Intravenous Tocilizumab
In Clinical Trials
The efficacy of IV tocilizumab monotherapy or combination therapy with csDMARDs in improving disease activity, structural joint damage and health-related quality of life (HRQOL) in adult patients with moderate to severe active RA was firmly established in several large (n > 300), randomized, controlled trials (RCTs) of ≥ 24 weeks’ duration [4,5,6,7,8,9,10,11,12,13,14]. Most of these trials [4,5,6,7, 9,10,11,12, 14] have been reviewed in detail [1] and are briefly summarized here. Discussion focuses on the recommended EU dosage regimen of tocilizumab 8 mg/kg once every 4 weeks (Sect. 4).
In Longer-Duration Established RA
As monotherapy [4, 6, 7], tocilizumab significantly improved ACR20, 50 and 70 response rates and DAS28 remission rates compared with methotrexate [4], csDMARD [7] or adalimumab [6] monotherapy (Table 2). In AMBITION, the ACR20 response rate at 24 weeks (primary endpoint) with tocilizumab was superior to that of methotrexate (Table 2), with significant between-group differences (BGDs) observed from 2 weeks onwards [4]. At 24 weeks in the ADACTA trial, tocilizumab monotherapy was superior to adalimumab monotherapy for the mean change in DAS28 score (− 3.3 vs. − 1.8; BGD − 1.5; p < 0.0001) (primary endpoint) and was more effective than adalimumab in terms of secondary outcomes (Table 2) [6].
Table 2 Efficacy of intravenous tocilizumab in adults with moderate to severe active rheumatoid arthritis in large (n > 300), double-blind (or X-ray reader blind [7]), multicentre, phase 3 (or phase 4 [6]) trials of ≥ 24 weeks’ duration
As combination therapy with methotrexate [5, 10] or csDMARDs [11, 12], add-on tocilizumab was more effective than methotrexate or csDMARDs alone in improving clinical signs and symptoms of disease (Table 2). Several other endpoints also favoured (p < 0.05) tocilizumab combination therapy at 24 weeks, including improvements in swollen (SJC) and tender joint counts (TJC) [5, 10, 12], CRP levels and ESR [11, 12], HRQOL measures [5, 10, 12], SF-36 physical function scores [5, 10] and FACIT-fatigue (FACIT-F) scores [5, 10, 12].
Tocilizumab (+ methotrexate) therapy significantly improved radiographic outcomes compared with methotrexate alone at 52 [9] and 104 [15] weeks in the 2-year LITHE trial [9, 15], with these benefits maintained during the 3-year long-term extension (LTE) study [16]. At 52 [9] and 104 [15] weeks, tocilizumab recipients experienced significantly less radiographic progression of structural joint damage, including changes from baseline in Genant-mTSS (coprimary endpoint; p < 0.01), erosion scores (p < 0.05) and joint space narrowing (JSN) scores (p < 0.05). In terms of HRQOL, tocilizumab recipients experienced significantly (p < 0.0001) greater improvements in the adjusted mean AUC for change in HAQ-DI score (coprimary endpoint) than methotrexate recipients at 52 [9] and 104 [15] weeks, with significantly (p < 0.05) more tocilizumab recipients achieving a clinically meaningful improvement (i.e. a decrease of ≥ 0.3 in HAQ-DI score) in physical function at 52 weeks [15]. The beneficial effects of tocilizumab combination therapy on radiographic outcomes and HAQ-DI scores were maintained after ≤ 5 years’ treatment [16].
The beneficial effects of long-term (≤ 5 years) tocilizumab monotherapy (n = 134) or combination therapy (n = 109) on clinical signs and symptoms of RA were maintained or improved during the LTE of AMBITION [17]. The short- and long-term (≤ 4.6 years’ exposure) efficacy of tocilizumab combination therapy was confirmed in pooled analyses of RCTs, their LTE studies and a PK study [18]. Similarly, in a meta-analysis of six Japanese RCTs, improvements in clinical signs and symptoms of RA were sustained during ≤ 9 years’ tocilizumab therapy [19].
In Early-Stage RA
Tocilizumab (+ methotrexate) therapy was also effective in improving the clinical signs and symptoms of RA in patients with early-stage disease who were methotrexate- or biologic DMARD (bDMARD)-naive (FUNCTION) [8] or methotrexate-naive (U-Act-Early) [13] (Table 2). For example, in the 2-year FUNCTION trial, clinical response rates at 24 weeks (primary timepoint for primary outcome) in terms of DAS28 remission rates (primary outcome) and ACR20, 50 and 70 response rates were all significantly higher with tocilizumab combination therapy than with methotrexate (+ placebo), as was the DAS28 remission rate with tocilizumab monotherapy versus methotrexate alone (Table 2) [8]. These clinical outcomes also significantly (p < 0.05) favoured tocilizumab combination therapy over methotrexate (+ placebo) at 52 weeks [8] and were maintained at 104 weeks [20]. With tocilizumab monotherapy, the DAS28 remission rate was significantly higher than with methotrexate monotherapy at 24 weeks, with other clinical outcomes numerically higher in the tocilizumab monotherapy group (Table 2) [8].
At 52 weeks, tocilizumab (+ methotrexate) recipients had significantly greater improvements in radiographic outcomes than methotrexate recipients in terms of van der Heijde mTSS (mean change 0.08 vs. 1.14; p = 0.0001) and erosion scores (0.05 vs. 0.63; p = 0.0006), with no significant BGD in JSN scores (0.03 vs. 0.51) [8]. Improvements in radiographic outcomes were numerically higher in the tocilizumab monotherapy group than in the methotrexate group [8]. The beneficial effects of tocilizumab combination therapy on radiographic outcomes were maintained at 104 weeks [20].
Adding Versus Switching to Tocilizumab
In the 3-year ACT-RAY trial, there were no significant BGDs at week 24 between adding (+ methotrexate) or switching to tocilizumab for DAS28 remission rates (primary endpoint) or secondary outcomes, including ACR response rates (Table 2) and radiographic progression [14]. The clinically meaningful improvements in clinical and radiographic responses achieved at 24 weeks were maintained at 52 weeks with both regimens [21]. At 2 years, there were generally no significant BGDs in clinical and radiographic outcomes, with efficacy maintained in both treatment groups [22]. Patients who achieved sustained remission (i.e. DAS28 < 2.6 at two consecutive 12-week visits) between weeks 52 to 104 discontinued tocilizumab treatment, and if remission was maintained, csDMARDs and then methotrexate were discontinued, with 76% of patients completing 2 years’ treatment. More tocilizumab recipients achieved drug-free remission in the add-on than switch arm (8.6% of 243 patients vs. 3.1% of 229 patients; p = 0.01). In these respective arms, 53.1 and 47.6% of patients achieved tocilizumab-free remission; of whom, 82.5 and 88.5% experienced flare within 52 weeks, with the majority of patients responding rapidly to tocilizumab retreatment [22].
In the Real-World Setting
Extensive evidence from several large, prospective, post-marketing studies (n = 557–1681) [23,24,25,26,27,28,29], including ACT-UP (a multinational, umbrella project involving 16 multicentre, observational studies sharing a set of design elements, patient selection criteria and core data) [23], and registry databases (n = 1491–7901) (French REGATE [30]; TOCERRA collaboration (9 EU registries) [31, 32]; Japanese post-marketing surveillance [33]; BSRBR-RA (UK) [34]; Germany [35]; US CORRONA Registry [36]), have firmly established the efficacy of IV tocilizumab in the clinical practice setting.
In ACT-UP, the efficacy of tocilizumab monotherapy (n = 506) or combination therapy (+ csDMARD; n = 830) was generally similar after 6 months’ treatment, with most patients continuing tocilizumab treatment throughout the study (primary endpoint) [80 vs. 87%; log-rank p < 0.001] [23]. At 6 months, mean changes from baseline for DAS28 scores with tocilizumab monotherapy and combination therapy were − 2.9 and − 3.2 (n = 178 and 365) and mean changes from baseline in CDAI scores were − 20.3 and − 22.3 (n = 186 and 416), with 94.4 and 92.1% of patients achieving a EULAR good or moderate response (n = 178 and 365). The tocilizumab dosing regimen was based on local label recommendations, with ≥ 94.5% of patients in both groups initiating tocilizumab treatment at a dose of 8 mg/kg [23].
In the global ACT-iON study in RA patients with an inadequate response to csDMARDs and initiating biologic therapy, patients initiating tocilizumab 8 mg/kg once every 4 weeks experienced significantly (p < 0.001) greater improvements in DAS28 scores at week 24 (primary endpoint; adjusted mean BGD − 0.831) and 52 (adjusted mean BGD − 0.910) than those initiating a TNF inhibitor (TNFi) [27]. With the exception of changes in TJC scores, adjusted mean changes from baseline for secondary endpoints all favoured tocilizumab over TNFi therapy at 24 weeks (p < 0.05), including improvements in ESR, CRP levels, and scores for SJC, CDAI, SDAI, HAQ-DI, FACIT-F and pain VAS. The benefits of tocilizumab over TNFi therapy persisted at 52 weeks for mean adjusted changes in ESR and scores for SJC, CDAI, SDAI, HAQ-DI and pain VAS (p < 0.05), with TJC scores also favouring tocilizumab at 52 weeks (p = 0.004). At 52 weeks, tocilizumab recipients were less likely to discontinue treatment than TNFi recipients (cumulative probability of drug discontinuation 15 vs. 27%; p < 0.001) [27].
In the open-label, multinational, phase 3b, ACT-SURE trial, patients with active RA (i.e. DAS > 3.2) who had an inadequate response to csDMARDs or csDMARDs plus a TNFi were randomized to tocilizumab (± csDMARD) for 24 weeks [24]. Treatment with TNFi was discontinued at the start of the study, with patients switching to tocilizumab with or without a washout period (n = 976 TNFi-naive, 298 TNFi-experienced with washout, and 470 TNFi recent use with no washout). At 24 weeks, ACR20 response rates in the TNFi-naive, TNFi-experienced and TNFi-recent use groups were 71, 61 and 63%, respectively (efficacy was a secondary outcome) [24]. Rates of DAS28 remission in these respective groups were 62, 49 and 50%, with LDA achieved by 75, 61 and 62% of patients [24].
In the open-label, multicentre, phase 3b ACT-STAR trial in treatment-experienced RA patients who had an inadequate response to prior csDMARDs or bDMARDs, ACR20 response rates at 24 weeks were 40–50%, ACR50 response rates were 24–27%, DAS28 remission was achieved by 20–25% of patients and LDA by 31–46% of patients across groups randomized to tocilizumab 8 mg/kg monotherapy (n = 163), tocilizumab 4 or 8 mg/kg (+ csDMARDs) (n = 363) or tocilizumab 8 mg/kg (+ csDMARD; n = 360) [29]. Efficacy was a secondary outcome in this trial; unlike phase 3 clinical trials, eligible patients were not required to have a minimum CRP or ESR, or a washout period prior to study entry [29].
In the French 12-month ACT-SOLO study in tocilizumab-naive patients with RA (n = 577; mean RA duration 10.9 years; 98% of patients were treatment experienced), 40% of patients initiated tocilizumab as monotherapy and 60% as combination therapy (+ csDMARD) [25]. The primary objective was to describe factors influencing the use of tocilizumab as monotherapy or combination therapy. At 12 months, there was no difference in the median rate of retention in the tocilizumab monotherapy and combination therapy groups (67 vs. 71%). In multivariate analyses, after exclusion of dyslipidemia as a factor (since this was correlated with age), independent factors for monotherapy (all p < 0.05) were aged ≥ 65 years [odds ratio (OR) 1.56], no methotrexate within the previous 2 years (OR 5.74), a past history of serious infectious disease (OR 2.03) and a higher baseline DAS28 (OR 1.22). There were no BGDs in terms of efficacy outcomes at 1 year, including ACR20, 50 and 70 response rates, DAS28, SDAI and CDAI remission and low-disease activity (LDA) rates, EULAR good or moderate response rates and changes in HAQ-DI scores [25].
In the CORRONA study in tocilizumab-naive patients with RA (mean disease duration 10.5–15 years) who had prior exposure to ≥ 1 TNFi, improvements in disease activity measures at 6 months indicated that tocilizumab monotherapy was as effective as treatment with a TNFi plus methotrexate, irrespective of the methotrexate dosage (i.e. methotrexate dose ≤ 10, > 10 to ≤ 15, > 15 to ≤ 20 or > 20 mg) (abstract) [36]. For the primary outcome of the mean change in CDAI score at 6 months, improvements were similar between the tocilizumab monotherapy group and all TNFi combination therapy groups, as was the likelihood of achieving LDA (i.e. CDAI score ≤ 10) [36].
Tocilizumab significantly improved markers of anaemia [i.e. haemoglobin (Hb) and haematocrit (Hct) levels] during 2 years’ treatment in RA patients (n = 3732), irrespective of baseline anaemia status, in a real-world, longitudinal cohort study utilizing US CMER (n = 153,788) [37]. In tocilizumab recipients, adjusted mean increases in Hb levels at 24 months in the overall population and in those with anaemia at baseline were 0.23 and 0.72 g/dL, with respective improvements in Hct levels of 0.96 and 2.06%. There was an 86% increase (OR 1.86; 95% CI 1.43–2.00; p < 0.001) in the likelihood of achieving an increase in Hb of ≥ 1 g/dL in the tocilizumab cohort than in the tofacitinib (n = 3126), other bDMARD (n = 55,694) and non-biologic DMARD (n = 91,236) cohorts, with no clinically relevant changes in Hb levels in these latter three cohorts. Initiating tocilizumab within 1 year of RA diagnosis was associated with a 95% increase (OR 1.95; 95% CI 1.19–3.21) in the likelihood of achieving an increase in Hb level at 6 months compared with initiating treatment 1 year post RA diagnosis. Conversely, early initiation of treatment in the other cohorts had no impact on the likelihood of achieving better Hb levels (ORs 0.98–1.19). In the tocilizumab, tofacitinib, other bDMARD and non-biologic DMARD group, 26, 29, 21 and 24% of patients, respectively, had anaemia at index date, with corresponding mean times to initiation of therapy from RA diagnosis of 39, 39, 12 and 4 months [37].
Subcutaneous Tocilizumab
In Clinical Trials
The efficacy of SC tocilizumab monotherapy (MUSASHI [38]) or combination therapy (BREVACTA [39] and SUMMACTA [40]) was investigated in multicentre, phase 3 trials in adults with moderate to severe active RA who had an inadequate response to csDMARD(s) [38,39,40] and/or bDMARD(s) [38]. Each trial comprised a 24-week double-blind phase and a 72- [39, 40] or 84-week [38, 41], open-label phase (with a 1-week dose-interruption period between these two phases in SUMMACTA [40]). All participants in BREVACTA and SUMMACTA received concomitant csDMARDs [39, 40]. In BREVACTA, escape therapy with tocilizumab 162 mg once weekly was permitted from week 12 in patients with an inadequate response (i.e. < 20% improvement from baseline in SJC and TJC) to tocilizumab 162 mg once every 2 weeks or placebo (16.5 vs. 41.1% of patients received escape therapy) [39]. The primary endpoint in all trials was the percentage of patients achieving an ACR20 response at week 24 [38,39,40], with safety a coprimary endpoint in SUMMACTA [40].
The impact of discontinuing methotrexate (i.e. tocilizumab monotherapy) versus continuing methotrexate (i.e. tocilizumab plus methotrexate) in patients who had achieved LDA (i.e. DAS28 ≤ 3.2) after 24 weeks of methotrexate plus tocilizumab 162 mg weekly (patients weighing ≥ 100 kg) or every other week (patients weighing < 100 kg) was evaluated in the 52-week, double-blind, multicentre, phase 3 COMP-ACT trial (abstracts) [42,43,44]. Patients weighing < 100 kg who had not achieved LDA at week 12 could escalate their tocilizumab dosage from 162 mg every other week to 162 mg once weekly [44]. Patients achieving LDA at week 24 were randomized to tocilizumab monotherapy (n = 147 evaluable) or tocilizumab plus methotrexate (n = 147 evaluable) until week 52. The primary outcome was the mean change in DAS28 score from week 24 to 40. At 24 weeks, DAS28 scores were similar in both groups [44]. At baseline patients had a mean disease duration of 6.8 years and mean DAS28 score of 6.3 [43].
Versus Placebo
At 24 weeks, the ACR20 response rate was significantly higher with add-on tocilizumab than add-on placebo, as were secondary clinical outcomes of ACR50 and 70 response rates and DAS28 remission rates (Table 3) [39]. In patients who switched to once-weekly tocilizumab escape therapy, the ACR20 response rate 12 weeks after escape in those initially randomized to tocilizumab once every 2 weeks was 58% and in those initially randomized to placebo was 72%. In exploratory subgroup analyses, ACR20, 50 and 70 response rates in the tocilizumab and placebo groups in patients receiving concomitant methotrexate or another DMARD at baseline were generally consistent with those in the overall population, as were these response rates in patients with an inadequate response to a DMARD or TNFi. Radiographic outcomes also favoured tocilizumab combination therapy, with significantly lower mean changes in mTSS (0.62 vs. 1.23; p = 0.0149) and erosion score (0.26 vs. 0.65; p = 0.0078) at 24 weeks in tocilizumab than placebo recipients [39]. Least square mean (LSM) changes in patient-reported outcomes (PROs) also significantly (p < 0.001) favoured tocilizumab combination therapy over add-on placebo at 12 weeks, including SF-36 MCS and PCS scores and HAQ-DI scores (abstract) [45]. In addition, significantly (p < 0.05) more tocilizumab than placebo recipients reported scores that were at least the minimum clinically important difference for all PROs and numerically more tocilizumab recipients reported scores of at least the normative value at week 12 [45].
Table 3 Efficacy of subcutaneous tocilizumab monotherapy or combination therapy in multicentre trials in adults with moderate to severe, active rheumatoid arthritis who had an inadequate response to csDMARDs [38,39,40, 47] and/or bDMARDs [38], or who were methotrexate-naive [47]
IV Versus SC Tocilizumab
In the Japanese MUSASHI study, SC tocilizumab monotherapy was noninferior to IV tocilizumab monotherapy at 24 weeks in terms of ACR20 response rate in the per-protocol population (Table 3), with sensitivity analyses in the modified intent-to-treat (ITT) population consistent with this result [38]. There were no significant BGDs in terms of secondary outcomes, including ACR50 and 70 response rates (Table 3), and DAS28 (Table 3), CDAI (16 vs. 23%) and Boolean (16 vs. 16%) remission rates [38].
At 24 weeks, there were no significant differences in efficacy between the add-on SC and IV tocilizumab groups for primary and secondary outcomes in SUMMACTA (Table 3) [40]. Improvements in mean HAQ-DI scores from baseline to week 24 were similar with SC and IV tocilizumab combination therapy, as were CDAI remission rates (13.5 vs. 15%) [40]. LSM improvements in PROs were also similar in the SC and IV tocilizumab combination therapy groups at 24 weeks, including scores for HAQ-DI, SF-36 PCS and MCS, with add-on tocilizumab treatment resulting in clinically meaningful improvements in all PROs [45].
Impact of Discontinuation of Methotrexate in Patients with Low Disease Activity
In the 52-week COMP-ACT trial, discontinuation of methotrexate at week 24 (tocilizumab monotherapy) was noninferior to continuation of methotrexate (+ tocilizumab) for changes in DAS28 score from week 24 to 40 [mean change in DAS28 score 0.46 vs. 0.14; BGD 0.318 (95% CI 0.045–0.592)], indicating that patients who achieve LDA can effectively discontinue methotrexate therapy [44]. There were also no BGDs for changes in PROs from week 24 to 40, including mean changes in patient global assessment, pain, FACIT-F and HAQ-DI scores [43]. In addition, a similar proportion of patients in the tocilizumab monotherapy and combination therapy groups had an HAQ-DI score of < 0.5 at weeks 24 (randomization), 40 and 52 [43]. There were also no significant BGDs for mean changes from week 24 to week 40 in bone erosion, synovitis, osteitis and cartilage loss scores (assessed in the hands and wrists) or in the proportion of patients with no progression in each of these outcomes [42].
Longer-Term Treatment
The efficacy of tocilizumab was maintained during the 72- and 84-week extension phases in SUMMACTA [40] and MUSASHI [41] (no data reported for BREVACTA [39]), and during a further 84-week, open-label, single-arm, phase 3b extension study of BREVACTA and SUMMACTA [46]. In the phase 3b study, mean DAS28, CDAI and SDAI scores remained stable with add-on tocilizumab once weekly (n = 173) or once every 2 weeks (n = 44) [46]. Overall, at week 36 (i.e. after ≈ 132 weeks’ treatment), 62% of patients achieved an ACR20 response, 49 and 36% achieved LDA and disease remission by DAS28 criteria, 41 and 11% achieved LDA and remission by CDAI criteria, and 41 and 14% achieved LDA and remission by SDAI criteria; after week 36, patient numbers were insufficient for analyses to be conducted [46].
In the Real-World Setting
In TOZURA, a multinational (total of 22 countries), umbrella project involving 11 single-arm, multicentre studies, 24 weeks’ tocilizumab provided similar efficacy in patients with moderate to severe RA, irrespective of whether it was used as monotherapy (n = 353) or in combination with a csDMARD (n = 1451) (abstract) [47]. Retention rates at 24 weeks were similar in the monotherapy and combination therapy groups (79.3 and 85.6%), with no significant BGDs for mean changes from baseline in DAS28 and CDAI scores, the proportion of patients achieving DAS28 (Table 3) or CDAI remission, and ACR20 (Table 3), ACR50 (Table 3), ACR70 (Table 3) and ACR90 response rates [47].