Clinical and structural remission rates increased annually and radiographic progression was continuously inhibited during a 3-year administration of tocilizumab in patients with rheumatoid arthritis: A multi-center, prospective cohort study by the Michinoku Tocilizumab Study Group

Figures & data

Figure 1. (a) Kaplan–Meier estimate of the probability of continuing treatment with TCZ. The upper black line indicates the continuation rate when the reason for discontinuation was limited to inadequate response (IR) or adverse events (AEs). The lower gray line indicates the total continuation rate. (b) Changes in DAS28-ESR in all patients. Mean values are shown. Bars indicate standard deviation (SD). (c) Disease activity over time. The categories are based on the DAS28-ESR (<2.6: remission, ≥2.6 and <3.2: low disease activity, 3.2–5.1: moderate disease activity, and <5.1: high disease activity). (d) Percentage of patients achieving each component of the Boolean-based remission criteria or achieving remission at 0, 6, 12, 24, and 36 months.

Table 1. Baseline characteristics of the patients.

	Group
	I	II	III
Number of patients	693	544 (264: 280)	50 (32: 18)
Age (years)	59.5 ± 13.4	59.4 ± 13.0 (60.1 ± 13.2: 58.8 ± 12.8)	58.0 ± 11.9 (59.7 ± 2.2: 54.8 ± 2.3)
Female (%)	82.1	82.5 (83.7: 81.4)	88.0 (90.6: 83.3)
Disease duration (years)	9.5 ± 8.9	9.6 ± 8.7 (10.0 ± 9.2: 9.2 ± 8.2)	10.9 ± 9.9 (11.2 ± 1.8: 10.8 ± 2.5)
Stage 1/2/3/4 (%)	14/25/30/32	14/24/28/34 (18/20/23/39: 10/28/34/29)	17/12/17/44 (22/19/19/41: 22/17/22/39)
Class 1/2/3/4 (%)	22/56/21/1	25/56/18/1 (30/59/11/0: 20/54/25/1)^a	30/60/10/0 (47/53/0/0: 22/67/11/0)^a
CRP (mg/dL)	2.6 ± 2.9	2.5 ± 2.7 (1.9 ± 2.3: 3.0 ± 2.9)^b	2.0 ± 2.1 (1.7 ± 0.4: 2.5 ± 0.5)
ESR (mm/1 h)	49.3 ± 33.1	49.0 ± 33.2 (44.0 ± 30.0: 53.6 ± 35.1)^b	40.5 ± 29.1 (34.2 ± 4.4: 52.1 ± 8.1)
TJC [0–28 joints]	6.1 ± 6.0	6.1 ± 6.1 (5.2 ± 5.3: 7.0 ± 6.6)^b	5.3 ± 4.7 (5.1 ± 0.9: 5.7 ± 1.0)
SJC [0–28 joints]	5.4 ± 5.1	5.5 ± 5.2 (4.9 ± 4.5: 6.0 ± 5.7)^b	5.0 ± 3.8 (4.3 ± 0.6: 6.3 ± 1.0)
VAS (mm)	55.1 ± 25.7	55.2 ± 25.9 (52.4 ± 25.3: 57.8 ± 26.2)^b	49.1 ± 23.5 (49.2 ± 4.1: 48.8 ± 5.9)
DAS28-ESR	–	5.1 ± 1.4 (4.8 ± 1.3: 5.3 ± 1.4)^b	4.8 ± 1.2 (4.6 ± 0.2: 5.1 ± 0.3)
History of TNFi use (%)	54.4	51.4 (0: 100)^c	18.0 (9.4: 33.3)^c
Baseline MTX use (%)	56.9	55.7 (52.3: 59.3)	34.0 (34.3: 38.9)
Baseline PSL use (%)	67.1	66.0 (58.3: 73.6)^c	67.3 (65.6: 70.6)

Group I: entire cohort; Group II: patients for whom clinical efficacy was evaluated by DAS28ESR and Boolean remission rates; Group III: patients for whom joint damage was assessed by mTSS. In group II, data for patients who did not receive TNFi appear to the left of the colon in parentheses, and data for patients who had previously received TNFi appear to the right. In group III, data for patients whose ΔmTSS score during the 3-year study ≤ 1.5 appear to the left of the colon in parentheses, and data for patients whose ΔmTSS during the 3-year study > 1.5 appear on the right. Statistically significant differences (p < 0.05) were observed by ^athe Mann–Whitney U-test, ^bWelch's t test, or ^ca test for the difference in the population proportions. Values are mean ± standard deviation (SD). Stage, Steinbrocker stage; Class, Steinbrocker class; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; TJC, tender joint count; SJC, swollen joint count; DAS28-ESR, the 28-joint disease activity score using ESR; TNFi, tumor necrosis factor inhibitor; MTX, methotrexate; PSL, prednisolone.

Figure 2. (a) Changes in DAS28-ESR according to the history of TNFi use. Mean values are shown. Bars indicate SD. (b) Changes in DAS28-ESR according to disease activity at baseline. (c) Changes in DAS28-ESR according to age. (d) Change in DAS28-ESR according to comorbidities.

Table 2. Factors influencing Boolean remission.

	12 months		36 months
	Odds ratio (95% CI)	p value	Odds ratio (95% CI)	p value
Univariate analysis for achieving Boolean remission
Age	0.98 (0.96–1.00)	<0.05	0.98 (0.96–1.00)	<0.05
Disease duration	0.96 (0.93–0.99)	<0.01	1.00 (0.97–1.03)	0.74
Stage 3 + 4 vs 1 + 2	0.43 (0.27–0.68)	<0.01	0.57 (0.34–0.95)	<0.05
Class 3 + 4 vs 1 + 2	0.19 (0.08–0.45)	<0.01	0.76 (0.37–1.56)	0.46
CRP	0.98 (0.90–1.06)	0.59	0.99 (0.90–1.09)	0.81
ESR	0.99 (0.98–1.00)	<0.05	1.00 (0.99–1.01)	0.85
TJC	0.90 (0.86–0.95)	<0.01	0.93 (0.88–0.97)	<0.01
SJC	0.93 (0.88–0.97)	<0.01	0.94 (0.89–0.99)	<0.05
PGA-VAS	0.98 (0.97–0.99)	<0.01	0.99 (0.98–1.00)	<0.01
DAS28ESR	0.66 (0.55–0.79)	<0.01	0.73 (0.61–0.88)	<0.01
History of TNFi use	0.48 (0.30–0.76)	<0.01	0.44 (0.26–0.73)	<0.01
Baseline MTX use	0.96 (0.62–1.50)	0.87	0.70 (0.42–1.16)	0.16
Baseline PSL use	0.73 (0.45–1.16)	0.18	0.76 (0.44–1.30)	0.31
Multivariate analysis for achieving Boolean remission
Age	0.99 (0.97–1.01)	0.19	0.98 (0.96–1.00)	0.07
Disease duration	0.98 (0.94–1.01)	0.27	0.97 (0.94–1.01)	0.16
Stage 3 + 4 vs 1 + 2	0.52 (0.59–0.92)	<0.05	0.51 (0.29–0.90)	<0.05
Class 3 + 4 vs 1 + 2	0.38 (0.15–0.96)	<0.05
ESR	0.99 (0.98–1.01)	0.26
TJC	0.91 (0.83–1.00)	0.06	0.94 (0.87–1.02)	0.11
SJC	0.94 (0.96–1.02)	0.13	0.96 (0.90–1.04)	0.33
PGA-VAS	0.98 (0.96–0.99)	<0.01	0.98 (0.97–0.99)	<0.01
DAS28ESR	1.50 (0.79–2.85)	0.22	1.08 (0.73–1.58)	0.71
History of TNFi use	0.49 (0.29–0.82)	<0.01	0.43 (0.26–0.71)	<0.01

Figure 3. (a) Annual radiographic progression over 3 years. Data from plain radiography were compared between baseline and 1 year in 48 patients, between 1 year and 2 years in 42 patients, and between 2 years and 3 years in 44 patients to calculate the ΔmTSS/year. (b) Cumulative probability plot of annual changes in mTSS from baseline to 1 year, from 2 to 2 years, and from 2 to 3 years. (c) Cumulative probability plot of changes in mTSS from baseline to 3 years. Data from plain radiography were compared between baseline and 3 years in 50 patients to calculate the ΔmTSS/3 years.

Table 3. Predictor of structural remission during 3 years.

Month	3	6	9	12
CRP ≤ 1 mg/dL	c.i.	0.5951	c.i.	c.i.
ESR ≤ 15 mm/1 h	0.0102	0.2532	0.6327	0.5878
TJC ≤ 1	0.0754	0.0023	0.6046	0.1206
SJC ≤ 1	0.0364	0.0063	0.0013	0.0010
Boolean	0.1794	0.0276	0.0002	0.0073
DAS28ESR < 2.6	0.0920	0.0076	0.1301	0.1206
DAS28ESR < 1.54	0.0150	0.1234	0.1775	0.0471

p values were determined by Fisher's exact test. c.i., computation incapable. The significance level was adjusted by Bonferroni method and set at 0.05/4 = 0.0125. The numbers which were less than 0.0125 were boldfaced.