Background/Purpose: Abnormal function of high density lipoprotein (HDL) has been implicated as a potential mechanism for the increased cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA).  The current work evaluated changes in HDL function and HDL-associated proteins over two years of follow-up in early RA patients receiving either methotrexate (MTX) monotherapy or combination therapies in the Treatment of Early Rheumatoid Arthritis (TEAR) trial.

Methods:

TEAR was a 2-year investigator-initiated randomized control trial of 755 DMARD-naïve early RA patients who were randomized to initiate aggressively-titrated MTX monotherapy, MTX + etanercept (ETA), or triple therapy (TT) [MTX + sulfasalazine + hydroxychloroquine].  Serum specimens from 550 TEAR participants were included in this analysis and 4 time points (0, 24, 48, and 102 weeks) were assessed.  HDL’s anti-oxidant capacity, paraoxonase 1 (PON-1) activity, HDL-associated haptoglobin (HDL-Hp), HDL-associated apolipoprotein AI (HDL-apoAI), and myeloperoxidase (MPO) levels were measured by previously published assays and sandwich/direct ELISA. (A&R 2009; 60: 2870, 2013; A&R  2013 doi:10.1002/art.38118(epub ahead of print)). Repeated measures analysis was performed using mixed effect linear models with autoregressive covariate structure to model the within-subject covariance over time.  Log transformation was performed on all outcome measurements.

Results:

Mixed effect models controlling for traditional CV risk factors, TEAR treatment, prednisone use, and statin use demonstrated significant associations of systemic inflammation measured by C-reactive Protein (CRP) with HDL’s anti-oxidant capacity and HDL-associated proteins within patients over time.  Specifically, decreases in CRP over time were associated with improvements in the HDL function profile including increases in PON1 activity and HDL-apoA1 levels, and decreases in the HDL inflammatory index (HII) and HDL-Hp (Table).   Similar results were observed with substitution of ESR or DAS28 in place of CRP in the regression models (data not shown).  Treatment assignment was not consistently associated with changes in HDL function or associated proteins over time.

Conclusion:

Decreases in systemic inflammation and RA disease activity were associated with improvements in HDL’s anti-oxidant capacity and associated HDL-proteins in early RA patients treated with MTX, MTX + ETA, or TT in the TEAR trial.  Additional work is warranted to further evaluate abnormal HDL function as a potential mechanism and therapeutic target for increased CV risk in patients with active RA.

Table: Percentage Change in HDL Function Marker by Covariate in Multivariate Repeated Measures

Analyses.

	HII		PON1 Activity		HDL-Hp		HDL-ApoAI		MPO
	Effects	p	Effects	p	Effects	P	Effects	p	Effects	p
CRP, (per 10 unit decrease)	-2.34%	<0.01	3.42%	<0.01	-3.53%	<0.01	8.74%	<0.01	-1.91%	0.07
Race (overall)		0.05		<0.01		0.03		0.21		<0.01
AA vs Caucasian	-18.53%	0.03	45.64%	<0.01	-13.82%	0.05	56.88%	0.13	37.64%	<0.01
AA vs Others	-25.27%	0.02	14.90%	0.39	-22.74%	0.01	98.60%	0.09	12.84%	0.30
Others vs Caucasian	9.03%	0.36	26.76%	0.05	11.55%	0.14	-21.01%	0.43	21.98%	0.02
BMI (per unit increase)	1.19%	<0.01	-0.31%	0.51	0.74%	0.01	-2.79%	0.02	-0.17%	0.61
Female vs. Male	-7.91%	0.18	7.17%	0.37	-0.52%	0.91	0.99%	0.96	-15.09%	<0.01
Disease Duration (per year increase)	0.59%	0.15	-0.03%	0.95	0.06%	0.86	0.23%	0.86	-0.94%	0.01

Percentage change in HDL function variables are shown per categorical variable or per unit change in continuous variables as specified.  Only significant associations besides time are shown in the table.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/improvement-in-high-density-lipoprotein-function-in-early-rheumatoid-arthritis-patients-treated-with-methotrexate-monotherapy-or-combination-therapy-in-the-treatment-of-early-rheumatoid-arthritis-tria/