Persistence with biologic agents for the treatment of rheumatoid arthritis in Japan

Figures & data

Figure 1 Definition of persistence in base case (60 days medication gap).

Figure 2 Study population.

Note: Data are presented as n (%) unless indicated.
Abbreviations: DMARDs, disease-modifying antirheumatic drugs; RA, rheumatoid arthritis.

Table 1 Characteristics of biologic-naïve and -continuing patients

Characteristics	Biologic-continuing patients, n (%)	Biologic-naïve patients, n (%)	P-value
RA patients	2,265	272
Age (mean ± SD)	59.90±13.25	58.69±14.59	0.1575
≤60 years	1,018 (45%)	129 (47%)
61–75 years	1,036 (46%)	116 (43%)
>75 years	211 (9%)	27 (10%)
Sex			0.236
Male	463 (20%)	64 (23%)
Female	1,802 (80%)	208 (77%)
CCI score (mean ± SD)	3.60±2.27	4.22±2.89	<0.001
≤2	855 (38%)	81 (30%)
3–5	1,023 (45%)	126 (46%)
>5	387 (17%)	65 (24%)
Comorbidity
Myocardial infarction	90 (4%)	9 (3%)	0.593
Congestive heart failure	629 (28%)	88 (32%)	0.113
Peripheral vascular disease	225 (10%)	36 (13%)	0.090
Cerebrovascular disease	279 (12%)	43 (16%)	0.102
Dementia	33 (1%)	5 (2%)	0.625
Chronic lung disease	598 (26%)	84 (31%)	0.115
Ulcer	1,013 (45%)	104 (38%)	0.042
Chronic liver disease	886 (39%)	154 (57%)	<0.001
Diabetes	2,265 (7%)	19 (7%)	0.777
Blood disorder disease	8 (0%)	1 (0%)	0.970
Moderate or severe kidney disease	96 (4%)	19 (7%)	0.040
Diabetes with end organ damage	83 (4%)	15 (6%)	0.135
Moderate or severe liver disease	8 (0%)	1 (0%)	0.970
Tumor and cancer	250 (11%)	23 (8%)	0.085

Abbreviations: CCI, Charlson Comorbidity Index; RA, rheumatoid arthritis; SD, standard deviation.

Figure 3 Kaplan–Meier curves for biologic agent patients.

Figure 4 Kaplan–Meier curves of naïve biologic agent patients.

Table 2 Persistence rates and 95% CIs

Biologic agents	Overall, % (95% CI)			Biologic-naïve patients, % (95% CI)			Biologic-continuing patients, % (95% CI)
	6 months	12 months	18 months	6 months	12 months	18 months	6 months	12 months	18 months
Etanercept	87.5 (85.2–89.5)	79.5 (76.7–81.9)	70.6 (67.5–73.5)	97.9 (86.1–99.7)	89.6 (76.7–95.5)	86.6 (72.3–93.8)	86.9 (84.5–89.0)	78.9 (76.0–81.5)	69.8 (66.6–72.8)
Adalimumab	91.1 (87.8–93.6)	84.3 (80.3–87.6)	78.7 (74.2–82.6)	100	96.9 (79.8–99.6)	96.9 (79.8–99.6)	90.3 (86.7–92.9)	83.2 (78.8–86.7)	77.2 (72.4–81.2)
Infliximab	95.8 (93.8–97.2)	93.5 (91.2–95.3)	91.5 (88.9–93.6)	98.8 (91.8–99.8)	97.6 (90.7–99.4)	97.6 (90.7–99.4)	95.3 (93.0–96.8)	92.8 (90.2–94.8)	90.5 (87.5–92.8)
Golimumab	93.9 (87.6–97.0)	91.2 (84.3–95.2)	85.6 (77.5–90.9)	100	100	100	91.9 (83.7–96.1)	88.5 (79.7–93.6)	81.5 (71.6–88.2)
Tocilizumab	94.5 (91.8–96.4)	89.1 (85.6–91.8)	84.2 (80.2–87.4)	98.0 (86.6–99.7)	96.0 (84.9–98.9)	93.7 (81.7–97.9)	94.5 (91.0–96.1)	88.1 (84.2–91.1)	82.8 (78.5–86.4)
Abatacept	96.8 (92.6–98.7)	95.6 (90.9–97.9)	94.9 (90.0–97.4)	96.8 (79.8–99.6)	93.7 (77.2–98.4)	93.7 (77.2–98.4)	96.8 (91.8–98.8)	96.0 (90.7–98.3)	95.2 (89.6–97.8)

Abbreviation: CI, confidence interval.

Table 3 P-values of log rank tests

Biologic agents	Overall					Biologic-naïve patients					Biologic-continuing patients
	ADL	IFX	GOL	TCZ	ABT	ADL	IFX	GOL	TCZ	ABT	ADL	IFX	GOL	TCZ	ABT
ETN	0.007	<0.001	0.011	<0.001	<0.001	0.142	0.018	0.068	0.258	0.388	0.012	<0.001	0.030	<0.001	<0.001
ADL	–	<0.001	0.340	0.063	<0.001	–	0.836	0.358	0.573	0.557	–	<0.001	0.398	0.082	<0.001
IFX	–	–	0.024	<0.001	0.203	–	–	0.418	0.297	0.320	–	–	0.013	0.001	0.102
GOL	–	–	–	0.999	0.008	–	–	–	0.226	0.190	–	–	–	0.777	0.002
TCZ	–	–	–	–	0.001	–	–	–	–	0.925	–	–	–	–	0.001

Note: The numbers show the result of our comparison between one biologic vs another biologic agent.

Abbreviations: ABT, abatacept; ADL, adalimumab; ETN, etanercept; GOL, golimumab; IFX, infliximab; TCZ, tocilizumab.

Table 4 Cox regression

Patient characteristics	Hazard ratio (95% confidence interval)
	Overall patients (n=2,537)	Biologic-naïve patients (n=272)	Biologic-continuing patients (n=2,265)
Age
≤60 years	Reference	Reference	Reference
61–75 years	0.88 (0.67–1.05)	1.05 (0.29–3.80)	0.83 (0.66–1.04)
>75 years	0.60 (0.40–0.91)	1.83 (0.34–9.95)	0.56 (0.37–0.86)
Sex
Male	Reference	Reference	Reference
Female	1.03 (0.79–1.34)	0.49 (0.14–1.73)	1.05 (0.80–1.38)
CCI score
≤2	Reference	Reference	Reference
3–5	1.33 (1.03–1.70)	5.29 (0.94–41.21)	1.26 (0.98–1.61)
>5	1.89 (1.40–2.57)	1.87×10^9	1.93 (1.42–2.62)
Biologic agent
Etanercept	Reference	Reference	Reference
Adalimumab	0.76 (0.57–1.02)	0.30 (0.03–2.68)	0.78 (0.58–1.05)
Infliximab	0.32 (0.22–0.45)	0.23 (0.04–1.23)	0.32 (0.22–0.46)
Golimumab	0.46 (0.24–0.87)	9.59×10^−19	0.52 (0.27–0.97)
Tocilizumab	0.51 (0.37–0.71)	0.29 (0.05–1.53)	0.52 (0.37–0.72)
Abatacept	0.20 (0.10–0.44)	0.49 (0.09–2.67)	0.16 (0.07–0.39)
Naïve
Naïve patients	Reference
Continuing biologic patients	3.01 (1.69–5.38)
	LR χ^2(12)=119.90	LR χ^2(12)=18.62	LR χ^2(12)=92.01
	Prob > χ^2=0.0000	Prob > χ^2=0.0286	Prob > χ^2=0.0000

Abbreviations: CCI, Charlson Comorbidity Index; LR (χ²), likelihood ratio chi-square; Prob, probability.

Table 5 Persistence rates (%) and 95% CIs of biologic-naïve patients for 30- and 120-day gap definition

Biologic agents	Overall, % (95% CI)			Biologic-naïve patients, % (95% CI)			Biologic-continuing patients, % (95% CI)
	6 months	12 months	18 months	6 months	12 months	18 months	6 months	12 months	18 months
30-day gap
Etanercept	68.2 (65.1–71.2)	55.7 (52.4–58.8)	46.1 (42.8–49.3)	87.5 (74.3–94.2)	68.8 (53.6–79.8)	58.3 (42.4–71.3)	67.2 (63.9–70.2)	54.9 (51.6–58.2)	45.5 (42.1–48.8)
Adalimumab	83.5 (79.4–86.9)	71.3 (66.5–75.5)	65.2 (60.1–69.7)	90.6 (73.7–96.9)	81.2 (63.0–91.1)	72.4 (51.6–85.4)	82.9 (78.5–86.5)	70.4 (65.3–74.8)	64.4 (59.1–69.2)
Infliximab	92.0 (89.4–94.9)	86.0 (82.9–88.6)	83.3 (79.9–86.1)	95.2 (87.7–98.2)	91.6 (83.1–95.9)	91.6 (83.1–95.9)	91.4 (88.6–93.6)	85.1 (81.6–87.9)	81.9 (78.2–85.0)
Golimumab	92.1 (85.4–95.8)	86.8 (79.1–91.8)	80.3 (71.6–86.6)	100	96.3 (76.5–99.5)	90.6 (66.5–97.7)	89.7 (81.1–94.5)	83.9 (74.3–90.1)	76.9 (66.6–84.5)
Tocilizumab	57.3 (52.3–62.0)	45.4 (40.5–50.2)	34.4 (29.7–39.1)	82.0 (68.3–90.2)	66.0 (51.1–77.3)	46.6 (31.5–60.4)	53.8 (48.5–58.9)	42.5 (37.3–47.6)	32.6 (27.7–37.5)
Abatacept	91.7 (86.2–95.1)	88.6 (82.5–92.6)	85.7 (79.2–90.4)	96.8 (79.8–99.6)	93.7 (77.2–98.4)	89.7 (71.9–96.6)	90.5 (83.8–94.5)	87.3 (80.1–92.0)	84.7 (77.1–89.9)
120-day gap
Etanercept	92.6 (90.7–94.1)	88.3 (86.0–90.2)	82.4 (79.7–84.7)	100	97.9 (86.1–99.7)	94.9 (80.9–98.7)	92.2 (90.2–93.8)	87.8 (85.4–89.8)	81.7 (78.9–84.2)
Adalimumab	94.5 (91.7–96.4)	90.1 (86.6–92.7)	86.4 (82.6–89.5)	100	100	100	94.0 (91.0–96.1)	89.2 (85.4–92.0)	85.3 (81.1–88.6)
Infliximab	96.1 (94.2–97.4)	94.2 (92.0–95.9)	92.8 (90.3–94.6)	98.8 (91.7–99.8)	97.6 (90.7–99.4)	97.6 (90.7–99.4)	95.7 (93.5–97.2)	93.7 (91.1–95.5)	91.9 (89.2–94.1)
Golimumab	93.9 (87.6–97.0)	91.2 (84.3–95.2)	85.6 (77.5–90.9)	100	100	100	92.0 (83.9–96.1)	88.5 (79.7–93.6)	81.5 (71.6–88.2)
Tocilizumab	97.3 (95.1–98.5)	93.8 (91.0–95.8)	91.5 (88.3–93.8)	100	98.0 (86.6–99.7)	98.0 (86.6–99.7)	100	100	100
Abatacept	100	100	99.3 (95.3–99.9)	100	100	100	96.9 (94.4–98.3)	93.2 (90.0–95.4)	90.6 (87.0–93.2)

Abbreviation: CI, confidence interval.

Table 6 Parametric regression (Weibull distribution with 60 days gap definition)

Patient characteristics	Hazard ratio (95% confidence interval)
	Overall patients (n=2,537)	Biologic-naïve patients (n=272)	Biologic-continuing patients (n=2,265)
Age
≤60 years	Reference	Reference	Reference
61–75 years	0.84 (0.67–1.05)	1.04 (0.29–3.76)	0.83 (0.66–1.04)
>75 years	0.60 (0.40–0.91)	1.89 (0.35–10.32)	0.56 (0.37–0.86)
Sex
Male	Reference	Reference	Reference
Female	1.03 (0.79–1.34)	0.48 (0.13–1.70)	1.05 (0.80–1.38)
CCI score
≤2	Reference	Reference	Reference
3–5	1.33 (1.03–1.70)	25.22 (0.82–251.41)	1.26 (0.98–1.62)
>5	1.90 (1.40–2.57)	71.82 (−23.45 to 962.12)	1.93 (1.42–2.63)
Biologic agent
Etanercept	Reference	Reference	Reference
Adalimumab	0.76 (0.57–1.02)	0.29 (0.03–2.65)	0.78 (0.58–1.05)
Infliximab	0.31 (0.22–0.45)	0.22 (0.04–1.21)	0.32 (0.22–0.45)
Golimumab	0.46 (0.24–0.87)	1.59×10^−8	0.51 (0.27–0.97)
Tocilizumab	0.51 (0.36–0.71)	0.28 (0.05–1.48)	0.51 (0.37–0.72)
Abatacept	0.20 (0.09–0.43)	0.48 (0.09–2.61)	0.16 (0.07–0.39)
Naïve
Naïve patients	Reference	NA	NA
Continuing biologic patients	3.02 (1.69–5.40)	NA	NA
/ln_p	0.0066 (−0.1022–0.1035)	0.5010 (−0.0548–1.0569)	−0.0121 (−0.1167, 0.09259)
p	1.0007 (0.9028–1.1091)	1.6505 (0.9467–2.8775)	0.9880 (0.8898–1.0970)
1/p	0.9989 (0.9016–1.108)	0.6105 (0.3475–1.0056)	1.0121 (0.9116–1.1238)
	LR χ^2(12)=121.36	LR χ^2(12)=18.91	LR χ^2(12)=93.30
	Prob > χ^2=0.0000	Prob > χ^2=0.0415	Prob > χ^2=0.0000

Abbreviations: CCI, Charlson Comorbidity Index; LR (χ²), likelihood ratio chi-square; Prob, probability; NA, not applicable.