This study was a multi-center, randomized, blinded, double-dummy trial of tocilizumab in active RA patients who had an inadequate response to low dose MTX treatment in Japan. The results of this study confirmed the excellent efficacy of tocilizumab monotherapy for signs and symptoms as shown in previous studies [7
]. Since MTX is an anchor drug in RA treatment, it is noteworthy that tocilizumab treatment is a very efficacious treatment for the patients with an inadequate response to MTX. In addition, switching MTX therapy to tocilizumab monotherapy was safe and effective.
The dose of MTX prior to enrollment was 10–25 mg/week in CHARISMA study, which was conducted in Europe [13
], while all patients in this study were treated with MTX 8 mg/week. The dosage 8 mg of MTX/week in this trial is the maximum dosage approved in Japan. The Japanese government recommends 6–8 mg/week of MTX based on the evidence from the Japanese clinical trials of MTX for RA [14
]. The MTX dosage used in Japan is lower than that used in Western populations treated in the EU or US. The average body weight of the patients in this study was 54 kg, and much lower than those of EU and US patients. Additionally, all patients were given folic acid in the CHARISMA study, in contrast to only 51% of the patients in this study. Considering these factors, the differences in the clinical efficacy of MTX between the CHARISMA study and this study might not be so large as expected when looking at the difference in the MTX dose.
Maini et al. demonstrated in the CHARISMA study, that adding MTX to tocilizumab increased the efficacy in terms of ACR50 and ACR70 response rates, although there was no difference in ACR20 response rates between the tocilizumab 8 mg/kg monotherapy and the tocilizumab 8 mg/kg plus MTX. Thus, the combination with MTX may be a therapeutic option, if the toxicity is not increased. In this study, however, even monotherapy with tocilizumab 8 mg/kg induced DAS28 remission at 6 months in about 40% of patients. Furthermore, since anti-tocilizumab antibodies are not detected without use of MTX, the combination with MTX is not required to suppress the emergence of anti-tocilizumab antibodies as long as 8 mg/kg of tocilizumab is used. Therefore, tocilizumab will be useful for the patients who do not tolerate MTX.
This double-blind study of tocilizumab also confirms the previous finding that IL-6 receptor inhibition improves serum VEGF levels of RA patients [16
]. Serum VEGF levels markedly decreased during tocilizumab therapy compared to the treatment with MTX. VEGF is produced by macrophages, fibroblasts surrounding microvessels, vascular smooth muscle cells, synovial lining cells in synovium [17
], neutrophils in synovial fluid [18
], and peripheral blood mononuclear cells [19
] from patients with RA. VEGF is a potent angiogenic factor and thought to be responsible for the angiogenesis necessary to oxygenate the hypertrophic synovial tissues of the affected joints of RA patients [20
]. VEGF also induces vascular permeability and mediates inflammation [22
]. Therefore, the decrease in VEGF may be an important part of the mechanism how IL-6 receptor inhibition with tocilizumab exerts its therapeutic efficacy in RA. Since serum VEGF levels correlate with disease activity scores and radiographic progression in RA patients [16
], the dramatic decrease in VEGF also underlines the efficacy of tocilizumab. The normalization of VEGF by blockade of IL-6 function alone indicates that IL-6 is essential for the VEGF production in this disease.
Tocilizumab monotherapy was generally well tolerated. There was no specific type of infection related to tocilizumab therapy. There is no indication for an increased risk of reactivation of latent tuberculosis, which is often a problem in anti-TNF therapy [26
]. In this study patients did not receive prophylactic medication nor were they screened for latent or active tuberculosis at the time of screening.
The increase in TC observed is in concordance with observations in previous studies of tocilizumab [7
]. This may be secondary to the improvement in inflammation. Furthermore, there was no cardiovascular adverse event related to the increase in TC. However, further investigation will be required to evaluate whether or not tocilizumab might increase the risk for developing ischemic heart diseases.
The mean value elevations of liver functional tests (AST, ALT and total bilirubin) were seen in the tocilizumab group as well as in the control group, but they were within normal range. Liver functional tests abnormalities were more frequently observed in the control group than in the tocilizumab group. Moreover, most of them were grade 1 according to the NCI-CTC. These abnormalities were clinically not significant and no hepatitis was observed. Therefore, tocilizumab monotherapy appears to be as tolerable as MTX in terms of liver function.