis of laboratory parameters continue to support an acceptable safety profile of UPA 15 mg QD for moderate-to-severe RA.

Objective

The C-reactive protein (CRP) level and erythrocyte sedimentation rate (ESR) are important disease activity biomarkers in rheumatoid arthritis (RA). This study aimed to determine to what extent obesity biases these biomarkers.

Methods

Body mass index (BMI) associations with CRP level and ESR were assessed in 2 RA cohorts: the cross-sectional Body Composition (BC) cohort (n = 451), including whole-body dual x-ray absorptiometry measures of fat mass index; and the longitudinal Veterans Affairs Rheumatoid Arthritis (VARA) registry (n = 1,652), using multivariable models stratified by sex. For comparison, associations were evaluated in the general population using the National Health and Nutrition Examination Survey.

Results

Among women with RA and in the general population, greater BMI was associated with greater CRP levels, especially among women with severe obesity (P < 0.001 for BMI ≥35 kg/m² versus 20-25 kg/m² ). This association remained after adjustment for joint counts and patient global health scores (P < 0.001 in BC and P < 0.01 in VARA), but was attenuated after adjustment for fat mass index (P = 0.17). Positive associations between BMI and ESR in women were more modest. In men with RA, lower BMI was associated with higher CRP levels and ESR, contrasting with positive associations among men in the general population.

Conclusion

Obesity is associated with higher CRP levels and ESR in women with RA. This association is related to fat mass and not RA disease activity. Low BMI is associated with higher CRP levels in men with RA; this unexpected finding remains incompletely explained but likely is not a direct effect of adiposity.

Background

Adipokines have inflammatory and fibrotic properties that may be critical in interstitial lung disease (ILD). We examined associations of serum adipokine levels with CT imaging-based measures of subclinical ILD and lung function among community-dwelling adults.

Methods

A subset of the original Multi-Ethnic Study of Atherosclerosis cohort (n = 1,968) had adiponectin, leptin, and resistin measured during follow-up visits (2002-2005). We used regression models to examine associations of adiponectin, leptin, and resistin levels with (1) high-attenuation areas (HAAs) from CT scans (2004-2005, n = 1,144), (2) interstitial lung abnormalities (ILAs) from CT scans (2010-2012, n = 872), and (3) FVC from spirometry (2004-2006, n = 1,446). We used -(1/HAA²), which we denoted with H, to model HAA as our outcome to meet model assumptions.

Results

Higher adiponectin was associated with lower HAA on CT imaging among adults with a BMI ≥ 25 kg/m² (P for BMI interaction = .07). Leptin was more strongly associated with ILA among never smokers compared with ever smokers (P for smoking interaction = .004). For every 1-SD increment of log-transformed leptin, the percent predicted FVC was 3.8% lower (95% CI, -5.0 to -2.5). Higher serum resistin levels were associated with greater HAA on CT in a fully adjusted model. For every 1-SD increment of log-transformed resistin there was an increase in H of 14.8 (95% CI, 3.4-26.3).

Conclusions

Higher adiponectin levels were associated with lower HAA on CT imaging among adults with a higher BMI. Higher leptin and resistin levels were associated with lower FVC and greater HAA, respectively.

Abstract Introduction In cross-sectional studies, patients with rheumatoid arthritis (RA) have higher coronary artery calcium (CAC) than controls. However, their rate of progression of CAC and the predictors of CAC progression have heretofore remained unknown. Methods Incidence and progression of CAC were compared in 155 patients with RA and 835 control participants. The association of demographic characteristics, traditional cardiovascular risk factors, RA disease characteristics and selected inflammatory markers with incidence and progression of CAC were evaluated. Results The incidence rate of newly detected CAC was 8.2/100 person-years in RA and 7.3/100 person-years in non-RA control subjects [IRR 1.1 (0.7-1.8)]. RA patients who developed newly detectable CAC were older (59±7 vs. 55±6 years old, p=0.03), had higher triglyceride levels (137±86 vs. 97±60 mg/dL, p=0.03), and higher systolic blood pressure (129±17 vs. 117±15 mm Hg, p=0.01) compared to those who did not develop incident CAC. Differences in blood pressure and triglyceride levels remained significant after adjustment for age (p<=0.05). RA patients with any CAC at baseline had a median rate of yearly progression of 21 (7–62) compared to 21 (5–70) Agatston units in controls. No statistical differences between RA progressors and RA non-progressors were observed for inflammatory markers or for RA disease characteristics. Conclusions The incidence and progression of CAC did not differ between RA and non-RA participants. In patients with RA, incident CAC was associated with older age, higher triglyceride levels, and higher blood pressure, but not with inflammatory markers or RA disease characteristics.

Objectives

Evaluate risk of major adverse cardiovascular events (MACE) with tofacitinib versus tumour necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA) with or without a history of atherosclerotic cardiovascular disease (ASCVD) in ORAL Surveillance.

Methods

Patients with RA aged ≥50 years with ≥1 additional CV risk factor received tofacitinib 5 mg or 10 mg two times per day or TNFi. Hazard rations (HRs) were evaluated for the overall population and by history of ASCVD (exploratory analysis).

Results

Risk of MACE, myocardial infarction and sudden cardiac death were increased with tofacitinib versus TNFi in ORAL Surveillance. In patients with history of ASCVD (14.7%; 640/4362), MACE incidence was higher with tofacitinib 5 mg two times per day (8.3%; 17/204) and 10 mg two times per day (7.7%; 17/222) versus TNFi (4.2%; 9/214). HR (combined tofacitinib doses vs TNFi) was 1.98 (95% confidence interval (CI) 0.95 to 4.14; interaction p values: 0.196 (for HR)/0.059 (for incidence rate difference)). In patients without history of ASCVD, MACE HRs for tofacitinib 5 mg two times per day (2.4%; 30/1251) and 10 mg two times per day (2.8%; 34/1234) versus TNFi (2.3%; 28/1237) were, respectively, 1.03 (0.62 to 1.73) and 1.25 (0.76 to 2.07).

Conclusions

This post hoc analysis observed higher MACE risk with tofacitinib versus TNFi in patients with RA and history of ASCVD. Among patients without history of ASCVD, all with prevalent CV risk factors, MACE risk did not appear different with tofacitinib 5 mg two times per day versus TNFi. Due to the exploratory nature of this analysis and low statistical power, we cannot exclude differential MACE risk for tofacitinib 5 mg two times per day versus TNFi among patients without history of ASCVD, but any absolute risk excess is likely low.

Trial registration number

NCT02092467.