Tile had higher CRP levels (main effect of group: P = 0.021, main effect of time: P,0.001, interaction effect: P,0.001) and DAS28 scores (main effect of group: P = 0.011, main effect of time: P = 0.016, interaction effect: P,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 mean6SD. P-values are calculated by ANOVA repeated measures. See the Table 1 for abbreviations. doi:10.1371/journal.pone.0068975.gLDL cholesterol levels (log transformed value: c = 0.294, P,0.001, Figure S2C). We further investigated whether serum adipokines affect the radiographic progression of RA linked to LDL cholesterolemia. To this end, we stratified the patients depending on serum Title Loaded From File leptin or adiponectin concentrations. As seen in Figure 3A, patients with high serum leptin (?6.888 ng/ml) showed a higher adjusted probability of radiographic progression than those with low leptin (, 16.888 ng/ml). The increase in radiographic progression by high leptin was synergistic with LDL cholesterolemia (P,0.001). Interestingly, LDL cholesterolemia significantly increased radiographic progression in patients with high leptin levels (OR = 1.035, 95 CI: [1.016?.033], P,0.001) but not in those with low leptin levels (OR = 1.010 [0.996?.023], P = 0.167), demonstrating a Title Loaded From File dichotomy of leptin effect on radiographic progression under the conditions of LDL cholesterolemia (Figure 3A). In contrast to leptin, there was no difference in the effect of high (?.682 ng/ml) versus low adiponectin (,1.682 ng/ml) on radiographic progression (OR = 1.020 [1.003?.037] and P = 0.018 for the high adiponectin subgroup; OR = 1.022 [1.009?.036] and P = 0.001 for the low adiponectin subgroup) (Figure 3B). Moreover, the effect of adiponectin in both subgroups was additive but not synergistic (P = NS).DiscussionInflammatory cytokines play a pathogenic role in abnormalities of lipid metabolism in a variety of disorders, including diabetes, obesity, metabolic syndrome, and atherosclerosis [35]. In regard to RA, reduced HDL cholesterol and elevated lipoprotein(a) correlated with elevated serum CRP levels and inflammatory activity [24]. Inflammatory activation may also drive higher LDL cholesterol levels in RA [24,25]. Moreover, effective control of RA can thus reverse adverse lipid profiles [20]. Previous studies have demonstrated the relationship between disease activity andDyslipidemia and Radiographic Progression in RATable 1. Association between patient characteristics and radiographic progression at two years.Variables Age, years Female, n ( ) Body mass index, kg/m2 Disease duration, years Rheumatoid factor1, n ( ) ACPA1, n ( ) DAS28 Baseline ESR, mm/hour Time-integrated ESR Baseline CRP, mg/dl Time-integrated CRP Methotrexate, n ( ) Anti-TNF a, n ( ) Time-integrated HDL cholesterol Time-integrated triglyceride Time-integrated LDL cholesterolRA patients with radiographic progression (n = 61) 54 (49?1) 50 (82.0) 22.1 (19.9?4.2) 8 (3?7) 48 (78.7) 55 (90.2) 4.4 (3.1?.5) 31 (16?1) 1068 (558?040) 0.43 (0.09?.57) 24.9 (5.1?0.5) 53 (86.9) 7 (11.5) 1344 (1146?488) 2280 (1668?336) 23977191 3098 (2557?886)RA patients without radiographic progression (n = 181) 52 (45?2) 138 (75.8) 23.1 (20.6?5.4) 6 (3?1) 117 (64.6) 134 (73.6) 3.9 (2.9?.3) 22 (12?9) 720 (384?272) 0.21 (0.08?.82) 10.3 (2.4?3.4) 134 (74.0) 19 (10.5) 1272 (1080?512) 2112 (1560?280) 2798 (2318?182)P-value{0.113 0.271 0.074 0.044 0.042 0.007 0.137 0.052.Tile had higher CRP levels (main effect of group: P = 0.021, main effect of time: P,0.001, interaction effect: P,0.001) and DAS28 scores (main effect of group: P = 0.011, main effect of time: P = 0.016, interaction effect: P,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 mean6SD. P-values are calculated by ANOVA repeated measures. See the Table 1 for abbreviations. doi:10.1371/journal.pone.0068975.gLDL cholesterol levels (log transformed value: c = 0.294, P,0.001, Figure S2C). We further investigated whether serum adipokines affect the radiographic progression of RA linked to LDL cholesterolemia. To this end, we stratified the patients depending on serum leptin or adiponectin concentrations. As seen in Figure 3A, patients with high serum leptin (?6.888 ng/ml) showed a higher adjusted probability of radiographic progression than those with low leptin (, 16.888 ng/ml). The increase in radiographic progression by high leptin was synergistic with LDL cholesterolemia (P,0.001). Interestingly, LDL cholesterolemia significantly increased radiographic progression in patients with high leptin levels (OR = 1.035, 95 CI: [1.016?.033], P,0.001) but not in those with low leptin levels (OR = 1.010 [0.996?.023], P = 0.167), demonstrating a dichotomy of leptin effect on radiographic progression under the conditions of LDL cholesterolemia (Figure 3A). In contrast to leptin, there was no difference in the effect of high (?.682 ng/ml) versus low adiponectin (,1.682 ng/ml) on radiographic progression (OR = 1.020 [1.003?.037] and P = 0.018 for the high adiponectin subgroup; OR = 1.022 [1.009?.036] and P = 0.001 for the low adiponectin subgroup) (Figure 3B). Moreover, the effect of adiponectin in both subgroups was additive but not synergistic (P = NS).DiscussionInflammatory cytokines play a pathogenic role in abnormalities of lipid metabolism in a variety of disorders, including diabetes, obesity, metabolic syndrome, and atherosclerosis [35]. In regard to RA, reduced HDL cholesterol and elevated lipoprotein(a) correlated with elevated serum CRP levels and inflammatory activity [24]. Inflammatory activation may also drive higher LDL cholesterol levels in RA [24,25]. Moreover, effective control of RA can thus reverse adverse lipid profiles [20]. Previous studies have demonstrated the relationship between disease activity andDyslipidemia and Radiographic Progression in RATable 1. Association between patient characteristics and radiographic progression at two years.Variables Age, years Female, n ( ) Body mass index, kg/m2 Disease duration, years Rheumatoid factor1, n ( ) ACPA1, n ( ) DAS28 Baseline ESR, mm/hour Time-integrated ESR Baseline CRP, mg/dl Time-integrated CRP Methotrexate, n ( ) Anti-TNF a, n ( ) Time-integrated HDL cholesterol Time-integrated triglyceride Time-integrated LDL cholesterolRA patients with radiographic progression (n = 61) 54 (49?1) 50 (82.0) 22.1 (19.9?4.2) 8 (3?7) 48 (78.7) 55 (90.2) 4.4 (3.1?.5) 31 (16?1) 1068 (558?040) 0.43 (0.09?.57) 24.9 (5.1?0.5) 53 (86.9) 7 (11.5) 1344 (1146?488) 2280 (1668?336) 23977191 3098 (2557?886)RA patients without radiographic progression (n = 181) 52 (45?2) 138 (75.8) 23.1 (20.6?5.4) 6 (3?1) 117 (64.6) 134 (73.6) 3.9 (2.9?.3) 22 (12?9) 720 (384?272) 0.21 (0.08?.82) 10.3 (2.4?3.4) 134 (74.0) 19 (10.5) 1272 (1080?512) 2112 (1560?280) 2798 (2318?182)P-value{0.113 0.271 0.074 0.044 0.042 0.007 0.137 0.052.
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