Comparison of baseline characteristics between the bDMARDs/tsDMARDs group and cDMARDs group
The data of a total of 2949 patients for baseline, 2565 for 1-year follow up, 2073 for 2-year follow up, 1612 for 3-year follow up, and 1197 for 4-year follow up were collected in the KOBIO registry. After excluding non-eligible data, 917 patients (baseline), 826 patients (1-year follow up), 789 patients (2-year follow up), 691 patients (3-year follow up), and 520 patients (4-year follow up) were included in the analysis (Figure 1). RA patients using bDMARDs/tsDMARDs experienced a longer disease duration and showed a higher DAS28 score. The most commonly used bDMARD/tsDMARD was TNF-α inhibitors (48.7%). For laboratory findings the inflammatory markers, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were significantly higher in the bDMARDs/tsDMARDs group than the cDMARDs group, whereas total cholesterol (TC), LDL-C, and TG levels were higher in the cDMARDs group. When analysing AIP, the bDMARDs/tsDMARDs and cDMARDs groups were comparable (Table 1). In subgroup analysis, TC was higher in the cDMARDs group than the TNF-α inhibitor group, and LDL-C was higher in the cDMARDs group than the tocilizumab group (Supplementary Table 1).
Table 1. Baseline characteristics of RA patients with bDMARDs/tsDMARDs and cDMARDs
|
RA patients with bDMARDs or tsDMARDs
|
RA patients with cDMARDs
|
P
|
(N=696)
|
(N=221)
|
Female, N (%)
|
590 (84.8%)
|
188 (85.1%)
|
1.000
|
Age (years)
|
55.1 ± 12.8
|
55.4 ± 11.9
|
0.717
|
Disease duration (years)
|
8.2 ± 7.7
|
6.7 ± 7.6
|
0.016
|
BMI (kg/m2)
|
22.5 ± 3.3
|
22.9 ± 3.2
|
0.063
|
Smoking
|
|
0.826
|
Never
|
594 (85.3%)
|
184 (83.6%)
|
Ex-smoker
|
51 ( 7.3%)
|
18 ( 8.2%)
|
Current smoker
|
51 ( 7.3%)
|
18 ( 8.2%)
|
Hypertension, N (%)
|
197 (28.3%)
|
64 (29.0%)
|
0.918
|
Ischemic heart disease, N (%)
|
16 ( 2.3%)
|
2 ( 0.9%)
|
0.306
|
Congestive heart failure, N (%)
|
11 ( 1.6%)
|
0 ( 0.0%)
|
0.127
|
DM without complication, N (%)
|
70 (10.1%)
|
16 (7.2%)
|
0.263
|
DM with complication, N (%)
|
8 (1.1%)
|
2 (0.9%)
|
1.000
|
Stroke, N (%)
|
6 ( 0.9%)
|
1 ( 0.5%)
|
0.868
|
Obesity, N (%)
|
14 ( 2.0%)
|
5 ( 2.3%)
|
1.000
|
ESR (mm/hr)
|
47.9 ± 26.3
|
31.9 ± 26.5
|
< 0.001
|
CRP (mg/dL)
|
2.3 ± 3.0
|
0.7 ± 1.6
|
< 0.001
|
DAS28-ESR
|
5.7 ± 1.0
|
3.5 ± 1.3
|
< 0.001
|
DAS28-CRP
|
5.0 ± 1.0
|
2.8 ± 1.2
|
< 0.001
|
bDMARDs or tsDMARDs
|
|
|
TNF-α inhibitor
|
339 (48.7%)
|
|
Tocilizumab
|
200 (28.7%)
|
|
Abatacept
|
94 (13.5%)
|
|
JAKi (tofacitinib or baricitinib)
|
63 ( 9.1%)
|
|
cDMARDs
|
|
|
|
Methotrexate, N (%)
|
591 (84.9%)
|
195 (88.2%)
|
0.263
|
Hydroxychloroquine, N (%)
|
143 (20.5%)
|
92 (41.6%)
|
<0.001
|
Sulfasalazine, N (%)
|
59 ( 8.5%)
|
28 (12.7%)
|
0.085
|
Leflunomide, N (%)
|
160 (23.0%)
|
65 (29.4%)
|
0.065
|
Tacrolimus, N (%)
|
101 (14.5%)
|
20 ( 9.0%)
|
0.048
|
Rheumatoid factor positivity, N (%)
|
594 (87.0%)
|
182 (83.9%)
|
0.298
|
ACPA positivity, N (%)
|
515 (86.3%)
|
162 (85.3%)
|
0.821
|
Total cholesterol (mg/dL)
|
175.3 ± 37.0
|
182.5 ± 34.0
|
0.011
|
HDL-C (mg/dL)
|
58.3 ± 23.0
|
58.6 ± 16.4
|
0.812
|
LDL-C (mg/dL)
|
76.2 ± 49.0
|
84.1 ± 46.9
|
0.034
|
Triglyceride (mg/dL)
|
102.6 ± 51.2
|
116.4 ± 74.6
|
0.011
|
AIP
|
-0.142 ± 0.249
|
-0.108 ± 0.292
|
0.129
|
AIP category
|
|
0.089
|
Low risk (AIP<0.11)
|
582 (83.6%)
|
174 (78.7%)
|
Intermediate risk (0.11≤AIP≤0.21)
|
57 ( 8.2%)
|
18 ( 8.1%)
|
High risk (AIP>0.21)
|
57 ( 8.2%)
|
29 (13.1%)
|
ACPA, anti-citrullinate protein antibody; AIP, atherogenic index of plasma; bDMARDs, biologic disease-modifying antirheumatic drugs; BMI, body mass index; cDMARDs, conventional disease-modifying antirheumatic drugs; CRP, C-reactive protein; DAS28, disease activity score-28; DM, diabetes mellitus; ESR, erythrocyte sedimentation rate; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; JAKi, janus kinase inhibitor; TNF-α, tumor necrosis factor α
Comparison of lipid profile and AIP over 1-year to 4-year follow up between bDMARDs/tsDMARDs and cDMARDs groups, and subgroup analysis
For the 1-year follow up data, LDL-C was significantly higher in the bDMARDs/tsDMARDs than in the cDMARDs group, however other lipid profiles and AIP were comparable between the groups (Table 2). In subgroup analysis, TC of the tocilizumab group was significantly higher than the TNF-α inhibitor and cDMARDs groups, and HDL-C was higher in the JAKi group than the abatacept group (Table 3).
Table 2. Comparison between RA patients with bDMARDs / JAKi and cDMARDs of 1-year follow up lipid profile and AIP
|
RA patients with bDMARDs or JAKi
|
RA patients with cDMARDs
|
P
|
(N=652)
|
(N=174)
|
Total cholesterol (mg/dL)
|
184.0 [161.0;209.0]
|
181.0 [159.0;203.0]
|
0.212
|
HDL-C (mg/dL)
|
59.0 [49.0;69.0]
|
59.0 [49.0;68.0]
|
0.652
|
LDL-C (mg/dL)
|
95.0 [66.8;120.0]
|
85.5 [44.0;112.0]
|
0.005
|
Triglyceride (mg/dL)
|
109.0 [76.0;152.0]
|
97.5 [72.0;137.0]
|
0.164
|
AIP
|
-0.090 ± 0.286
|
-0.116 ± 0.269
|
0.275
|
AIP category
|
|
0.704*
|
Low risk (AIP<0.11)
|
498 (76.4%)
|
138 (79.3%)
|
Intermediate risk (0.11≤AIP≤0.21)
|
54 ( 8.3%)
|
12 ( 6.9%)
|
High risk (AIP>0.21)
|
100 (15.3%)
|
24 (13.8%)
|
* The Mantel–Haenszel χ2 test was used.
AIP, atherogenic index of plasma; bDMARDs, biologic disease-modifying antirheumatic drugs; cDMARDs, conventional disease-modifying antirheumatic drugs;
HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; JAKi, janus kinase inhibitor
Table 3. Comparison of lipid profile and AIP between RA patients with cDMARDs, TNF-α inhibitor, tocilizumab, abatacept and JAKi (1-year follow up data)
|
RA patients with cDMARDs
|
RA patients with TNF-α inhibitor
|
RA patients with tocilizumab
|
RA patients with Abatacept
|
RA patients with JAKi
|
P
|
(N=174)
|
(N=319)
|
(N=209)
|
(N=87)
|
(N=37)
|
Total cholesterol (mg/dL)
|
181.0 [159.0;203.0] †
|
181.0 [160.0;206.0] ‡
|
192.0 [165.0;219.0] †‡
|
183.0 [156.0;204.0]
|
183.0 [164.0;212.0]
|
0.040
|
HDL-C (mg/dL)
|
59.0 [49.0;68.0]
|
59.0 [48.0;68.0]
|
60.0 [50.0;70.0]
|
56.0 [46.0;67.0] ⁑
|
68.0 [54.0;76.0] ⁑
|
0.037
|
LDL-C (mg/dL)
|
85.5 [44.0;112.0]
|
94.0 [68.0;117.5]
|
99.0 [56.0;122.0]
|
94.0 [72.0;121.7]
|
97.0 [75.0;118.0]
|
0.050
|
Triglyceride (mg/dL)
|
97.5 [72.0;137.0]
|
107.0 [76.0;142.0]
|
112.0 [77.0;165.0]
|
111.0 [80.5;152.5]
|
110.0 [71.0;147.0]
|
0.398
|
AIP
|
-0.116 ± 0.269
|
-0.095 ± 0.280
|
-0.086 ± 0.291
|
-0.066 ± 0.242
|
-0.121 ± 0.388
|
0.362
|
AIP category
|
|
0.451*
|
Low risk (AIP<0.11)
|
138 (79.3%)
|
251 (78.7%)
|
153 (73.2%)
|
66 (75.9%)
|
28 (75.7%)
|
Intermediate risk (0.11≤AIP≤0.21)
|
12 ( 6.9%)
|
21 ( 6.6%)
|
22 (10.5%)
|
10 (11.5%)
|
1 ( 2.7%)
|
High risk (AIP>0.21)
|
24 (13.8%)
|
47 (14.7%)
|
34 (16.3%)
|
11 (12.6%)
|
8 (21.6%)
|
* The Mantel–Haenszel χ2 test was used.
† Significant difference in total cholesterol between cDMARDs group and tocilizumab group demonstrated by post-hoc analysis via Tukey method.
‡ Significant difference in total cholesterol between TNF-α inhibitor group and tocilizumab group demonstrated by post-hoc analysis via Tukey method.
⁑ Significant difference in HDL-C between abatacept group and JAKi group demonstrated by post-hoc analysis via Tukey method.
AIP, atherogenic index of plasma; cDMARDs, conventional disease-modifying antirheumatic drugs; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; JAKi, janus kinase inhibitor; TNF-α, tumor necrosis factor α
When analysing the 2-year follow up data, the lipid profile and AIP of the bDMARDs/tsDMARDs and cDMARDs groups showed no significant differences (Supplementary Table 2-1). In subgroup analysis, HDL-C was higher in the JAKi group (median HDL-C 73.5 mg/dL) than the TNF-α inhibitor, tocilizumab, abatacept, and cDMARDs groups (median HDL-C 57.0, 59.0, 57.0, 61.0 mg/dL, respectively, Supplementary Table 2-2).
For the 3- and 4-year follow up data, lipid profile and AIP did not show significant differences when comparing the bDMARDs/tsDMARDs and cDMARDs groups (Supplementary Table 3-1, 4-1), or in subgroup analysis (Supplementary Table 3-2, Table 4-2).
Associated factors of dyslipidaemia and comparison of new onset dyslipidaemia between bDMARDs/tsDMARDs and cDMARDs groups, and subgroup analysis
The mean follow up duration for the bDMARDs/tsDMARDs group and the cDMARDs group was 30.1 ± 17.4 and 34.4 ± 16.7 months, respectively. During the observation period, dyslipidaemia was observed in 59 patients (8.5%) of the bDMARDs/tsDMARDs group and 15 patients (6.8%) of the cDMARDs group, with the difference being non-significant (P=0.508). A cumulative hazard proportion curve of dyslipidaemia occurrence did not show a significant difference between the bDMARDs/tsDMARDs group and cDMARDs groups (Figure 2A, P=0.06). The occurrence of dyslipidaemia was similar after dividing bDMARDs/tsDMARDs into each medication subgroup (Figure 2B, P=0.3). In univariate cox proportional analysis, older age (HR=1.033, P=0.004), TNF-α inhibitor use (HR=3.461, P=0.018), tocilizumab use (HR=3.654, P=0.014), abatacept use (HR=3.724, P=0.032), and JAKi use (HR=5.761, P=0.044) were associated with dyslipidaemia occurrence (Table 4). Following multivariate analysis, older age (HR=1.029, P=0.005) and combined hypertension (HR=2.206, P=0.013) showed significant association, whereas bDMARDs/tsDMARDs use did not (Table 4).
Table 4. Univariable and multivariable cox regression analysis of predicting new onset dyslipidemia
|
Univariable
|
Multivariate
|
HR
|
95% CI
|
P
|
HR
|
95% CI
|
P
|
Age (year)
|
1.033
|
1.010, 1.055
|
0.004
|
1.029
|
1.009, 1.050
|
0.005
|
Female
|
1.106
|
0.539, 2.270
|
0.783
|
|
|
|
Disease duration (year)
|
0.972
|
0.938, 1.008
|
0.126
|
|
|
|
BMI (kg/m2)
|
1.006
|
0.927, 1.093
|
0.881
|
|
|
|
Hypertension
|
1.835
|
0.944, 3.568
|
0.073
|
2.206
|
1.183, 4.116
|
0.013
|
Diabetes mellitus
|
1.023
|
0.443, 2.362
|
0.958
|
|
|
|
DAS28-ESR
|
0.901
|
0.507, 1.600
|
0.722
|
|
|
|
DAS28-CRP
|
0.907
|
0.523, 1.572
|
0.728
|
|
|
|
Rheumatoid factor positivity
|
1.259
|
0.608, 2.609
|
0.535
|
|
|
|
ACPA positivity
|
0.984
|
0.476, 2.032
|
0.965
|
|
|
|
TNF-α inhibitor
|
3.461
|
1.237, 9,688
|
0.018
|
1.787
|
0.931, 3.429
|
0.081
|
Tocilizumab
|
3.654
|
1.301, 10.267
|
0.014
|
1.918
|
0.925, 3.980
|
0.080
|
Abatacept
|
3.724
|
1.118, 12.399
|
0.032
|
2.099
|
0.861, 5.121
|
0.103
|
JAKi
|
5.761
|
1.050, 31.620
|
0.044
|
3.070
|
0.675, 13.972
|
0.147
|
Methotrexate
|
0.947
|
0.446, 2.012
|
0.888
|
|
|
|
Hydroxychloroquine
|
0.921
|
0.479, 1.769
|
0.804
|
|
|
|
Sulfasalazine
|
0.260
|
0.035, 1.904
|
0.185
|
|
|
|
Leflunomide
|
0.940
|
0.520, 1.700
|
0.838
|
|
|
|
Tacrolimus
|
0.750
|
0.336, 1.677
|
0.484
|
|
|
|
ACPA, anti-citrullinate protein antibody; BMI, body mass index; CI, confidence interval; CRP, C-reactive protein; DAS28, disease activity score-28; ESR, erythrocyte sedimentation rate; HR, hazard ratio; JAKi, janus kinase inhibitor; TNF-α, tumor necrosis factor α