LDL Cholesterolemia as a Novel Risk Factor for Radiographic Progression of Rheumatoid Arthritis: A Single-Center Prospective Study

<div><p>Dyslipidemia has been implicated in various musculoskeletal diseases, including rheumatoid arthritis (RA). Evidence is emerging that there might be a pathogenic interaction among inflammation, dyslipidemia, and adipokines. We prospectively investigated the association of cumulative lipid levels with radiographic progression of RA. RA patients (n = 242) underwent plasma cholesterol assessment at four visits. Disease activity parameters and X-rays of the hands and feet were also serially monitored in these patients. The cumulative inflammatory burden and lipid levels were estimated by time-integrated values. Serum leptin and adiponectin concentrations were determined by ELISA. When patients were divided into three groups according to time-integrated lipid levels, as expected, patients with LDL cholesterol and/or triglyceride levels in the third tertile had persistently higher ESR and CRP levels. In parallel, a more rapid radiographic progression over two years was observed in patients with higher LDL cholesterol and/or triglyceride levels. In multivariate analysis, time-integrated LDL cholesterol was independently associated with radiographic progression. Particularly, the risk of radiographic progression was 5.6-fold in a subgroup with both LDL cholesterol and triglyceride levels in the third tertile. Moreover, LDL cholesterol synergistically increased the adjusted probability of radiographic progression in patients with high serum leptin levels but not in those without. These results demonstrate that LDL cholesterolemia is a novel serum marker that can be used to predict radiographic progression of RA, which seems to be related to circulatory leptin levels. We suggest that personalized and more aggressive anti-rheumatic therapy is required for dyslipidemic subgroups in RA patients.</p></div

Logistic regression analysis of radiographic progression at two years according to lipid levels.

<p>OR = odds ratio, CI = confidence interval. Basic model is comprised of age, body mass index, disease duration, presence of anti-cyclic citrullinated peptide antibody and rheumatoid factor, time-integrated erythrocyte sedimentation rate levels, time-integrated C-reactive protein levels, and methotrexate use.</p

Effect of serum leptin levels on radiographic progression linked to LDL cholesterolemia.

<p>Adjusted cumulative probability plots for radiographic progression according to LDL cholesterol levels in patients with RA were stratified again by leptin levels (<b>A</b>) and adiponectin levels (<b>B</b>). In each panel, the upper cut-off value is represented by the red line (≧16.888 ng/ml for leptin and ≧1.682 µg/ml for adiponectin), and the lower cut-off value is the blue line (<16.888 ng/ml for leptin and <1.682 µg/ml for adiponectin). The upper and lower 95% confidence limits are depicted by the grey lines surrounding the average probability plot.</p

Comparison of the effects of LDL cholesterol levels, other lipid levels, and conventional prognostic factors on radiographic progression of rheumatoid arthritis.

<p>(<b>A</b>) Adjusted odds ratio of radiographic progression with combination of time-integrated LDL cholesterol and triglyceride levels. (<b>B</b>) Adjusted odds ratio of radiographic progression with combination of time-integrated LDL cholesterol and HDL cholesterol levels. The first tertile of lipid levels (dark gray column) was the reference group. All were adjusted for the following variables: age, body mass index, disease duration, presence of ACPA and RF, time-integrated ESR levels, time-integrated CRP levels, and methotrexate use. <i>P</i>-values are obtained from comparison with the reference group. *<i>P</i><0.05 for the blue column. (<b>C</b>) Receiver operating characteristic curves of time-integrated LDL cholesterol, time-integrated ESR levels, time-integrated CRP levels, RF, and ACPA for prediction of radiographic progression. Area under the curve was 0.609 for time-integrated LDL cholesterol, 0.631 for ESR, 0.648 for CRP, 0.634 for RF, and 0.648 for ACPA. See the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0068975#pone-0068975-t001" target="_blank">Table 1</a> for abbreviations.</p

Changes in ESR, CRP level, and DAS28 during the follow-up period according to time-integrated lipid tertile.

<p>Patients with LDL cholesterol levels in the third tertile had persistently higher ESR levels (main effect of group: <i>P</i><0.001, main effect of time: <i>P</i><0.001, interaction effect: <i>P</i><0.001), CRP levels (main effect of group: <i>P</i><0.001, main effect of time: <i>P</i><0.001, interaction effect: <i>P</i><0.001), and DAS28 scores (main effect of group: <i>P</i> = 0.014, main effect of time: <i>P</i> = 0.016, interaction effect: <i>P</i><0.001) than those with levels in the first tertile. Patients with triglycerides levels in the third tertile had higher CRP levels (main effect of group: <i>P</i> = 0.021, main effect of time: <i>P</i><0.001, interaction effect: <i>P</i><0.001) and DAS28 scores (main effect of group: <i>P</i> = 0.011, main effect of time: <i>P</i> = 0.016, interaction effect: <i>P</i><0.001) than those with levels in the first tertile. No difference was found in ESR, CRP, and DAS28 according to HDL cholesterol levels. Values are expressed as mean±SD. <i>P</i>-values are calculated by ANOVA repeated measures. See the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0068975#pone-0068975-t001" target="_blank">Table 1</a> for abbreviations.</p

Patient disposition flow diagram of pooled safety population.

<p>Patient disposition flow diagram of pooled safety population.</p

Baseline Patient Characteristics in Pooled Safety Populations^a.

<p>Abbreviations: ACPA, anti-citrullinated peptide antibody; CRP, C-reactive protein; DAS28, disease activity score in 28 joints; ESR, erythrocyte sedimentation rate; HAQ-DI, Health Assessment Questionnaire Disease Index; MTX, methotrexate; OCR200, ocrelizumab 200 mg×2; OCR500, ocrelizumab 500 mg×2; PBO, placebo; RA, rheumatoid arthritis; RF, rheumatoid factor; SJC, swollen joint count; TJC, tender joint count.</p>a<p>Data shown as ranges (minimum and maximum values) across the 4 trials.</p>b<p>All patients in all studies received background MTX 7.5 to 25 mg/week (7.5 to 20 mg/week in FILM), except for in SCRIPT, in which MTX or leflunomide was permitted.</p

Cumulative probability of B-cell repletion in each clinical trial.

<p>(A) STAGE; (B) SCRIPT; (C) FEATURE and (D) FILM. B-cell repletion was defined as a return of CD19+ levels to baseline or 80 cells/µL, whichever was lower. Data summarized under the PBO/OL OCR500+MTX, OCR200/OL OCR500+MTX and OCR500/OL OCR500+MTX treatment groups are OL data only. The x-axis represents the number of weeks since the first infusion of the last course of OCR. MTX, methotrexate; OCR200, ocrelizumab 200 mg×2; OCR500, ocrelizumab 500 mg×2; OL, open-label; PBO, placebo.</p

Rates of serious infectious events (SIEs) by region.

<p>(A) STAGE; (B) SCRIPT; (C) FILM. MTX, methotrexate; OCR200, ocrelizumab 200 mg×2; OCR500, ocrelizumab 500 mg×2; PBO, placebo. “Asia” includes China, Hong Kong, Indonesia, Malaysia, Philippines, Republic of Korea, Singapore, Taiwan, Thailand and Japan; “Other” includes North and South America, Europe and South Africa.</p

Summary of Safety During the Double-Blind, Placebo-Controlled Periods^a.

<p>Abbreviations: AE, adverse event; DMARD, disease-modifying antirheumatic drug; IR, inadequate responder; IRR, infusion-related reaction; MTX, methotrexate; OCR200, ocrelizumab 200 mg×2; OCR500, ocrelizumab 500 mg×2; PBO, placebo; TNF, tumor necrosis factor.</p>a<p>Multiple events in individual patients were only counted once. Serious infections were defined as those requiring intravenous antibiotics and/or hospitalization or classified as serious by the investigator. Any opportunistic infection was classified as a serious infection.</p>b<p>All patients in all studies received background MTX 7.5 to 25 mg/week (7.5 to 20 mg/week in FILM), except for in SCRIPT, in which MTX or leflunomide was permitted.</p