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Comparative effectiveness of subcutaneous sarilumab 200 mg biweekly, subcutaneous Tocilizumab 162 mg biweekly, and intravenous Tocilizumab 8 mg/kg every 4 weeks in patients with rheumatoid arthritis: a prospective cohort study

Arthritis Research & Therapy volume 27, Article number: 52 (2025) Cite this article

Abstract

Background

While targeting the interleukin-6 receptor (IL-6R) through the use of sarilumab (SAR) or tocilizumab (TCZ) has become a major therapeutic approach for rheumatoid arthritis (RA), direct comparisons between IL-6R inhibitors (IL-6Ris) for treating RA have not been conducted. We aimed to compare the effectiveness of subcutaneous sarilumab (SAR-SC), subcutaneous tocilizumab (TCZ-SC), and intravenous TCZ (TCZ-IV) against RA in a multicenter cohort study.

Methods

Within the target trial emulation framework, an incident new-user and active-comparator cohort design was used. The source population was the entire cohort of a multicenter prospective study (the ANSWER cohort study) in Japan from 2009 to 2023. We consecutively included patients with IL-6Ri-naïve RA who initiated treatment with SAR-SC 200 mg biweekly, TCZ-SC 162 mg biweekly, or TCZ-IV 8 mg/kg every 4 weeks as the approved starting dose and dosing interval at baseline. The primary outcome of interest was the change in the clinical disease activity index (CDAI) at 24 weeks.

Results

In total, 1001 IL-6Ri-naïve patients were included (SAR-SC 200 mg biweekly, 201 patients; TCZ-SC 162 mg biweekly, 546; TCZ-IV 8 mg/kg every 4 week, 254). The improvement in CDAI at 24 weeks (primary outcome) was statistically significantly greater in the SAR-SC group than in the TCZ-SC group (-2.53, 95% confidence interval (CI): -4.38 to -0.69, p = 0.007), but that in TCZ-IV was not significantly different from that in TCZ-SC (1.00, 95% CI: -0.68 to 2.69, p = 0.243). Similar results were noted regarding the changes in CDAI at weeks 4, 12, and 48. The retention rates at 48 weeks in SAR-SC and TCZ-IV did not significantly differ from that in TCZ-SC.

Conclusions

SAR-SC 200 mg biweekly initiation was associated with a statistically significantly greater decrease in disease activity than TCZ-SC 162 mg biweekly in IL-6Ri-naïve patients with RA. In contrast, no statistically significant differences were identified between TCZ-IV 8 mg/kg every 4 week and TCZ-SC 162 mg biweekly. However, the effect size of our findings should necessitate careful consideration of the cost difference between TCZ-SC 162 mg biweekly including its biosimilars and SAR-SC 200 mg biweekly.

Background

Targeting the interleukin-6 receptor (IL-6R) through the use of sarilumab (SAR) or tocilizumab (TCZ) has become a major therapeutic approach for rheumatoid arthritis (RA). SAR and TCZ are two different types of antibodies with distinct routes of administration, dosages, affinities to IL-6Rs, and potencies of IL-6 signaling inhibition [1,2,3]. SAR is a fully human monoclonal antibody directed against IL-6Rα, whereas TCZ is a recombinant humanized anti-IL-6R monoclonal antibody. The affinity of SAR for the human IL-6R is approximately 20-fold greater than that of TCZ, and SAR was approximately 4-fold more potent than TCZ for blocking IL-6 signaling in a luciferase reporter assay [4]. Although SAR has shown higher affinities to IL-6Rs than TCZ and strong inhibition of IL-6 signaling, these were largely affected by dosage and routes of administration. However, direct comparisons of efficacy between SAR and TCZ have not been conducted in patients with RA in the real-world settings.

The approved starting dose and dosing interval for TCZ differ across Europe, the USA, and Japan [5]. In Europe, the approved dosing regimen for subcutaneous TCZ (TCZ-SC) is 162 mg weekly; however, in the USA, TCZ-SC is started at a dose of 162 mg every other week in patients weighing less than 100 kg, with the dosing interval being reduced to every week based on clinical response. In Japan, the starting dosing interval for TCZ-SC is 2 weeks irrespective of body weight, which may be decreased to a week based on clinical response. The intravenous (IV) dose of TCZ is 8 mg/kg every 4 weeks in Europe and Japan. In the USA, the recommended starting dose is 4 mg/kg IV every 4 weeks, which could be increased to 8 mg/kg IV in case of insufficient response. By contrast, the same dose of SAR-SC of 200 mg every 2 weeks is approved across Europe, the USA, and Japan [5]. The U.S. Food and Drug Administration approved a wider dosing interval for TCZ-SC and a lower dose of TCZ-IV due to safety concerns [5]. While TCZ-SC 162 mg with different dosing intervals was compared with TCZ-IV 8 mg/kg monthly in several studies [6,7,8], it is essential to additionally compare the effectiveness of TCZ-SC and TCZ-IV in the common clinical population that comprises patients who previously received biological disease-modifying anti-rheumatic drugs (bDMARDs) or Janus kinase inhibitors (JAKis) and have lower disease activity levels than those in randomized controlled trials.

Thus, this longitudinal multicenter cohort study aimed to compare the effectiveness of SAR-SC 200 mg biweekly, TCZ-SC 162 mg biweekly, and TCZ-IV 8 mg/kg monthly in patients with RA using target trial emulation.

Methods

Study design

We utilized the framework to emulate a clinical trial (hereafter referred to as the target trial) that would randomize patients with RA to initiate treatment with SAR-SC, TCZ-SC, or TCZ-IV in an unblinded manner (Supplementary Table S1) [9, 10]. For our emulated target trial, we used an incident new-user and active-comparator cohort design to compare changes in disease activity and retention rate among patients with RA initiating an IL-6R inhibitor (IL-6Ri). The reporting of the study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement (Supplementary Table S2) [11].

Source population

The source population was the entire cohort of the Kansai Consortium for Well-Being of Rheumatic Disease Patients (ANSWER) study [12,13,14]. The ANSWER cohort is a longitudinal observational multicenter registry of patients with RA in Japan (Supplementary Data S1). The data collection for this cohort started in 2009 and is still ongoing; however, only the data collected until 2023 was used in the current analysis.

Study population

Patients with RA meeting the following prespecified criteria were included: aging ≥ 16 years old, diagnosed with RA according to the 2010 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria [15], IL-6Ri-naïve, and started receiving SAR-SC, TCZ-SC, or TCZ-IV with the approved starting dose and dosing interval at baseline. TCZ-IV was administered at a dose of 8 mg/kg every 4 weeks. Treatment with TCZ-SC was initiated with a dose of 162 mg every 2 weeks, and the dosing interval was decreased to every week based on clinical response. SAR-SC was administered at a dose of 200 mg every 2 weeks. The baseline was defined as the moment when patients initiated or switched to one of the IL-6Ri treatments. In addition, we did not set any requirements for the disease activity score as there is residual disease activity even when the remission criteria of the Clinical Disease Activity Index (CDAI) are met and the goal of our study is quantifying the effects of IL-6Ris under realistic conditions. We excluded patients who had previously used an IL-6Ri at baseline but permitted patients with previous use of tumor necrosis factor inhibitors (TNFis), cytotoxic T-lymphocyte-associated protein 4 immunoglobulin, or JAKis. The use of any conventional synthetic DMARDs was permitted while hydroxychloroquine, anakinra, and rituximab were not approved for use in patients with RA in Japan during the study period.

Treatment groups and outcome measures

Regarding treatment groups, only those undergoing treatment with the approved starting dose and dosing interval in Japan were included. Stepdown strategies during a treatment course such as dose reduction and spacing were acceptable. Follow-up started the day of first dispensing (target trial index date) and continued for 48 weeks or until the end of the study period (October 31, 2023), loss to follow-up, discontinuation of the index medication (> 60 days following the expiration date of the last dispensed supply), initiation of the active comparator medication, or death.

The primary outcome of interest was the CDAI at week 24 [16]. Additional secondary outcomes included the CDAI at 4, 12, and 48 weeks, the disease activity score in 28 joints (DAS28)-erythrocyte sedimentation rate (ESR) at 24 and 48 weeks [17], drug retention rate at 48 weeks, and cause-specific retention rate at 48 weeks. Temporary discontinuations (less than two months) followed by reintroduction of the same medication were not recorded as discontinuations. The reasons for discontinuing IL-6Ri were recorded by physicians as follows: drug inefficacy, achievement of clinical remission, toxic adverse events, patient preference (including financial reasons), and loss to follow-up. Loss to follow-up was considered a censoring event. Regarding the cause-specific retention rate, the reasons for drug discontinuation included lack of effectiveness, adverse events, and RA remission after IL-6Ri initiation [18]. We also conducted post-hoc analyses using the simplified disease activity index (SDAI) or serum CRP levels as an outcome [19].

Covariate assessment

We considered age, sex, disease duration, body mass index, rheumatoid factor (RF) positivity, anti-citrullinated peptide antibody (ACPA) positivity, CDAI at baseline, serum C-reactive protein (CRP) levels, concomitant use of corticosteroids, methotrexate, sulfasalazine, or other conventional synthetic DMARDs; the number of previously administered bDMARDs or JAKis, past history of inadequate response (IR) to bDMARDs/JAKi, anemia defined as hemoglobin levels < 11.9 g/dL for females or < 13.6 g/dL for males [20,21,22], and thrombocytosis defined as platelet levels > 450,000/µL [23, 24] as priori covariates (Supplementary Data S2).

Statistical analysis

Differences among the groups were analyzed using analysis of variance or the Kruskal-Wallis test for continuous variables and Fisher’s exact test for categorical variables. Differences between the two groups were assessed based on standardized differences. An inverse probability weighting (IPW) approach accounted for differences in baseline variables between the treatment groups [25]. The multiple propensity score was estimated using multinomial logistic regression, with the treatment category as the dependent variable. Because a previous simulation study showed that soluble IL-6R occupancy levels were 98% for SAR-SC 200 mg biweekly, 99% for TCZ-IV 8 mg/kg every month, and 84% for TCZ-SC 162 mg biweekly [26], we pre-specified two pairwise comparisons with TCZ-SC as the comparator. Stabilized weights were used to preserve the original data’s sample size (Supplementary Data S3) [25]. As for disease activity, the outcome analysis relied on the IPW difference, with a 95% confidence interval (CI) derived from linear mixed-effect models with robust variance [27]. We used weighted mixed-effect models for repeated measures with an unstructured covariance structure. Regarding retention rates, IPW-adjusted Kaplan–Meier curves were drawn and IPW hazard ratios (HR) with 95% CI were calculated from Cox proportional hazard models with robust variance. These Cox proportional hazard models also included calendar time as a confounder.

We explored the potential effect modifications of changes in CDAI by baseline characteristics (Supplementary Data S4). We also conducted an additional exploratory analysis limited to patients with moderate to high disease activity at baseline to address differences in the proportion of achieving low disease activity or remission among IL-6Ris.

We used multiple imputation by chained equations to impute missing values at baseline (Supplementary Data S5). We generated 80 independently imputed datasets. For each dataset, we estimated parameters from the multiple propensity score-based IPW and pooled the resulting parameters (the “Within approach”) according to Rubin’s rules [28].

Statistical analyses were conducted using R version 4.3.1 (R Development Core Team, Vienna, Austria). Statistical significance was set at p < 0.025 for primary outcomes after applying the Bonferroni correction for multiple comparisons.

Results

Patient characteristics

Of 12,248 patients with RA in the ANSWER cohort, 4218 patients started receiving a bDMARD or JAKi, accounting for a total of 7878 treatment courses. In addition, 1001 IL6Ri-naïve patients (mean age, 61.5 years; 81.6% women) met the research criteria and, therefore, started treatment with an IL-6Ri (SAR-SC 200 mg biweekly, 201 patients; TCZ-SC 162 mg biweekly, 546; TCZ-IV 8 mg/kg every 4 weeks, 254) (Supplementary Figure S1). Baseline patient characteristics based on treatment groups are summarized separately (Table 1). The kernel densities of the observed and imputed values were similar (Supplementary Figure S2). These results provide evidence that the imputations were reasonable. Patients receiving SAR-SC 200 mg biweekly were older and had the shortest disease duration and the highest disease activity, and more likely to be bDMARD/JAKi-naïve compared to patients in the other two treatment groups. Patients initiated on TCZ-SC 162 mg biweekly tended to be female and had the lowest disease activity among patients in all treatment groups. Patients who started TCZ-IV 8 mg/kg monthly showed the longest disease duration, higher use of prednisolone and methotrexate, and a larger number of previously administered bDMARDs and JAKis.

Table 1 Patient characteristics at the beginning of IL-6 receptor inhibitor therapya
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Among the TCZ-SC 162 mg biweekly group, 35 patients (6.4%) decreased to every week based on clinical response. None of the patients required dose reduction. However, treatment spacing was observed in 2 patients (1.0%) in the SAR-SC 200 mg biweekly group, 17 (3.1%) in the TCZ-SC 162 mg biweekly group, and 5 (2.0%) in the TCZ-IV 8 mg/kg monthly group.

Changes in CDAI and DAS28-ESR during IL-6Ri therapy

The overlap of stabilized weight distributions by group is shown in Supplementary Figure S3 and Table S3, and the standardized differences in the main baseline variables before and after IPW are illustrated in Supplementary Figure S4. The distributions of baseline variables were well balanced after IPW; however, some standardized differences in baseline CDAI among the multiply imputed data sets were ≥ 0.10 and were, therefore, included in the subsequent models. According to the adjusted analysis, the change in CDAI at week 24 was − 10.18 (95% CI: -11.99 to -8.36) in the SAR-SC 200 mg biweekly group, -7.64 (-8.62 to -6.67) in TCZ-SC 162 mg biweekly, and − 6.64 (-8.33 to -4.95) in TCZ-IV 8 mg/kg monthly (Fig. 1). The weighted analysis of the multiple imputed data sets found that the difference in the change in CDAI at week 24 as the primary outcome was − 2.53 (95% CI: -4.38 to -0.69, p = 0.007) lower in the SAR-SC 200 mg biweekly group than in the TCZ-SC 162 mg biweekly group, whereas that in TCZ-IV 8 mg/kg monthly was not significantly different from that in TCZ-SC 162 mg biweekly (1.00, 95% CI: -0.68 to 2.69, p = 0.243) (Table 2). A sensitivity analysis using truncated weights yielded similar results. The adjusted analysis also revealed that the change in CDAI at week 48 was − 11.16 (95% CI: -13.14 to -9.18) in the SAR-SC 200 mg biweekly group, -8.40 (-9.49 to -7.31) in TCZ-SC 162 mg biweekly, and − 8.39 (-10.20 to -6.58) in TCZ-IV 8 mg/kg monthly (Fig. 1). The results were also similar when the weighted analysis was performed for the change in CDAI at weeks 4, 12, and 48 (Table 2). The crude and weighted analyses using change in DAS28-ESR at weeks 24 and 48 as secondary outcomes also showed similar results (Table 2). The post-hoc analysis using change in SDAI or as an outcome showed similar results (Table 2).

Fig. 1
figure 1

Change in CDAI after introducing IL-6 receptor inhibitor. The diagram is based on adjusted data. Mean ± standard error is shown. Abbreviations: CDAI, clinical disease activity index; IV, intravenous; SAR, sarilumab; SC, subcutaneous; TCZ, tocilizumab

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Table 2 Difference in change in CDAI, DAS28-ESR, SDAI, and CRP during IL-6 receptor inhibitor therapyb
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Exploratory analyses of the effect modifications revealed that, compared with TCZ-SC 162 mg biweekly, the effect of TCZ-IV 8 mg/kg monthly on change in CDAI was more prominent in patients who were in remission or had low disease activity at baseline than in patients who had moderate or high disease activity (Δ = -1.31, 95% CI: -0.07 to -2.56, p for interaction = 0.038) and the effect of SAR-SC 200 mg biweekly was higher in patients with thrombocytosis at baseline than in patients without (Δ = -8.30, 95% CI: -14.98 to -1.63, p for interaction = 0.015) (Supplementary Table S4). In addition, the exploratory analysis limited to patients with moderate to high disease activity demonstrated similar results regarding the change in CDAI (Supplementary Table S5). By contrast, no statistically significant differences in the proportion of patients achieving low disease activity or remission at week 24 were identified between SAR-SC 200 mg biweekly and TCZ-IV 8 mg/kg monthly compared with TCZ-SC 162 biweekly (Supplementary Table S5).

Overall and cause-specific retention rates

After adjustment for confounders, the retention rates in the SAR-SC 200 mg biweekly (HR: 1.13, 95% CI: 0.72 to 1.77, p = 0.581) and TCZ-IV 8 mg/kg monthly groups (HR: 1.25, 95% CI: 0.84 to 1.84, p = 0.264) did not significantly differ from that the TCZ-SC 162 mg biweekly group (Table 3; Fig. 2). The rates of drug discontinuation for each cause were compared among the three groups (Table 3). The rate of drug discontinuation due to lack of effectiveness was not significantly different among the three groups after adjustment for confounders. Compared to that in the TCZ-SC 162 biweekly group, the rate of drug discontinuation due to adverse events was significantly higher in the TCZ-IV 8 mg/kg monthly group (HR: 2.51, 95% CI: 1.45 to 4.34, p = 0.001) but did not differ in the SAR-SC 200 mg biweekly (HR: 1.20, 95% CI: 0.59 to 2.42, p = 0.609).

Table 3 Retention rate and cause-specific retention rate during IL-6 receptor inhibitor therapya
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Fig. 2
figure 2

Adjusted drug retention compared between SAR-SC, TCZ-SC, and TCZ-IV. Abbreviations: IL-6Ri, interleukin 6 receptor inhibitor; IV, intravenous; SAR, sarilumab; SC, subcutaneous; TCZ, tocilizumab

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Discussion

This longitudinal multicenter study with target trial emulation showed that SAR-SC 200 mg biweekly use was associated with a numerically greater decrease in disease activity among IL-6Ri-naïve patients with RA than TCZ-SC 162 mg biweekly use. In contrast, no statistically significant differences were identified between TCZ-SC 162 mg biweekly and TCZ-IV 8 m/kg every 4 weeks. Retention rates were not statistically different among the three groups. To our knowledge, this is the first report in a real-world setting comparing disease activity and drug retention rates between SAR-SC 200 mg biweekly, TCZ-SC 162 mg biweekly, and TCZ-IV 8 mg/kg monthly in patients with RA.

Regarding efficacy, previous studies did not directly compare SAR with TCZ. The interim results of the prospective observational study showed that SAR-SC 200 mg biweekly improved the CDAI comparably in the TCZ-IR, bDMARD/JAKi-naïve, JAKi-IR, and other bDMARD-IR groups over 6 months of treatment [29]. Another randomized controlled trial involving TNFi-IR patients showed no clinically meaningful differences in safety between SAR-SC and TCZ-IV; however, this trial was not designed to assess the efficacy [30]. In addition, the open-label extension study after the double-blind phase showed clinical response was achieved after the switch to SAR-SC in some patients who were non-responders on TCZ-IV and most patients responding to TCZ-IV maintained response when switching to SAR [31]. By contrast, some patients increased disease activity by switching from TCZ-SC to SAR-SC [32]. Our study compared SAR-SC 200 mg biweekly and TCZ-SC 162 mg biweekly in real-world settings.

Several experimental and pharmacological studies have examined the difference in IL-6 signaling inhibition and IL-6R binding characteristics between SAR and TCZ. A simulation study of soluble IL-6R occupancy derived from in vitro pharmacokinetic/pharmacodynamic data showed that receptor occupancy was greater with SAR-SC 200 mg biweekly (98%), TCZ-SC 162 mg weekly (> 99%), and TCZ-IV 8 mg/kg every 4 weeks (99%) than with TCZ-SC 162 mg biweekly (84%) at steady-state trough concentrations [26]. Although the simulation study suggests that a higher dose or increased dosing frequency of TCZ is comparable to SAR-SC in terms of soluble IL-6R occupancy, the study primarily addressed the trans-signaling pathway and did not assess classic signaling and trans-presentation through membranous IL-6R [33]. This distinction may be crucial as both signaling pathways contribute to the pathophysiology of RA. In addition, structural analyses showed that both SAR and TCZ bind to the D3 domain of IL-6R [34]. Although the binding surfaces of the two antibodies largely overlap, the detailed interactions are different. These differences in binding interactions may also influence their efficacy in inhibiting IL-6 signaling.

Previous randomized controlled studies and an observational study compared TCZ-SC 162 mg with different dosing intervals with TCZ-IV 8 mg/kg every 4 weeks [6,7,8]. A randomized controlled study demonstrated similar efficacy in combination with conventional synthetic DMARDs between weekly TCZ-SC 162 mg weekly and TCZ-IV 8 mg/kg monthly in patients with high disease activity [6, 35]. By contrast, in another randomized controlled phase III trial that included patients with high disease activity, biweekly TCZ-SC 162 mg monotherapy demonstrated comparable efficacy and safety to TCZ-IV 8 mg/kg monotherapy; however, the response rate at week 24 was numerically higher in the TCZ-IV 8 mg/kg monthly group than in the TCZ-SC 162 mg biweekly group [7]. In addition, a study involving a pan-European collaboration of registries where the majority of patients had moderate disease activity and were treated with TCZ-SC 162 mg every 2 weeks or TCZ-IV 8 mg/kg every 4 weeks showed that TCZ-SC and TCZ-IV had no statistically significant differences in effectiveness in terms of CDAI and DAS-ESR [8]. These findings suggest that the efficacy of TCZ-SC 162 mg and TCZ-IV 8 mg/kg monthly are comparable in some patients. Meanwhile, because the pharmacodynamic profile of weekly TCZ-SC 162 mg was the most consistent with that of TCZ-IV 8 mg/kg monthly [6], weekly TCZ-SC might be more effective than biweekly TCZ-SC in patients with higher disease activity receiving monotherapy. Although our results are consistent with those of previous studies, our study also suggests that TCZ-SC 162 mg biweekly and TCZ-IV 8 mg/kg monthly may have similar efficacy in IL-6Ri-naïve patients with prior bDMARD or JAKi exposure and lower disease activity in real-world settings.

In contrast to disease activity, retention rates were not significantly different among SAR-SC 200 mg biweekly, TCZ-IV 8 mg/kg monthly, and TCZ-SC 162 mg biweekly. There are several speculations to be considered. First, within the framework of causal inference, the retention rate is a less valid outcome than disease activity because the retention rate is affected by patient or doctor preference, comorbidity, and the number of alternative treatment options [36]. In addition, the retention rate is a composite outcome representing findings with different directions such as ineffectiveness, adverse events, or remission. For example, even when disease activity shows modest improvement, treatment with a bDMARD may be continued owing to comorbidity. Therefore, the retention rate may not exactly account for the effectiveness of bDMARDs. Second, the difference in the change in CDAI between SAR-SC 200 mg biweekly and TCZ-SC 162 mg biweekly may be clinically small and not lead to switching to another bDMARD. Considering that the minimally important difference in CDAI was 6.0 in patients with moderate disease activity, SAR-SC 200 mg biweekly, TCZ-IV 8 mg/kg monthly, and TCZ-SC 162 mg biweekly all achieved the cutoff [37]. Because the minimally important difference is the smallest change in score that patients regard as important, the smallest worthwhile effect should be considered in terms of the difference in outcomes among interventions [38]. Even though the smallest worthwhile effect of DMARDs was not identified in patients with RA, the exploratory analysis limited to patients with moderate to high disease activity also demonstrated no statistically significant differences in the proportion of patients achieving low disease activity or remission between SAR-SC 200 mg biweekly and TCZ-IV 8 mg/kg monthly compared with TCZ-SC 162 biweekly. Therefore, the effect size of our primary outcome necessitates careful consideration of the associated costs. With the introduction of TCZ-SC biosimilars, a CDAI difference of approximately 2.5 may not justify the cost difference between TCZ-SC biosimilars 162 mg biweekly and SAR-SC 200 mg biweekly.

The generalizability of our results depends on the approved doses across countries because the starting dosing interval and dose of TCZ differ among Europe, the USA, and Japan. Considering that the dosing interval of TCZ-SC in the USA is the same as that in the study, SAR-SC 200 mg biweekly may be an option for patients requiring IL-6Ri therapy in the USA and Japan. In addition, because the dose of TCZ-IV 8 mg/kg monthly in Europe is identical to that in our study, administering TCZ-SC every 2 weeks may be sufficient for some of stable patients who are undergoing treatment with TCZ-IV and want to switch to SC administration in Europe and Japan.

The strength of our study lies in the large number of patients included, multicenter recruitment, and prospectively collected detailed longitudinal clinical data. In addition, we used the framework of target trial emulation and simultaneously compared the three treatment strategies.

However, the present study has several limitations. First, comorbidities such as diabetes mellitus or respiratory diseases were not adjusted for as confounders among the three groups because the registry does not include comorbidity data, although these comorbidities seemed to be mainly prognostic factors for the retention rate rather than disease activity. In addition, because patients receiving SAR-SC 200 mg biweekly had the shortest disease duration and the highest disease activity, and were more likely to be bDMARD/JAKi-naïve compared to patients in the other two treatment groups, these characteristics would bias this group toward more favorable clinical responses. Despite adjusting for the available confounders among the groups and using propensity score-based IPW to reduce the effect of confounders to a minimum, there may be residual confounding and unmeasured confounding factors. Second, the decision to discontinue treatment and the reasons for treatment discontinuation (e.g., lack of effectiveness or adverse events) depended on the judgment of each physician rather than standardized criteria. Third, we could not examine the effect of IL-6Ris on radiographic changes and patient-reported outcomes. Fourth, because we did not compare TCZ-SC 162 mg weekly with other therapies, our findings of SAR-SC 200 mg vs. TCZ-SC 162 mg biweekly cannot be simply extrapolated in the countries where starting dosing interval of TCZ-SC is 162 mg weekly. Fifth, because our cohort mainly included normal-weight patients and dose of TCZ-IV changes according to their body weight, further studies are needed to examine the effectiveness of TCZ-IV compared with other therapies in obese patients.

Conclusions

This target trial emulation study using real-life clinical data of IL-6Ri-naïve patients with RA showed that SAR-SC 200 mg biweekly was associated with a statistically significantly greater decrease in disease activity than TCZ-SC 162 mg biweekly. In contrast, no statistically significant differences were identified between TCZ-IV 8 mg/kg every 4 weeks and TCZ-SC 162 mg biweekly. However, the effect size of our findings should necessitate careful consideration of the cost difference between TCZ-SC 162 mg biweekly including its biosimilars and SAR-SC 200 mg biweekly. Because unmeasured confounding factors may exist, accurately powered head-to-head trials or further studies using other datasets are warranted to draw more conclusive estimates of the comparative effectiveness and safety of IL-6Ris in patients with RA. In addition, because we did not compare TCZ-SC 162 mg weekly with other therapies, additional studies are needed to examine the effectiveness of TCZ-SC 162 mg weekly compared with SAR-SC 200 mg biweekly.

Data availability

All data generated or analysed during this study are included in this published article and its supplementary information files.

Abbreviations

ACPA:

Anti-citrullinated peptide antibody

bDMARD:

Biological disease-modifying anti-rheumatic drug

CDAI:

Clinical Disease Activity Index

CI:

Confidence interval

CRP:

C-reactive protein

DAS28:

Disease activity score in 28 joints

ESR:

Erythrocyte sedimentation rate

HR:

Hazard ratio

IL-6R:

Interleukin-6 receptor

IPW:

Inverse probability weighting

IV:

Intravenous

IR:

Inadequate response

JAKi:

Janus kinase inhibitor

RF:

Rheumatoid factor

SAR:

Sarilumab

SC:

Subcutaneous

SDAI:

Simplified disease activity index

STROBE:

Strengthening the Reporting of Observational Studies in Epidemiology

TCZ:

Tocilizumab

TNFi:

Tumor necrosis factor inhibitor

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Acknowledgements

We would like to thank Editage (www.editage.com) for the English language editing.

Funding

This study used data from ANSWER Cohort Association supported by grants from 12 pharmaceutical companies (AbbVie GK, Asahi Kasei, Ayumi, Chugai, Eisai, Eli Lilly Japan K.K, Janssen K.K, Ono, Sanofi K.K, Teijin Healthcare, Taisho, and UCB Japan) and an information technology services company (CAC). This study was conducted as an investigator-initiated study. These companies had no roles in study design, data collection, data analysis, data interpretation, or writing of the report.

Author information

Authors and Affiliations

  1. Department of Advanced Medicine for Rheumatic Diseases, Kyoto University Graduate School of Medicine, 54, Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan

    Akira Onishi, Masao Tanaka, Takayuki Fujii & Koichi Murata

  2. Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Takayuki Fujii, Koichi Murata & Shuichi Matsuda

  3. Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Kosaku Murakami

  4. Department of Clinical Immunology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan

    Motomu Hashimoto & Ryu Watanabe

  5. Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osaka, Japan

    Yuji Nozaki & Chisato Ashida

  6. Department of Health Information Management, Kurashiki Sweet Hospital, Okayama, Japan

    Wataru Yamamoto

  7. Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan

    Hirotaka Yamada & Sho Sendo

  8. Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan

    Kosuke Ebina

  9. Department of Sports Medical Biomechanics, Osaka University Graduate School of Medicine, Osaka, Japan

    Kosuke Ebina

  10. First Department of Internal Medicine, Kansai Medical University, Osaka, Japan

    Hidehiko Makino & Yonsu Son

  11. Department of Internal Medicine (IV), Osaka Medical and Pharmaceutical University, Osaka, Japan

    Yumiko Wada & Kenichiro Hata

  12. Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Akio Morinobu

Authors
  1. Akira Onishi
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  2. Masao Tanaka
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  3. Takayuki Fujii
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  19. Akio Morinobu
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Contributions

AO conceived and designed the study, conducted the statistical analyses, and drafted the manuscript. AO, MT, TF, KM, KM, MH, RW, YN, CA, WY, HY, SS, KE, MH, YS, YW, KH, SM, and AM collected the data, discussed the study design, read the manuscript, and approved the manuscript submission.

Corresponding author

Correspondence to Akira Onishi.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Kyoto University (approval number: R0357). This study was conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all participants.

Consent for publication

Not applicable.

Competing interests

The Department of Advanced Medicine for Rheumatic Diseases is supported by Nagahama City, Shiga, Japan; Toyooka City, Hyogo, Japan; and two pharmaceutical companies (AYUMI Pharmaceutical Co., and Asahi Kasei Pharma Corp.). The above-mentioned pharmaceutical companies were not involved in the study design, manuscript writing, or manuscript submission and will not be involved in data collection and analysis. AO received research grants and/or speaker fees from Pfizer Inc., Bristol-Myers Squibb., Advantest, Asahi Kasei Pharma Corp., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K. K., Ono Pharmaceutical Co., UCB Japan Co., Mitsubishi Tanabe Pharma Co., Eisai Co. Ltd., Abbvie Inc., Takeda Pharmaceutical Co. Ltd., and Daiichi Sankyo Co. Ltd. MT received speaker fees from AbbVie GK, Asahi Kasei Pharma Corp., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., Kyowa Kirin Co., Ltd., Pfizer Inc., Taisho Pharmaceutical Co., Ltd., Tanabe Mitsubishi Pharma Corp., Teijin Pharma, Ltd., UCB Japan Co., Ltd. TF received speaker fees from AbbVie GK, Asahi Kasei Pharma Corp., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., and Janssen Pharmaceutical K.K. KMurata received a speaking fee from Eisai Co. Ltd., Chugai Pharmaceutical Co. Ltd.; Asahi Kasei Pharma Corp., Bristol-Myers Squibb, Mitsubishi Tanabe Pharma Co., Janssen Pharmaceutical K.K. and Daiichi Sankyo Co. Ltd. KMurakami received speaker fees from Eisai Co. Ltd., Chugai Pharmaceutical Co. Ltd., Pfizer Inc., Bristol-Myers Squibb, Mitsubishi Tanabe Pharma Corporation, UCB Japan Co. Ltd., Daiichi Sankyo Co. Ltd., and Astellas Pharma Inc. MH received research grants and/or speaker fees from Abbvie, Asahi Kasei, Astellas, Ayumi, Bristol Meyers, Chugai, EA Pharma, Eisai, Daiichi Sankyo, Eli Lilly, Nihon Shinyaku, Novartis Pharma, and Tanabe Mitsubishi. RW has received speaker bureau from Asahi-Kasei, Chugai, Eli Lilly, Sanofi, and GSK and research grants from AbbVie. Y.N. has received research grants from AbbVie Japan GK, Eisai Co., and Mitsubishi Tanabe Pharma Corp. and speaker fees from AbbVie Japan GK, Astellas Pharma, Asahi Kasei, Chugai Pharmaceutical Co., Eisai Co., Eli Lilly Japan K.K., Daiichi-Sankyo, GlaxoSmithKline K.K., Mitsubishi Tanabe Pharma Corp., Novartis Japan, Takeda, Ono, Otsuka Co., Pfizer, Janssen, and UCB Japan. HY has received speaker fees from AbbVie, Asahi Kasei Pharma, Astellas, Bristol-Myers Squibb, Chugai, Eisai, Gilead Sciences, Ono, Pfizer and Taiho Pharmaceutical. KE is affiliated with the Department of Sports Medical Biomechanics, Osaka University Graduate School of Medicine, which is supported by Asahi-Kasei. KE has received research grants from Asahi-Kasei and Teijin Pharma. KE has received a speaker fee from AbbVie, Amgen, Argenx, Asahi-Kasei, Astellas, Ayumi, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Janssen, Mitsubishi-Tanabe, Ono Pharmaceutical, Pfizer, Sanofi, Taisho, Teijin Pharma, and UCB Japan. YS has received speaking fees from Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K.,Eisai Co., Ltd., and AbbVie G.K. KH received speaker fees from Abbvie, Asahi-Kasei, Astellas, Chugai, Eisai, Eli Lilly, Gilead Sciences, Janssen, and Mitsubishi-Tanabe. SM received speaker fees from Taisho, Chugai, Daiichi-Sankyo, Asahi-Kasei, Ayumi, and Mitsubishi-Tanabe.AM received honoraria from AbbVie G.K., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Eisai Co. Ltd., Pfizer Inc., Bristol-Myers Squibb., Mitsubishi Tanabe Pharma Co., Astellas Pharma Inc., and Gilead Sciences Japan and has received research grants from AbbVie G.K., Asahi Kasei Pharma Corp., Chugai Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Co., and Eisai Co. Ltd. The remaining authors have no competing interests to be reported.

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Onishi, A., Tanaka, M., Fujii, T. et al. Comparative effectiveness of subcutaneous sarilumab 200 mg biweekly, subcutaneous Tocilizumab 162 mg biweekly, and intravenous Tocilizumab 8 mg/kg every 4 weeks in patients with rheumatoid arthritis: a prospective cohort study. Arthritis Res Ther 27, 52 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13075-025-03514-x

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Keywords

Arthritis Research & Therapy

ISSN: 1478-6362

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