Modern Rheumatology

, Volume 22, Issue 3, pp 370–375

Early aggressive intervention with tocilizumab for rheumatoid arthritis increases remission rate defined using a Boolean approach in clinical practice

Authors

    • Department of Orthopedic Surgery and Rheumatology, Nagoya University HospitalNagoya University, School of Medicine
  • Atsushi Kaneko
    • Department of Orthopedic SurgeryNagoya Medical Center
  • Yuji Hirano
    • Department of RheumatologyToyohashi Municipal Hospital
  • Hisato Ishikawa
    • Department of RheumatologyNagano Red Cross Hospital
  • Hiroyuki Miyake
    • Department of Orthopedic SurgeryIchinomiya Municipal Hospital
  • Hideki Takagi
    • Department of Orthopedic SurgeryNagoya Kyoritsu Hospital
  • Yuichiro Yabe
    • Department of RheumatologyTokyo Kosei Nenkin Hospital
  • Takefumi Kato
    • Kato Orthopedic Clinic
  • Kenya Terabe
    • Department of Orthopedic SurgeryFukuroi Municipal Hospital
  • Naoki Fukaya
    • Department of Orthopedic SurgeryKariya-Toyota General Hospital
  • Hiroki Tsuchiya
    • Department of Orthopedic SurgeryNagoya Kyoritsu Hospital
  • Tomone Shioura
    • Department of Orthopedic SurgeryShizuoka Kosei Hospital
  • Koji Funahashi
    • Department of Orthopedic Surgery and Rheumatology, Nagoya University HospitalNagoya University, School of Medicine
  • Masatoshi Hayashi
    • Department of Orthopedic Surgery and Rheumatology, Nagoya University HospitalNagoya University, School of Medicine
  • Daizo Kato
    • Department of Orthopedic Surgery and Rheumatology, Nagoya University HospitalNagoya University, School of Medicine
  • Hiroyuki Matsubara
    • Department of Orthopedic Surgery and Rheumatology, Nagoya University HospitalNagoya University, School of Medicine
  • Naoki Ishiguro
    • Department of Orthopedic Surgery and Rheumatology, Nagoya University HospitalNagoya University, School of Medicine
    • Department of Orthopedic Surgery, Faculty and Graduate School of MedicineNagoya University
Original Article

DOI: 10.1007/s10165-011-0528-2

Cite this article as:
Kojima, T., Kaneko, A., Hirano, Y. et al. Mod Rheumatol (2012) 22: 370. doi:10.1007/s10165-011-0528-2

Abstract

The goal of treating rheumatoid arthritis (RA) should be remission, for which a new definition was proposed in 2011. To determine which patients can achieve the new Boolean-based definition of remission in clinical practice, we analyzed factors associated with remission in 123 patients who received tocilizumab for 52 weeks. We found that patients with short disease duration (<4.8 years) had a significantly higher rate of remission (31.7%) than those with longer disease duration, and patient global assessment was the most important factor for achieving remission. Multivariate analysis revealed the following predictors of remission: short disease duration [<4.8 years; odds ratio (OR) 2.5, 95% confidence interval (CI) 1.4–4.7] and lower disease activity [28-joint disease activity score–erythrocyte sedimentation rate (DAS28-ESR) <5.23; OR 2.5, 95% CI 1.2–5.1). In this study, we showed that remission, as newly defined using a Boolean approach, is a realistic goal for patients treated with tocilizumab with short disease duration in real-world clinical practice.

Keywords

Rheumatoid arthritisRemissionTocilizumabPatient-reported outcomeInterleukin 6

Introduction

The goal of treating rheumatoid arthritis (RA) is remission [1]. Clinical trials report that early intervention is associated with better outcomes for patients treated with biologics [24]. Accordingly, early intervention is recommended by the European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) [5, 6]. Remission is now defined using a Boolean approach [swollen joints ≤1, tender joints ≤1, C-reactive protein (CRP) ≤1 mg/dl, and patient global assessment ≤1 cm on a 10-cm visual analog scale (VAS)] or index-based definition [Simplified Disease Activity Index (SDAI) <3.3] [7]. Because treatments should be evaluated based on these criteria for remission, it is important to know whether this is a realistic goal in real-world clinical practice.

Tocilizumab, a humanized monoclonal antibody that binds to and inhibits the interleukin-6 (IL-6) receptor, was approved in 2008 in Japan. The efficacy of tocilizumab for RA was demonstrated in several clinical trials [811], and its effectiveness in clinical practice is under investigation [12]. We focused on the importance of short disease duration at initiation of aggressive treatment with tocilizumab for achieving new remission (Boolean approach) in actual clinical practice.

Methods

Tsurumai Biologics Communication Registry

A new registry of patients starting treatment with biologics in 2008, named Tsurumai Biologics Communication (TBC), was developed to explore the long-term prognosis of treatment with biologics in clinical practice. Data were collected prospectively from 2008, as well as retrospectively for patients who had been treated with biologics up until 2008. This study was approved by the Ethics Committee of Nagoya University, School of Medicine. Patient anonymity was maintained during data collection, and the security of personal information was strictly controlled. All patients (n = 134) who underwent tocilizumab treatment between May 2008 and September 2009 at Nagoya University Hospital and 12 other institutes (Tsurumai Biologics Communication Study Group) and were registered in Tsurumai Biologics Communication Registry (TBCR) were enrolled. All patients analyzed in this study were registered in TBCR prospectively.

All patients met the 1987 ACR classification criteria for RA. Tocilizumab (8 mg/kg) was infused every 4 weeks according to the drug label and the Japan College of Rheumatology guidelines for tocilizumab therapy. Demographic data, including disease duration, concomitant treatments (methotrexate and prednisolone), joint damage (Steinblocker stage), and daily dysfunction (Steinblocker class) were recorded at the initiation of treatment (baseline). The following parameters were recorded at baseline and 52 weeks later: tender joint count (TJC) on 28 joints, swollen joint count (SJC) on 28 joints, patient global assessment of disease activity [VAS–general health (VAS-GH)], erythrocyte sedimentation rate (ESR), and serum CRP levels. We evaluated remission at 52 weeks using the 2011 definition of remission developed for use in RA clinical trials (Boolean approach) as well as the 28-joint disease activity score (DAS28)-ESR definition of remission. We analyzed baseline characteristics to determine those associated with remission.

Statistical analyses

Continuous variables are expressed as mean ± standard deviation (SD) and categorical variables as percentages. We categorized patients into three groups based on tertile values of disease duration: short (<4.8 years), medium (<12 years), and long (>12 years). We evaluated differences in patient characteristics among the groups using the Kruskal–Wallis test for continuous variables and chi-square test for categorical variables. For cases in which tocilizumab therapy was discontinued, the last observation carried forward method was used. To determine predictors of Boolean-defined remission, we performed univariate followed by multivariate logistic regression analyses in which we dichotomized age, DAS28-ESR, and serum CRP levels based on lowest tertile values. All data were analyzed using JMP version 8.0 (SAS Institute Japan, Tokyo, Japan). P < 0.05 was considered significant.

Results

Of 134 patients, 11 who moved while undergoing tocilizumab therapy were excluded from the analysis because we were unable to determine the final treatment status within 52 weeks. Nineteen patients discontinued treatment and were included in the analysis using the last observation carried forward method. We thus analyzed results for 123 patients. Of 19 patients who discontinued treatment, five cases were in the short-duration (insufficient effectiveness n = 2; adverse event n = 1; patient convenience n = 2); six in the medium-duration (adverse events n = 3; inadequate response n = 2; pregnancy n = 1); and eight in the long-duration (adverse events n = 7; insufficient effectiveness n = 1) groups. Baseline characteristics of the 123 patients are shown in Table 1 by patient group. There was a significant difference in the proportion of those with low joint damage grade (Steinblocker stage I and II; short 85.4%, medium 25%, long 7.1%: P < 0.001) and daily dysfunction (Steinblocker class short 92.7%, medium 60%, and long 35.7%; P < 0.001) by disease duration.
Table 1

Patient demographics and baseline disease characteristics

Patient characteristics

Total (n = 123)

Short duration (n = 41)

(≤4.8 years)

Medium duration (n = 40)

(4.8–12.0 years)

Long duration (n = 42)

(≥12.0 years)

P value

Age (years)

57 ± 13

52 ± 14

56 ± 14

61 ± 10

0.009*

Women (%)

78

71

75

88

0.14

Disease duration (years)

10.0 ± 8.5

2.2 ± 1.4

8.3 ± 2.1

19.4 ± 7.5

<0.0001*

No. of previous anti-TNF agents

48 (39)

18 (44)

12 (30)

18 (43)

0.61

 0 (%)

50 (41)

17 (41)

19 (48)

14 (33)

 1 (%)

21 (17)

6 (15)

7 (17)

8 (19)

 2 (%)

4 (3)

0 (0)

2 (5)

2 (5)

 3 (%)

    

RF positive (%)

97

95

94

100

0.47

MTX use at baseline (%)

39

41

45

31

0.4

Weekly MTX dose at baseline (mg)

7.1 ± 2.1

7.6 ± 2.5

7.0 ± 1.3

6.7 ± 2.3

0.58

Corticosteroid use at baseline (%)

63

56

85

69

0.018**

Prednisolone dose (mg/day)

4.7 ± 2.2

5.2 ± 1.9

4.9 ± 2.4

4.0 ± 1.9

0.06

Tender joint count (28 joints assessed)

9.4 ± 7.8

8.2 ± 6.4

9.3 ± 8.0

9.1 ± 8.0

0.94

Swollen joint count (28 joints assessed)

7.4 ± 6.3

8.2 ± 6.2

6.5 ± 5.0

6.6 ± 6.1

0.22

General health (VAS, mm)

53 ± 25

53 ± 26

57 ± 24

57 ± 26

0.66

ESR (mm/h)

68.5 ± 35.1

66.8 ± 33.5

71.8 ± 30.9

63.9 ± 37.3

0.42

CRP (mg/dl)

3.1 ± 3.1

3.5 ± 3.4

3.8 ± 2.3

3.0 ± 2.8

0.11

DAS28-ESR

5.8 ± 1.4

5.8 ± 1.4

5.8 ± 1.2

5.7 ± 1.4

0.83

CRP C-reactive protein, DAS disease activity score, ESR erythrocyte sedimentation rate, MTX methotrexate, RF rheumatoid factor

* Kruskal–Wallis test, ** chi-square test

Tocilizumab treatment effectiveness is summarized in Fig. 1. Remission rate according to the Boolean criteria was significantly higher for patients with short (31.4%) than medium (10%) and long (2.4%) duration. Similarly, DAS28-ESR-defined remission was significantly higher in the short- (63.4%) than in the medium- (37.5%) and long- (28.6%) duration groups.
https://static-content.springer.com/image/art%3A10.1007%2Fs10165-011-0528-2/MediaObjects/10165_2011_528_Fig1_HTML.gif
Fig. 1

Boolean core measure set of patients categorized by disease duration at 52 weeks. CRP C-reactive protein, DAS disease activity score, SJC swollen joint count, TJC tender joint count. *P < 0.05; **P < 0.01 (Fisher’s exact test, JMP Ver. 8.0)

The proportion of patients with SJC ≤1 did not differ among patient groups; however, the proportion with TJC ≤1 and VAS-GH ≤1 was significantly lower, with longer disease duration. Serum CRP levels were normalized by tocilizumab treatment in almost all patients in the three groups. One hundred fifteen patients (94%) achieved CRP ≤1 mg/dl. Achievement of remission criteria in objective values (SJC ≤1, TJC ≤1, and CRP ≤1 mg/dl) was related to achievement of subjective values (VAS-GH ≤1 cm) (Fig. 2). The proportion of patients who achieved remission criteria in objective values (SJC ≤1, TJC ≤1, and CRP ≤1 mg/dl) was significant higher in the short disease duration group compared with patients in the medium and long disease duration groups (Fig. 2a). Interestingly, the proportion of patients who achieved all remission criteria (SJC ≤1, TJC ≤1, CRP ≤1 mg/dl, and VAS-GH ≤1 cm) among patients who achieved remission criteria in objective values (SJC ≤1, TJC ≤1, and CRP ≤1 mg/dl) was significantly higher in the short (65%) than in the long (9%) disease duration group (Fig. 2b). Inversely, 26% of patients with CRP ≤1 mg/dl did not achieve any other criteria (SJC ≤1, TJC ≤1, VAS-GH ≤1 cm).
https://static-content.springer.com/image/art%3A10.1007%2Fs10165-011-0528-2/MediaObjects/10165_2011_528_Fig2_HTML.gif
Fig. 2

Relationship between achieving remission criteria in objective and subjective values. a Percentage of patients who met tender joint count (TJC) ≤1, swollen joint count (SJC) ≤1, and C-reactive protein (CRP) ≤1 mg/dl in each disease duration group. Asterisk indicates chi-square test. b Proportion of patients with visual analog scale–general health (VAS-GH) ≤1 cm among patients who met TJC ≤1, SJC ≤1, and CRP ≤1 mg/dl. Asterisk chi-square test

Univariate regression analysis revealed that achieving Boolean-defined remission with tocilizumab therapy was associated with short disease duration [<4.8 years; odds ratio (OR) 7.2, 95% confidence interval (95% CI) 2.3–21.9], lower disease activity (DAS28-ESR <5.23; OR 3.9, 95% CI 1.4–11.1), and no concomitant use of corticosteroids (OR 3.4, 95% CI 1.2–9.6). Multivariate logistic analysis confirmed that short disease duration (OR 2.5, 95% CI 1.4–4.7) and lower disease activity (OR 2.5, 95% CI 1.2–5.1) were independent factors for achieving Boolean-defined remission with tocilizumab therapy (Table 2).
Table 2

Univariate and multivariate analysis of factors associated with remission (Boolean approach) at 52 weeks

Variables

Univariate analysis

Multivariate analysis

Odds ratio (95% CI)

Odds ratio (95% CI)

Disease duration (first tertile, <4.8 years)

7.15 (2.34–21.88)

2.53 (1.35–4.72)

DAS28-ESR (lowest tertile, <5.23)

3.93 (1.39–11.09)

2.51 (1.23–5.12)

No corticosteroid use

3.44 (1.23–9.58)

1.63 (0.87–3.03)

Age (youngest tertile, 24–52 years)

1.75 (0.63–4.83)

1.42 (0.76–2.72)

No previous use of anti-TNF agent

1.69 (0.62–4.62)

1.15 (0.61–2.16)

CRP (lowest tertile, <1.28 mg/dl)

1.33 (0.47–3.73)

1.46 (0.70–3.06)

MTX use

1.30 (0.47–3.57)

1.02 (0.54–1.95)

Gender (female)

0.98 (0.29–3.27)

1.28 (0.60–2.72)

Significance for the bold values: In univariate analysis, p value for disease duration, 0.002, for DAS-ESR, 0.046, for no corticisteroid use, 0.004. In multivariate analysis, p value for disease duration, 0.002, for DAS-ESR, 0.009

CI Confidence interval, CRP C-reactive protein, DAS disease activity score, MTX methotrexate, TNF tumor necrosis factor

Discussion

We demonstrated that disease duration <5 years is one of the most important factors for achieving RA remission with tocilizumab in actual clinical practice. Tocilizumab is thought to directly suppress CRP expression [13]. We found that serum CRP levels were completely normalized in almost all patients, indicating that tocilizumab was pharmacologically active in these patients. In addition, the SJC was reduced to less than one joint in patients with short disease duration and those with longer disease duration, suggesting that tocilizumab exerts effects regardless of disease duration.

Our results demonstrate that the patient global assessment rated on a VAS was the most critical component of remission according to the Boolean-based definition; however, we do not know which factors influenced this assessment. As mentioned in the ACR/EULAR statement of the newly proposed definition of remission [7], it is not clear whether patient global assessment is sufficient to capture their experience of outcomes. In several clinical trials, patient-reported pain was suggested to be another important factor influencing remission [7]. Irreversible structural damage, which may be related to longer disease duration, can cause mechanical pain despite suppression of inflammation. Smolen et al. [14] reported that irreversible structural damage should be related to physical function (joint damage-related physical disability), i.e., physical dysfunction remaining after suppression of inflammation. This dysfunction could impact VAS-GH. Although we did not precisely determine joint structural damage, Steinblocker joint damage and daily dysfunction were clearly related to disease duration.

Furthermore, we previously reported relationships among psychosocial factors, disease status, and quality of life in patients with RA [15] and demonstrated that the combined effects of inflammation and depression in the presence of severe pain were linearly increased by serum CRP levels and depression severity, independently [16]. The two types of persistent pain are nociceptive/inflammatory and neuropathic [17]. Neuropathic pain is produced by a lesion or dysfunction of the peripheral or central nervous system [18]. Nociceptive/inflammatory pain is responsive to anti-inflammatory therapy, whereas neuropathic pain is complex and difficult to treat. Our findings indicated that both types of pain coexist in RA patients. Long-standing pain in patients with longer disease duration could cause this neuropathic pain.

The main limitation of this study is that we evaluated only patients who underwent tocilizumab therapy. An important issue is the difference in remission achievement between tocilizumab and antitumor necrosis factor alpha (anti-TNF-α) agents. However, comparing the two is difficult in clinical practice. One reason is that levels of acute-phase reactants such as CRP are improved with tocilizumab treatment compared with treatment with anti-TNF-α agents [19]. Based on the definition of remission using a Boolean approach, CRP ≤1 should be achieved in most cases involving tocilizumab treatment. Another reason is that, in addition to disease duration, critical factors may affect efficacy and remission in treatment with anti-TNF-α agents, such as MTX dose and previous failure of other anti-TNF-α agents. MTX dose is critical for the efficacy of anti-TNF-α agents; however, MTX dose was limited to 8 mg/week in Japan until 2011. Accordingly, we do not yet have sufficient patient data on doses of MTX >8 mg/week in our register. The previous failure of anti-TNF-α agents may also be involved in efficacy. Although these points can also be argued for tocilizumab, MTX use and previous use of anti-TNF-α agents were not associated with achievement of remission in this study. For these reasons, we limited our analysis to patients treated with tocilizumab.

It would be interesting to determine whether differences exist in the mechanisms of pain reduction between nociceptive/inflammatory pain and neuropathic pain when targeting TNF-α and IL-6. Further studies are needed to evaluate the ability of patient-reported outcomes, including mental and physical function, to fully capture patient satisfaction with treatment.

In conclusion, we demonstrated that remission, as newly defined, may be a realistic goal for patients with short disease duration in actual clinical practice. Thus, patients who have a good chance of achieving remission may benefit from aggressive therapy including biologics.

Acknowledgments

We thank Dr. Toshihisa Kanamono (Department of Orthopedic Surgery, Nagano Red Cross Hospital, Nagano, Japan), Dr. Yukiyoshi Oh-ishi (Department of Rheumatology, Toyohashi Municipal Hospital, Toyohashi, Japan), Dr. Yoshito Etoh (Department of Orthopedic Surgery, Higashi Nagoya National Hospital, Nagoya, Japan), Dr. Masahiro Kobayakawa (Department of Orthopedic Surgery, Fukuroi Municipal Hospital, Fukuroi, Japan), and Dr. Seiji Tsuboi (Department of Orthopedic Surgery, Shizuoka Kosei Hospital, Shizuoka, Japan) for their kind suggestions. The study was funded by a Grant from the Ministry of Health, Labour and Welfare, “Study for mortality-based optimal management of patients with rheumatoid arthritis in the biologic era” (chaired by Prof. H. Yamanaka, Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, Japan).

Conflict of interest

N. Ishiguro, T. Kojima, and A. Kaneko received lecture fees (less than $5,000) from Chugai Pharma Corporation. The other authors declare no conflicts of interest.

Copyright information

© Japan College of Rheumatology 2011