Characteristics of the patients
This study enrolled 306 patients in total (Figure 1). Four patients were withdrawn before treatment either due to their ineligibility or at the patients' request. A total of 302 patients received study drugs. A total of 134 patients in the tocilizumab group and 131 patients in the DMARDs group completed 52 weeks treatment. Discontinuation occurred in 23 patients in the tocilizumab group and 14 patients in the DMARDs group. The reported reasons for withdrawal are shown in Figure 1.
Figure 1Randomisation, reasons for withdrawal, and numbers of patients who completed the trial. DMARDs, disease‐modifying antirheumatic drugs; Tocilizumab, humanised anti‐interleukin‐6 receptor antibody.
Demographics and baseline disease characteristics did not differ between the two groups (Table 1).
Table 1Patient demographics and clinical characteristics at baseline*
Mean disease duration was 2.3 years. Patients had active disease, indicated by a DAS28 score of 6.5 and CRP of 48 mg/L at baseline. Moreover, TSS at baseline was 29.4, which was very high despite the relatively short disease duration. The mean estimated yearly progression rate, calculated from the baseline TSS divided by disease duration for each patient, was 13.3 Sharp units.
Treatment in the conventional DMARD group
At baseline, 67% of the patients in the DMARDs group received methotrexate (MTX): 37% received a combination of MTX and DMARDs, 30% received MTX monotherapy, and 22% received DMARDs and/or immunosuppressants other than MTX, besides corticosteroids. The dose of MTX was 7.1±1.9 mg/week (mean±SD) in patients treated with MTX. During the study, 123 patients (85%) received MTX: 81 (56%) received a combination of MTX and DMARDs, 42 (29%) received MTX monotherapy, and 20 (14%) received DMARDs and/or immunosuppressants other than MTX, besides corticosteroids. The dose of MTX was 8.0±2.1 mg/week in patients treated with MTX (Japanese government recommends 6–8 mg/week of MTX based on the evidence from the Japanese clinical trial of MTX for RA).26,27
Besides MTX, salazosulfapyridine (41%), bucillamine (23%), mizoribine (8%) and D‐penicillamine (8%) were frequently used in more than 5% of the patients.
Reliability of radiographic scoring
Intra‐reader intraclass correlation coefficients for erosion, joint space narrowing and TSS were all 0.99 for both readers. Inter‐reader intraclass correlation coefficients for erosion, joint space narrowing and TSS were 0.98, 0.96 and 0.98, respectively.
Radiographic evaluation of joint damage
Figure 2 shows the cumulative probability plots of the change from baseline to week 52 in the TSS. The space between the curves indicates different treatment effects with a considerable difference in favour of the tocilizumab monotherapy group. The plots representing the TSS changes in the tocilizumab group clearly shifted to the right compared with those in the conventional DMARDs, indicating that fewer patients in the tocilizumab group showed radiographic progression and also a smaller amount of progression than those in the DMARDs group. At week 52, 56% of patients receiving tocilizumab had no radiographic progression (i.e., change from baseline in the TSS
0.5) compared with 39% of patients receiving conventional DMARDs (p<0.01). Moreover, more patients receiving tocilizumab monotherapy had negative TSS scores than those receiving conventional DMARDs (24 patients and 18 patients at week 52, respectively).
Figure 2Cumulative probability distribution of radiographic changes in total Sharp/van der Heijde scores from baseline to week 52 for patients treated with tocilizumab or with conventional DMARDs. The space between the curves indicates the different (more ...)
The mean changes in the TSS as well as erosion scores at week 28 were statistically significantly less in the tocilizumab group than in the DMARDs group with an ANCOVA model (Table 2).
Table 2Change in radiographic scores
The efficacy was more evident at week 52. In addition to the TSS and erosion score, joint space narrowing scores also showed significantly less change in the tocilizumab group than in the DMARD group. In the tocilizumab group, patients who achieved a higher ACR response showed less radiological progression at week 52 (in the patients with ACR70 response (n
73), mean TSS 1.6; 95% CI 0.3 to 2.8). A similar effect was observed in the DMARDs group (in the patients with ACR70 response (n
8), mean TSS 1.5; 95% CI –0.6 to 3.6).
At week 52, proportions of the patients achieving ACR20, ACR50, and ACR70 response were 78%, 64%, and 44% in the tocilizumab group and 34%, 13%, and 6% in the DMARD group, respectively, indicating the superiority of tocilizumab monotherapy to conventional DMARD therapy (p<0.001, for each comparison) although clinical efficacy was assessed unblinded (Figure 3A).
Figure 3Percentage of responders according to the American College of Rheumatology (ACR) improvement criteria and the Disease Activity Score in 28 joints (DAS28) as well as mean change in Modified Health Assessment Questionnaire (MHAQ) scores. (more ...)
Greater reduction in DAS28 scores and higher remission rates were also observed in the tocilizumab group than in the DMARDs group (Figure 3B). At week 52, clinical remission (defined as DAS28 <2.6)28
was achieved in 59% of patients receiving tocilizumab, but only in 3% of patients receiving DMARDs (p<0.001). Major clinical response (ACR70 response for 6 consecutive months) was achieved in 24% of patients receiving tocilizumab compared with only 2% of patients receiving DMARDs during the study period of 52 weeks.
Physical function and health‐related quality of life
Tocilizumab monotherapy significantly improved MHAQ scores compared to conventional DMARDs (Figure 3C). A decrease of >0.22 units in HAQ scores represents significant clinical improvement and the minimum clinically important difference.29
Such improvement was seen in 40% of the patients treated with tocilizumab as early as week 4, the first scheduled study visit, and was even more evident at week 52 (68% in the tocilizumab group and 40% in the DMARDs group, p<0.001).
The percentages of patients with adverse events were 89% and 82% in the tocilizumab and DMARD groups, respectively. Most of adverse events were mild or moderate. Table 3 shows frequent adverse events observed in at least 5% of the patients.
Table 3Adverse events observed in at least 5% of patients*
Nasopharyngitis was the most common adverse event, but the incidences were similar in both groups.
Serious adverse events were reported in 18% and 13% in the tocilizumab group and DMARDs group, respectively. In the tocilizumab group, 12 serious infections were reported: 3 (1.9%) patients with pneumonia, 2 (1.3%) with upper respiratory tract infection, 2 (1.3%) with cellulitis, 1 (0.6%) each with gastroenteritis, herpes zoster, herpes simplex, perianal abscess and an unidentified infection. In the DMARD group, 8 serious infections were reported: 3 (2.1%) patients with gastroenteritis, 2 (1.4%) with pneumonia, and 1 (0.7%) each with upper respiratory tract infection, herpes zoster and sepsis. All the serious adverse events improved with appropriate treatment. There was no significant prolongation of infection by the tocilizumab treatment. Tuberculosis was not observed in this 1‐year study without required screening or prophylactic use of any antituberculous drug.
Three malignancies were reported in the tocilizumab group: 2 patients with breast cancer (including 1 lobular carcinoma in situ) and 1 with colon cancer, which were improved or resolved by appropriate treatment (including surgery). No malignancies were reported in the DMARD group.
Drug‐related infusion reactions were reported 14 times in 11 (7.0%) patients of the tocilizumab group: 3 with transient increase in blood pressure, 2 with injection site redness, 2 with headache, 2 with nausea, 2 with skin eruption, and 1 each with vomiting, pruritus, and malaise. All the infusion reactions were mild, and no patient withdrew from the study as a consequence.
Laboratory test abnormalities were reported in 61% and 31% of patients in the tocilizumab and DMARD groups, respectively. In the tocilizumab group, lipid metabolism‐related reactions were common. Anomalous increases in total cholesterol (TC), triglycerides, and low‐density lipoprotein cholesterol were reported in 38%, 17%, and 26% of the patients, respectively, and most of them were grade 1 according to the National Cancer Institute Common Toxicity Criteria. Twenty‐seven patients were treated (HMG‐CoA reductase inhibitor, 26 cases; fenofibrate, 1 case) and their cholesterol levels improved during the study. Tocilizumab monotherapy also raised high‐density lipoprotein cholesterol (HDLC) levels to above the normal range in 24% of patients. The atherogenic index, calculated by (TC–HDLC)/HDLC, did not change during the study period of 52 weeks. No cardiovascular complications were observed in association with abnormal lipid profile.
Anti‐tocilizumab antibodies were detected in 4 patients (2.5%). Only one patient showed a skin eruption at the third injection, while the other three were asymptomatic. They were all withdrawn according to the study protocol.