Introduction
The introduction of biologic agents into the rheumatoid arthritis (RA) treatment landscape has altered both therapeutic strategies as well as patient outcomes [
1‐
3]. Indeed, the aim of medical treatment of RA patients has shifted from the short-term improvement of the quality of life (QOL) through pain relief to the long-term improvement of QOL by the prevention of joint damage and improved mortality. Tumor necrosis factor (TNF) is considered to be a major cytokine involved in RA pathogenesis, and anti-TNF therapy using monoclonal antibodies or fusion proteins was the first anti-cytokine therapy to be developed for RA [
4‐
6]. Anti-TNF therapy has achieved great success in suppressing rheumatoid inflammation and preventing the progression of joint damage in RA patients [
7‐
9], thereby confirming that TNF indeed appears to be critically involved in the pathogenesis of RA synovitis. However, TNF is not the only cytokine involved in RA pathogenesis, and several candidate cytokines represent potential therapeutic targets for anti-cytokine therapy. Interestingly, the interleukin 1 (IL-1) receptor antagonist anakinra did not demonstrate a significant therapeutic effect in the treatment of RA [
10], even though IL-1 is believed to be involved in the pathogenesis of RA synovitis [
11], leading to the conclusion that not all cytokines are necessarily successful therapeutic targets for RA anti-cytokine therapy.
Tocilizumab, a monoclonal antibody directed against the IL-6 receptor, was developed in Japan through a collaborative effort of Osaka University and Chugai Pharmaceutical Co. (Tokyo, Japan) [
12]. After a series of carefully conducted preclinical studies, tocilizumab was evaluated in RA patients, in whom it demonstrated promising efficacy [
13‐
15]. The efficacy of tocilizumab was assessed in several different patient groups in both Japan and Western countries, and it has been shown to improve the signs and symptoms of RA patients, to suppress the radiological progression of joint damage [
16], and to improve the QOL and physical disability [
17]. However, the utility of tocilizumab has not been well documented in daily clinical practice outside of the clinical trial setting.
Tocilizumab was first approved as a therapy for RA in Japan in April 2008, and approximately 9,000 Japanese RA patients had received tocilizumab by the end of 2009. Although, as mentioned above, the efficacy and safety of tocilizumab have been well established in several randomized control trials (RCTs), given the differences between the patient populations that participate in RCTs versus those treated in clinical practice, it is also necessary to evaluate the efficacy and safety of this agent in the daily clinical rheumatology practice setting. We have therefore conducted a retrospective study of tocilizumab use in daily rheumatology practice in three rheumatology institutes in Japan and analyzed factors potentially associated with tocilizumab efficacy. Here, we describe the clinical profiles of RA patients seen in daily rheumatology practice during the first 6 months of tocilizumab treatment.
Discussion
This study was conducted to determine the efficacy of tocilizumab therapy and to identify other factors associated with the effectiveness of tocilizumab therapy in Japanese RA patients receiving treatment in a university hospital outpatient setting at three rheumatic disease institutions. A study of the efficacy of tocilizumab in daily practice in a study group in the Kyushu area demonstrated the significant efficacy of this new biologic [
25]. Many investigator-oriented studies of tocilizumab are currently being conducted in Japan, and more data should be available in the near future.
During the study period, only three anti-TNF therapies (infliximab, etanercept, and adalimumab) were available to treat RA in Japan; no other biologic agents, including abatacept and rituximab, was available. Tocilizumab was first approved in Japan in April 2008, and results from clinical studies on its efficacy and safety in RA patients seen in daily rheumatology practice outside the clinical trial setting are quite important for evaluation purposes.
All of the patients enrolled in this study were essentially MTX-resistant, two-thirds were anti-TNF therapy-resistant, and the average DAS28 at baseline was 5.70. Consequently, these patients had severe RA. Based on our results, tocilizumab therapy was highly efficacious in these RA patients seen in daily clinical practice, and the overall remission rate at 24 weeks was as high as 40.7%.
It is difficult to compare efficacy in clinical studies with strict inclusion and exclusion criteria to that observed in daily clinical practice. The Japan College of Rheumatology provides a guideline for tocilizumab use [
19] to which most rheumatologists comply; however, the regulations of this guideline are much less stringent compared to the inclusion and exclusion criteria of clinical studies. Even after these differences are taken into consideration, the efficacy of tocilizumab demonstrated in our study is comparable to or even higher than those reported in clinical studies. The remission rates in our study were 40.7% in the overall study population, 49.2% in patients who concomitantly received MTX, and 30.0% in patients who did not concomitantly receive MTX, while remission rates in previously reported clinical studies ranged from 27% in the OPTION study [
17] to 59% in the SAMURAI study [
10]. The tocilizumab-induced remission rate in the SAMURAI study was remarkably high, most likely because this study was conducted in early RA patients whose average disease duration was 2 years [
10]. In contrast, the average disease duration of patients in our study was 12.4 years. Since tocilizumab directly reduces acute-phase reactants, such as CRP and ESR [
26], it is not surprising that decreases in the ESR and CRP levels were among the most prominently changed DAS28 components, as shown in Fig.
1. However, other factors, including TJC, SJC, and GH, were also significantly decreased; thus, the higher remission rates observed in this study must not have been solely dependent on the potent suppression of acute-phase reactants by tocilizumab.
Concomitant use of MTX resulted in a rapid and sustained response to tocilizumab, even though the average MTX dose was relatively low (average at baseline: 8.7 mg/week) compared to that used in Western countries. Government regulations have limited the maximum dose of MTX to 8 mg/week in Japan; however, many rheumatologists prescribe higher MTX doses off-label [
24,
27]. It is remarkable that such low-dose MTX potentiates tocilizumab action in severe RA patients. The differences in baseline characteristics between patients who did and did not concomitantly receive MTX may have accounted for this result, since patients who received MTX had a longer disease duration, higher disease activity, and lower usage of anti-TNF therapies. It is likely that tocilizumab was prescribed in combination with MTX in patients who had a lower risk of adverse events and as monotherapy in patients with a higher risk. Due to the observational nature of this study, safety issues associated with combined tocilizumab/MTX were not sufficiently evaluated; however, considering the high retention rate (Fig.
4) and laboratory profiles (Table
2) associated with tocilizumab therapy with or without MTX, the addition of MTX does not appear to significantly increase the risk of adverse events. As the addition of MTX to the therapeutic regimen may enhance the efficacy of tocilizumab, concomitant use of MTX is recommended with tocilizumab therapy in patients in whom safety is not a concern.
An interesting finding was the lack of any differences in tocilizumab efficacy in patients who did or did not previously receive anti-TNF therapy, suggesting that clinical response to tocilizumab therapy is independent of the prior use of anti-TNF agents. This result is inconsistent with the report of Nakashima et al. [
25], in which the authors reported a higher efficacy of tocilizumab in biologic naïve patients. It is highly possible that the definition of MTX-refractory or anti-TNF refractory differs between rheumatologists. Although the baseline DAS28-ESR values in our study (5.7) and that of Nalashima et al. (5.5) were comparable, the average dose of MTX at baseline was higher in our study (8.7 ± 3.1 vs. 6.8 ± 2.1 mg/week). This higher dose means that the definition of MTX-refractory was more stringent in our study than in that of Nakashima et al. and that our RA patients had more active disease. It is reasonable to assume that the severity of RA in patients would affect the clinical outcome after tocilizumab therapy.
Clinical data on rituximab and abatacept demonstrate that both of these agents reduce disease activity in patients with inadequate responses to anti-TNF therapy. However, the remission rates of these non-TNF biologic agents in anti-TNF-naïve or -refractory populations differ. For abatacept, the remission rate in MTX-resistant patients (AIM study) was 14.8% [
28], while that in anti-TNF therapy-refractory patients (ATTAIN study) was 10.0% [
29]. In the case of rituximab, the American College of Rheumatology (ACR) 70% rate in MTX-resistant patients (DANCER study) was 20% [
30], and that in anti-TNF therapy-refractory patients (REFLEX study) was 12% [
31]. In contrast to rituximab and abatacept, remission rates observed in tocilizumab clinical studies were quite similar between MTX-resistant patients (OPTION, 27% [
17]; TOWARD, 30% [
32]) and anti-TNF therapy-refractory patients (RADIATE, 30% [
33]). Although it may not be appropriate to compare the results of clinical trials conducted in these different patient population, it is interesting to realize that the results from tocilizumab clinical studies have been fairly consistent despite the patient population.
TNF is widely accepted as an important cytokine [
4], and it is known to induce IL-6 activity [
34,
35]; however, IL-6 activity is not totally dependent on TNF stimulation [
1,
36,
37]. The results of our study also suggest that tocilizumab has mechanisms of action that are unique from those of anti-TNF agents. As such, TNF represents an important therapeutic option for anti-TNF agent non-responders as well as disease-modifying antirheumatic drug (DMARD) non-responders.
In an attempt to identify predisposing factors for tocilizumab efficacy, we analyzed factors associated with remission using the demographic characteristics of our RA patients as the explanatory variables for logistic regression. The results of this analysis revealed that a low DAS28 at baseline and a younger age were associated with the induction of remission. Although patients at an earlier disease stage have been reported to be more sensitive to anti-rheumatic treatments [
38], disease duration in our study did not appear to be correlated with remission. Since this study was conducted as a retrospective analysis of data collected in daily practice, many confounding factors could have potentially influenced the data. However, considering the high remission rate observed in the SAMURAI study (59%) [
16], which was conducted in early RA patients in Japan, tocilizumab may prove to be most efficacious in younger patients and/or in those with early-stage disease.
Since IL-6 has pleiotropic actions, some of which are inconsistent with TNF actions, the inhibition of IL-6 action by tocilizumab may cause unexpected adverse reactions. Thus, the safety profile associated with tocilizumab needs to be carefully evaluated. With respect to laboratory parameters, decreased WBC counts and increased liver enzyme levels and/or serum cholesterol levels have been reported to be associated with tocilizumab use [
15,
39]. However, in our study, although significant WBC count decreases and AST/ALT and TC increases were observed, these changes were tolerable (Table
2). Only two patients discontinued tocilizumab due to hepatic disorders (Table
3), and the liver enzyme levels returned to normal after the discontinuation of tocilizumab therapy. Interestingly, liver enzyme levels significantly increased in patients who concomitantly received MTX, but not in those who did not receive MTX, which is consistent with the findings of previous studies [
16,
17,
32,
33]. Among 47 patients who discontinued tocilizumab, 12 did so due to insufficient efficacy, while 26 discontinued because of adverse events. Among the latter, six patients discontinued due to pneumonia. Pneumonia was the most frequent adverse event observed in previous Japanese post-marketing surveillance (PMS) evaluation of infliximab [
40] and etanercept [
27], which is consistent with the results of our study. However, it should be noted that susceptibility to infection is an important concern not only in association with anti-TNF therapies but also with the anti–IL-6 activity of tocilizumab.
The safety profile of tocilizumab therapy was recently extensively investigated in Japan using an all-case registered PMS study conducted by Chugai Pharmaceutical under the auspices of the regulatory authority of the Japanese government, with effective suggestions from the subcommittee of the Japan College of Rheumatology. A total of 9,000 cases were registered from April 2008 to December 2009, and an interim analysis is currently being conducted. The final analysis is expected to describe the safety profile of and risk factors associated with tocilizumab therapy on a large scale.
In conclusion, this REACTION study confirmed the efficacy of tocilizumab in Japanese patients with RA. Tocilizumab was also well tolerated, and the retention rate at 24 weeks was 79.5%. The promising efficacy of tocilizumab in improving measures of disease activity and preventing progression of this disabling disease has allowed this agent to become one of the critical advances in the management of RA in recent years. The present data should facilitate a more efficacious use of this expensive biological agent in daily rheumatology practice, not only in Japan but also in many countries throughout the world.
Acknowledgments
The authors thank all medical staff in the three institutions for providing data. This work was supported partly by a Research Grant-In-Aid for Scientific Research by the Ministry of Health, Labor and Welfare of Japan, the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the University of Occupational and Environmental Health, Japan.