Tocilizumab as monotherapy or combination therapy for treating active rheumatoid arthritis: a meta-analysis of efficacy and safety reported in randomized controlled trials

In the management of rheumatoid arthritis (RA), conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) are recommended as first-line treatment in DMARD-naïve patients for achieving remission [1–3]. Patients who have inadequate response to csDMARDs as defined by not achieving the treatment target should receive add-on therapy with a biological DMARD (bDMARD) if they have factors linked to poor prognosis (e.g., early joint damage or seropositivity). However, data obtained from large cohort studies reveal that approximately one-third of patients with RA discontinue all csDMARDs and initiate bDMARD monotherapy, mainly because of intolerance or noncompliance in taking the csDMARD [4–6]. Adverse events (AEs) are the main reason for withdrawal (>70 % of patients), with gastrointestinal symptoms being most frequently observed (>30 % of patients) [6, 7].

For patients in whom continuing csDMARD therapy is not feasible, it is important to know the effectiveness and safety of switching to bDMARD monotherapy. To this day, there is no clear preference as to which biologic agent (e.g., tumor necrosis factor inhibitors (infliximab, etanercept, adalimumab, certolizumab pegol, golimumab), rituximab (targeting B-cells), abatacept (targeting T cells) or tocilizumab (TCZ) (inhibiting interleukin 6 signaling [8]) is preferable if monotherapy must be initiated, because of a lack of head-to-head comparisons. In ADACTA, [9] a randomized, double-blind, controlled study, TCZ was shown to be superior to adalimumab in patients requiring monotherapy and could thus potentially be suitable as first-line biologic therapy. To our knowledge, this is hitherto the only bDMARD monotherapy superiority study reported. Several randomized phase III studies have shown that switching to TCZ monotherapy or combination therapy is efficacious in achieving rapid and sustained improvements within patients who do not achieve the treatment aim with csDMARD therapy [10–20]. However, there is no consensus as to whether TCZ as monotherapy is as effective as TCZ combined with csDMARDs. Although several studies have compared switching to TCZ monotherapy with add-on combination therapy, this has not yet been analyzed in meta-analyses. The objective of this study was to evaluate the efficacy and safety in patients with RA of TCZ monotherapy versus add-on TCZ combination therapy, and both TCZ therapies versus continuing the current csDMARD therapy, by performing a systematic review and meta-analyses.

This is the first meta-analysis comparing the efficacy and safety of TCZ monotherapy versus TCZ add-on combination therapy in patients with RA. Our results show that the efficacy of TCZ_MONO is nearly equivalent to TCZ_COMBI in the management of active RA. Although the effect estimate for achieving DAS28 < 2.6 and ACR50 response was significantly higher with the TCZ_COMBI strategy, this is at the cost of a significant increase in the risk of SAEs when compared to TCZ_MONO. Thus, if patients do not achieve the treatment target after initiating csDMARD therapy because of intolerance, switching to TCZ_MONO is a feasible option in clinical practice, whereas similar efficacy can be expected compared to inadequate responders to csDMARDs who switch to add-on TCZ_COMBI therapy.

TCZ is the first biologic agent to show comparable efficacy when used as monotherapy or combination therapy, whereas other biologic agents have consistently been reported to be significantly less effective when used as monotherapy [30–33]. To determine if TCZ_MONO is also superior to other biologic monotherapies, it is necessary to make direct comparisons in patients who require this therapy. However, the ADACTA study [9] is hitherto the only head-to-head randomized trial comparing two different biologic monotherapies (adalimumab versus TCZ), whereas TCZ was found to be superior for reducing signs and symptoms of RA in patients for whom continuation of MTX was discouraged. These findings are endorsed in a network analysis indirectly comparing biologic monotherapy trials, whereas TCZ has also been associated with greater efficacy than aTNFα [34]. However, further research is needed to determine the potential superiority of TCZ as first-line biologic therapy.

The results of our meta-analyses confirm and extend findings from previous studies. Although systematic reviews often do not directly lead to new insights, our review provides stronger evidence compared to clinical trials and also has several other advantages. Meta-analyses are able to examine rare events more adequately by accruing data from several studies and therefore increasing the likelihood of finding relevant differences. The majority of the studies included in our systematic review had samples sizes calculated on the basis of efficacy outcomes, which are frequently observed, and were thus not powered to detect significant differences in the incidence of less frequent events such as SAEs.

In this review, five studies [10, 19, 20, 27, 28] were included that compared TCZ_MONO with TCZ_COMBI and none of them demonstrated a significant difference between the two strategies in the incidence of SAEs. However, our meta-analyses showed a significantly higher risk (RR 1.40; 95 % 1.03, 1.92, p = 0.03) of SAEs with the TCZ_COMBI strategy. By pooling effect estimates, meta-analyses are better able to determine the true efficacy and safety of therapy compared to individual studies, and are therefore essential for making future recommendations on the management of RA. Apart from more adequately estimating the benefit and harms of a therapy, meta-analyses are also able to evaluate the inconsistency between studies and quantify treatment effects, and are invaluable to practitioners, as they summarize the latest evidence [35, 36].

In our meta-analysis, TCZ was only assessed at a dose of 8 mg/kg. Previous clinical trials [10, 12, 14, 17, 20, 37] consistently report superior efficacy of 8 mg/kg compared to 4 mg/kg in decreasing disease activity and preventing radiographic evidence of progression. The findings of these studies were confirmed in several systematic reviews, whereas meta-analyses have shown significantly greater efficacy with the 8-mg/kg dose [38, 39]. In another review performed by Campbell et al. [40], the risk of AEs was not significantly different between the two different doses, which supports the superior dose–response relationship of the higher dose. TCZ inhibits the binding of IL-6 to its receptor, which has its direct effects on acute phase reactants (APR) such as CRP and ESR. Although reduction in APR was sustained in patients treated with 8 mg/kg, these decreases were not maintained with 4 mg/kg, possibly indicating less sufficient targeting of the IL-6 pathway and therefore resulting in less efficacy [14, 17, 41].

In this review we also evaluated the efficacy and safety of both TCZ strategies versus csDMARD therapy. According to current guidelines, newly diagnosed patients with RA should receive csDMARD therapy as the first-line treatment, and in the case of inefficacy or intolerability, switch to or add a biologic DMARD. Before making assumptions as to whether TCZ_MONO or TCZ_COMBI would be adequate to decrease symptoms in patients not achieving the treatment target with csDMARD therapy alone, it is necessary to compare the efficacy of both these strategies with the standard of care. Although a proportion of patients did not initially achieve remission with csDMARD therapy, this does not necessary mean that this therapy was not effective at all. Thus, the efficacy of TCZ_MONO could be not significantly better than that of the csDMARD therapy in these patients who are more difficult to treat, and then, switching to TCZ_MONO would thus not be a good option for patients who do not respond to csDMARDs.

Although this is the first meta-analysis comparing TCZ_MONO with csDMARD therapy, TCZ_COMBI has already been compared to csDMARD therapy in previous meta-analyses [38–40]. Our meta-analysis of this treatment-control combination differs to these studies because: (1) several new large RCTs have been published; (2) 24-week results were obtained from studies with longer follow up; and (3) we performed sensitivity analyses to assess the heterogeneity between studies. The results of our meta-analyses show that switching to TCZ_MONO and TCZ_COMBI therapy is superior to continuing csDMARD therapy alone in patients with active RA. However, the treatment effect of TCZ is likely to be enhanced by the study design of the RCTs, because in studies with a csDMARD comparator group [10–18], patients were already on this therapy prior to inclusion, except in the FUNCTION study [27], whereas 81 % of the patients were DMARD-naïve.

TCZ, as monotherapy or combination therapy, has also shown to be effective as first-line therapy in newly diagnosed treatment-naïve patients with RA. In U-Act-Early [42], a recently published randomized, multicenter, three-parallel-arm, double-blind, treat-to-target study, DMARD-naïve patients were allocated to start on TCZ_MONO, TCZ_COMBI or MTX therapy. Both TCZ strategies were found to be more effective in achieving sustained remission (TCZ_COMBI 86 %, TCZ_MONO 83 %) compared to MTX (44 %, p < 0.001). This study endorses the immediate initiation of TCZ in early RA, with or without MTX, when used in a treat-to-target approach, including tapering of medication when remission is achieved.

Several weaknesses are apparent in this meta-analyses, which will be addressed. First, studies included in our review were heterogeneous in respect to csDMARD therapy. The majority used MTX monotherapy [10, 12, 14–17, 19] as control therapy; however, in four studies [11, 13, 18, 20] several csDMARDs were permitted. Furthermore, MTX was given at a lower dose in Japanese studies [11, 15] compared to studies performed in Caucasian populations [10, 12, 14, 16, 17, 19] because of the different health regulations. Second, the treatment efficacy of TCZ as assessed using the DAS28 should be interpreted with caution because of the prominent effect of IL-6 inhibition by TCZ on APR, which can lead to exaggerated response rates when compared to csDMARD or other bDMARD therapies. Thus, we also used ACR response criteria for evaluating efficacy, which yielded similar findings when compared to DAS28, endorsing the superiority of switching to TCZ_MONO or TCZ_COMBI therapy compared to continuing csDMARD therapy. Third, studies also differed with respect to study duration. Sensitivity analyses were performed to assess whether studies with follow up shorter or longer than 24 weeks reported systematically different treatment effects. In general, the effect estimates and the between-study variation did not change significantly and thus, does not change our previous conclusions. However, it may indicate that other factors such as demographic characteristics (e.g., early versus established RA) and prior DMARD use (e.g., MTX-naïve versus non-naïve patients) probably contribute more to the heterogeneity. Unfortunately because of the limited number of studies included in this review, we were not able to explore these potential sources of between-study variability.

In conclusion, in the management of active RA, switching to TCZ_MONO is a good option for patients who cannot tolerate csDMARDs, whereas similar efficacy can be expected compared to TCZ_COMBI therapy. Although TCZ_COMBI is marginally superior to TCZ_MONO in terms of achieving DAS28 < 2.6 and ACR50 response, this is at the cost of a significantly increased risk of SAEs. TCZ is the first biologic agent to show comparable efficacy when used as monotherapy or combination therapy.